Trial Outcomes & Findings for Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) (NCT NCT02013167)

NCT ID: NCT02013167

Last Updated: 2024-03-05

Results Overview

Overall survival (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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

405 participants

Primary outcome timeframe

From randomization until the data cut-off date of 04 January 2016; median observation time was 11.8 months in the SOC group and 11.7 months in the blinatumomab group.

Results posted on

2024-03-05

Participant Flow

This study was conducted at 101 centers in 21 countries in Asia, Australia, Europe, and Latin and North America. The first participant was enrolled on 03 January 2014 and treated on 06 January 2014. The last participant enrolled on 25 September 2015 and the data cutoff date for this report was 04 January 2016.

Participants were randomized in a 2:1 ratio to either blinatumomab or standard of care (SOC) chemotherapy regimens. Randomization was stratified by age (\< 35 years vs ≥ 35 years), prior salvage therapy (yes vs no), and prior allogeneic hematopoietic stem cell transplantation (HSCT) (yes vs no) as assessed at the time of consent.

Participant milestones

Participant milestones
Measure	Standard of Care Chemotherapy Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Overall Study STARTED	134	271
Overall Study Received Treatment	109	267
Overall Study COMPLETED	33	93
Overall Study NOT COMPLETED	101	178

Reasons for withdrawal

Reasons for withdrawal
Measure	Standard of Care Chemotherapy Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Overall Study Withdrawal by Subject	15	14
Overall Study Sponsor Decision	1	3
Overall Study Lost to Follow-up	0	1
Overall Study Death	85	160

Baseline Characteristics

Blinatumomab Versus Standard of Care Chemotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.	Total n=405 Participants Total of all reporting groups
Age, Continuous	41.1 years STANDARD_DEVIATION 17.3 • n=5 Participants	40.8 years STANDARD_DEVIATION 17.1 • n=7 Participants	40.9 years STANDARD_DEVIATION 17.2 • n=5 Participants
Age, Customized < 35 years	60 participants n=5 Participants	124 participants n=7 Participants	184 participants n=5 Participants
Age, Customized 35 to 54 years	33 participants n=5 Participants	80 participants n=7 Participants	113 participants n=5 Participants
Age, Customized 55 to 64 years	26 participants n=5 Participants	34 participants n=7 Participants	60 participants n=5 Participants
Age, Customized ≥ 65 years	15 participants n=5 Participants	33 participants n=7 Participants	48 participants n=5 Participants
Sex: Female, Male Female	57 Participants n=5 Participants	109 Participants n=7 Participants	166 Participants n=5 Participants
Sex: Female, Male Male	77 Participants n=5 Participants	162 Participants n=7 Participants	239 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=5 Participants	26 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	122 Participants n=5 Participants	243 Participants n=7 Participants	365 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 participants n=5 Participants	4 participants n=7 Participants	5 participants n=5 Participants
Race/Ethnicity, Customized Asian	9 participants n=5 Participants	19 participants n=7 Participants	28 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	3 participants n=5 Participants	5 participants n=7 Participants	8 participants n=5 Participants
Race/Ethnicity, Customized White	112 participants n=5 Participants	228 participants n=7 Participants	340 participants n=5 Participants
Race/Ethnicity, Customized Multiple	0 participants n=5 Participants	2 participants n=7 Participants	2 participants n=5 Participants
Race/Ethnicity, Customized Other	8 participants n=5 Participants	12 participants n=7 Participants	20 participants n=5 Participants
Age Stratification at Randomization < 35 years	60 participants n=5 Participants	123 participants n=7 Participants	183 participants n=5 Participants
Age Stratification at Randomization ≥ 35 years	74 participants n=5 Participants	148 participants n=7 Participants	222 participants n=5 Participants
Prior Salvage Therapy Stratification at Randomization Yes	80 participants n=5 Participants	164 participants n=7 Participants	244 participants n=5 Participants
Prior Salvage Therapy Stratification at Randomization No	54 participants n=5 Participants	107 participants n=7 Participants	161 participants n=5 Participants
Prior Allogeneic Hematopoietic Stem Cell Transplant (HCST) Yes	46 participants n=5 Participants	94 participants n=7 Participants	140 participants n=5 Participants
Prior Allogeneic Hematopoietic Stem Cell Transplant (HCST) No	88 participants n=5 Participants	177 participants n=7 Participants	265 participants n=5 Participants
Standard of Care Chemotherapy Regimen Received FLAG ± anthracycline	56 participants n=5 Participants	0 participants n=7 Participants	56 participants n=5 Participants
Standard of Care Chemotherapy Regimen Received High-dose methotrexate	30 participants n=5 Participants	0 participants n=7 Participants	30 participants n=5 Participants
Standard of Care Chemotherapy Regimen Received Clofarabine	26 participants n=5 Participants	0 participants n=7 Participants	26 participants n=5 Participants
Standard of Care Chemotherapy Regimen Received HIDAC	22 participants n=5 Participants	0 participants n=7 Participants	22 participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization until the data cut-off date of 04 January 2016; median observation time was 11.8 months in the SOC group and 11.7 months in the blinatumomab group.

Population: All randomized participants

Overall survival (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.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Overall Survival	4.0 months Interval 2.9 to 5.3	7.7 months Interval 5.6 to 9.6

SECONDARY outcome

Timeframe: 12 weeks

Population: All randomized participants

Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete Remission (CR) was defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets \> 100,000/μl, and absolute neutrophil count (ANC) \> 1,000/μl. CR must have occurred within 12 weeks of the first dose of therapy.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Percentage of Participants With Complete Remission Within 12 Weeks of Treatment Initiation	15.7 percentage of participants Interval 10.0 to 23.0	33.6 percentage of participants Interval 28.0 to 39.5

SECONDARY outcome

Timeframe: 12 weeks

Population: All randomized participants

Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets \> 100,000/μl, and ANC \> 1,000/μl. Complete Remission with partial hematological recovery (CRh\*) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts: platelets \> 50,000/μl, and ANC \> 500/μl. Complete remission with incomplete hematological recovery (CRi) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets \> 100,000/μl or ANC \> 1000 (but not both).

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Percentage of Participants With Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi) Within 12 Weeks of Treatment Initiation	24.6 percentage of participants Interval 17.6 to 32.8	43.9 percentage of participants Interval 37.9 to 50.0

SECONDARY outcome

Timeframe: 6 months

Population: All randomized participants

Event free survival was defined as the time from randomization until a documented relapse after achieving CR/CRh\*/CRi or death, whichever occurred first. Participants who failed to achieve a CR/CRh\*/CRi within 12 weeks of treatment initiation were considered as non-responders and assigned an EFS duration of 1 day. Participants still alive and relapse-free were censored on their last disease assessment date. A relapse event was any one of the following: * Hematological relapse: proportion of blasts in bone marrow \>5% or blasts in peripheral blood after documented CR or CRh\* or CRi * Progressive disease: An increase from baseline of at least 25% of bone marrow blasts or an absolute increase of at least 5,000 cells/μL in the number of circulating leukemia cells * Extramedullary relapse: extramedullary lesion that is new or increased by 50% from nadir as assessed by Cheson criteria. The Kaplan-Meier estimate of EFS at 6 months is reported.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Event Free Survival (EFS)	12.5 percentage of participants Interval 7.2 to 19.2	30.7 percentage of participants Interval 25.0 to 36.5

SECONDARY outcome

Timeframe: Up to the data cut-off date of 04 January 2016; median observation time was 10.8 months in the SOC group and 7.0 months in the blinatumomab group.

Population: Randomized participants with a best response of complete remission within 12 weeks of treatment initiation.

Duration of complete remission, calculated only for participants who achieved a CR, was calculated from the date a CR was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=21 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=91 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Duration of Complete Remission	7.8 months Interval 2.2 to 19.0	8.3 months Interval 5.7 to 10.7

SECONDARY outcome

Timeframe: Up to the data cut-off date of 04 January 2016; median observation time was 10.8 months in the SOC group and 7.2 months in the blinatumomab group.

Population: Randomized participants with a best response of CR/CRh\*/CRi within 12 weeks of treatment initiation.

Duration of CR/CRh\*/CRi, calculated only for participants who achieved a CR/CRh\*/CRi, was calculated from the date a CR/CRh\*/CRi was first achieved until the earliest date of a disease assessment indicating a relapse event or death, whichever occurred first. Participants who did not have a relapse event were censored on their last disease assessment date.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=33 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=119 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Duration of Complete Remission/Complete Remission With Partial Hematological Recovery/Complete Remission With Incomplete Hematological Recovery (CR/CRh*/CRi)	4.6 months Interval 1.8 to 19.0	7.3 months Interval 5.8 to 9.9

SECONDARY outcome

Timeframe: 12 weeks

Population: All randomized participants

Bone marrow samples were evaluated for MRD remission by a central laboratory. MRD remission was defined as the occurrence of an MRD level below 10\^-4 measured by quantitative reverse transcription polymerase chain reaction (PCR) or flow cytometry.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Percentage of Participants With Minimal Residual Disease (MRD) Within 12 Weeks of Treatment Initiation	14.2 percentage of participants Interval 8.8 to 21.3	29.9 percentage of participants Interval 24.5 to 35.7

SECONDARY outcome

Timeframe: Up to the data cut-off date of 04 January 2016; maximum time on study was 23 months.

Population: All randomized participants

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=134 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=271 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT)	23.9 percentage of participants Interval 16.9 to 32.0	24.0 percentage of participants Interval 19.0 to 29.5

SECONDARY outcome

Timeframe: From first dose of protocol-specified therapy until 30 days after the last dose, up to the data cut-off date of 04 January 2016; median duration of treatment was 5 days in the SOC group and 70 days in the blinatumomab group.

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

Adverse events (AEs) were graded for severity according to the CTCAE version 4.0, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Treatment-related adverse events (TRAEs) were those assessed by the investigator as possibly related to blinatumomab based on response to the question: Is there a reasonable possibility that the event may have been caused by blinatumomab or other protocol-specified therapies/procedures?

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=109 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=267 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Number of Participants With Adverse Events Any adverse event	108 participants	263 participants
Number of Participants With Adverse Events AE grade ≥ 2	106 participants	256 participants
Number of Participants With Adverse Events AE grade ≥ 3	100 participants	231 participants
Number of Participants With Adverse Events AE grade ≥ 4	67 participants	133 participants
Number of Participants With Adverse Events Serious adverse events	49 participants	165 participants
Number of Participants With Adverse Events AEs leading to interruption of study drug	6 participants	86 participants
Number of Participants With Adverse Events AEs leading to discontinuation of study drug	9 participants	33 participants
Number of Participants With Adverse Events Life-threatening adverse events	26 participants	55 participants
Number of Participants With Adverse Events Fatal adverse events	19 participants	51 participants
Number of Participants With Adverse Events Treatment-related adverse events	92 participants	214 participants
Number of Participants With Adverse Events Treatment-related AE grade ≥ 2	89 participants	195 participants
Number of Participants With Adverse Events Treatment-related AE grade ≥ 3	78 participants	143 participants
Number of Participants With Adverse Events Treatment-related AE grade ≥ 4	51 participants	57 participants
Number of Participants With Adverse Events Serious treatment-related adverse events	34 participants	74 participants
Number of Participants With Adverse Events TRAEs leading to interruption of study drug	6 participants	58 participants
Number of Participants With Adverse Events TRAEs leading to discontinuation of study drug	8 participants	19 participants
Number of Participants With Adverse Events Treatment-related life-threatening adverse events	17 participants	21 participants
Number of Participants With Adverse Events Treatment-related fatal adverse events	8 participants	8 participants

SECONDARY outcome

Timeframe: 100 days, from the date of allogeneic HSCT until the data cut-off date of 04 January 2016

Population: Randomized participants with a best response of CR/CRh\*/CRi within 12 weeks of treatment initiation and who received an allogeneic HSC without anti-cancer therapy prior to allogeneic HSCT.

The analysis of 100-day mortality after allogeneic HSCT was assessed for participants who achieved a best response of CR/CRh\*CTi within 12 weeks of treatment initiation, who received an allogeneic HSCT and did not receive any additional anticancer treatment before the transplant. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=12 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=38 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant	0.0 percentage of participants Could not be estimated due to the low number of events	12.4 percentage of participants Interval 4.8 to 29.9

SECONDARY outcome

Timeframe: Samples were collected on day 29 at the end of cycle 2 and 30 days after the last dose of blinatumomab (median duration of treatment was 70 days).

Population: Participants who received blinatumomab with available post-baseline antibody data.

Anti-blinatumomab binding antibodies were evaluated using a validated electrochemiluminescence (ECL)-based assay (binding assay). Samples positive for binding were analyzed using a cell-based bioassay to determine if the detected antibodies had neutralizing properties (neutralizing assay).

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=171 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Number of Participants With Anti-blinatumomab Antibodies Binding antibody positive	5 participants	—
Number of Participants With Anti-blinatumomab Antibodies Neutralizing antibody positive	3 participants	—

SECONDARY outcome

Timeframe: From randomization until the data cut-off date of 04 January 2016; EORTC QLQ-C30 was assessed on day 1, 8, 15, and 29 during cycle 1; days 1, 15, and 29 in cycle 2 and each consolidation cycle, and 30-days following the last dose of drug treatment.

Population: EORTC QLQ-C30 analysis set included all randomized participants with a non-missing baseline and at least 1 non-missing postbaseline result of any EORTC QLQ-C30 scales/item.

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is a 30-item questionnaire that assesses the health related quality of life of cancer patients. The EORTC QLQ-C30 consists of a global health status/quality of life (QoL) scale, 5 functional scales, 3 symptom scales, and 6 single items. The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life durig the past week on a scale from 1 (very poor) to 7 (excellent). The scale score was derived as the sum of each score and transformed to a scale from 0 to 100 where higher scores represent a high QoL. Time to a ≥10-point decrease from baseline GHS/QoL or death, whichever came first, was calculated from baseline. Participants still alive and without a 10-point decrease in GHS/QoL EORTC QLQ-C30 were censored on their last EORTC QLQ-C30 assessment date.

Outcome measures

Outcome measures
Measure	Standard of Care Chemotherapy n=95 Participants Participants received one of four prespecified, investigator-chosen chemotherapy regimens for 2 induction cycles. Participants who achieved a bone marrow response, CR/CRh\/CRi within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of SOC chemotherapy. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive SOC therapy for an additional 12 months.	Blinatumomab n=247 Participants Participants received blinatumomab by continuous intravenous infusion (CIVI) over 4 weeks followed by a 2 week treatment-free interval for 2 induction cycles. Participants who achieved a bone marrow response, complete remission, or complete remission with partial or incomplete hematologic recovery (CR/CRh\/CRi) within 2 induction cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Participants who received 2 induction and up to 3 consolidation cycles of therapy and continued to have a bone marrow response or CR/CRh\/CRi could continue to receive blinatumomab for an additional 12 months (4 cycles), where 1 cycle consisted of 4 weeks of CIVI followed by an 8-week treatment-free period. The initial dose of blinatumomab was 9 μg/day for the first 7 days of treatment, increased to 28 μg/day starting on day 8 through day 29 and for all subsequent cycles.
Time to a 10-point Decrease From Baseline in Global Health Status and Quality of Life or Death	1.0 months Interval 0.5 to 1.5	1.7 months Interval 1.1 to 3.6

Adverse Events

Standard of Care Chemotherapy

Serious events: 49 serious events

Other events: 105 other events

Deaths: 0 deaths

Blinatumomab

Serious events: 165 serious events

Other events: 250 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

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