Phase III Randomized Trial of Steroids +Tyrosine Kinase Inhibitor Induction with Chemotherapy or Blinatumomab for Newly Diagnosed BCR-ABL-positive Acute Lymphoblastic Leukemia in Adults.

Inclusion Criteria

- ELIGIBILITY CRITERIA FOR PREREGISTRATION (TO STEP 0)

- 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

- 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

- 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

- Patient must not have unstable epilepsy that requires treatment

- Patients with lymphoid blast crisis CML are not eligible

- ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1

- 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

- 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

- 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

- 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

- 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 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

- 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

- 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.

- 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

- 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

- 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

- 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)

- 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

- Step 3 (Re-Induction): Patients must have resolved any serious infectious

complications related to therapy

- Step 3 (Re-Induction): Any significant medical complications related to therapy must

have resolved

Exclusion Criteria

- 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