PRIMARY OBJECTIVE:
I. To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to
chemotherapy alone in patients with BCR-ABL-negative B cell precursor acute lymphoblastic
leukemia (ALL) who are minimal residual disease (MRD) negative after induction and
intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of
residual blasts.
SECONDARY OBJECTIVES:
I. To compare the relapse-free survival (RFS) of blinatumomab in conjunction with
chemotherapy to chemotherapy alone in MRD negative patients after induction and
intensification chemotherapy.
II. To compare the OS and RFS of those patients who are MRD positive (+) at step 3
randomization/registration and then convert to MRD negative (-) after 2 cycles of
blinatumomab to those patients who are MRD- at randomization and remain MRD- after 2 cycles
of blinatumomab or consolidation chemotherapy.
III. To assess the toxicities of blinatumomab in this patient population. IV. To assess the
toxicities of the modified E2993 chemotherapy regimen in this patient population.
V. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant
after treatment with or without blinatumomab.
LABORATORY OBJECTIVES:
I. To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage
ALL, and to compare the OS (and RFS) of patients with BCR-ABL-like phenotype with those
without BCR-ABL-like phenotype.
II. To evaluate the incidence of anti-blinatumomab antibody formation.
OUTLINE:
INDUCTION CHEMOTHERAPY: Patients receive cytarabine intrathecally (IT) on day 1; daunorubicin
hydrochloride intravenously (IV) over 10-15 minutes on days 1, 8, 15, and 22; vincristine
sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-7 (and 15-21
for patients age < 55 years only); methotrexate IT on day 14; pegaspargase intramuscularly
(IM) or IV on day 18 (patients age < 55 years); and CD20 positive patients may optionally
receive rituximab IV on day 8 and 15. Beginning on day 29, patients with absolute neutrophil
count (ANC) >= 0.75 x 10^9/L and platelets > 75 x 10^9/L (patients with delayed hematologic
recovery) (patients with residual disease that is delaying count begin treatment immediately)
receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes
or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14,
29-42, pegaspargase IM or IV on day 15 (patients age < 55 years), patients receiving
treatment for central nervous system (CNS) 2 or 3 leukemia in cycle 1 receive methotrexate IT
on days 1, 8, 15, and 22, and CD20 positive patients may optionally receive rituximab IV on
days 8 and 15.
INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of cycle 2 of induction
therapy, patients receive intensification therapy comprising high-dose methotrexate IV over 2
hours on days 1 and 8, and pegaspargase IM or IV on day 9.
Patients are then randomized to 1 of 2 treatment arms.
Patients randomized to the blinatumomab group receive blinatumomab IV continuously on days
1-28. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or
unacceptable toxicity. Patients may then undergo allogeneic stem cell transplant (SCT) or
proceed to consolidation therapy per investigator discretion.
CONSOLIDATION THERAPY: Beginning after the second cycle of blinatumomab (patients randomized
to the blinatumomab group) or after intensification therapy (patients not randomized to
blinatumomab), patients receive cytarabine IV over 30 minutes or SC on days 1-5, etoposide IV
over 1 hour on days 1-5, methotrexate IT on day 1, and pegaspargase IM or IV on day 5, and
CD20 positive patients may optionally receive rituximab IV on day 5. Beginning 4 weeks from
day 1 of cycle 1, patients receive cytarabine, etoposide, methotrexate, and CD20 positive
patients may receive rituximab as in cycle 1. Beginning 4 weeks from day 1 of cycle 2,
patients receive daunorubicin hydrochloride IV over 10-15 minutes on day 1, 8, 15, and 22;
vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-7 (and
15-21 for patients age < 55 years); methotrexate IT on day 2; cyclophosphamide IV over 30
minutes on day 29; cytarabine IV over 30 minutes or SC on days 30-33 and 37-40;
mercaptopurine PO on days 29-42 and CD20 positive patients may receive rituximab on day 8.
Beginning 8 weeks from day 1 of cycle 3, patients receive cytarabine, etoposide,
methotrexate, and CD20 positive patients may optionally receive rituximab as in cycle 1.
Patients randomized to blinatumomab repeat cycle 4 and then receive blinatumomab IV
continuously on days 1-28.
MAINTENANCE THERAPY: Within 6 weeks after beginning last cycle of consolidation therapy,
patients receive mercaptopurine PO daily, methotrexate PO or IV over 2 hours once weekly for
2.5 years, vincristine sulfate IV on day 1 every 3 months, prednisone PO on days 1-5 every 3
months, and methotrexate IT on day 1 every 3 months. Treatment continues for up to 2.5 years
in the absence of disease progression or unacceptable toxicity.
Patients undergo x-ray imaging during screening, lumbar puncture while on study, and bone
marrow aspiration, bone marrow biopsy, and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then every 12 months for 5 years.