PRIMARY OBJECTIVE:
I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia
chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib
mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL
chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone.
SECONDARY OBJECTIVES:
I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated
with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone
or the more intensive EsPhALL chemotherapy backbone.
II. To determine the feasibility of administration of imatinib after allogeneic
hematopoietic stem cell transplantation (HSCT) in high risk (HR) Ph+ ALL patients.
III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with
EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.
IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL
patients between the two randomized arms.
V. To evaluate EFS and overall survival (OS) of all eligible Ph+ALL patients enrolled on
the study.
VI. To evaluate OS in SR Ph+ ALL patients. VII. To evaluate OS in HR Ph+ ALL patients.
VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients
enrolled on the study.
EXPLORATORY OBJECTIVES:
I. To describe the toxicities associated with post-HSCT administration of imatinib in HR
Ph+ALL patients.
II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy
plus imatinib (no transplant), overall and between both randomized arms.
III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at
various time points during therapy.
IIIa. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals
post-HSCT and explore the association of these measurements with long-term outcome.
IIIb. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR)
polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays.
IV. To determine and validate if IKZF1 deletions alone (IKZF1del) or with other
transcription factor deletions (ie, IKZF1 plus subtype [IKZF1plus]) or other identified
genetic lesions predict poor outcomes in Ph+/ABL-class Ph-like ALL in patients treated on
AALL1631.
V. To determine the frequency and prognostic significance of p190 and p210 BCR::ABL1
fusion variants in pediatric Ph+ ALL/ABL-class Ph-like ALL.
VI. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine and
methotrexate) during the maintenance phase in SR Ph+ ALL patients.
VIa. To identify factors associated with poor adherence. VIb. To determine association
between relapse risk and adherence to each oral chemotherapeutic agent (separately and
combined).
VII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and
identify factors associated with poor adherence.
VIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous
imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more
intensive EsPhALL chemotherapy backbone.
IX. To determine the potential therapeutic impact of major secondary events via
pharmacologic inhibitor screens in existing/engineered cell models of Ph+ and ABL-class
Ph-like ALL harboring secondary events and to test the in vivo activity of the most
compelling candidate compounds from pilot studies using patient-derived xenograft (PDX)
models established from Ph+ and ABL-class Ph-like ALL samples collected from patients
treated on AALL1631.
X. To decipher the molecular and cellular heterogeneity of chronic myelogenous leukemia
(CML)-like versus typical Ph+ ALL via single-cell genomics and functional assays and
investigate CML-like phenotypes via single-cell ribonucleic acid (RNA) and
deoxyribonucleic acid (DNA) sequencing to identify distinct transcriptomic and mutational
profiles that will provide novel opportunities for diagnostic and therapeutic
interventions.
OUTLINE:
INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days
1-14.
INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or
twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone
intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22,
daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate
intrathecally (IT) on day 29.
INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35,
cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28,
cytarabine IV or subcutaneously (SC) on days 3-6, 10-13, 17-20, and 24-27, and
methotrexate IT on days 10 and 24.
POST-INDUCTION THERAPY: Patients classified as standard risk are randomized to 1 of 2
arms. Patients with high risk are assigned to Arm C.
ARM A:
CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21,
methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1
and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on
days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, high dose
cytarabine IV over 3 hours and pegaspargase or calaspargase pegol IV over 1-2 hours on
day 5, and filgrastim SC or IV on days 7-11 in the absence of disease progression or
unexpected toxicity.
CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21,
methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose
methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5,
vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days
2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, dexrazoxane
hydrochloride IV over 15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on
day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC
or IV on days 7-11 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high
dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5,
etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic
hydrocortisone IT on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day
6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or
unexpected toxicity.
DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days
1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21,
vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and
doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or
calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or
unexpected toxicity.
DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63,
cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49,
cytarabine IV over 1-30 minutes or SC on days 38-41 and 45-48, and methotrexate IT on
days 38 and 45in the absence of disease progression or unexpected toxicity.
INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28,
methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the
absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days
1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21,
vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and
doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or
calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or
unexpected toxicity.
DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49,
cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49,
cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on
days 36 and 43 in the absence of disease progression or unexpected toxicity.
MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate
PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO
on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for
up to 104 weeks from the start of Induction IA in the absence of disease progression or
unexpected toxicity.
ARM B:
INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63,
vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days
1, 15, 29, and 43, leucovorin calcium or levoleucovorin PO or IV on days 3-4, 17-18,
31-32, and 45-46, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in
the absence of disease progression or unexpected toxicity.
DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days
1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21,
vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and
doxorubicin IV over 3-15 minutes on days 1, 8, and 15, and pegaspargase or calaspargase
pegol IV over 1-2 hours or IM on day 4 in the absence of disease progression or
unexpected toxicity.
DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56,
cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42,
cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29
and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase or
calaspargase pegol IV over 1-2 hours on day 43 in the absence of disease progression or
unexpected toxicity.
INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD
or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15
minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase
or calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease
progression or unexpected toxicity.
MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine
sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or
methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO
on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1
and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in
the absence of disease progression or unexpected toxicity.
ARM C:
CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine,
therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone,
leucovorin calcium or levoleucovorin, high dose cytarabine, and pegaspargase or
calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC or IV on day 7 in
the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine,
therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate,
ifosfamide, leucovorin calcium or levoleucovorin, dexrazoxane hydrochloride, daunorubicin
hydrochloride, pegaspargase or calaspargase pegol, and filgrastim as Arm A Consolidation
Block 2 in the absence of disease progression or unexpected toxicity.
CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide,
methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase or calaspargase pegol,
and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3
hours on days 1-2 in the absence of disease progression or unexpected toxicity.
HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed
Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in
Arm A.
POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the
in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up every year for 3 years.