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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03914625
Other study ID # NCI-2019-02187
Secondary ID NCI-2019-02187AA
Status Recruiting
Phase Phase 3
First received
Last updated
Start date July 3, 2019
Est. completion date June 30, 2029

Study information

Verified date May 2024
Source National Cancer Institute (NCI)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 and significance of discordance between multiparameter flow cytometry defined MRD and HTS MRD at end of Induction. 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 information / eligibility

Status Recruiting
Enrollment 6720
Est. completion date June 30, 2029
Est. primary completion date June 30, 2029
Accepts healthy volunteers No
Gender All
Age group 365 Days to 31 Years
Eligibility Inclusion Criteria: - 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. - 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). - B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment). - B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment). - 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). - All patients and/or their parents or legal guardians must sign a written informed consent. - All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met. Exclusion Criteria: - 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. - 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. - 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. - Patients who have received > 72 hours of hydroxyurea within 1 week (7 days) prior to the start of systemic protocol therapy. - 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. - Patient must not have acute undifferentiated leukemia (AUL). - 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. - 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). - 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. - Patients with known Charcot-Marie-Tooth disease. - Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype. - Patients requiring radiation at diagnosis. - 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. - Lactating females who plan to breastfeed their infants. - 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


Related Conditions & MeSH terms


Intervention

Drug:
Asparaginase Erwinia chrysanthemi
Given IV or IM
Biological:
Blinatumomab
Given IV
Drug:
Cyclophosphamide
Given IV
Cytarabine
Given IT or IV
Dexamethasone
Given PO or IV
Doxorubicin Hydrochloride
Given IV
Leucovorin Calcium
Given PO or IV
Mercaptopurine
Given PO
Mercaptopurine Oral Suspension
Given PO
Methotrexate
Given IT or IV
Pegaspargase
Given IV or IM
Prednisolone
Given PO or IV
Prednisone
Given PO or IV
Radiation:
Radiation Therapy
Undergo cranial radiation therapy
Radiation Therapy
Undergo testicular radiation therapy
Drug:
Thioguanine
Given PO
Vincristine Sulfate
Given IV

Locations

Country Name City State
Australia Monash Medical Center-Clayton Campus Clayton Victoria
Australia John Hunter Children's Hospital Hunter Regional Mail Centre New South Wales
Australia Women's and Children's Hospital-Adelaide North Adelaide South Australia
Australia Royal Children's Hospital Parkville Victoria
Australia Perth Children's Hospital Perth Western Australia
Australia Queensland Children's Hospital South Brisbane Queensland
Australia The Children's Hospital at Westmead Westmead New South Wales
Canada Alberta Children's Hospital Calgary Alberta
Canada University of Alberta Hospital Edmonton Alberta
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 The Montreal Children's Hospital of the MUHC Montreal Quebec
Canada Children's Hospital of Eastern Ontario Ottawa Ontario
Canada CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL) Quebec
Canada Janeway Child Health Centre Saint John's Newfoundland and Labrador
Canada Jim Pattison Children's Hospital Saskatoon Saskatchewan
Canada Saskatoon Cancer Centre Saskatoon Saskatchewan
Canada Centre Hospitalier Universitaire de Sherbrooke-Fleurimont Sherbrooke Quebec
Canada Hospital for Sick Children Toronto Ontario
Canada British Columbia Children's Hospital Vancouver British Columbia
Canada CancerCare Manitoba Winnipeg Manitoba
New Zealand Christchurch Hospital Christchurch
New Zealand Starship Children's Hospital Grafton Auckland
Puerto Rico HIMA San Pablo Oncologic Hospital Caguas
Puerto Rico University Pediatric Hospital San Juan
United States Children's Hospital Medical Center of Akron Akron Ohio
United States Albany Medical Center Albany New York
United States Presbyterian Hospital Albuquerque New Mexico
United States University of New Mexico Cancer Center Albuquerque New Mexico
United States Lehigh Valley Hospital-Cedar Crest Allentown Pennsylvania
United States Texas Tech University Health Sciences Center-Amarillo Amarillo Texas
United States Providence Alaska Medical Center Anchorage Alaska
United States C S Mott Children's Hospital Ann Arbor Michigan
United States Mission Hospital Asheville North Carolina
United States Children's Healthcare of Atlanta - Egleston Atlanta Georgia
United States Augusta University Medical Center Augusta Georgia
United States Children's Hospital Colorado Aurora Colorado
United States Dell Children's Medical Center of Central Texas Austin Texas
United States Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland
United States Sinai Hospital of Baltimore Baltimore Maryland
United States University of Maryland/Greenebaum Cancer Center Baltimore Maryland
United States Eastern Maine Medical Center Bangor Maine
United States Walter Reed National Military Medical Center Bethesda Maryland
United States Children's Hospital of Alabama Birmingham Alabama
United States Saint Luke's Cancer Institute - Boise Boise Idaho
United States Dana-Farber Cancer Institute Boston Massachusetts
United States Massachusetts General Hospital Cancer Center Boston Massachusetts
United States Tufts Children's Hospital Boston Massachusetts
United States Montefiore Medical Center - Moses Campus Bronx New York
United States Maimonides Medical Center Brooklyn New York
United States University of Vermont and State Agricultural College Burlington Vermont
United States UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina
United States Medical University of South Carolina Charleston South Carolina
United States West Virginia University Charleston Division Charleston West Virginia
United States Carolinas Medical Center/Levine Cancer Institute Charlotte North Carolina
United States Novant Health Presbyterian Medical Center Charlotte North Carolina
United States University of Virginia Cancer Center Charlottesville Virginia
United States T C Thompson Children's Hospital Chattanooga Tennessee
United States Lurie Children's Hospital-Chicago Chicago Illinois
United States University of Chicago Comprehensive Cancer Center Chicago Illinois
United States University of Illinois Chicago Illinois
United States Cincinnati Children's Hospital Medical Center Cincinnati Ohio
United States Cleveland Clinic Foundation Cleveland Ohio
United States Rainbow Babies and Childrens Hospital Cleveland Ohio
United States Columbia Regional Columbia Missouri
United States Prisma Health Richland Hospital Columbia South Carolina
United States Nationwide Children's Hospital Columbus Ohio
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 Geisinger Medical Center Danville Pennsylvania
United States Dayton Children's Hospital Dayton Ohio
United States Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver Colorado
United States Blank Children's Hospital Des Moines Iowa
United States Ascension Saint John Hospital Detroit Michigan
United States Children's Hospital of Michigan Detroit Michigan
United States Kaiser Permanente Downey Medical Center Downey California
United States City of Hope Comprehensive Cancer Center Duarte California
United States Duke University Medical Center Durham North Carolina
United States Michigan State University Clinical Center East Lansing Michigan
United States El Paso Children's Hospital El Paso Texas
United States Inova Fairfax Hospital Falls Church Virginia
United States Sanford Broadway Medical Center Fargo North Dakota
United States Broward Health Medical Center Fort Lauderdale Florida
United States Golisano Children's Hospital of Southwest Florida Fort Myers Florida
United States Cook Children's Medical Center Fort Worth Texas
United States University of Florida Health Science Center - Gainesville Gainesville Florida
United States Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital Grand Rapids Michigan
United States Saint Vincent Hospital Cancer Center Green Bay Green Bay Wisconsin
United States BI-LO Charities Children's Cancer Center Greenville South Carolina
United States East Carolina University Greenville North Carolina
United States Hackensack University Medical Center Hackensack New Jersey
United States Connecticut Children's Medical Center Hartford Connecticut
United States Penn State Children's Hospital Hershey Pennsylvania
United States Memorial Regional Hospital/Joe DiMaggio Children's Hospital Hollywood Florida
United States Kapiolani Medical Center for Women and Children Honolulu Hawaii
United States Tripler Army Medical Center Honolulu Hawaii
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 Edwards Comprehensive Cancer Center Huntington West Virginia
United States Ascension Saint Vincent Indianapolis Hospital Indianapolis Indiana
United States Riley Hospital for Children Indianapolis Indiana
United States University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa
United States University of Mississippi Medical Center Jackson Mississippi
United States Nemours Children's Clinic-Jacksonville Jacksonville Florida
United States Bronson Methodist Hospital Kalamazoo Michigan
United States Children's Mercy Hospitals and Clinics Kansas City Missouri
United States East Tennessee Childrens Hospital Knoxville Tennessee
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 Sunrise Hospital and Medical Center Las Vegas Nevada
United States University Medical Center of Southern Nevada Las Vegas Nevada
United States Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center Lebanon New Hampshire
United States University of Kentucky/Markey Cancer Center Lexington Kentucky
United States Arkansas Children's Hospital Little Rock Arkansas
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 Cedars Sinai Medical Center Los Angeles California
United States Children's Hospital Los Angeles Los Angeles California
United States Mattel Children's Hospital UCLA Los Angeles California
United States Norton Children's Hospital Louisville Kentucky
United States Palms West Radiation Therapy Loxahatchee Groves Florida
United States Covenant Children's Hospital Lubbock Texas
United States UMC Cancer Center / UMC Health System Lubbock Texas
United States Atrium Health Navicent Macon Georgia
United States Valley Children's Hospital Madera California
United States University of Wisconsin Carbone Cancer Center - University Hospital Madison Wisconsin
United States Marshfield Medical Center-Marshfield Marshfield Wisconsin
United States Loyola University Medical Center Maywood Illinois
United States Vannie Cook Children's Clinic McAllen Texas
United States Banner Children's at Desert Mesa Arizona
United States Miami Cancer Institute Miami Florida
United States Nicklaus Children's Hospital Miami Florida
United States University of Miami Miller School of Medicine-Sylvester Cancer Center Miami Florida
United States Children's Hospital of Wisconsin Milwaukee Wisconsin
United States NYU Langone Hospital - Long Island Mineola New York
United States Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis Minnesota
United States University of Minnesota/Masonic Cancer Center Minneapolis Minnesota
United States USA Health Strada Patient Care Center Mobile Alabama
United States West Virginia University Healthcare Morgantown West Virginia
United States Morristown Medical Center Morristown New Jersey
United States The Children's Hospital at TriStar Centennial Nashville Tennessee
United States Vanderbilt University/Ingram Cancer Center Nashville Tennessee
United States Jersey Shore Medical Center Neptune New Jersey
United States Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital New Brunswick New Jersey
United States Saint Peter's University Hospital New Brunswick New Jersey
United States Yale University New Haven Connecticut
United States The Steven and Alexandra Cohen Children's Medical Center of New York New Hyde Park New York
United States Children's Hospital New Orleans New Orleans Louisiana
United States Ochsner Medical Center Jefferson New Orleans Louisiana
United States Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York
United States Memorial Sloan Kettering Cancer Center 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 NYP/Weill Cornell Medical Center New York New York
United States Newark Beth Israel Medical Center Newark New Jersey
United States Children's Hospital of The King's Daughters Norfolk Virginia
United States Advocate Children's Hospital-Oak Lawn Oak Lawn Illinois
United States Kaiser Permanente-Oakland Oakland California
United States UCSF Benioff Children's Hospital Oakland Oakland California
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States Children's Hospital and Medical Center of Omaha Omaha Nebraska
United States University of Nebraska Medical Center Omaha Nebraska
United States Children's Hospital of Orange County Orange California
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 Lucile Packard Children's Hospital Stanford University Palo Alto California
United States Advocate Children's Hospital-Park Ridge Park Ridge Illinois
United States Saint Joseph's Regional Medical Center Paterson New Jersey
United States Sacred Heart Hospital Pensacola Florida
United States Saint Jude Midwest Affiliate Peoria Illinois
United States Children's Hospital of Philadelphia Philadelphia Pennsylvania
United States Saint Christopher's Hospital for Children Philadelphia Pennsylvania
United States Phoenix Childrens Hospital Phoenix Arizona
United States Children's Hospital of Pittsburgh of UPMC Pittsburgh Pennsylvania
United States Legacy Emanuel Children's Hospital Portland Oregon
United States Oregon Health and Science University Portland Oregon
United States Naval Medical Center - Portsmouth Portsmouth Virginia
United States Rhode Island Hospital Providence Rhode Island
United States Renown Regional Medical Center Reno Nevada
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Carilion Children's Roanoke Virginia
United States Mayo Clinic in Rochester Rochester Minnesota
United States University of Rochester Rochester New York
United States Beaumont Children's Hospital-Royal Oak Royal Oak Michigan
United States Sutter Medical Center Sacramento Sacramento California
United States University of California Davis Comprehensive Cancer Center Sacramento California
United States Cardinal Glennon Children's Medical Center Saint Louis Missouri
United States Mercy Hospital Saint Louis Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Johns Hopkins All Children's Hospital Saint Petersburg Florida
United States Primary Children's Hospital Salt Lake City Utah
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 Naval Medical Center -San Diego San Diego California
United States Rady Children's Hospital - 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 Memorial Health University Medical Center Savannah Georgia
United States Maine Children's Cancer Program Scarborough Maine
United States Seattle Children's Hospital Seattle Washington
United States Sanford USD Medical Center - Sioux Falls Sioux Falls South Dakota
United States Providence Sacred Heart Medical Center and Children's Hospital Spokane Washington
United States Baystate Medical Center Springfield Massachusetts
United States Southern Illinois University School of Medicine Springfield Illinois
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 Madigan Army Medical Center Tacoma Washington
United States Mary Bridge Children's Hospital and Health Center Tacoma Washington
United States Saint Joseph's Hospital/Children's Hospital-Tampa Tampa Florida
United States Tampa General Hospital Tampa Florida
United States Scott and White Memorial Hospital Temple Texas
United States ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital Toledo Ohio
United States Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center Torrance California
United States Banner University Medical Center - Tucson Tucson Arizona
United States Natalie Warren Bryant Cancer Center at Saint Francis Tulsa Oklahoma
United States New York Medical College Valhalla New York
United States Children's National Medical Center Washington District of Columbia
United States MedStar Georgetown University Hospital Washington District of Columbia
United States Saint Mary's Hospital West Palm Beach Florida
United States Alfred I duPont Hospital for Children Wilmington Delaware
United States Northwestern Medicine Central DuPage Hospital Winfield Illinois
United States Wake Forest University Health Sciences Winston-Salem North Carolina
United States UMass Memorial Medical Center - University Campus Worcester Massachusetts

Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico, 

Outcome

Type Measure Description Time frame Safety issue
Other To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL FlowSom high resolution clustering approach to identify cellular subsets and/or activation states (endophenotypes) that distinguish cases from controls. Perform secondary analysis using the "diffCyt" framework to identify those cell clusters that differ significantly between groups. 5 years
Other Neurocognitive, functional, and quality of life outcomes in patients with DS and ALL Measured by caregiver (parent/legal guardian) using questionnaires that rate executive function, behavior, adaptive skills, and quality of life. 5 years
Other Prevalence of minimal marrow disease (MMD) in B-LLy Correlate MMD at diagnosis with outcome in patients with B-LLy. 5 years
Other Genetic landscape of B-ALL lacking a clonal Ig sequence Will be measured by performing targeted sequencing (hemoglobin [heme] deoxyribonucleic acid [DNA] mutation and ribonucleic acid [RNA] fusion panels) on samples from all identified patients without a clonal Ig sequence with banked material and compare to matched subjects with clonal Ig sequences. Will determine associations between having or lacking a clonal Ig sequence and discrete mutations/fusions using Fisher's exact test. Will also be assessed with a 1-sided alpha of 0.05, a log-rank test. 5 years
Other Association between flow cytometry Will be determined by MRD and HTS of IgH loci from the BM in NCI SR B-ALL patients who are MRD positive by flow cytometry. Will use the Kendall's Tau-b rank correlation coefficient accounting for the left censoring inherent to sensitivity of the methods. 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 the end of induction
Primary 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 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. 5.3 years
Primary DFS in boys in the SR-favorable subset of SR B-ALL with or without Down syndrome (DS) 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. 5.1 years
Secondary 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 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. 5.1 years
Secondary DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen 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. 5.1 years
Secondary 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 Percent of DS-high patients with treatment related mortalities will be reported with 95% confidence interval. 2.3 years
Secondary DFS of DS-High B-ALL patients when intensive elements of chemotherapy are replaced with 3 cycles of blinatumomab 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. 5.3 years
Secondary DFS of patients with localized B-lymphoblastic lymphoma (B-LLy) receiving standard risk acute lymphoblastic leukemia therapy 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. 5 years
Secondary 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) 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. 3.3 years
Secondary 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 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. 1 year
Secondary 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 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. 1 year
Secondary Peripheral blood (PB) samples using HTS MRD vs. bone marrow (BM) results at EOI 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. 1 year
Secondary BM using HTS MRD vs. BM by flow cytometry at EOC in patients who were Day 29 MRD positive by flow cytometry 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. 1 year
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