Testing the Use of Steroids and Tyrosine Kinase Inhibitors With Blinatumomab or Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia in Adults
- Conditions
- B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow Aspiration and BiopsyProcedure: Echocardiography TestProcedure: ElectrocardiographyProcedure: Lumbar PunctureProcedure: Multigated Acquisition Scan
- Registration Number
- NCT04530565
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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
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 QD or ponatinib 30mg/day PO QD on days 1-21, methotrexate IV over 24 hours and IT on day 1, and cytarabine IV over 2 hours BID 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 BID 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 29 or 30.
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 every 3 months for first 2 years (from study registration), every 6 months for years 3-5, and then every 12 months for years 6-10.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 348
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ELIGIBILITY CRITERIA FOR PRE-REGISTRATION (TO STEP 0)
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Patient must be >= 18 and =< 75 years of age
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Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-3
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Patient must be newly diagnosed with B acute lymphoblastic leukemia (B-ALL) or is suspected to have acute lymphoblastic leukemia (ALL)
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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 ECOG-American College of Radiology Imaging Network (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, with recommendation 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
-
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Patient must not have a diagnosis of BCR/ABL T-ALL
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Patient must not have received chemotherapy for B-ALL. Patients who received up to five days of therapy (hydroxyurea and/or steroids of any kind) with the aim to reduce disease burden prior to study registration to Step 1 are eligible
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Patient must not have unstable epilepsy that requires treatment
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Patients with lymphoid blast crisis chronic myeloid leukemia (CML) are not eligible
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ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 1
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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
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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)
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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
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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)
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Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and 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)
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Estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation) (obtained =< 28 days prior to step 1 registration)
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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
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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
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Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
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For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy, if indicated
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Patients with a history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load and if indicated, on treatment
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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
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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
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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
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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
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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
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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
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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)
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AST(SGOT) and ALT(SGPT) =< 2 X the institutional upper limit of normal (ULN)
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Estimated creatinine clearance > 45 mL/min (based on Cockcroft-Gault equation)
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Investigators must confirm which TKI patient is to receive.
- NOTE: Patients with known T315I mutation status should receive ponatinib treatment
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For patients under age 70, intended chemotherapy regimen must have been determined prior to randomization
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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
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Patients must have resolved any serious infectious complications related to therapy
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Any significant medical complications related to therapy must have resolved
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ELIGIBILITY CRITERIA FOR REGISTRATION TO STEP 3 (RE-INDUCTION)
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Institution has received centralized MRD results confirming positive status
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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
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For patients under age 70 and previously assigned to Arm C, intended chemotherapy regimen must have been determined
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Step 3 (Re-Induction): Patients must have resolved any serious infectious complications related to therapy
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Step 3 (Re-Induction): Any significant medical complications related to therapy must have resolved
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Arm A (steroid, TKI), Single Arm Pre-Induction Dasatinib 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. Arm A (steroid, TKI), Single Arm Pre-Induction Echocardiography Test 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. Arm A (steroid, TKI), Single Arm Pre-Induction Electrocardiography 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. Arm A (steroid, TKI), Single Arm Pre-Induction Lumbar Puncture 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. Arm A (steroid, TKI), Single Arm Pre-Induction Multigated Acquisition Scan 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. Arm A (steroid, TKI), Single Arm Pre-Induction Ponatinib Hydrochloride 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. Arm A (steroid, TKI), Single Arm Pre-Induction Prednisone 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. Arm B (steroid, TKI, chemotherapy) Biospecimen Collection See Detailed Description. Arm B (steroid, TKI, chemotherapy) Bone Marrow Aspiration and Biopsy See Detailed Description. Arm B (steroid, TKI, chemotherapy) Dasatinib See Detailed Description. Arm A (steroid, TKI), Single Arm Pre-Induction Biospecimen Collection 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. Arm A (steroid, TKI), Single Arm Pre-Induction Bone Marrow Aspiration and Biopsy 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. Arm B (steroid, TKI, chemotherapy) Cyclophosphamide See Detailed Description. Arm B (steroid, TKI, chemotherapy) Cytarabine See Detailed Description. Arm B (steroid, TKI, chemotherapy) Dexamethasone See Detailed Description. Arm B (steroid, TKI, chemotherapy) Doxorubicin Hydrochloride See Detailed Description. Arm B (steroid, TKI, chemotherapy) Echocardiography Test See Detailed Description. Arm B (steroid, TKI, chemotherapy) Electrocardiography See Detailed Description. Arm B (steroid, TKI, chemotherapy) Lumbar Puncture See Detailed Description. Arm B (steroid, TKI, chemotherapy) Mesna See Detailed Description. Arm B (steroid, TKI, chemotherapy) Methotrexate See Detailed Description. Arm B (steroid, TKI, chemotherapy) Multigated Acquisition Scan See Detailed Description. Arm B (steroid, TKI, chemotherapy) Ponatinib Hydrochloride See Detailed Description. Arm B (steroid, TKI, chemotherapy) Vincristine Sulfate See Detailed Description. Arm C (steroid, TKI, chemotherapy, immunotherapy) Biospecimen Collection 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Blinatumomab 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Bone Marrow Aspiration and Biopsy 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Dasatinib 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Dexamethasone 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Echocardiography Test 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Electrocardiography 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Lumbar Puncture 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Mesna 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Methotrexate 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Multigated Acquisition Scan 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 29 or 30. 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 C (steroid, TKI, chemotherapy, immunotherapy) Ponatinib Hydrochloride 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 29 or 30. 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 (steroid, TKI, chemotherapy, immunotherapy) Biospecimen Collection 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Blinatumomab 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Bone Marrow Aspiration and Biopsy 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Cyclophosphamide 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Dasatinib 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Dexamethasone 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Echocardiography Test 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Electrocardiography 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Lumbar Puncture 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Methotrexate 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. Arm E (steroid, TKI, chemotherapy) Dasatinib 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Multigated Acquisition Scan 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. Arm D (steroid, TKI, chemotherapy, immunotherapy) Ponatinib Hydrochloride 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. Arm E (steroid, TKI, chemotherapy) Biospecimen Collection 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. Arm E (steroid, TKI, chemotherapy) Bone Marrow Aspiration and Biopsy 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. Arm E (steroid, TKI, chemotherapy) Cyclophosphamide 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. Arm E (steroid, TKI, chemotherapy) Cytarabine 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. Arm E (steroid, TKI, chemotherapy) Dexamethasone 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. Arm E (steroid, TKI, chemotherapy) Doxorubicin Hydrochloride 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. Arm E (steroid, TKI, chemotherapy) Echocardiography Test 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. Arm E (steroid, TKI, chemotherapy) Electrocardiography 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. Arm E (steroid, TKI, chemotherapy) Lumbar Puncture 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. Arm E (steroid, TKI, chemotherapy) Methotrexate 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. Arm E (steroid, TKI, chemotherapy) Multigated Acquisition Scan 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. Arm E (steroid, TKI, chemotherapy) Ponatinib Hydrochloride 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. Arm E (steroid, TKI, chemotherapy) Vincristine Sulfate 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.
- Primary Outcome Measures
Name Time Method Overall survival (OS) Time between randomization and death from any cause, assessed up to 10 years from the date of registration 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.
- Secondary Outcome Measures
Name Time Method Rate of minimal residual disease (MRD) negativity At week 15 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.
Event free survival (EFS) 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 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
Rate of MRD negativity After re-induction 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.
Incidence of adverse events Up to 10 years from the date of registration All toxicity grades and reportable adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Trial Locations
- Locations (206)
University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States
Anchorage Associates in Radiation Medicine
🇺🇸Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
🇺🇸Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
🇺🇸Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
🇺🇸Anchorage, Alaska, United States
Alaska Women's Cancer Care
🇺🇸Anchorage, Alaska, United States
Anchorage Oncology Centre
🇺🇸Anchorage, Alaska, United States
Katmai Oncology Group
🇺🇸Anchorage, Alaska, United States
Providence Alaska Medical Center
🇺🇸Anchorage, Alaska, United States
Mercy Hospital Fort Smith
🇺🇸Fort Smith, Arkansas, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸Burbank, California, United States
Community Cancer Institute
🇺🇸Clovis, California, United States
University Oncology Associates
🇺🇸Clovis, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
🇺🇸Irvine, California, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸Orange, California, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Hawaii Cancer Care - Westridge
🇺🇸'Aiea, Hawaii, United States
Pali Momi Medical Center
🇺🇸'Aiea, Hawaii, United States
Queen's Cancer Center - Pearlridge
🇺🇸'Aiea, Hawaii, United States
The Cancer Center of Hawaii-Pali Momi
🇺🇸'Aiea, Hawaii, United States
Hawaii Cancer Care Inc - Waterfront Plaza
🇺🇸Honolulu, Hawaii, United States
Queen's Cancer Cenrer - POB I
🇺🇸Honolulu, Hawaii, United States
Queen's Medical Center
🇺🇸Honolulu, Hawaii, United States
Straub Clinic and Hospital
🇺🇸Honolulu, Hawaii, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, United States
Hawaii Cancer Care Inc-Liliha
🇺🇸Honolulu, Hawaii, United States
Kuakini Medical Center
🇺🇸Honolulu, Hawaii, United States
Queen's Cancer Center - Kuakini
🇺🇸Honolulu, Hawaii, United States
The Cancer Center of Hawaii-Liliha
🇺🇸Honolulu, Hawaii, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Wilcox Memorial Hospital and Kauai Medical Clinic
🇺🇸Lihue, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Saint Luke's Cancer Institute - Fruitland
🇺🇸Fruitland, Idaho, United States
Saint Luke's Cancer Institute - Meridian
🇺🇸Meridian, Idaho, United States
Saint Luke's Cancer Institute - Nampa
🇺🇸Nampa, Idaho, United States
Saint Luke's Cancer Institute - Twin Falls
🇺🇸Twin Falls, Idaho, United States
OSF Saint Anthony's Health Center
🇺🇸Alton, Illinois, United States
Loyola Center for Health at Burr Ridge
🇺🇸Burr Ridge, Illinois, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸Evanston, Illinois, United States
NorthShore University HealthSystem-Glenbrook Hospital
🇺🇸Glenview, Illinois, United States
NorthShore University HealthSystem-Highland Park Hospital
🇺🇸Highland Park, Illinois, United States
Loyola Medicine Homer Glen
🇺🇸Homer Glen, Illinois, United States
Northwestern Medicine Lake Forest Hospital
🇺🇸Lake Forest, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Marjorie Weinberg Cancer Center at Loyola-Gottlieb
🇺🇸Melrose Park, Illinois, United States
SSM Health Good Samaritan
🇺🇸Mount Vernon, Illinois, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Mary Greeley Medical Center
🇺🇸Ames, Iowa, United States
McFarland Clinic - Ames
🇺🇸Ames, Iowa, United States
McFarland Clinic - Boone
🇺🇸Boone, Iowa, United States
McFarland Clinic - Trinity Cancer Center
🇺🇸Fort Dodge, Iowa, United States
McFarland Clinic - Jefferson
🇺🇸Jefferson, Iowa, United States
McFarland Clinic - Marshalltown
🇺🇸Marshalltown, Iowa, United States
Central Care Cancer Center - Garden City
🇺🇸Garden City, Kansas, United States
Central Care Cancer Center - Great Bend
🇺🇸Great Bend, Kansas, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
University of Kansas Hospital-Indian Creek Campus
🇺🇸Overland Park, Kansas, United States
Mercy Hospital Oklahoma City
🇺🇸Oklahoma City, Oklahoma, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸Westwood, Kansas, United States
The James Graham Brown Cancer Center at University of Louisville
🇺🇸Louisville, Kentucky, United States
LSU Health Sciences Center at Shreveport
🇺🇸Shreveport, Louisiana, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
🇺🇸Ann Arbor, Michigan, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
🇺🇸Brighton, Michigan, United States
Trinity Health Medical Center - Brighton
🇺🇸Brighton, Michigan, United States
Henry Ford Cancer Institute-Downriver
🇺🇸Brownstown, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Canton
🇺🇸Canton, Michigan, United States
Trinity Health Medical Center - Canton
🇺🇸Canton, Michigan, United States
Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
Hematology Oncology Consultants-Clarkston
🇺🇸Clarkston, Michigan, United States
Newland Medical Associates-Clarkston
🇺🇸Clarkston, Michigan, United States
Henry Ford Macomb Hospital-Clinton Township
🇺🇸Clinton Township, Michigan, United States
Henry Ford Medical Center-Fairlane
🇺🇸Dearborn, Michigan, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Weisberg Cancer Treatment Center
🇺🇸Farmington Hills, Michigan, United States
Cancer Hematology Centers - Flint
🇺🇸Flint, Michigan, United States
Genesee Hematology Oncology PC
🇺🇸Flint, Michigan, United States
Genesys Hurley Cancer Institute
🇺🇸Flint, Michigan, United States
Hurley Medical Center
🇺🇸Flint, Michigan, United States
Allegiance Health
🇺🇸Jackson, Michigan, United States
Trinity Health Saint Mary Mercy Livonia Hospital
🇺🇸Livonia, Michigan, United States
Henry Ford Saint John Hospital - Macomb Medical
🇺🇸Macomb, Michigan, United States
Henry Ford Medical Center-Columbus
🇺🇸Novi, Michigan, United States
Michigan Healthcare Professionals Pontiac
🇺🇸Pontiac, Michigan, United States
Newland Medical Associates-Pontiac
🇺🇸Pontiac, Michigan, United States
Trinity Health Saint Joseph Mercy Oakland Hospital
🇺🇸Pontiac, Michigan, United States
MyMichigan Medical Center Saginaw
🇺🇸Saginaw, Michigan, United States
Oncology Hematology Associates of Saginaw Valley PC
🇺🇸Saginaw, Michigan, United States
Henry Ford Macomb Health Center - Shelby Township
🇺🇸Shelby, Michigan, United States
MyMichigan Medical Center Tawas
🇺🇸Tawas City, Michigan, United States
Henry Ford West Bloomfield Hospital
🇺🇸West Bloomfield, Michigan, United States
Saint Mary's Oncology/Hematology Associates of West Branch
🇺🇸West Branch, Michigan, United States
Huron Gastroenterology PC
🇺🇸Ypsilanti, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
🇺🇸Ypsilanti, Michigan, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Baptist Memorial Hospital and Cancer Center-Desoto
🇺🇸Southhaven, Mississippi, United States
Saint Louis Cancer and Breast Institute-Ballwin
🇺🇸Ballwin, Missouri, United States
Central Care Cancer Center - Bolivar
🇺🇸Bolivar, Missouri, United States
Saint Charles Health System
🇺🇸Bend, Oregon, United States
Siteman Cancer Center at West County Hospital
🇺🇸Creve Coeur, Missouri, United States
Freeman Health System
🇺🇸Joplin, Missouri, United States
Mercy Hospital Joplin
🇺🇸Joplin, Missouri, United States
Research Medical Center
🇺🇸Kansas City, Missouri, United States
Mercy Clinic-Rolla-Cancer and Hematology
🇺🇸Rolla, Missouri, United States
Phelps Health Delbert Day Cancer Institute
🇺🇸Rolla, Missouri, United States
Heartland Regional Medical Center
🇺🇸Saint Joseph, Missouri, United States
Saint Louis Cancer and Breast Institute-South City
🇺🇸Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital South
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital
🇺🇸Saint Peters, Missouri, United States
Mercy Hospital Springfield
🇺🇸Springfield, Missouri, United States
CoxHealth South Hospital
🇺🇸Springfield, Missouri, United States
Mercy Hospital Washington
🇺🇸Washington, Missouri, United States
Saint Patrick Hospital - Community Hospital
🇺🇸Missoula, Montana, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
University of Cincinnati Cancer Center-UC Medical Center
🇺🇸Cincinnati, Ohio, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
MetroHealth Medical Center
🇺🇸Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
University of Cincinnati Cancer Center-West Chester
🇺🇸West Chester, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Clackamas Radiation Oncology Center
🇺🇸Clackamas, Oregon, United States
Providence Cancer Institute Clackamas Clinic
🇺🇸Clackamas, Oregon, United States
Bay Area Hospital
🇺🇸Coos Bay, Oregon, United States
Providence Newberg Medical Center
🇺🇸Newberg, Oregon, United States
Providence Willamette Falls Medical Center
🇺🇸Oregon City, Oregon, United States
Providence Portland Medical Center
🇺🇸Portland, Oregon, United States
Providence Saint Vincent Medical Center
🇺🇸Portland, Oregon, United States
Saint Charles Health System-Redmond
🇺🇸Redmond, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸Allentown, Pennsylvania, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸Bethlehem, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Pocono Medical Center
🇺🇸East Stroudsburg, Pennsylvania, United States
Lehigh Valley Hospital-Hazleton
🇺🇸Hazleton, Pennsylvania, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸Pittsburgh, Pennsylvania, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸Wilkes-Barre, Pennsylvania, United States
Prisma Health Cancer Institute - Spartanburg
🇺🇸Boiling Springs, South Carolina, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Cancer Institute - Easley
🇺🇸Easley, South Carolina, United States
Prisma Health Cancer Institute - Butternut
🇺🇸Greenville, South Carolina, United States
Prisma Health Cancer Institute - Faris
🇺🇸Greenville, South Carolina, United States
Prisma Health Greenville Memorial Hospital
🇺🇸Greenville, South Carolina, United States
Prisma Health Cancer Institute - Eastside
🇺🇸Greenville, South Carolina, United States
Prisma Health Cancer Institute - Greer
🇺🇸Greer, South Carolina, United States
Prisma Health Cancer Institute - Seneca
🇺🇸Seneca, South Carolina, United States
Vanderbilt-Ingram Cancer Center Cool Springs
🇺🇸Franklin, Tennessee, United States
Baptist Memorial Hospital and Cancer Center-Memphis
🇺🇸Memphis, Tennessee, United States
Vanderbilt Breast Center at One Hundred Oaks
🇺🇸Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Providence Regional Cancer System-Aberdeen
🇺🇸Aberdeen, Washington, United States
PeaceHealth Saint Joseph Medical Center
🇺🇸Bellingham, Washington, United States
Providence Regional Cancer System-Centralia
🇺🇸Centralia, Washington, United States
Swedish Cancer Institute-Edmonds
🇺🇸Edmonds, Washington, United States
Providence Regional Cancer Partnership
🇺🇸Everett, Washington, United States
Swedish Cancer Institute-Issaquah
🇺🇸Issaquah, Washington, United States
Kadlec Clinic Hematology and Oncology
🇺🇸Kennewick, Washington, United States
Providence Regional Cancer System-Lacey
🇺🇸Lacey, Washington, United States
PeaceHealth Saint John Medical Center
🇺🇸Longview, Washington, United States
Pacific Gynecology Specialists
🇺🇸Seattle, Washington, United States
Swedish Medical Center-Ballard Campus
🇺🇸Seattle, Washington, United States
Swedish Medical Center-Cherry Hill
🇺🇸Seattle, Washington, United States
Swedish Medical Center-First Hill
🇺🇸Seattle, Washington, United States
PeaceHealth United General Medical Center
🇺🇸Sedro-Woolley, Washington, United States
Providence Regional Cancer System-Shelton
🇺🇸Shelton, Washington, United States
PeaceHealth Southwest Medical Center
🇺🇸Vancouver, Washington, United States
Providence Saint Mary Regional Cancer Center
🇺🇸Walla Walla, Washington, United States
Providence Regional Cancer System-Yelm
🇺🇸Yelm, Washington, United States
Marshfield Medical Center-EC Cancer Center
🇺🇸Eau Claire, Wisconsin, United States
Gundersen Lutheran Medical Center
🇺🇸La Crosse, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
🇺🇸Madison, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Marshfield Medical Center - Minocqua
🇺🇸Minocqua, Wisconsin, United States
Marshfield Medical Center-Rice Lake
🇺🇸Rice Lake, Wisconsin, United States
Marshfield Medical Center-River Region at Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
Marshfield Medical Center - Weston
🇺🇸Weston, Wisconsin, United States
Rambam Medical Center
🇮🇱Haifa, Israel
Shaare Zedek Medical Center
🇮🇱Jerusalem, Israel
Centro Comprensivo de Cancer de UPR
🇵🇷San Juan, Puerto Rico
San Juan City Hospital
🇵🇷San Juan, Puerto Rico