Trial Outcomes & Findings for 05-001: Treatment of Acute Lymphoblastic Leukemia in Children (NCT NCT00400946)

Last Updated: 2026-02-13

Results Overview

Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on CTCAEv3.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

800 participants

Primary outcome timeframe

30-week post-induction asparaginase treatment period

Results posted on

2026-02-13

Participant Flow

Patients enrolled from April 22, 2005 to Dec 13, 2011.

Participant milestones

Participant milestones
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	IM-EC [Directly Assigned] Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.	Ineligible for Randomization All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for \>72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.	Expansion Cohort Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.
Overall Study STARTED	231	232	42	51	244
Overall Study Evaluable for CNS Directed-Treatment	231	232	42	21	227
Overall Study Evaluable for Day 18 Marrow Morphology	158	161	19	13	152
Overall Study Evaluable for Day 32 MRD	166	167	33	12	168
Overall Study Eligible and Treated	231	232	42	46	243
Overall Study COMPLETED	217	221	40	4	206
Overall Study NOT COMPLETED	14	11	2	47	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	IM-EC [Directly Assigned] Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.	Ineligible for Randomization All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for \>72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.	Expansion Cohort Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.
Overall Study Ineligible	0	0	0	5	1
Overall Study Induction Failure	0	0	0	11	8
Overall Study Induction Death	0	0	0	13	3
Overall Study Lost to Follow-up	1	1	0	0	1
Overall Study Remission Death	1	1	0	0	1
Overall Study Relapse	9	2	1	1	5
Overall Study Transplant in CR1	0	0	0	10	1
Overall Study Withdrawal by Subject	2	5	1	5	8
Overall Study Clinical	1	2	0	2	9
Overall Study Other	0	0	0	0	1

Baseline Characteristics

05-001: Treatment of Acute Lymphoblastic Leukemia in Children

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	IM-EC [Directly Assigned] n=42 Participants Ph+ ALL patients did not participate in asparaginase randomization but were directly assigned to receive intramuscular E coli L-asparaginase during post-induction therapy. Patients who were eligible but declined randomization were also directly assigned to receive intramuscular E coli L-asparaginase.	Ineligible for Randomization n=51 Participants All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who did not achieve complete remission and were not assigned a final risk group by the end of the induction phase of treatment were not eligible for randomization. Patients who developed severe pancreatitis (defined as symptoms persisting for \>72 h) during induction were not eligible for randomization and received no further doses of asparaginase. Patients who had hypersensitivity to intravenous PEG-asparaginase during induction were also ineligible for randomization, but received twice-weekly IM-EC (25 000 IU/m2) during the post-induction treatment phases.	Expansion Cohort n=244 Participants Patients were enrolled in an expansion cohort to determine the prognostic significance of response to remission induction chemotherapy as measured by morphologic and minimal residual disease (MRD), and to further evaluate the efficacy of patients by final risk classification.	Total n=800 Participants Total of all reporting groups
Sex: Female, Male Male	120 Participants n=6 Participants	135 Participants n=6 Participants	21 Participants n=12 Participants	30 Participants n=1267 Participants	137 Participants n=15 Participants	443 Participants n=122 Participants
Age, Categorical <=18 years	231 Participants n=6 Participants	232 Participants n=6 Participants	42 Participants n=12 Participants	51 Participants n=1267 Participants	244 Participants n=15 Participants	800 Participants n=122 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=6 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=1267 Participants	0 Participants n=15 Participants	0 Participants n=122 Participants
Age, Categorical >=65 years	0 Participants n=6 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=1267 Participants	0 Participants n=15 Participants	0 Participants n=122 Participants
Sex: Female, Male Female	111 Participants n=6 Participants	97 Participants n=6 Participants	21 Participants n=12 Participants	21 Participants n=1267 Participants	107 Participants n=15 Participants	357 Participants n=122 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	40 Participants n=6 Participants	48 Participants n=6 Participants	3 Participants n=12 Participants	13 Participants n=1267 Participants	48 Participants n=15 Participants	152 Participants n=122 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	165 Participants n=6 Participants	170 Participants n=6 Participants	35 Participants n=12 Participants	34 Participants n=1267 Participants	180 Participants n=15 Participants	584 Participants n=122 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	26 Participants n=6 Participants	14 Participants n=6 Participants	4 Participants n=12 Participants	4 Participants n=1267 Participants	16 Participants n=15 Participants	64 Participants n=122 Participants
Age Classification < 10 years old	176 Participants n=6 Participants	165 Participants n=6 Participants	35 Participants n=12 Participants	26 Participants n=1267 Participants	196 Participants n=15 Participants	598 Participants n=122 Participants
Age Classification >/= 10 years old	55 Participants n=6 Participants	67 Participants n=6 Participants	7 Participants n=12 Participants	25 Participants n=1267 Participants	48 Participants n=15 Participants	202 Participants n=122 Participants

PRIMARY outcome

Timeframe: 30-week post-induction asparaginase treatment period

Population: The analysis dataset is comprised of all randomized patients.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Asparaginase-Related Toxicity Rate	26 percentage of participants Interval 20.0 to 32.0	28 percentage of participants Interval 22.0 to 34.0	—	—	—

SECONDARY outcome

Timeframe: Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

Population: The analysis dataset is comprised of all randomized patients.

Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as \>25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
5-Year Disease-Free Survival	.89 probability Interval 0.85 to 0.93	.90 probability Interval 0.86 to 0.94	—	—	—

SECONDARY outcome

Timeframe: Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

Population: The analysis dataset is comprised of all randomized patients who consented to research studies with an evaluable sample for analysis of serum asparaginase activity at the respective post-induction assessment timepoints.

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Post-Induction Nadir Serum Asparaginase Activity Level Week 17 NSAA Level	0.159 IU/mL Standard Deviation 0.161	0.787 IU/mL Standard Deviation 0.303	—	—	—
Post-Induction Nadir Serum Asparaginase Activity Level Week 5 NSAA Level	0.129 IU/mL Standard Deviation 0.108	0.726 IU/mL Standard Deviation 0.322	—	—	—
Post-Induction Nadir Serum Asparaginase Activity Level Week 11 NSAA Level	0.143 IU/mL Standard Deviation 0.131	0.773 IU/mL Standard Deviation 0.231	—	—	—
Post-Induction Nadir Serum Asparaginase Activity Level Week 23 NSAA Level	0.180 IU/mL Standard Deviation 0.261	0.757 IU/mL Standard Deviation 0.255	—	—	—
Post-Induction Nadir Serum Asparaginase Activity Level Week 29 NSAA Level	0.123 IU/mL Standard Deviation 0.102	0.806 IU/mL Standard Deviation 0.313	—	—	—

SECONDARY outcome

Timeframe: Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

Population: The analysis dataset is comprised of all randomized patients who consented to research studies with a one post-induction evaluable sample for analysis of serum asparaginase activity.

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Post-Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL ever during post-induction therapy.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=170 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=168 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate	71 percentage of participants Interval 63.0 to 77.0	99 percentage of participants Interval 96.0 to 99.0	—	—	—

SECONDARY outcome

Timeframe: Assessed daily during remission induction days 4-32.

Population: The analysis dataset is comprised of eligible and treated patients. This excludes the 6 enrolled but ineligible patients. Rates in this overall study cohort will be compared against historical controls (in particular patients treated with a more intensive induction regimen).

Infection toxicity rate is defined as the percentage of patients who experience bacterial or fungal infection of grade 3 or higher with treatment attribution of possibly, probably or definite based on CTCAEv3 during remission induction phase of combination chemotherapy.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=794 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Induction Infection Toxicity Rate	26 percentage of participants Interval 23.0 to 30.0	—	—	—	—

SECONDARY outcome

Timeframe: Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.

Serum asparaginase activity (NSAA) levels were estimated based on established methods.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=794 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Induction Serum Asparaginase Activity Level Day 25 NSAA Level	.048 IU/mL Interval 0.025 to 0.076	—	—	—	—
Induction Serum Asparaginase Activity Level Day 4 NSAA Level	.694 IU/mL Interval 0.556 to 0.868	—	—	—	—
Induction Serum Asparaginase Activity Level Day 11 NSAA Level	.505 IU/mL Interval 0.306 to 0.632	—	—	—	—
Induction Serum Asparaginase Activity Level Day 18 NSAA Level	.211 IU/mL Interval 0.15 to 0.259	—	—	—	—

SECONDARY outcome

Timeframe: Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.

Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL at a given timepoint.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=794 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
Induction Therapeutic Nadir Serum Asparaginase Activity Rate Day 11 NSAA Rate	96 percentage of participants	—	—	—	—
Induction Therapeutic Nadir Serum Asparaginase Activity Rate Day 18 NSAA Rate	87 percentage of participants	—	—	—	—
Induction Therapeutic Nadir Serum Asparaginase Activity Rate Day 25 NSAA Rate	12 percentage of participants	—	—	—	—
Induction Therapeutic Nadir Serum Asparaginase Activity Rate Day 4 NSAA Rate	97 percentage of participants	—	—	—	—

SECONDARY outcome

Population: The analysis dataset is comprised of B cell ALL patients who achieved an induction complete remission with an evaluable sample at day 32 for analysis of MRD.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=50 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=496 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
5-Year Disease-Free Survival by MRD Day 32 Status	.79 probability Interval 0.6 to 0.86	.90 probability Interval 0.87 to 0.93	—	—	—

SECONDARY outcome

Population: The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at day 18 (optional submission) for analysis of marrow morphology.

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=284 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=26 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status n=193 Participants Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
5-Year Disease-Free Survival by Bone Marrow Day 18 Status	.89 probability Interval 0.85 to 0.92	.78 probability Interval 0.54 to 0.9	.88 probability Interval 0.82 to 0.92	—	—

SECONDARY outcome

Population: The analysis dataset is comprised of patients who achieved an induction complete remission with an evaluable sample at diagnosis for analysis of CNS-directed therapy .

Outcome measures

Outcome measures
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=579 Participants Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=114 Participants Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Hypocellular Day 18 Bone Marrow Status n=9 Participants Hypocellular marrow morphology at day 18 was defined as empty blasts.	Traumatic Tap With Blasts n=32 Participants Traumatic Tap with Blasts: with blast cells and \>100 RBCs on a wet prep	Traumatic Tap Without Blasts n=19 Participants Traumatic Tap without Blasts: without blast cells and \>100 RBCs on a wet prep
5-year Disease-Free Survival by CNS Directed Treatment Group	.89 probability Interval 0.87 to 0.92	.89 probability Interval 0.82 to 0.94	1.00 probability NA-not applicable since all patients were disease-free at 5 years.	.84 probability Interval 0.67 to 0.93	.87 probability Interval 0.58 to 0.97

Adverse Events

Intramuscular Native E Coli L-asparaginase (IM-EC)

Serious events: 132 serious events

Other events: 40 other events

Deaths: 1 deaths

Intravenous PEG-asparaginase (IV-PEG)

Serious events: 142 serious events

Other events: 38 other events

Deaths: 1 deaths

Overall

Serious events: 574 serious events

Other events: 118 other events

Deaths: 2 deaths

Serious adverse events

Other adverse events

Additional Information

Lynda Vrooman, MD

Dana-Farber Cancer Institute

Phone: 6176322659

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 participants at risk Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 participants at risk Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Overall n=794 participants at risk Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
Investigations INR	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Vascular disorders Acute vascular leak syndrome	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations ADH secretion abnormality (eg SIADH)	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations Alkaline phosphatase	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Psychiatric disorders Anxiety	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Cardiac disorders Atrial flutter	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Musculoskeletal and connective tissue disorders Back- pain	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Respiratory, thoracic and mediastinal disorders Bronchopulmonary- hemorrhage	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Cardiac disorders Cardiac-other	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Gastrointestinal disorders Cecum/appendix- hemorrhage	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Vascular disorders Chyle or lymph leakage	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Nervous system disorders CNS cerebrovascular ischemia	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations Coagulation-other	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations Creatinine	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Death - multiorgan failure	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Death - sudden death	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Edema limb	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Gastrointestinal disorders Enteritis	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Nervous system disorders Head/headache	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Blood and lymphatic system disorders Hematologic-other	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Blood and lymphatic system disorders Hemolysis	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Metabolism and nutrition disorders Hypoalbuminemia	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- bladder	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- bronchus	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- cervix	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- dental-tooth	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- middle ear	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- muscle	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- soft tissue	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- spleen	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- brain	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- brain + spinal	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- dental-tooth	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- eye NOS	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- lens	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- lip/perioral	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- liver	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- paranasal	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- pleura	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.

Other adverse events
Measure	Intramuscular Native E Coli L-asparaginase (IM-EC) n=231 participants at risk Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Intravenous PEG-asparaginase (IV-PEG) n=232 participants at risk Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.	Overall n=794 participants at risk Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. All patients received a single dose of intravenous PEG-asparaginase 2500 IU/m2 during multi-agent induction. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization wherein patients received either E. coli L-asparaginase or peg-asparaginase. Standard risk and high-risk patients began post-induction randomized asparaginase therapy at the start of the CNS phase, whereas very high-risk patients began asparaginase therapy on day 8 of consolidation phase IC. Patients who did not achieve complete remission by the end of the induction phase were not eligible for randomization, were removed from protocol treatment, and received alternative therapy according to the discretion of their treating physician. Further details are provided in the study description section.
Psychiatric disorders Agitation	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Immune system disorders Allergy-other	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Respiratory, thoracic and mediastinal disorders Atelectasis	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Injury, poisoning and procedural complications Chemoradiation dermatitis	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Chest/thoracic pain NOS	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Respiratory, thoracic and mediastinal disorders Cough	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations Creatinine	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Metabolism and nutrition disorders Dehydration	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Gastrointestinal disorders Enteritis	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Extremity-lower (gait/walking)	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Fatigue	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Blood and lymphatic system disorders Hemoglobin	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
General disorders and administration site conditions Hypothermia	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- bladder	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- bronchus	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- external ear	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- eye NOS	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- kidney	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- lung	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- lymphatic	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection Gr0-2 neut- meninges	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- bronchus	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- catheter relate	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- eye NOS	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- larynx	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- middle ear	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- peritoneal	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- pharynx	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- urinary tract	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ gr3-4 neut- wound	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.43% 1/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ unk ANC catheter related	0.43% 1/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ unk ANC skin (cellulitis)	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ unk ANC ungual (nails)	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ unk ANC upper airway NOS	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Infections and infestations Infection w/ unk ANC wound	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Investigations Lipase	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.
Gastrointestinal disorders Muco/stomatitis (symptom) anus	0.00% 0/231 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.00% 0/232 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.	0.13% 1/794 • Adverse events (AE) were continuously monitored and reported every 3 months during treatment except bony events (avascular necrosis and fracture) which were followed up to 10 years. Treatment duration for this study cohort was a median (range) of 757 days (1-881 days). Data is reported for the entire study cohort (n=794) and comparing randomized arms (n=231/n=232), other non-randomized reporting groups are not reported separately since the intent was not to compare rates between these groups. Reporting included (trt-related, all grades \[G\] unless specified): asparaginase-related allergy, symptomatic pancreatitis (\>G1), thrombotic or bleeding complications requiring intervention (\>G1), infections (\>G2), symptomatic osteonecrosis (\>G1), bone fractures and seizures. All other G4-5 AEs were also collected, excl G4 hematological and G4 asymptomatic elevated aminotransferases. Maximum grade toxicity by type was calculated with serious and other AEs defined as G3-5 and G1-2, respectively.