PRIMARY OBJECTIVE:
I. To compare undetectable measurable residual disease (MRD) event-free survival (EFS)
rate of the experimental arm (A) to standard arm (B) with EFS defined as time from
randomization to occurrence of an event.
SECONDARY OBJECTIVES:
I. To determine overall response rate (complete response [CR], CR + complete remission
with incomplete platelet counts [CRp], CR + complete remission with partial hematologic
recovery [CRh], CR + complete remission with incomplete blood count recovery [CRi]) at
designated time points (after cycle 1, after cycle 2, end of intensive phase) in each
treatment arm.
II. To determine rate of flow cytometry MRD-negativity (undetectable or detectable <
10^-4) at designated time points (after cycle 1, after cycle 2, end of intensive phase)
in each treatment arm.
III. To compare MRD response by central aspirate multiparameter flow cytometry (Wood lab)
to next generation sequencing MRD assessment (clonoSEQ, Adaptive) of blood and bone
marrow at designated time points (after cycle 1, after cycle 2, and end of intensive
phase) and to determine association with outcome, in each treatment arm.
IV. To determine the event-free survival (EFS) standard-definition (event defined as
failure to achieve morphologic remission by cycle 2, hematologic relapse, death),
disease-free survival (DFS), overall survival (OS) of each arm (median, 6-month, 1-year,
2-year, 3-year) in each treatment arm.
V. To determine proportion of patients who proceed to allogeneic transplant after initial
response (without intervening salvage therapy) in each treatment arm.
VI. To determine rate of liver toxicity (grade 3-5 alanine aminotransferase [ALT]
increase, aspartate aminotransferase [AST] increase, bilirubin increase, alkaline
phosphatase increase).
VII. To describe the safety and tolerability of each arm including rate of grade 3-5
non-hematologic toxicity and treatment-related mortality (grade 5 toxicity VIII. To
determine rate of delays in intensive-phase chemotherapy due to neutropenia and
thrombocytopenia (in responding patients).
IX. To assess the baseline variations in comorbidity burden, physical, nutritional, and
cognitive function of the study participants, and explore the association between
comorbidity burden, physical, nutritional, and cognitive function, and the outcomes of
therapy (grade 3-5 non-hematological toxicities, and OS).
X. To explore the longitudinal changes in physical, nutritional, and cognitive function
among the experimental and control groups.
XI. To compare the burden of patient-reported symptomatic adverse events between
treatment arms using the Patient Reported Outcomes - Common Terminology Criteria for
Adverse Events (PRO-CTCAE).
XII. To correlate specific karyotype groups (normal or various primary and secondary
chromosomal abnormalities) with clinical and laboratory parameters.
XIII. To correlate specific karyotype groups with response rates, response duration, MRD,
and survival in patients treated on this study.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A:
INDUCTION: Patients receive cyclophosphamide intravenously (IV) over 3 hours every 12
hours (Q12H) on days 1-3 of cycles 1, 3, 5, and 7, vincristine IV on days 1 and 8 of
cycle 1, 3, 5, and 7, dexamethasone IV or orally (PO) on days 1-4 and 11-14 of cycles 1,
3, 5, and 7, inotuzumab ozogamicin IV over 1 hour on days 2 and 8 of cycles 1-4,
methotrexate IV over 24 hours on day 1 of cycles 2, 4, 6, and 8, cytarabine IV over 3
hours Q12H on days 2-3 of cycles 2, 4, 6, and 8, and methylprednisolone IV over 2 hours
Q12H on days 1-3. Patients with leukemic blasts expressing CD20 also receive rituximab IV
on days 2 and 8 of cycles 1-4. For patients >= 70 years of age, treatment repeats every
28 days for 2 cycles (an additional 2 cycles may be given at the discretion of the
principal investigator [PI]) in the absence of disease progression or unacceptable
toxicity. For patients < 70 years of age, treatment repeats every 28 days for 8 cycles in
the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive vincristine IV on day 1, prednisone PO daily on days 1-5,
mercaptopurine PO twice daily (BID) on days 1-28, and methotrexate PO weekly. Treatment
repeats every 28 days for up to 24 cycles or 2 years, whichever comes first, in the
absence of disease progression or unacceptable toxicity.
ARM B:
INDUCTION: Patients receive cyclophosphamide IV over 3 hours Q12H on days 1-3 of cycle 1,
3, 5, and 7, vincristine IV on days 1 and 8 of cycles 1, 3, 5, and 7, dexamethasone IV or
PO on days 1-4 and 11-14 of cycle 1, 3, 5, and 7, doxorubicin IV over 24 hours on day 4
of cycles 1, 3, 5, and 7, methotrexate IV over 24 hours on day 1 of cycles 2, 4, 6, and
8, cytarabine IV over 3 hours Q12H on days 2-3 of cycles 2, 4, 6, and 8, and
methylprednisolone IV over 2 hours Q12H on days 1-3 of cycles 2, 4, 6, and 8. Patients
with leukemic blasts expressing CD20 also receive rituximab IV on days 2 and 8 of cycles
1-4. For patients >= 70 years of age, treatment repeats every 28 days for 2 cycles (an
additional 2 cycles may be given at the discretion of the PI) in absence of disease
progression or unacceptable toxicity. For patients < 70 years of age, treatment repeats
every 28 days for 8 cycles in the absence of disease progression or unacceptable
toxicity.
MAINTENANCE: Patients receive vincristine IV on day 1, prednisone PO daily on days 1-5,
mercaptopurine PO BID on days 1-28, and methotrexate PO weekly. Treatment repeats every
28 days for up to 24 cycles or 2 years, whichever comes first, in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2 months until 1 year
after completion of therapy, every 3 months until 2 years after completion of therapy,
and then every 6 months until 5 years from study registration.