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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.