Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy
- Conditions
- Testicular LeukemiaB Lymphoblastic LymphomaB Acute Lymphoblastic LeukemiaMixed Phenotype Acute LeukemiaCentral Nervous System Leukemia
- Interventions
- Procedure: Biospecimen CollectionProcedure: Bone Marrow AspirationProcedure: Bone Marrow BiopsyProcedure: Bone ScanProcedure: Computed TomographyProcedure: Magnetic Resonance ImagingOther: Questionnaire AdministrationRadiation: Radiation TherapyProcedure: Positron Emission Tomography
- Registration Number
- NCT03959085
- Lead Sponsor
- Children's Oncology Group
- Brief Summary
This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial will also study the outcomes of patients with mixed phenotype acute leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk ALL chemotherapy.
The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy: Induction and Consolidation. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-consolidation treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance II, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of delayed intensification. Other aims of this study include investigating whether treating both males and females with the same duration of chemotherapy maintains outcomes for males who have previously been treated for an additional year compared to girls, as well as to evaluate the best ways to help patients adhere to oral chemotherapy regimens. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.
- Detailed Description
PRIMARY OBJECTIVE:
I. To compare in a randomized manner the 5-year disease-free survival (DFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with modified Berlin-Frankfurt-Munster (mBFM) chemotherapy without delayed intensification (DI) part 2, but with the addition of two blocks of inotuzumab ozogamicin, versus those treated with full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab ozogamicin.
SECONDARY OBJECTIVES:
I. To describe the 5-year DFS for a favorable risk subset of National Cancer Institute (NCI) HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex.
II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL including toxicity experienced during phases of therapy subsequent to inotuzumab ozogamicin.
III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase pegol (C-MTX).
IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX.
EXPLORATORY OBJECTIVES:
I. To describe the therapy administered, disease response, and survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy either during Induction, at end of induction (EOI), or at end of consolidation (EOC).
II. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy.
III. To determine the impact of proposed adherence-enhancing interventions on adherence to oral 6-mercaptopurine in patients with ALL.
OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm V.
All patients with B-ALL receive Induction and Consolidation therapy:
INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients \>= 10 years old receive prednis(ol)one PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8, 15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients with testicular disease at diagnosis that does not resolve by the end of induction will undergo radiation therapy over 12 once daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.
POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response, patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients that are \< 10 years, have CNS1, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01% are assigned to Arm I. Patients with HR B-ALL who are surface CD22 positive at diagnosis and have MRD \< 0.01% by the end of Consolidation, are randomized to either Arm II or III.
ARM I: HR-FAV B-ALL (Patients that are \< 10 years, have CNS1 status, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01%)
INTERIM MAINTENANCE: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for subsequent cycles. Patients also receive vincristine IV on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
Patients with HR B-ALL who have MRD \< 0.01% by the end of Consolidation, and leukemic blasts positive for surface CD22 at diagnosis are randomized to Arm II or Arm III.
ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29 and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
INTERIM MAINTENANCE II: Patients receive vincristine on days 1, 11, 21, 31 and 41, methotrexate IV over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (Part I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71 and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease undergo cranial radiation therapy over 10 fractions during the first 4 weeks.
ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.
ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation therapy over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age.
ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV or infusion over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or (calaspargase) 23 or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age.
MAINTENANCE: Patients receive vincristine IV on days 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions over 4 weeks.
Patients undergo blood sample collection and bone marrow aspiration and biopsy on study. B-LLy patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and/or bone scan on study.
After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 4997
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B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL1732. Note that central confirmation of MPAL diagnosis must occur within 22 days of enrollment for suspected MPAL patients. If not performed within this time frame, patients will be taken off protocol.
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APEC14B1 is not a requirement for B-LLy patients but for institutional compliance every patient should be offered participation in APEC14B1. B-LLy patients may directly enroll on AALL1732.
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Patients must be > 365 days and < 25 years of age
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White blood cell count (WBC) criteria for patients with B-ALL (within 7 days prior to the start of protocol-directed systemic therapy):
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Age 1-9.99 years: WBC >= 50,000/uL
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Age 10-24.99 years: Any WBC
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Age 1-9.99 years: WBC < 50,000/uL with:
- Testicular leukemia
- CNS leukemia (CNS3)
- Steroid pretreatment.
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White blood cell count (WBC) criteria for patients with MPAL (within 7 days prior to the start of protocol-directed systemic therapy):
- Age 1-24.99 years: any WBC NOTE: Patients enrolled as suspected MPAL but found on central confirmatory testing to have B-ALL must meet the B-ALL criteria above (age, WBC, extramedullary disease, steroid pretreatment) to switch to the B-ALL stratum before the end of induction.
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Patient has newly diagnosed B-ALL or MPAL (by World Health Organization [WHO] 2016 criteria) with >= 25% blasts on a bone marrow (BM) aspirate;
- OR If a BM aspirate is not obtained or is not diagnostic of acute leukemia, the diagnosis can be established by a pathologic diagnosis of acute leukemia on a BM biopsy;
- OR A complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells if a bone marrow aspirate or biopsy cannot be performed.
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Patient has newly diagnosed B-LLy Murphy stages III or IV.
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Patient has newly diagnosed B-LLy Murphy stages I or II with steroid pretreatment.
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Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted.
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Central nervous system (CNS) status must be determined prior to enrollment based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment and cytoreduction. It is recommended that intrathecal cytarabine be administered at the time of the diagnostic lumbar puncture. This is usually done at the time of the diagnostic bone marrow or venous line placement to avoid a second lumbar puncture. This is allowed prior to enrollment. Systemic chemotherapy must begin within 72 hours of this intrathecal therapy.
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All patients and/or their parents or legal guardians must sign a written informed consent.
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All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met.
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Patients with Down syndrome are not eligible (patients with Down syndrome and B-ALL are eligible for AALL1731, regardless of NCI risk group).
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With the exception of steroid pretreatment and steroid cytoreduction or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of B-ALL, MPAL, or B-LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1732.
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Patients who have received > 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy.
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Patients with B-ALL or MPAL who do not have sufficient diagnostic bone marrow submitted for APEC14B1 testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
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Patients with acute undifferentiated leukemia (AUL) are not eligible.
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For Murphy stage III/IV B-LLy patients, or stage I/II patients with steroid pretreatment, the following additional exclusion criteria apply:
- T-lymphoblastic lymphoma.
- Morphologically unclassifiable lymphoma.
- Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
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Patients with known Charcot-Marie-Tooth disease.
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Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
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Patients requiring radiation at diagnosis.
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Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
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Lactating women who plan to breastfeed their infants while on study and for 2 months after the last dose of inotuzumab ozogamicin.
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of study participation. For those patients randomized to inotuzumab ozogamicin, there is a minimum of 8 months after the last dose of inotuzumab ozogamicin for females and 5 months after the last dose of inotuzumab ozogamicin for males.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (HR-FAV B-ALL) Questionnaire Administration See detailed description for Arm I Arm IV (MPAL) Bone Marrow Biopsy See detailed description for Arm IV. Arm I (HR-FAV B-ALL) Bone Marrow Biopsy See detailed description for Arm I Arm I (HR-FAV B-ALL) Bone Marrow Aspiration See detailed description for Arm I Arm I (HR-FAV B-ALL) Biospecimen Collection See detailed description for Arm I Arm I (HR-FAV B-ALL) Pegaspargase See detailed description for Arm I Arm II (HR B-ALL CONTROL) Bone Marrow Biopsy See detailed description for Arm II. ARM V (B-LLY) Vincristine Sulfate See detailed description for Arm V. Arm I (HR-FAV B-ALL) Calaspargase Pegol See detailed description for Arm I Arm I (HR-FAV B-ALL) Leucovorin Calcium See detailed description for Arm I Arm II (HR B-ALL CONTROL) Biospecimen Collection See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Bone Marrow Aspiration See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Calaspargase Pegol See detailed description for Arm II. Arm I (HR-FAV B-ALL) Cyclophosphamide See detailed description for Arm I Arm I (HR-FAV B-ALL) Daunorubicin Hydrochloride See detailed description for Arm I Arm I (HR-FAV B-ALL) Mercaptopurine See detailed description for Arm I Arm IV (MPAL) Biospecimen Collection See detailed description for Arm IV. Arm I (HR-FAV B-ALL) Methotrexate See detailed description for Arm I ARM V (B-LLY) Biospecimen Collection See detailed description for Arm V. Arm II (HR B-ALL CONTROL) Cyclophosphamide See detailed description for Arm II. Arm I (HR-FAV B-ALL) Prednisolone See detailed description for Arm I Arm I (HR-FAV B-ALL) Vincristine Sulfate See detailed description for Arm I Arm II (HR B-ALL CONTROL) Daunorubicin Hydrochloride See detailed description for Arm II. Arm III (HR B-ALL EXPERIMENTAL) Pegaspargase See detailed description for Arm III. Arm II (HR B-ALL CONTROL) Thioguanine See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Leucovorin Calcium See detailed description for Arm II. Arm III (HR B-ALL EXPERIMENTAL) Calaspargase Pegol See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Daunorubicin Hydrochloride See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Radiation Therapy See detailed description for Arm III. Arm II (HR B-ALL CONTROL) Radiation Therapy See detailed description for Arm II. Arm III (HR B-ALL EXPERIMENTAL) Leucovorin Calcium See detailed description for Arm III. Arm II (HR B-ALL CONTROL) Methotrexate See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Pegaspargase See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Questionnaire Administration See detailed description for Arm II. Arm IV (MPAL) Bone Marrow Aspiration See detailed description for Arm IV. Arm IV (MPAL) Daunorubicin Hydrochloride See detailed description for Arm IV. Arm II (HR B-ALL CONTROL) Vincristine Sulfate See detailed description for Arm II. Arm III (HR B-ALL EXPERIMENTAL) Biospecimen Collection See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Bone Marrow Aspiration See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Cyclophosphamide See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Inotuzumab Ozogamicin See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Bone Marrow Biopsy See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Vincristine Sulfate See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Questionnaire Administration See detailed description for Arm III. Arm IV (MPAL) Leucovorin Calcium See detailed description for Arm IV. ARM V (B-LLY) Bone Marrow Biopsy See detailed description for Arm V. ARM V (B-LLY) Questionnaire Administration See detailed description for Arm V. Arm IV (MPAL) Dexamethasone See detailed description for Arm IV. Arm IV (MPAL) Mercaptopurine See detailed description for Arm IV. Arm IV (MPAL) Questionnaire Administration See detailed description for Arm IV. ARM V (B-LLY) Magnetic Resonance Imaging See detailed description for Arm V. ARM V (B-LLY) Pegaspargase See detailed description for Arm V. Arm IV (MPAL) Radiation Therapy See detailed description for Arm IV. ARM V (B-LLY) Bone Scan See detailed description for Arm V. ARM V (B-LLY) Daunorubicin Hydrochloride See detailed description for Arm V. Arm IV (MPAL) Vincristine Sulfate See detailed description for Arm IV. ARM V (B-LLY) Computed Tomography See detailed description for Arm V. ARM V (B-LLY) Cytarabine See detailed description for Arm V. ARM V (B-LLY) Methotrexate See detailed description for Arm V. ARM V (B-LLY) Bone Marrow Aspiration See detailed description for Arm V. ARM V (B-LLY) Positron Emission Tomography See detailed description for Arm V. ARM V (B-LLY) Leucovorin Calcium See detailed description for Arm V. ARM V (B-LLY) Radiation Therapy See detailed description for Arm V. Arm I (HR-FAV B-ALL) Cytarabine See detailed description for Arm I Arm I (HR-FAV B-ALL) Dexamethasone See detailed description for Arm I Arm I (HR-FAV B-ALL) Doxorubicin Hydrochloride See detailed description for Arm I Arm I (HR-FAV B-ALL) Thioguanine See detailed description for Arm I Arm II (HR B-ALL CONTROL) Cytarabine See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Doxorubicin Hydrochloride See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Dexamethasone See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Mercaptopurine See detailed description for Arm II. Arm II (HR B-ALL CONTROL) Prednisolone See detailed description for Arm II. Arm III (HR B-ALL EXPERIMENTAL) Cytarabine See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Dexamethasone See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Doxorubicin Hydrochloride See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Mercaptopurine See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Methotrexate See detailed description for Arm III. Arm III (HR B-ALL EXPERIMENTAL) Thioguanine See detailed description for Arm III. Arm IV (MPAL) Calaspargase Pegol See detailed description for Arm IV. Arm IV (MPAL) Cyclophosphamide See detailed description for Arm IV. Arm IV (MPAL) Cytarabine See detailed description for Arm IV. Arm IV (MPAL) Doxorubicin Hydrochloride See detailed description for Arm IV. Arm IV (MPAL) Methotrexate See detailed description for Arm IV. Arm IV (MPAL) Pegaspargase See detailed description for Arm IV. Arm IV (MPAL) Prednisolone See detailed description for Arm IV. Arm IV (MPAL) Thioguanine See detailed description for Arm IV. ARM V (B-LLY) Calaspargase Pegol See detailed description for Arm V. ARM V (B-LLY) Doxorubicin Hydrochloride See detailed description for Arm V. ARM V (B-LLY) Cyclophosphamide See detailed description for Arm V. ARM V (B-LLY) Dexamethasone See detailed description for Arm V. ARM V (B-LLY) Prednisolone See detailed description for Arm V. ARM V (B-LLY) Thioguanine See detailed description for Arm V.
- Primary Outcome Measures
Name Time Method Improvement in 5-year disease-free survival (DFS) From end of consolidation (EOC) to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years Improvement in 5-year disease-free survival (DFS) with modified Berlin-Frankfurt-Münster (mBFM) chemotherapy without delayed intensification (DI) part 2 but with inotuzumab ozogamicin, versus full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab ozogamicin. Power calculations are based on detecting an improvement in post consolidation DFS with the addition of InO to standard therapy for high risk (HR) B-acute lymphoblastic leukemia (ALL). All survival time analyses assume a Weibull distribution with shape parameter of 0.6 (based on historical data). Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using intent-to-treat (ITT) analysis based on randomized group.
- Secondary Outcome Measures
Name Time Method Incidence of adverse events for the integration of inotuzumab ozogamicin into the mBFM chemotherapy backbone in HR B-ALL Up to 5 years Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Will be monitored and reported.
5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi escalating intravenous MTX without leucovorin rescue + pegaspargase or calapargase pegol From study entry to first event (induction failure, Induction death, end of induction (EOI) minimal residual disease (MRD) >= 5%, EOC MRD >= 0.01%, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
Overall survival (OS) Time from study entry to death or date of last contact for those alive at last contact, assessed up to 5 years OS rates will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto.
5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX From study entry to first event (progressive disease, induction death, relapse, second malignancy, remission death) or date of last contact, assessed up to 5 years Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
5-year DFS for favorable risk subset of NCI HR B-ALL (HR favorable) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD MTX) Interim Maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex From EOC to first event (relapse, second malignant neoplasm, remission death) or date of last contact, assessed up to 5 years Will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. Estimation of treatment effect will be done using ITT analysis based on randomized group.
Trial Locations
- Locations (229)
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
HIMA San Pablo Oncologic Hospital
🇵🇷Caguas, Puerto Rico
Miami Cancer Institute
🇺🇸Miami, Florida, United States
USA Health Strada Patient Care Center
🇺🇸Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸Anchorage, Alaska, United States
Banner Children's at Desert
🇺🇸Mesa, Arizona, United States
Phoenix Childrens Hospital
🇺🇸Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
🇺🇸Downey, California, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
🇺🇸Long Beach, California, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Mattel Children's Hospital UCLA
🇺🇸Los Angeles, California, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
UCSF Benioff Children's Hospital Oakland
🇺🇸Oakland, California, United States
Kaiser Permanente-Oakland
🇺🇸Oakland, California, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸Palo Alto, California, United States
Sutter Medical Center Sacramento
🇺🇸Sacramento, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Rady Children's Hospital - San Diego
🇺🇸San Diego, California, United States
Naval Medical Center -San Diego
🇺🇸San Diego, California, United States
UCSF Medical Center-Mission Bay
🇺🇸San Francisco, California, United States
Santa Barbara Cottage Hospital
🇺🇸Santa Barbara, California, United States
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
🇺🇸Denver, Colorado, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Alfred I duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
MedStar Georgetown University Hospital
🇺🇸Washington, District of Columbia, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Broward Health Medical Center
🇺🇸Fort Lauderdale, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Palms West Radiation Therapy
🇺🇸Loxahatchee Groves, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Sacred Heart Hospital
🇺🇸Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Tampa General Hospital
🇺🇸Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Atrium Health Navicent
🇺🇸Macon, Georgia, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Saint Luke's Cancer Institute - Boise
🇺🇸Boise, Idaho, United States
Lurie Children's Hospital-Chicago
🇺🇸Chicago, Illinois, United States
University of Illinois
🇺🇸Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
🇺🇸Chicago, Illinois, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Advocate Children's Hospital-Oak Lawn
🇺🇸Oak Lawn, Illinois, United States
Advocate Children's Hospital-Park Ridge
🇺🇸Park Ridge, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Northwestern Medicine Central DuPage Hospital
🇺🇸Winfield, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
Wesley Medical Center
🇺🇸Wichita, Kansas, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Children's Hospital New Orleans
🇺🇸New Orleans, Louisiana, United States
Ochsner Medical Center Jefferson
🇺🇸New Orleans, Louisiana, United States
Eastern Maine Medical Center
🇺🇸Bangor, Maine, United States
Maine Children's Cancer Program
🇺🇸Scarborough, Maine, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸Bethesda, Maryland, United States
Tufts Children's Hospital
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Baystate Medical Center
🇺🇸Springfield, Massachusetts, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
C S Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Henry Ford Health Saint John Hospital
🇺🇸Detroit, Michigan, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital
🇺🇸Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
Corewell Health Children's
🇺🇸Royal Oak, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Saint Joseph's Regional Medical Center
🇺🇸Paterson, New Jersey, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
University of Missouri Children's Hospital
🇺🇸Columbia, Missouri, United States
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
Cardinal Glennon Children's Medical Center
🇺🇸Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Children's Hospital and Medical Center of Omaha
🇺🇸Omaha, Nebraska, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University Medical Center of Southern Nevada
🇺🇸Las Vegas, Nevada, United States
Sunrise Hospital and Medical Center
🇺🇸Las Vegas, Nevada, United States
Alliance for Childhood Diseases/Cure 4 the Kids Foundation
🇺🇸Las Vegas, Nevada, United States
Summerlin Hospital Medical Center
🇺🇸Las Vegas, Nevada, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Jersey Shore Medical Center
🇺🇸Neptune, New Jersey, United States
Saint Peter's University Hospital
🇺🇸New Brunswick, New Jersey, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
Presbyterian Hospital
🇺🇸Albuquerque, New Mexico, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Maimonides Medical Center
🇺🇸Brooklyn, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸New York, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
New York Medical College
🇺🇸Valhalla, New York, United States
Mission Hospital
🇺🇸Asheville, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
East Carolina University
🇺🇸Greenville, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Children's Hospital Medical Center of Akron
🇺🇸Akron, Ohio, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Rainbow Babies and Childrens Hospital
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Natalie Warren Bryant Cancer Center at Saint Francis
🇺🇸Tulsa, Oklahoma, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸Allentown, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Penn State Children's Hospital
🇺🇸Hershey, Pennsylvania, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Saint Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Rhode Island Hospital
🇺🇸Providence, Rhode Island, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Prisma Health Richland Hospital
🇺🇸Columbia, South Carolina, United States
BI-LO Charities Children's Cancer Center
🇺🇸Greenville, South Carolina, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
T C Thompson Children's Hospital
🇺🇸Chattanooga, Tennessee, United States
East Tennessee Childrens Hospital
🇺🇸Knoxville, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Texas Tech University Health Sciences Center-Amarillo
🇺🇸Amarillo, Texas, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸El Paso, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸Lubbock, Texas, United States
Vannie Cook Children's Clinic
🇺🇸McAllen, Texas, United States
Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
Methodist Children's Hospital of South Texas
🇺🇸San Antonio, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
University of Virginia Cancer Center
🇺🇸Charlottesville, Virginia, United States
Inova Fairfax Hospital
🇺🇸Falls Church, Virginia, United States
Children's Hospital of The King's Daughters
🇺🇸Norfolk, Virginia, United States
Naval Medical Center - Portsmouth
🇺🇸Portsmouth, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Carilion Children's
🇺🇸Roanoke, Virginia, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Providence Sacred Heart Medical Center and Children's Hospital
🇺🇸Spokane, Washington, United States
Mary Bridge Children's Hospital and Health Center
🇺🇸Tacoma, Washington, United States
Madigan Army Medical Center
🇺🇸Tacoma, Washington, United States
Kingston Health Sciences Centre
🇨🇦Kingston, Ontario, Canada
West Virginia University Charleston Division
🇺🇸Charleston, West Virginia, United States
Edwards Comprehensive Cancer Center
🇺🇸Huntington, West Virginia, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
John Hunter Children's Hospital
🇦🇺Hunter Regional Mail Centre, New South Wales, Australia
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
Women's and Children's Hospital-Adelaide
🇦🇺North Adelaide, South Australia, Australia
Monash Medical Center-Clayton Campus
🇦🇺Clayton, Victoria, Australia
Royal Children's Hospital
🇦🇺Parkville, Victoria, Australia
Perth Children's Hospital
🇦🇺Perth, Western Australia, Australia
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Children's Hospital
🇨🇦London, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke-Fleurimont
🇨🇦Sherbrooke, Quebec, Canada
Jim Pattison Children's Hospital
🇨🇦Saskatoon, Saskatchewan, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)
🇨🇦Quebec, Canada
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
University Pediatric Hospital
🇵🇷San Juan, Puerto Rico