A Study to Investigate Blinatumomab in Combination With Chemotherapy in Patients With Newly Diagnosed B-Lymphoblastic Leukemia
- Conditions
- B Acute Lymphoblastic LeukemiaB Lymphoblastic LymphomaDown Syndrome
- Interventions
- Radiation: Radiation Therapy
- Registration Number
- NCT03914625
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This phase III trial studies how well blinatumomab works in combination with chemotherapy in treating patients with newly diagnosed, standard risk B-lymphoblastic leukemia or B-lymphoblastic lymphoma with or without Down syndrome. Monoclonal antibodies, such as blinatumomab, may induce changes in the body's immune system and may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs, such as vincristine, dexamethasone, prednisone, prednisolone, pegaspargase, methotrexate, cytarabine, mercaptopurine, doxorubicin, cyclophosphamide, and thioguanine, 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. Leucovorin decreases the toxic effects of methotrexate. Giving monoclonal antibody therapy with chemotherapy may kill more cancer cells. Giving blinatumomab and combination chemotherapy may work better than combination chemotherapy alone in treating patients with B-ALL. This trial also assigns patients into different chemotherapy treatment regimens based on risk (the chance of cancer returning after treatment). Treating patients with chemotherapy based on risk may help doctors decide which patients can best benefit from which chemotherapy treatment regimens.
- Detailed Description
PRIMARY OBJECTIVES:
I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with standard risk (SR) B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg) B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI).
II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of interim maintenance I (IM1).
SECONDARY OBJECTIVES:
I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex.
II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen.
III. To determine if patients with DS-High achieve a reduction of treatment-related mortality (TRM) after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of delayed intensification \[DI\]) with 3 cycles of blinatumomab.
IV. To describe the DFS characterized by the replacement of intensive elements of standard chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.
V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic lymphoma (B-LLy) receiving standard risk B-ALL therapy.
VI. To compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- \< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship \[HMH\], including either food, housing or energy insecurity) and non-poor families (absence of HMH).
VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.
VII. To evaluate available peripheral blood (PB) samples at EOI using HTS MRD and compare the results against bone marrow (BM) results.
IX. To evaluate available end of Consolidation (EOC) BM samples using HTS in patients who were Day 29 MRD positive by flow cytometry and who have submitted EOC BM flow cytometry results.
EXPLORATORY OBJECTIVES:
I. To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL.
II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as measured by caregiver (parent/legal guardian) questionnaires.
III. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD at diagnosis with outcome in patients with B-LLy.
IV. To explore the significance of and genomic landscape of Ig clonal composition in pediatric B-ALL.
V. To explore the incidence of HTS MRD ≥ 0.01% versus (vs.) HTS MRD \< 0.01% in patients with multiparameter flow cytometry defined MRD \< 0.01% at end of Induction and genetically characterize those with discordance defined by the 0.01% threshold.
OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION, patients are either assigned or randomized to 1 of 7 arms.
NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1, vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is administered. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
\* After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION, while patients with SR-High complete high-risk (HR) CONSOLIDATION.
DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days 1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15 and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
\* After DS B-ALL INDUCTION, patients without high risk features and MRD \< 0.01 % complete SR CONSOLIDATION. Patients without high risk features and MRD \>= 0.01%, OR with high risk features and any MRD complete HR CONSOLIDATION.
NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2, vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and 29. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
\* After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION.
DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
\* After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION.
SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
\* After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A.
HR 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, vincristine IV push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days 15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with continued clinical evidence of DS or testicular leukemia (from diagnosis through the end of Induction) undergo testicular radiation therapy over 12 fractions once daily (QD).
\* After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD \< 1% are assigned to an arm including three blocks of blinatumomab.
ARM A:
* INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes undiluted or 10-15 minutes diluted on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity.
ARM B:
* BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit cycles 5-6), vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 when coinciding with IT methotrexate). DS patients receive methotrexate IT on day 1 (omit cycles 5-6), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 when coinciding with IT methotrexate), for DS patients and leucovorin IV or PO every 6 hours for 2 doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity.
ARM C:
* INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles, methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.
ARM D:
* BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.
DS-HIGH B-ALL:
* BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV continuously on days 1-28, methotrexate IT on day 1 (or on day 56 of Consolidation), and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and 44-46. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
* BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2 doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
* BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57, 64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.
All B-LLy patients:
* INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8 and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
* MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 4 weeks until complete blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2 years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 6720
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All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
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Age at diagnosis:
- Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
- Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
- Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
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B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
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B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
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Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;
- OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
- OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
- OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
- 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 (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
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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 National Cancer Institute (NCI) requirements for human studies must be met.
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Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
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With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.
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For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
- Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
- DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
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Patients who have received > 72 hours of hydroxyurea within 1 week (7 days) prior to the start of systemic protocol therapy.
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B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
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Patient must not have acute undifferentiated leukemia (AUL).
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Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).
- Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
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Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
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For LLy patients, 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.
- CNS positive disease or testicular involvement.
- M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.
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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 females who plan to breastfeed their infants.
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Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A (SR-Avg control) Asparaginase Erwinia chrysanthemi Arm A: See detailed description. Arm B (SR-Avg experimental) Asparaginase Erwinia chrysanthemi Arm B: See detailed description. Arm C (SR-High Control) Asparaginase Erwinia chrysanthemi Arm C: See detailed description. Arm D (SR-High experimental) Asparaginase Erwinia chrysanthemi Arm D See detailed description. B-LLy Asparaginase Erwinia chrysanthemi See detailed description. DS B-ALL Asparaginase Erwinia chrysanthemi See detailed description. NCI SR or HR DS B-ALL Asparaginase Erwinia chrysanthemi See detailed description. Arm A (SR-Avg control) Leucovorin Calcium Arm A: See detailed description. Arm B (SR-Avg experimental) Leucovorin Calcium Arm B: See detailed description. Arm C (SR-High Control) Leucovorin Calcium Arm C: See detailed description. Arm D (SR-High experimental) Leucovorin Calcium Arm D See detailed description. B-LLy Leucovorin Calcium See detailed description. DS B-ALL Leucovorin Calcium See detailed description. Arm A (SR-Avg control) Mercaptopurine Oral Suspension Arm A: See detailed description. Arm C (SR-High Control) Mercaptopurine Oral Suspension Arm C: See detailed description. Arm D (SR-High experimental) Mercaptopurine Oral Suspension Arm D See detailed description. DS B-ALL Mercaptopurine Oral Suspension See detailed description. NCI SR or HR DS B-ALL Mercaptopurine Oral Suspension See detailed description. Arm A (SR-Avg control) Pegaspargase Arm A: See detailed description. DS B-ALL Radiation Therapy See detailed description. Arm A (SR-Avg control) Cyclophosphamide Arm A: See detailed description. Arm A (SR-Avg control) Cytarabine Arm A: See detailed description. Arm A (SR-Avg control) Dexamethasone Arm A: See detailed description. Arm A (SR-Avg control) Doxorubicin Hydrochloride Arm A: See detailed description. Arm A (SR-Avg control) Mercaptopurine Arm A: See detailed description. Arm A (SR-Avg control) Methotrexate Arm A: See detailed description. Arm A (SR-Avg control) Prednisone Arm A: See detailed description. Arm A (SR-Avg control) Thioguanine Arm A: See detailed description. Arm A (SR-Avg control) Vincristine Sulfate Arm A: See detailed description. Arm B (SR-Avg experimental) Blinatumomab Arm B: See detailed description. Arm B (SR-Avg experimental) Cyclophosphamide Arm B: See detailed description. Arm B (SR-Avg experimental) Cytarabine Arm B: See detailed description. Arm B (SR-Avg experimental) Dexamethasone Arm B: See detailed description. Arm B (SR-Avg experimental) Doxorubicin Hydrochloride Arm B: See detailed description. Arm B (SR-Avg experimental) Mercaptopurine Arm B: See detailed description. Arm B (SR-Avg experimental) Mercaptopurine Oral Suspension Arm B: See detailed description. Arm B (SR-Avg experimental) Methotrexate Arm B: See detailed description. Arm B (SR-Avg experimental) Pegaspargase Arm B: See detailed description. Arm B (SR-Avg experimental) Thioguanine Arm B: See detailed description. Arm B (SR-Avg experimental) Vincristine Sulfate Arm B: See detailed description. Arm C (SR-High Control) Cyclophosphamide Arm C: See detailed description. Arm C (SR-High Control) Cytarabine Arm C: See detailed description. Arm C (SR-High Control) Dexamethasone Arm C: See detailed description. Arm C (SR-High Control) Doxorubicin Hydrochloride Arm C: See detailed description. Arm C (SR-High Control) Mercaptopurine Arm C: See detailed description. Arm C (SR-High Control) Methotrexate Arm C: See detailed description. Arm C (SR-High Control) Pegaspargase Arm C: See detailed description. Arm C (SR-High Control) Prednisolone Arm C: See detailed description. Arm C (SR-High Control) Prednisone Arm C: See detailed description. Arm C (SR-High Control) Thioguanine Arm C: See detailed description. Arm C (SR-High Control) Vincristine Sulfate Arm C: See detailed description. Arm D (SR-High experimental) Blinatumomab Arm D See detailed description. Arm D (SR-High experimental) Cyclophosphamide Arm D See detailed description. Arm D (SR-High experimental) Cytarabine Arm D See detailed description. Arm D (SR-High experimental) Dexamethasone Arm D See detailed description. Arm D (SR-High experimental) Doxorubicin Hydrochloride Arm D See detailed description. Arm D (SR-High experimental) Mercaptopurine Arm D See detailed description. Arm D (SR-High experimental) Methotrexate Arm D See detailed description. Arm D (SR-High experimental) Pegaspargase Arm D See detailed description. Arm D (SR-High experimental) Prednisolone Arm D See detailed description. Arm D (SR-High experimental) Prednisone Arm D See detailed description. Arm D (SR-High experimental) Thioguanine Arm D See detailed description. Arm D (SR-High experimental) Vincristine Sulfate Arm D See detailed description. B-LLy Cyclophosphamide See detailed description. B-LLy Cytarabine See detailed description. B-LLy Dexamethasone See detailed description. B-LLy Doxorubicin Hydrochloride See detailed description. B-LLy Mercaptopurine See detailed description. B-LLy Mercaptopurine Oral Suspension See detailed description. B-LLy Methotrexate See detailed description. B-LLy Pegaspargase See detailed description. B-LLy Prednisolone See detailed description. B-LLy Prednisone See detailed description. B-LLy Thioguanine See detailed description. B-LLy Vincristine Sulfate See detailed description. DS B-ALL Cyclophosphamide See detailed description. DS B-ALL Cytarabine See detailed description. DS B-ALL Dexamethasone See detailed description. DS B-ALL Doxorubicin Hydrochloride See detailed description. DS B-ALL Mercaptopurine See detailed description. DS B-ALL Methotrexate See detailed description. DS B-ALL Pegaspargase See detailed description. DS B-ALL Thioguanine See detailed description. DS B-ALL Vincristine Sulfate See detailed description. NCI SR or HR DS B-ALL Blinatumomab See detailed description. NCI SR or HR DS B-ALL Dexamethasone See detailed description. NCI SR or HR DS B-ALL Doxorubicin Hydrochloride See detailed description. NCI SR or HR DS B-ALL Leucovorin Calcium See detailed description. NCI SR or HR DS B-ALL Mercaptopurine See detailed description. NCI SR or HR DS B-ALL Methotrexate See detailed description. NCI SR or HR DS B-ALL Pegaspargase See detailed description. NCI SR or HR DS B-ALL Prednisolone See detailed description. NCI SR or HR DS B-ALL Prednisone See detailed description. NCI SR or HR DS B-ALL Vincristine Sulfate See detailed description.
- Primary Outcome Measures
Name Time Method DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS) 5.1 years DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and two-sided 80% confidence interval will be calculated.
Disease free survival (DFS) in randomization eligible patients with higher risk features (SR-High) or standard risk average (SR-Avg) B-ALL patients based on randomization with addition of blinatumomab 5.3 years Will be assessed in SR-High patients and SR-Avg B-ALL patients who are negative for MRD by flow cytometry but have detectable or indeterminate MRD as measured by high throughput sequencing (HTS) at end of induction (EOI), and patients with double trisomy of chromosomes 4 and 10 (DT) with MRD (flow) 0.01% - \< 0.1%. DFS is calculated as the time from randomization at the end of consolidation to first event (relapse, second malignancy, remission death) or censored at date of last contact. Five year DFS estimates will be calculated from the point of randomization for both groups. Two-sided 95% confidence intervals will be calculated.
- Secondary Outcome Measures
Name Time Method DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of interim maintenance (IM)1, regardless of sex 5.1 years DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
Treatment-related mortality in Down syndrome high risk (DS-high) patients after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of DI) with 3 cycles of blinatumomab 2.3 years Percent of DS-high patients with treatment related mortalities will be reported with 95% confidence interval.
Caregiver burden as measured by the Mean Total score from the Care of My Child with Cancer questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study 1 year The Mean Total score from the Care of My Child with Cancer questionnaire from end of Maintenance Cycle 1. Mean scores and 95% confidence intervals will be reported by randomization group.
Caregiver burden as measured by the At-Work Productivity Loss summary score from the Caregiver Work Limitations questionnaire among a subset of children enrolled in the HMH and neurocognitive outcome study 1 year The Mean Total score from the Care of My Child with Cancer questionnaire from end of Maintenance Cycle 1. Mean scores and 95% confidence intervals will be reported by randomization group.
BM using HTS MRD vs. BM by flow cytometry at EOC in patients who were Day 29 MRD positive by flow cytometry 1 year Will use the Kendall's Tau-b rank correlation coefficient accounting for the left censoring inherent to sensitivity of the methods30. A high positive value would be strong evidence that HTS of IgH loci determined-MRD from the BM at EOC retains the relative information contained in the flow-cytometry-determined readings. An estimate and 95% Confidence interval will be calculated using pairs of banked samples at EOC.
DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen 5.1 years DFS is calculated as the time from end of induction to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab 5.3 years DFS is calculated as the time from the end of consolidation to first event (relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 80% confidence interval will be calculated.
DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy 5 years DFS is calculated as the time from study enrollment to first event (disease progression, relapse, second malignancy, remission death) or censored at date of last contact. A five year DFS estimate and a two-sided 95% confidence interval will be calculated.
Change in neurocognitive functioning from baseline to end-of-therapy between children from poor (defined as presence of household material hardship [HMH], including either food, housing or energy insecurity) and non-poor families (absence of HMH) 3.3 years Neurocognitive functioning will be measured by the CogState Cognitive Composite at end of induction therapy and at follow-up one year off-therapy among patients with ALL ages 4-\< 10 years at the time of diagnosis. Mean and 95% confidence interval for change scores will be reported by HMH group.
Peripheral blood (PB) samples using HTS MRD vs. bone marrow (BM) results at EOI 1 year Will use the Kendall's Tau-b rank correlation coefficient accounting for the left censoring inherent to sensitivity of the method. A high positive value would be strong evidence that the PB retains the relative information contained in the BM readings. An estimate and two-sided 95% Confidence interval will be calculated using banked SR-Average and SR-High samples at EOI.
Trial Locations
- Locations (228)
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, 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
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Atrium Health Navicent
🇺🇸Macon, Georgia, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, 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
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
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
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
Miami Cancer Institute
🇺🇸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
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
Kapiolani Medical Center for Women and Children
🇺🇸Honolulu, Hawaii, United States
Tripler Army Medical Center
🇺🇸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
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, 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
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
Saint Joseph's Regional Medical Center
🇺🇸Paterson, 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
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
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
The Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
M D Anderson Cancer Center
🇺🇸Houston, 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
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
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
Kingston Health Sciences Centre
🇨🇦Kingston, 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
HIMA San Pablo Oncologic Hospital
🇵🇷Caguas, Puerto Rico
University Pediatric Hospital
🇵🇷San Juan, Puerto Rico