Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults

Study Overview
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Brief Summary
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This phase III trial compares the effect of usual treatment of chemotherapy and steroids and a tyrosine kinase inhibitor (TKI) to the same treatment plus blinatumomab. Blinatumomab is a Bi-specific T-Cell Engager ('BiTE') that may interfere with the ability of cancer cells to grow and spread. The information gained from this study may help researchers determine if combination therapy with steroids, TKIs, and blinatumomab work better than the standard of care.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the overall survival (OS) following induction with steroids + TKI + blinatumomab versus induction with steroids + TKI + chemotherapy. SECONDARY OBJECTIVES: I. To compare the rate of minimal residual disease (MRD) negativity for patients treated with chemotherapy versus (vs) blinatumomab at the end of first induction (week 15). II. To evaluate the rate of the MRD negativity by treatment arm for those patients MRD positive after the first induction and administered of second induction. III. To compare event free survival (EFS) for patients initially randomized for chemotherapy vs blinatumomab. IV. To assess the toxicities of blinatumomab + TKI vs. TKI + chemotherapy in this patient population. V. To assess the toxicities of the chemotherapy regimen in this patient population. VI. To describe the outcome of patients who proceed to allogeneic stem cell transplant after treatment with blinatumomab + TKI only. OUTLINE: ARM A (PRE-INDUCTION): Patients receive prednisone orally (PO) once daily (QD) on days 1-21 and ponatinib hydrochloride (ponatinib) PO QD or dasatinib PO QD on days 1-21 based on investigator's choice. Patients are randomized to 1 of 2 arms (Arm B or C). Patients undergo bone marrow aspiration with biopsy, lumbar punctures, echocardiogram (ECHO), and multigated acquisition (MUGA) scans as indicated by investigator. ARM B (INDUCTION THERAPY): CYCLE 1: Patients receive cyclophosphamide intravenously (IV) twice daily (BID) on days 1-3, dexamethasone PO or IV on days 1-4 and 11-14, cytarabine intrathecally (IT) on day 1, doxorubicin hydrochloride (doxorubicin) IV on day 4, vincristine sulfate (vincristine) IV on days 4 and 11, and methotrexate IT on day 8. Patients also receive Mesna 600mg/m^2 IV as a 'chemoprotectant' via continuous infusion on days 1-3, (beginning 1 hour prior to cyclophosphamide and completed by 12 hours after the last dose of cyclophosphamide). CYCLE 2 (AGE 18-70): Starting in cycle 2, fit patients aged 18-70 receive dasatinib 70mg/day PO or ponatinib 30mg/day PO on days 1-21, methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours on days 2-3 of each cycle. On day 22 of cycle 2 or later, as soon as the absolute neutrophil count (ANC) is greater than 1000 cells/ul and platelets are greater than 50,000 cells/ul, patients receive hyper cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) for 2 additional cycles. CYCLE 2 (AGE > 70 or unfit < 70): Starting in cycle 2, patients age > 70 or younger unfit patients for Hyper-CVAD receive ponatinib PO QD or dasatinib PO QD on days 1-21 of each cycle. Patients also receive methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours on days 2-3 of each cycle. Cycle 1 and 2 regimens are each repeated once starting on day 22 of cycle 2, or later, but as soon as the ANC is greater than 1000 cells/ul and platelets are greater than 50,000 cells/ul. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve remission (significant reduction in the amount of leukemia in bone marrow and blood/MRD negative) after 4 cycles may receive alternative treatment, either consolidation with two cycles of Hyper-CVAD followed by TKI maintenance therapy or undergo allogeneic stem cell transplantation followed by maintenance therapy. Patients who do not achieve a remission (MRD positive) are assigned to Arm D. Patients who experience un-resolving renal failure or life-threatening infection which may require a treatment delay of 21 days cross-over to Arm C to receive the prescribed course of blinatumomab. ARM C (INDUCTION THERAPY): CYCLE 1: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28, followed by methotrexate IT on day 28 or 29. CYCLE 2: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. ARM D (RE-INDUCTION): Patients treated on Arm B who remain MRD positive at the end of induction therapy receive blinatumomab based re-induction identical to the regimen described for Arm C. ARM E (RE-INDUCTION): Patients treated on Arm C who remain MRD positive at the end of induction therapy receive chemotherapy based re-induction which is identical to regimen described for Arm B according to patient's age and the pre-specified chemotherapy arm. Patients whose molecular test remains MRD positive after re-induction proceed to follow-up at the discretion of the investigator or receive anti CD-19 CAR- T cell therapy, inotuzumab ozogamicin, intensive chemotherapy, or palliative care. Patients are followed up for 10 years from the date of registration.

Official Title
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A Phase III Randomized Trial of Steroids + Tyrosine Kinase Inhibitor (TKI) Induction With Chemotherapy or Blinatumomab for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia (ALL) in Adults

Conditions
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B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Biological: Blinatumomab
* Procedure: Bone Marrow Aspiration and Biopsy
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dasatinib
* Drug: Dexamethasone
* Drug: Doxorubicin Hydrochloride
* Procedure: Echocardiography
* Procedure: Electrocardiography
* Procedure: Lumbar Puncture
* Drug: Mesna
* Drug: Methotrexate
* Procedure: Multigated Acquisition Scan
* Drug: Ponatinib Hydrochloride
* Drug: Prednisone
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ELIGIBILITY CRITERIA FOR PREREGISTRATION (TO STEP 0) - INCLUSION Patient must be >= 18 and =< 75 years of age Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-3 Patient must be newly diagnosed with B-ALL or is suspected to have ALL Patient must have BCR-ABL1 positive disease. The diagnosis of ALL and the presence of BCR-ABL translocation must be confirmed centrally. Patients can be registered and begin Step 1 therapy while awaiting central laboratory eligibility confirmation NOTE: Bone marrow aspirate and/or peripheral blood specimen must be submitted to the American College of Radiology Imaging Network (ECOG-ACRIN) Leukemia Laboratory at MD Anderson Cancer Center to determine patient's eligibility for registration to Step 1 or confirm patient evaluability. Centrally fluorescence-activated cell sorting (FACS) analysis will be performed to determine B-ALL and to exclude acute myeloid leukemia (AML) or acute bi-phenotypic leukemia and baseline BCR-ABL status will be determined by fluorescent in situ hybridization (FISH). The ECOG-ACRIN Leukemia Laboratory will forward results within 48 hours of receipt of the specimen to the submitting institution. Bone marrow aspirate is to be from first pull (initial or re-direct). Specimens must contain sufficient blast cells. In cases where the bone marrow aspiration may be inadequate, or the bone marrow examination has already been performed prior to study consent and enrollment on Step 0, peripheral blood may be submitted, given that adequate circulating blasts are present (> 10%). If a diagnosis of BCR-ABL positive B-ALL has already been established by local Clinical Laboratory Improvement Act (CLIA) certified laboratories, the patient may be registered to Step 1 without waiting for central confirmation Patients who started any kind of TKI prior to study registration to Step 1 are allowed to proceed on the study if they received no more than 14 days of TKI ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1 - INCLUSION Patient must have a diagnosis of Philadelphia chromosome positive (Ph+) ALL that has been determined locally, and bone marrow and/or peripheral blood was sent and receipt confirmed for central confirmation or determined centrally by the ECOG-ACRIN Leukemia Laboratory at MD Anderson Cancer Center Total bilirubin =< 3 mg/dL (patients with Gilbert's syndrome must have a total bilirubin =< 5 mg/dL) (obtained =< 28 days prior to step 1 registration) Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X the institutional upper limit of normal (ULN) (obtained =< 28 days prior to step 1 registration) Estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation) (obtained =< 28 days prior to step 1 registration) Patients with acute organ dysfunction at step 1 registration, which may be attributed to leukemia can be registered regardless of lab results at presentation. Such patients will be allowed to register and can start Arm A steroid + TKI therapy but will only be allowed to proceed to Step 2 randomization if the eligibility criteria outlined is met Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy, if indicated Patients who presented with no evidence of acute organ dysfunction but during Step 0 experienced a rise in liver enzymes which investigator suspects to be a side effect of any of prescribed drugs, are allowed to be registered regardless of the level of liver enzymes. Step 2 Randomization must be withheld until the eligibility criteria outline is met but no more than 14 days after concluding Arm A therapy Patients with a history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load and if indicated, on treatment Patients with a prior malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better. An ECHO/MUGA is required. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better Investigators must confirm which TKI patient is to receive NOTE: Patients with known T315I mutation status should receive ponatinib treatment NOTE: In situations due to insurance coverage issues and the pre-selected TKI is not immediately available, patients can receive dasatinib or imatinib during Step 1. The investigator must re-specify dasatinib or ponatinib prior to Step 2 randomization and from then on patients must receive the pre-selected TKI only ELIGIBILITY CRITERIA FOR RANDOMIZATION TO STEP 2- INCLUSION Patient must have completed at least 7 and no more than 21 days of protocol-treatment on Arm A prior to step 2 randomization. (Days in which arm A therapy was withheld for any reason are not counted) NOTE: First day of steroids prescription after registration will be considered as the first day of study therapy. The selected TKI must be initiated prior to randomization Patients who presented with acute organ dysfunction within 2 weeks of registration to step 1 must have total bilirubin =< 2 X institutional upper limit of normal (ULN) AST(SGOT)/ ALT(SGPT) =< 2 X the institutional upper limit of normal (ULN) Estimated creatinine clearance > 45 mLg/min (based on Cockcroft-Gault equation) Investigators must confirm which TKI patient is to receive. NOTE: Patients with known T315I mutation status should receive ponatinib treatment For patients under age 70, intended chemotherapy regimen must have been determined prior to randomization Patients must have resolved any serious infectious complications related to therapy Any significant medical complications related to therapy must have resolved ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 3 (RE-INDUCTION) - INCLUSION Institution has received centralized MRD results confirming positive status Patients who presented with acute organ dysfunction within 2 weeks of registration to step 1 must have total bilirubin =< 2 X institutional ULN Patients who presented with acute organ dysfunction must have AST (SGOT)/ALT (SGPT) =< 2 X institutional upper limit of normal (ULN) Patients who presented with acute organ dysfunction must have an estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation) Investigators must confirm which TKI patient is to receive NOTE: Patients with known T315I mutation status should receive ponatinib treatment For patients under age 70 and previously assigned to Arm C, intended chemotherapy regimen must have been determined Exclusion Criteria: PREREGISTRATION (STEP 0) ELIGIBILITY CRITERIA - EXCLUSION Patient must not have a diagnosis of BCR/ABL T-ALL Patient must not have received chemotherapy for B-ALL. Patients who received up to five days of hydroxyurea or steroids of any kind with the aim to reduce disease burden prior to study registration to Step 1 are eligible Patient must not have unstable epilepsy that requires treatment Patients with lymphoid blast crisis CML are not eligible STEP 1 REGISTRATION ELIGIBILITY CRITERIA - EXCLUSION Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. A patient of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of step 1 registration, while on study treatment, and until at least six months after the last dose of study treatment Patient must not have active concomitant malignancy. Patients on chronic hormonal therapy for breast or prostate cancer or patients treated with maintenance with targeted agents but are in remission with no evidence for the primary malignancies are eligible Patient must not have complaints of symptoms and/or have clinical and/or radiological signs that indicate an uncontrolled infection or any other concurrent medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol STEP 2: RANDOMIZATION - ELIGIBILITY CRITERIA - EXCLUSION Patient must not have active central nervous system (CNS) involvement by leukemic blasts. Patients with signs of CNS involvement at presentation are eligible for randomization if clearance of blasts from the cerebrospinal fluid (CSF) is demonstrated

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (steroid, TKI), Single Arm Pre-Induction<br>Patients receive prednisone PO QD on days 1-21 and ponatinib PO QD or dasatinib PO QD on days 1-21 based on investigator's choice. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Electrocardiography<br>* Undergo ECG<br>* Other names: EKG;Procedure: Lumbar Puncture<br>* Undergo lumbar puncture<br>* Other names: Spinal Tap;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;|
| Experimental: Arm B (steroid, TKI, chemotherapy)<br>See Detailed Description. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IV or IT<br>* Other names: WR-28453;Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Electrocardiography<br>* Undergo ECG<br>* Other names: EKG;Procedure: Lumbar Puncture<br>* Undergo lumbar puncture<br>* Other names: Spinal Tap;Drug: Mesna<br>* Given IV<br>* Other names: Ziken;Drug: Methotrexate<br>* Given IV or IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Experimental: Arm C (steroid, TKI, chemotherapy, immunotherapy)<br>CYCLE 1: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28, followed by methotrexate IT on day 28 or 29. CYCLE 2: Patients receive ponatinib PO QD or dasatinib PO QD on days 1-28. Patients also receive dexamethasone PO or IV on day 1 and blinatumomab IV continuously on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Electrocardiography<br>* Undergo ECG<br>* Other names: EKG;Procedure: Lumbar Puncture<br>* Undergo lumbar puncture<br>* Other names: Spinal Tap;Drug: Mesna<br>* Given IV<br>* Other names: Ziken;Drug: Methotrexate<br>* Given IV or IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;|
| Experimental: Arm D (steroid, TKI, chemotherapy, immunotherapy)<br>Patients treated on Arm B who remain MRD positive at the end of induction therapy receive blinatumomab based re-induction identical to the regimen described for Arm C. Patients whose molecular test remains MRD positive after re-induction proceed to follow-up at the discretion of the investigator or receive anti CD-19 CAR- T cell therapy, inotuzumab ozogamicin, intensive chemotherapy, or palliative care. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Biological: Blinatumomab<br>* Given IV<br>* Other names: MT103;Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Electrocardiography<br>* Undergo ECG<br>* Other names: EKG;Procedure: Lumbar Puncture<br>* Undergo lumbar puncture<br>* Other names: Spinal Tap;Drug: Methotrexate<br>* Given IV or IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;|
| Experimental: Arm E (steroid, TKI, chemotherapy)<br>Patients treated on Arm C who remain MRD positive at the end of induction therapy receive chemotherapy based re-induction which is identical to regimen described for Arm B according to patient's age and the pre-specified chemotherapy arm. Patients whose molecular test remains MRD positive after re-induction proceed to follow-up at the discretion of the investigator or receive anti CD-19 CAR- T cell therapy, inotuzumab ozogamicin, intensive chemotherapy, or palliative care. | Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration and Biopsy<br>* Undergo bone marrow aspiration and biopsy<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Cytarabine<br>* Given IV or IT<br>* Other names: WR-28453;Drug: Dasatinib<br>* Given PO<br>* Other names: Sprycel;Drug: Dexamethasone<br>* Given PO or IV<br>* Other names: ZoDex;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Procedure: Echocardiography<br>* Undergo ECHO<br>* Other names: EC;Procedure: Electrocardiography<br>* Undergo ECG<br>* Other names: EKG;Procedure: Lumbar Puncture<br>* Undergo lumbar puncture<br>* Other names: Spinal Tap;Drug: Methotrexate<br>* Given IV or IT<br>* Other names: WR-19039;Procedure: Multigated Acquisition Scan<br>* Undergo MUGA<br>* Other names: Synchronized Multigated Acquisition Scanning;Drug: Ponatinib Hydrochloride<br>* Given PO<br>* Other names: Iclusig;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 |
| --- | --- | --- |
| Overall survival (OS) | Will compare OS following induction with steroids + tyrosine kinase inhibitor (TKI) + blinatumomab and induction with steroids + TKI + chemotherapy. Will be based on an intent-to-treat analysis. Estimates of OS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparisons of OS between treatment arms will be conducted using the one-sided stratified log-rank test with steroid responsiveness, type of TKI intended to receive and age at diagnosis, the same factors used in randomization, as stratification factors. Cox proportional hazards models of OS, stratified on the same factors used in the randomization, will be used to assess the effect of treatment by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities. | Time between randomization and death from any cause, assessed up to 10 years from the date of registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of minimal residual disease (MRD) negativity | Will be centrally evaluated. Will be compared between two arms using Fisher's exact test with a one-sided type I error rate of 2.5%. Multivariable logistic regression modeling will be used to adjust for other possible clinical and biological risk factors. For patients registered to Step 3 (re-induction), the rates of MRD negativity and their corresponding 95% confidence intervals after re-induction will be given by treatment arm. | At week 15 | 
| Event free survival (EFS) | Will be based on an intent-to-treat analysis. Estimates of EFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Comparisons of EFS between treatment arms will be conducted using the one-sided stratified log-rank test with steroid responsiveness, type of TKI intended to receive and age at diagnosis, the same factors used in randomization, as stratification factors. Cox proportional hazards models of EFS, stratified on the same factors used in the randomization, will be used to assess the effect of treatment by adjusting other possible clinical and biological risk factors, including cytogenetic abnormalities | Time from randomization to failure to achieve induction molecular remission by week 15, confirmed molecular relapse after molecular remission or to death in remission, assessed up to 10 years from the date of registration | 
| Rate of MRD negativity | Will be centrally evaluated. Will be compared between two arms using Fisher's exact test with a one-sided type I error rate of 2.5%. Multivariable logistic regression modeling will be used to adjust for other possible clinical and biological risk factors. For patients registered to Step 3 (re-induction), the rates of MRD negativity and their corresponding 95% confidence intervals after re-induction will be given by treatment arm. | After re-induction and safety | 
| Incidence of adverse events | All toxicity grades and reportable adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. | Up to 10 years from the date of registration |