Imatinib Mesylate and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This randomized phase III trial studies how well imatinib mesylate works in combination with two different chemotherapy regimens in treating patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Imatinib mesylate has been shown to improve outcomes in children and adolescents with Philadelphia chromosome positive (Ph+) ALL when given with strong chemotherapy, but the combination has many side effects. This trial is testing whether a different chemotherapy regimen may work as well as the stronger one but have fewer side effects when given with imatinib. The trial is also testing how well the combination of chemotherapy and imatinib works in another group of patients with a type of ALL that is similar to Ph+ ALL. This type of ALL is called ABL-class fusion positive ALL, and because it is similar to Ph+ ALL, is thought it will respond well to the combination of agents used to treat Ph+ ALL.

Detailed Description
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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 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 event free survival (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 prognostic significance of IKZF1 gene aberrations and deletions in Ph+ ALL. V. To determine frequency and prognostic significance of p190 and p210 BCR-ABL1 fusion variants in pediatric Ph+ 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. 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 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 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 PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 5-15 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 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 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 5-15 minutes, and doxorubicin IV over 1-15 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 5-15 minutes, and doxorubicin IV over 1-15 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 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 5-15 minutes, and doxorubicin IV over 1-15 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 22 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, high dose cytarabine, and pegaspargase or calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC 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, 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.

Official Title
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International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones

Conditions
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Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Calaspargase Pegol
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Dexamethasone
* Drug: Dexrazoxane Hydrochloride
* Drug: Doxorubicin
* Drug: Etoposide
* Biological: Filgrastim
* Drug: Ifosfamide
* Drug: Imatinib Mesylate
* Other: Laboratory Biomarker Analysis
* Drug: Leucovorin Calcium
* Drug: Mercaptopurine
* Drug: Mercaptopurine
* Drug: Methotrexate
* Drug: Methylprednisolone
* Drug: Pegaspargase
* Drug: Prednisolone
* Other: Questionnaire Administration
* Drug: Therapeutic Hydrocortisone
* Drug: Thioguanine
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For patients enrolled on APEC14B1 prior to enrollment on AALL1631, the required diagnostic bone marrow sample has been fulfilled For patients who have not previously enrolled on APEC14B1 prior to enrollment on AALL1631, a baseline diagnostic sample (or peripheral blood sample with blasts if marrow sample unavailable) must be available to develop an MRD probe In addition, laboratory reports detailing evidence of BCR-ABL1 fusion or ABL-class fusion must be submitted for rapid central review within 72 hours of study enrollment >= 1 year (365 days) and =< 21 years at ALL diagnosis Ph+ (BCR-ABL1 fusion): newly diagnosed de novo ALL (B-ALL or T-ALL) or mixed phenotypic acute leukemia (MPAL meeting 2016 World Health Organization [WHO] definition) with definitive evidence of BCR-ABL1 fusion by karyotype, fluorescence in situ hybridization (FISH) and/or molecular methodologies ABL-class fusion: newly diagnosed B-ALL with definitive evidence of ABL-class fusions. ABL-class fusions are defined as those involving the following genes: ABL1, ABL2, CSF1R, PDGFRB, PDGFRA. Methods of detection include fluorescence in-situ hybridization (FISH, e.g. using break-apart or colocalization signals probes), multiplex or singleplex reverse-transcription polymerase chain reaction (RT-PCR), whole transcriptome or panel-based ribonucleic acid (RNA)-sequencing (e.g. TruSight RNA Pan-Cancer Panel; Illumina, San Diego, CA, USA or similar) Ph+ patients must have previously started Induction therapy, which includes vincristine, a corticosteroid, pegaspargase, with or without anthracycline, and/or other standard cytotoxic chemotherapy Ph+ patients have not received more than 14 days of multiagent Induction therapy beginning with the first dose of vinCRIStine Ph+ patients may have started imatinib prior to study entry but have not received more than 14 days of imatinib ABL-class fusion patients must have previously completed the 4 or 5 weeks of multiagent Induction chemotherapy (Induction IA phase) ABL-class fusion patients may have started imatinib during Induction IA, at the same time of or after the first vinCRIStine dose Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2 Direct bilirubin =< 2.0 mg/dL Shortening fraction of >= 27% by echocardiogram Ejection fraction of >= 50% by radionuclide angiogram or echocardiogram Corrected QT interval, QTc < 480 msec Note: Repeat echocardiogram and electrocardiogram are not required if they were performed at or after initial ALL diagnosis, before study enrollment Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or serum creatinine within normal limits based on age/gender, as follows: 1 to < 2 years: maximum serum creatinine 0.6 mg/dL (both male and female) 2 to < 6 years: maximum serum creatinine 0.8 mg/dL (both male and female) 6 to < 10 years: maximum serum creatinine 1 mg/dL (both male and female) 10 to < 13 years: maximum serum creatinine 1.2 mg/dL (both male and female) 13 to < 16 years: maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female) >= 16 years: maximum serum creatinine 1.7 mg/dL (male), 1.4 mg/dL (female) Exclusion Criteria: Known history of chronic myelogenous leukemia (CML) ALL developing after a previous cancer treated with cytotoxic chemotherapy Active, uncontrolled infection, or active systemic illness that requires ongoing vasopressor support or mechanical ventilation Down syndrome Pregnancy and breast feeding Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs; a pregnancy test is required for female patients of childbearing potential Lactating females who plan to breastfeed their infants Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of treatment according to protocol Patients with congenital long QT syndrome, history of ventricular arrhythmias or heart block Prior treatment with dasatinib, or any TKI other than imatinib

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (imatinib mesylate, EsPhALL chemotherapy)<br>See Detailed Description | Drug: Calaspargase Pegol<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IV, SC, or IT<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given IV<br>* Other names: Zarxio;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given PO or IV<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Drug: Methylprednisolone<br>* Given IV<br>* Other names: Wyacort;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Given PO<br>* Other names: Sterane;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm B (imatinib mesylate, COG/BFM chemotherapy)<br>See Detailed Description. | Drug: Calaspargase Pegol<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IV, SC, or IT<br>* Other names: WR-28453;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given PO or IV<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Drug: Methylprednisolone<br>* Given IV<br>* Other names: Wyacort;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Given PO<br>* Other names: Sterane;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm C (imatinib mesylate, EsPhALL chemotherapy, HSCT)<br>See Detailed Description | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo HSCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Calaspargase Pegol<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IV, SC, or IT<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Dexrazoxane Hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: Doxorubicin<br>* Given IV<br>* Other names: Hydroxyldaunorubicin;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Biological: Filgrastim<br>* Given IV<br>* Other names: Zarxio;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Drug: Imatinib Mesylate<br>* Given PO<br>* Other names: STI571;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Leucovorin Calcium<br>* Given PO or IV<br>* Other names: Wellcovorin;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given IT<br>* Other names: WR-19039;Drug: Methylprednisolone<br>* Given IV<br>* Other names: Wyacort;Drug: Pegaspargase<br>* Given IV<br>* Other names: Polyethylene Glycol-L-Asparaginase;Drug: Prednisolone<br>* Given PO<br>* Other names: Sterane;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Therapeutic Hydrocortisone<br>* Given IT<br>* Other names: Rectoid;Drug: Thioguanine<br>* Given PO<br>* Other names: X 27;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) of Randomized Arms (standard risk [SR] Philadelphia chromosome [Ph+] acute lymphoblastic leukemia [ALL] patients) | Three-year DFS and 95% confidence intervals (CI) of SR Ph+ ALL patients treated continuous imatinib mesylate with high risk Children's Oncology Group (COG)-ALL chemotherapy backbone or more intensive European (Es)PhALL chemotherapy backbone. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DFS on Randomized Arms (SR Ph+ ALL and ABL-class fusion positive patients) | Three-year DFS (time from randomization to relapse, second malignancy, or death in complete remission) and 95% CI of SR pediatric Ph+ and ABL-class fusion positive patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. | Up to 3 years | 
| Feasibility of post hematopoietic stem cell transplantation (HSCT) imatinib mesylate administration after allogenic HSCT in high risk Ph+ ALL patients | The proportion of patients who receive at least 75% of intended doses. | Up to 2 years | 
| Event free survival (EFS) of high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate | Three-year EFS and 95% CI for high risk pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission, and post-HSCT imatinib mesylate. EFS is defined as the time from the date of bone marrow for minimal residual disease (MRD) assessment at end-IB to first event (resistant disease [MRD >= 10-2 or morphologic residual disease at end of consolidation block 3], relapse, progressive disease [i.e., MRD >= 10-2 at two post-HSCT time points separated by at least 2 weeks], second malignancy, or death in complete remission), or time to last follow-up for patients without events. | Up to 3 years | 
| Incidence of grade 3 or higher infections in standard risk Ph+ ALL patients in the two randomized arms | Evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The rate of infections during the post IB/pre-maintenance phases of treatment will be described for each randomization group. | Up to 3 years | 
| EFS of all Ph+ patients | Three-year EFS and 95% CI for Ph+ ALL patients. EFS here is defined as the time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignant, or death, whichever occurs first. | Up to 3 years | 
| Overall survival (OS) of all Ph+ patients | Three-year OS and 95% CI for Ph+ ALL patients. OS is defined as the time from study enrollment to death from any cause. | Up to 3 years | 
| OS of SR Ph+ patients | Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients | Up to 3 years | 
| OS of SR Ph+ patients by randomization group | Three-year OS (time from randomization to death from any cause) and 95% CI of SR pediatric Ph+ patients by randomization group: treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. | Up to 3 years | 
| OS of high risk Ph+ patients | Three-year OS (time from the date of MRD assessment at end-IB to death from any cause) and 95% CI of HR pediatric Ph+ patients. | Up to 3 years | 
| EFS of all eligibility ABL-class fusion positive ALL patients | Three-year EFS (time from enrollment until resistant disease, relapse, progressive disease post-HSCT, second malignancy, or death, whichever occurs first) and 95% CI of ABL-class fusion positive patients. | Up to 3 years | 
| OS of all eligibility ABL-class fusion positive ALL patients | Three-year OS (the time from study enrollment to death from any cause) and 95% CI of ABL-class fusion positive patients. | Up to 3 years |