Trial Outcomes & Findings for Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL) (NCT NCT02393859)

Last Updated: 2024-05-29

Results Overview

EFS is calculated from the time of randomization until the date of relapse or M2 marrow (representative bone marrow aspirate or biopsy with ≥ 5% and \< 25% blasts) after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: * M1 marrow * Peripheral blood without blasts * Absence of extramedullary leukemic involvement Months are calculated as days from randomization date to event/censor date, divided by 30.5.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

111 participants

Primary outcome timeframe

As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.

Results posted on

2024-05-29

Participant Flow

This study was conducted at 48 centers across 13 countries (Europe, Australia, Israel). The first participant was enrolled on 10 November 2015. The last participant enrolled on 30 August 2019. The primary completion date was 17 July 2019 and the study completion date was 21 November 2022.

After a 3-week screening period, participants were enrolled and randomized 1:1 into 1 of 2 treatment groups: High Risk Consolidation 3 (HC3) chemotherapy or blinatumomab. Randomization was stratified by age and bone marrow/minimal residual disease (MRD) status.

Participant milestones

Participant milestones
Measure	HC3 Chemotherapy One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day intravenous \[IV\] on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or intramuscularly \[IM\] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Overall Study STARTED	57	54
Overall Study Participants Treated	52	54
Overall Study Participants in the Primary Analysis Population	54	54
Overall Study Participants in the Final Analysis Population	57	54
Overall Study COMPLETED	16	33
Overall Study NOT COMPLETED	41	21

Reasons for withdrawal

Reasons for withdrawal
Measure	HC3 Chemotherapy One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day intravenous \[IV\] on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or intramuscularly \[IM\] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Overall Study Decision by Sponsor	2	4
Overall Study Withdrawal by Subject	11	6
Overall Study Death	27	10
Overall Study Lost to Follow-up	1	1

Baseline Characteristics

Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HC3 Chemotherapy n=57 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).	Total n=111 Participants Total of all reporting groups
Age, Continuous	6.6 years STANDARD_DEVIATION 4.3 • n=5 Participants	7.3 years STANDARD_DEVIATION 4.4 • n=7 Participants	7.0 years STANDARD_DEVIATION 4.4 • n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants	24 Participants n=7 Participants	58 Participants n=5 Participants
Sex: Female, Male Male	23 Participants n=5 Participants	30 Participants n=7 Participants	53 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	54 Participants n=5 Participants	53 Participants n=7 Participants	107 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	46 Participants n=5 Participants	50 Participants n=7 Participants	96 Participants n=5 Participants
Race/Ethnicity, Customized Other, Not Specified	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Stratification Factor: Age Category 1 to 9 years	41 Participants n=5 Participants	39 Participants n=7 Participants	80 Participants n=5 Participants
Stratification Factor: Age Category Other (< 1 year and > 9 years)	16 Participants n=5 Participants	15 Participants n=7 Participants	31 Participants n=5 Participants
Stratification Factor: Marrow/Minimal Residual Disease (MRD) M1 Marrow + MRD level ≥ 10^-3	17 participants n=5 Participants	15 participants n=7 Participants	32 participants n=5 Participants
Stratification Factor: Marrow/Minimal Residual Disease (MRD) M1 Marrow + MRD level < 10^-3	36 participants n=5 Participants	35 participants n=7 Participants	71 participants n=5 Participants
Stratification Factor: Marrow/Minimal Residual Disease (MRD) M2 Marrow	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants

PRIMARY outcome

Timeframe: As of the primary analysis data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months.

Population: Full Analysis Set: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (primary analysis population).

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=54 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)	7.4 months Interval 4.5 to 12.7	NA months Interval 12.0 to NA=not estimable (median EFS and upper confidence interval \[CI\] were not reached at time of data cutoff)

PRIMARY outcome

Timeframe: At final analysis, overall median follow-up time for EFS was 51.9 months.

Population: FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received (final analysis population).

EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a CR, failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with IP or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date. Participants were said to be in CR when they had the following: * M1 marrow * Peripheral blood without blasts * Absence of extramedullary leukemic involvement Months are calculated as days from randomization date to event/censor date, divided by 30.5.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=57 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Kaplan Meier Estimate: EFS (Final Analysis)	7.8 months Interval 5.8 to 13.4	NA months Interval 24.8 to Median and upper 95% CI were not estimable due to too few events.

SECONDARY outcome

Timeframe: At final analysis, overall median follow-up time for OS was 55.2 months.

Population: FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received.

OS was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive. Months were calculated as days from randomization date to event/censor date, divided by 30.5.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=57 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Kaplan Meier Estimate: Overall Survival (OS)	25.6 months Interval 17.5 to Upper 95% CI was not estimable due to too few events.	NA months Median and 95% CIs were not estimable due to too few events.

SECONDARY outcome

Timeframe: Up to End of Treatment (Cycle 1, Day 29)

Population: MRD Evaluable Set: participants for whom an evaluable baseline MRD marker can be found with either of the MRD assessment methods of PCR or flow cytometry.

At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. MRD response was defined as MRD level \< 10\^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment (Cycle 1 Day 29) with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=56 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation MRD Response by PCR	53.1 percentage of participants Interval 38.3 to 67.5	93.9 percentage of participants Interval 83.1 to 98.7
Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation MRD Response by Flow Cytometry	60.0 percentage of participants Interval 45.9 to 73.0	92.6 percentage of participants Interval 82.1 to 97.9

SECONDARY outcome

Timeframe: At final analysis, the overall maximum follow-up time was 82.0 months.

Population: FAS: randomized participants analyzed according to their randomized treatment assignment, regardless of the treatment received.

CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up. Relapse=presence of ≥1 of the following: * isolated bone marrow relapse (M3 marrow \[representative bone marrow aspirate or biopsy with ≥25% blasts\] in the absence of extramedullary involvement) * combined bone marrow relapse (M2 \[representative bone marrow aspirate or biopsy with ≥5% and \<25% blasts\] or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia) * central nervous system extramedullary relapse * testicular extramedullary relapse * extramedullary relapse at other sites Months were calculated as days from randomization to event/censor date, divided by 30.5.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=57 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Cumulative Incidence of Relapse (CIR)	7.9 months Interval 5.8 to 18.6	NA months NA=not estimable (median CIR and confidence intervals were not reached at final analysis)

SECONDARY outcome

Timeframe: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.

Population: Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received.

Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=52 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Fatal TEAEs	0 participants	0 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TEAEs	50 participants	54 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TEAEs Grade ≥ 3	43 participants	33 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Serious TEAEs	24 participants	15 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TEAEs Leading to Discontinuation of IP	0 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TEAEs Leading to Interruption of IP	2 participants	6 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TRAEs	41 participants	45 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TRAEs Grade ≥ 3	33 participants	9 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Serious TRAEs	15 participants	9 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Fatal TRAEs	0 participants	0 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TRAEs Leading to Discontinuation of IP	0 participants	2 participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) TRAEs Leading to Interruption of IP	2 participants	5 participants

SECONDARY outcome

Timeframe: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.

Population: Safety Analysis Set: who received protocol-specified therapy analyzed according to the treatment they received.

TEAEs of interest included capillary leak syndrome (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome, leukoencephalopathy, immunogenicity. Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=52 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Number of Participants With TEAEs of Interest Fatal ETE Events	0 participants	0 participants
Number of Participants With TEAEs of Interest CLS Events	1 participants	0 participants
Number of Participants With TEAEs of Interest CLS Events Grade ≥ 3	1 participants	0 participants
Number of Participants With TEAEs of Interest Serious CLS Events	1 participants	0 participants
Number of Participants With TEAEs of Interest Fatal CLS Events	0 participants	0 participants
Number of Participants With TEAEs of Interest CLS Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest CLS Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest CRS Events	1 participants	2 participants
Number of Participants With TEAEs of Interest CRS Events Grade ≥ 3	0 participants	0 participants
Number of Participants With TEAEs of Interest Serious CRS Events	0 participants	0 participants
Number of Participants With TEAEs of Interest Fatal CRS Events	0 participants	0 participants
Number of Participants With TEAEs of Interest CRS Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest CRS Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest DI Events	6 participants	9 participants
Number of Participants With TEAEs of Interest DI Events Grade ≥ 3	1 participants	1 participants
Number of Participants With TEAEs of Interest Serious DI Events	0 participants	1 participants
Number of Participants With TEAEs of Interest Fatal DI Events	0 participants	0 participants
Number of Participants With TEAEs of Interest DI Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest DI Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ELE Events	15 participants	7 participants
Number of Participants With TEAEs of Interest ELE Events Grade ≥ 3	9 participants	3 participants
Number of Participants With TEAEs of Interest Serious ELE Events	1 participants	0 participants
Number of Participants With TEAEs of Interest Fatal ELE Events	0 participants	0 participants
Number of Participants With TEAEs of Interest ELE Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ELE Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ETE Events	0 participants	4 participants
Number of Participants With TEAEs of Interest ETE Events Grade ≥ 3	0 participants	2 participants
Number of Participants With TEAEs of Interest Serious ETE Events	0 participants	0 participants
Number of Participants With TEAEs of Interest ETE Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ETE Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest INF Events	18 participants	25 participants
Number of Participants With TEAEs of Interest INF Events Grade ≥ 3	6 participants	11 participants
Number of Participants With TEAEs of Interest Serious INF Events	6 participants	4 participants
Number of Participants With TEAEs of Interest Fatal INF Events	0 participants	0 participants
Number of Participants With TEAEs of Interest IFN Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest IFN Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest IRWCD Events	4 participants	37 participants
Number of Participants With TEAEs of Interest IRWCD Events Grade ≥ 3	0 participants	2 participants
Number of Participants With TEAEs of Interest Serious IRWCD Events	0 participants	1 participants
Number of Participants With TEAEs of Interest Fatal IRWCD Events	0 participants	0 participants
Number of Participants With TEAEs of Interest IRWCD Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest IRWCD Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ME Events	0 participants	1 participants
Number of Participants With TEAEs of Interest ME Events Grade ≥ 3	0 participants	0 participants
Number of Participants With TEAEs of Interest Serious ME Events	0 participants	1 participants
Number of Participants With TEAEs of Interest Fatal ME Events	0 participants	0 participants
Number of Participants With TEAEs of Interest ME Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest ME Events Leading to Interruption of IP	0 participants	1 participants
Number of Participants With TEAEs of Interest NE Events	15 participants	26 participants
Number of Participants With TEAEs of Interest NE Events Grade ≥ 3	1 participants	3 participants
Number of Participants With TEAEs of Interest Serious NE Events	1 participants	5 participants
Number of Participants With TEAEs of Interest Fatal NE Events	0 participants	0 participants
Number of Participants With TEAEs of Interest NE Events Leading to Discontinuation of IP	0 participants	2 participants
Number of Participants With TEAEs of Interest NE Events Leading to Interruption of IP	1 participants	3 participants
Number of Participants With TEAEs of Interest NFN Events	28 participants	12 participants
Number of Participants With TEAEs of Interest NFN Events Grade ≥ 3	27 participants	11 participants
Number of Participants With TEAEs of Interest Serious NFN Events	12 participants	0 participants
Number of Participants With TEAEs of Interest Fatal NFN Events	0 participants	0 participants
Number of Participants With TEAEs of Interest NFN Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest NFN Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest PNC Events	1 participants	0 participants
Number of Participants With TEAEs of Interest PNC Events Grade ≥ 3	1 participants	0 participants
Number of Participants With TEAEs of Interest Serious PNC Events	1 participants	0 participants
Number of Participants With TEAEs of Interest Fatal PNC Events	0 participants	0 participants
Number of Participants With TEAEs of Interest PNC Events Leading to Discontinuation of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest PNC Events Leading to Interruption of IP	0 participants	0 participants
Number of Participants With TEAEs of Interest Tumour Lysis Syndrome Events	0 participants	0 participants
Number of Participants With TEAEs of Interest Leukoencephalopathy Events	0 participants	0 participants
Number of Participants With TEAEs of Interest Immunogenicity Events	0 participants	0 participants

SECONDARY outcome

Timeframe: Up to Day 29 (± 2 days).

Population: Safety Analysis Set: who received protocol-specified therapy analyzed according to the treatment they received.

Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=52 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=54 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Potassium ↑ BL Gr 0 → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Potassium ↓ BL Gr 0 → PB Gr 3	4 participants	5 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Potassium ↓ BL Gr 0 → PB Gr 4	1 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Albumin ↓ BL Gr 0 → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Calcium ↓ BL Gr 0 → PB Gr 4	1 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Alanine Aminotransferase ↑ BL Gr 0 → PB Gr 3	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Alanine Aminotransferase ↑ BL Gr 1 → PB Gr 3	9 participants	5 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Aspartate Aminotransferase ↑ BL Gr NA → PB Gr 3	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Aspartate Aminotransferase ↑ BL Gr 0 → PB Gr 3	2 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Aspartate Aminotransferase ↑ BL Gr 1 → PB Gr 3	5 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Aspartate Aminotransferase ↑ BL Gr 1 → PB Gr 4	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Gamma-Glutamyl Transferase ↑ BL Gr NA → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Gamma-Glutamyl Transferase ↑ BL Gr 0 → PB Gr 3	3 participants	4 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Gamma-Glutamyl Transferase ↑ BL Gr 1 → PB Gr 3	6 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Gamma-Glutamyl Transferase ↑ BL Gr 1 → PB Gr 4	0 participants	3 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Amylase ↑ BL Gr 0 → PB Gr 3	1 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Amylase ↑ BL Gr 0 → PB Gr 4	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Amylase ↑ BL Gr 1 → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lipase ↑ BL Gr 0 → PB Gr 3	3 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lipase ↑ BL Gr 0 → PB Gr 4	1 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Bilirubin ↑ BL Gr 0 → PB Gr 3	2 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Bilirubin ↑ BL Gr 0 → PB Gr 4	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Creatinine ↑ BL Gr NA → PB Gr 3	0 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Hemoglobin ↓ BL Gr 0 → PB Gr 3	1 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Hemoglobin ↓ BL Gr 1 → PB Gr 3	4 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Platelets ↓ BL Gr 0 → PB Gr 3	7 participants	6 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Platelets ↓ BL Gr 0 → PB Gr 4	13 participants	6 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Platelets ↓ BL Gr 1 → PB Gr 3	1 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Platelets ↓ BL Gr 1 → PB Gr 4	8 participants	2 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Leukocytes ↓ BL Gr 0 → PB Gr 3	2 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Leukocytes ↓ BL Gr 0 → PB Gr 4	4 participants	0 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Leukocytes ↓ BL Gr 1 → PB Gr 3	4 participants	4 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Leukocytes ↓ BL Gr 1 → PB Gr 4	7 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Neutrophils ↓ BL Gr 0 → PB Gr 3	4 participants	11 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Neutrophils ↓ BL Gr 0 → PB Gr 4	23 participants	3 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lymphocytes ↑ BL Gr 0 → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lymphocytes ↓ BL Gr 0 → PB Gr 3	1 participants	3 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lymphocytes ↓ BL Gr 0 → PB Gr 4	1 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lymphocytes ↓ BL Gr 1 → PB Gr 3	0 participants	1 participants
Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values Lymphocytes ↓ BL Gr 1 → PB Gr 4	1 participants	2 participants

SECONDARY outcome

Timeframe: From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.

Population: HSCT Analysis Set: participants who underwent an HSCT while in remission without any other anti-leukemic therapy.

The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT. The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=39 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab n=51 Participants One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)	5.1 percentage of participants Interval 1.3 to 19.0	3.9 percentage of participants Interval 1.0 to 14.8

SECONDARY outcome

Timeframe: Day 1 to Day 29.

Population: Safety Analysis Set: participants who received protocol-specified therapy analyzed according to the treatment they received. Participants in the blinatumumab arm with a post-baseline result.

Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies. Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=52 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) Binding Antibody Positive	0 participants	—
Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) Neutralizing Antibody Positive	0 participants	—

SECONDARY outcome

Timeframe: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15

Population: Pharmacokinetic (PK) Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=45 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)	884 pg/mL Standard Deviation 969	—

SECONDARY outcome

Timeframe: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15

Population: PK Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected.

Outcome measures

Outcome measures
Measure	HC3 Chemotherapy n=45 Participants One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m\^2/day IV on Days 1-6), vincrisitne (1.5 mg/m\^2/day IV on Days 1 and 6), daunorubicin (30 mg/m\^2 IV over 24 hours on Day 5), methotrexate (1 g/m\^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m\^2 IV for 1 hour on Days 2-4), and pegylated \[PEG\]-asparaginase (1000 U/m\^2 IV for 2 hours or IM on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m\^2 IV or IM every 48 hours for a total of 6 doses).	Blinatumomab One 4-week cycle of blinatumomab 15 μg/m\^2/day as a continuous intravenous infusion (CIVI).
Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)	1.14 L/hr/m^2 Standard Deviation 0.836	—

Adverse Events

HC3 Chemotherapy

Serious events: 24 serious events

Other events: 48 other events

Deaths: 28 deaths

Blinatumomab

Serious events: 15 serious events

Other events: 54 other events

Deaths: 11 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER