Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations
- Conditions
- B Acute Lymphoblastic Leukemia, BCR-ABL1-LikeB Acute Lymphoblastic LeukemiaCentral Nervous System LeukemiaTesticular Leukemia
- Interventions
- Other: Laboratory Biomarker AnalysisRadiation: Radiation Therapy
- Registration Number
- NCT02883049
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
This randomized phase III trial studies how well combination chemotherapy works in treating young patients with newly diagnosed B acute lymphoblastic leukemia that is likely to come back or spread, and in patients with Philadelphia chromosome (Ph)-like tyrosine kinase inhibitor (TKI) sensitive mutations. Chemotherapy drugs, 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. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells.
- Detailed Description
PRIMARY OBJECTIVES:
I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX). (Completed effective March 19, 2018) II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). (Completed effective February 15, 2017)
SECONDARY OBJECTIVES:
I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR B-ALL. (Completed effective March 19, 2018) II. To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in children, adolescents, and young adults with VHR B-ALL. (Completed effective February 15, 2017) III. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-interim maintenance intermediate dose methotrexate (IMIDM) and reduced vincristine (vincristine sulfate)/steroid pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR B-ALL will result in a \>= 65% 5-year DFS and \< 10% Induction mortality.
IV. To describe the outcomes for children and young adults with Philadelphia chromosome (Ph)-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus MBFM-IMHDM.
V. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR B-ALL.
VI. To estimate overall survival (OS) rates both overall and by regimen a) for HR B-ALL and b) VHR B-ALL patients.
VII. To determine the incidence of osteonecrosis (ON), defined by magnetic resonance (MR) imaging, and to characterize the natural history of clinically silent ON in children, adolescents, and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. (Completed accrual July 2016) VIII. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to \< 13 years) with HR- and VHR B-ALL at 1 year off therapy, is significantly higher than the normative population (\> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention.
EXPLORATORY OBJECTIVE:
I. To determine if the reduction of minimal residual disease (MRD) from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL receiving Experimental Arm 1 compared to the Control Arm. (Closed effective October 20, 2017)
OUTLINE:
INDUCTION THERAPY:
Patients without Down syndrome receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1 (and twice weekly thereafter for CNS2 patients \[except for days 8 and 29\]); vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 for CNS1 and CNS2 patients (plus days 15 and 22 for CNS3 patients). Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity.
Participants are stratified to 1 of 3 disease groups: HR B-ALL, VHR B-ALL and PH-like B-ALL a predicted TKI-sensitive mutation.
GROUP I - HR B-ALL: Patients are randomized to 1 of 2 treatment arms. (RANDOMIZATION CLOSED 03/19/2018)
CONSOLIDATION THERAPY (C):
ARM A HR B-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
ARM B HR B-ALL C: Patients receive consolidation therapy as in Arm I HR B-ALL C. Patients also receive ITT comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients with testicular leukemia also undergo RT as in Arm I HR B-ALL C. (CLOSED 03/19/2018)
INTERIM MAINTENANCE THERAPY (IM) ARM A HR B-ALL IM: Patients receive IM therapy comprising vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
ARM B HR B-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in Arm I HR-ALL IM. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018)
DELAYED INTENSIFICATION THERAPY (DI):
ARM A HR B-ALL DI: Patients receive DI therapy comprising vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO QD on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
ARM B HR B-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in Arm I HR B-ALL DI. (CLOSED 03/19/2018)
MAINTENANCE THERAPY (M):
ARM A HR B-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV over 1 minute on days 1, 29, and 57; methotrexate IT on day 1 (also day 29 of courses 1-4); prednisone PO BID on days 1-5, 29-33 (may receive methylprednisolone IV if PO is not tolerated), and 57-61; mercaptopurine PO QD on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity.
ARM B HR B-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in Arm I HR B-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018)
GROUP II: VHR B-ALL: Patients are randomized to 1 of 3 treatment arms. (RANDOMIZATION CLOSED 02/15/2017)
CONSOLIDATION THERAPY PART I: In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV over 1-30 minutes or SC on days 1-4 and 8-11; mercaptopurine PO QD on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); vincristine sulfate IV over 1 minute on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION THERAPY PART II:
ARM A VHR B-ALL C (CONTROL ARM): Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO QD on days 29-42; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
ARM B VHR B-ALL C (EXPERIMENTAL ARM 1): Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017)
ARM C VHR B-ALL C (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in Arm B VHR B-ALL C. (CLOSED 9/12/2014)
INTERIM MAINTENANCE THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION THERAPY PART II:
ARM A VHR B-ALL DI (CONTROL ARM): Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; thioguanine PO QD on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity.
ARM B VHR B-ALL DI (EXPERIMENTAL ARM 1): Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017)
ARM C VHR B-ALL DI (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in Arm II B VHR B-ALL DI. (Closed as of 9/12/2014)
INTERIM MAINTENANCE THERAPY PART II: In all arms, patients receive vincristine sulfate IV over 1 minute and methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
MAINENTANCE THERAPY: Patients with CNS3 disease at diagnosis undergo RT QD over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61 (may receive methylprednisolone IV if PO is not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO QD on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities.
GROUP III: PH-LIKE PREDICTED TKI-SENSITIVE KINASE MUTATION:
CONSOLIDATION THERAPY: Patients receive dasatinib PO QD on days 1-56, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32 and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15 and 22 (days 1 and 8 only for CNS3 patients), vincristine sulfate IV over 1 minute on days 15, 22, 43 and 50, and pegaspargase IV over 1-2 hours on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE THERAPY I: Patients receive dasatinib PO QD on days 1-63, vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29, and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION THERAPY: Patients receive dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8 and 15, methotrexate IT on days 1, 29 and 36, pegaspargase IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes day 29, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, and thioguanine PO on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE THERAPY II: Patients dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute 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, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours days 2 and 22.
MAINTENANCE THERAPY: Patients receive dasatinib PO QD on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29 and 57, prednisone PO BID or IV on days 1-5, 29-33 and 57-61, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (omit on days when MTX \[IT\] is given), mercaptopurine PO on days 1-84, methotrexate IT on day 1 (also day 29 of course 1 and 2, for patients who did not receive CNS radiation). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities.
Participants with Down syndrome are assigned to DS HR B-ALL:
INDUCTION THERAPY: All patients receive cytarabine IT on day 1; vincristine sulfate IV over 1 minute on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14 (may receive methylprednisolone IV if PO is not tolerated), pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
RAPID EARLY RESPONDERS (RER): Patients receive induction therapy comprising vincristine sulfate IV over 1 minute on days 15 and 22; dexamethasone PO BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
SLOW EARLY RESPONDERS (SER): Patients receive daunorubicin hydrochloride IV over 1-15 minutes on day 15 and Induction therapy as RER patients. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION THERAPY: All patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO QD on days 1-14 and 29-42; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity.
INTERIM MAINTENANCE THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 2-3, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity.
DELAYED INTENSIFICATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO QD on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39.
MAINTENANCE THERAPY: Patients with CNS3 disease undergo RT QD, 5 days a week, for 2 weeks (10 fractions total). Patients receive vincristine sulfate IV over 1 minute on day 1; prednisone PO BID or IV on days 1-5 (may receive methylprednisolone IV if PO not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO QD on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities.
After completion of study treatment, patients are followed up periodically for 10 years.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 5949
-
Patients must be enrolled on APEC14B1 and consented to Eligibility Screening on the Part A consent form prior to enrollment on AALL1131
-
White Blood Cell Count (WBC) Criteria
-
Age 1-9.99 years: WBC >= 50 000/uL
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Age 10-30.99 years: Any WBC
-
Age 1-30.99 years: Any WBC with:
- Testicular leukemia
- CNS leukemia (CNS3)
- Steroid pretreatment
-
-
Patients must have newly diagnosed B lymphoblastic leukemia (2008 World Health Organization [WHO] classification) (also termed B-precursor acute lymphoblastic leukemia); patients with Down syndrome are also eligible
-
Organ function requirements for patients with Ph-like ALL and a predicted TKI-sensitive mutation: patients identified as Ph-like with a TKI-sensitive kinase mutation must have assessment of organ function performed within 3 days of study entry onto the dasatinib arm of AALL1131
-
Creatinine clearance or radioisotope glomerular filtration rate (GFR) > 70mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
- Age: Maximum Serum Creatinine (mg/dL)
- 1 to < 6 months: 0.4 (male) 0.4 (female)
- 6 months to < 1 year: 0.5 (male) 0.5 (female)
- 1 to < 2 years: 0.6 (male) 0.6 (female)
- 2 < 6 years: 0.8 (male) 0.8 (female)
- 6 to < 10 years: 1.0 (male) 1.0 (female)
- 10 to < 13 years: 1.2 (male) 1.2 (female)
- 13 to < 16 years: 1.5 (male) 1.4 (female)
- > 16 years: 1.7 (male) 1.4 (female)
-
Direct bilirubin =< 3 x upper limit of normal (ULN) for age, and
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Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 10 x upper limit of normal (ULN) for age
-
Shortening fraction >= 27% by echocardiogram, or ejection fraction >= 50% by gated radionuclide study
- Patients must have an electrocardiogram (EKG) fewer than 6 days prior to enrollment on the dasatinib arm; patients who have had cardiac assessments by echocardiogram or radionuclide scan at the beginning of induction do not need to have these repeated prior to study entry; correct QT interval (QTc) < 450 msec on baseline electrocardiogram as measured by the Friderica or Bazett formula
- No major conduction abnormality (unless a cardiac pacemaker is present)
-
No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% at sea level if there is clinical indication for determination
-
Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled; however, drugs that induce CYP3A4/5 (carbamazepine, oxcarbazepine, phenytoin, primidone, phenobarbital) should be avoided
-
Eligibility criteria for the Longitudinal, Computerized Assessment of Neurocognitive Functioning study
- Patients must be aged 6 to 13 years at time of B-ALL diagnosis, enrolled on AALL1131
- Patients must be English-, French- or Spanish-speaking (languages in which the assessment is available)
- Patients must have no known history of neurodevelopmental disorder prior to diagnosis of B-ALL (e.g., Down syndrome, Fragile X, William's Syndrome, mental retardation)
- Patients must have no significant visual impairment that would prevent computer use and recognition of the visual test stimuli
-
Eligibility criteria for the National Cancer Institute (NCI) standard risk patients from AALL0932 enrolling on this study at the end of Induction
-
Effective March 19, 2018, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the HR B-ALL stratum of this study at the end of Induction:
- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 8 peripheral blood (PB) minimal residual disease (MRD) >= 1% and day 29 bone marrow (BM) MRD < 0.01%
- With favorable cytogenetics (ETV6-RUNX1 or double trisomies 4+10), with any day 8 PB MRD and day 29 BM MRD >= 0.01%
- Both NCI standard risk (SR) and HR patients without Down syndrome and with testicular disease at diagnosis, who do not meet other VHR criteria
-
Effective Amendment 6, patients enrolled on AALL0932, without Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 or the VHR stratum of AALL1131:
- Intrachromosomal amplification of chromosome 21 (iAMP21)
- Mixed-lineage leukemia (MLL) rearrangement
- Hypodiploidy (n < 44 chromosomes and/or a deoxyribonucleic acid [DNA] index < 0.81)
- Induction failure (M3 BM at day 29)
- Without favorable cytogenetics (no ETV6-RUNX1 or double trisomies 4+10), with day 29 BM MRD >= 0.01%
-
Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction:
- Day 29 MRD >= 0.01%
- MLL rearrangement
- Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)
-
DS HR B-ALL patients initially enrolled on AALL0932 or this study who have Induction failure (M3 BM day 29) or Philadelphia chromosome (BCR-ABL1) will not be eligible for post-Induction therapy on either trial (AALL0932 or AALL1131)
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All patients and/or their parents or legal guardians must sign a written informed consent
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All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met
- 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 any cancer diagnosed prior to the initiation of protocol therapy on AALL1131; patients cannot have secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy; patients receiving prior steroid therapy may be eligible for AALL1131
- Patients with BCR-ABL1 fusion are not eligible for post-induction therapy on this study but may be eligible to enroll in a successor Children's Oncology Group (COG) Philadelphia positive (Ph+) ALL trial by day 15 Induction
- DS HR B-ALL patients with Induction failure or BCR-ABL1
- Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs
- Lactating females are not eligible unless they have agreed not to breastfeed their infant
- Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
- Sexually active patients of reproductive potential are not eligible unless they have 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 Group II Arm A (VHR B-ALL - Control Arm) Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. DS HR B-ALL (SER) Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Daunorubicin Hydrochloride Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. DS HR B-ALL (RER) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Vincristine Sulfate Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. DS HR B-ALL (SER) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Leucovorin Calcium Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. DS HR B-ALL (SER) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Leucovorin Calcium Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Dasatinib Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (RER) Thioguanine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group III PH-like predicted TKI-sensitive kinase mutation Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Thioguanine Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. DS HR B-ALL (SER) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Thioguanine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm A (HR B-ALL) Vincristine Sulfate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Daunorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Thioguanine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Mercaptopurine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Methotrexate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Pegaspargase Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Prednisone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Radiation Therapy Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm A (VHR B-ALL - Control Arm) Thioguanine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Cyclophosphamide Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Cytarabine Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Doxorubicin Hydrochloride Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Etoposide Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Laboratory Biomarker Analysis Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Mercaptopurine Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Methotrexate Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Pegaspargase Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Prednisone Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm B (VHR B-ALL - Exp Arm1) (CLOSED 02/15/2017) Radiation Therapy Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Clofarabine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Cyclophosphamide Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Cytarabine Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Dexamethasone Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Doxorubicin Hydrochloride Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Etoposide Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group II Arm C (VHR B-ALL - Exp Arm 2) (CLOSED 09/12/2014) Laboratory Biomarker Analysis Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details. Group I Arm B (HR B-ALL) (CLOSED 03/19/2018) Hydrocortisone Sodium Succinate Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies. See outline for details.
- Primary Outcome Measures
Name Time Method DFS of Non-DS HR Post-induction Patients Receiving Intrathecal (IT) Methotrexate (MTX) Compared With Patients Receiving Intrathecal Triple Therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) Interim Maintenance High-dose Methotrexate Backbone At 5 years DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. Compared using 2-sided log rank test, alpha = 5%. (Completed effective March 19, 2018)
DFS of Non-DS VHR Post-Induction Patients Who Receive a Modified MBFM-IMHDM Regimen That Contains a Second IM (Control Arm) Compared to Patients Receive the Cyclophosphamide + Etoposide Containing Regimen (Experimental Arm 1) At 4 years (Completed effective February 15, 2017) DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. Compared using a 1-sided log rank test, alpha of 2.5%.
- Secondary Outcome Measures
Name Time Method The Prevalence of Cognitive Deficits Measured by CogState (Domain: Working Memory), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy Up to 10 years The percentage of patients with abnormal results (Z ≤ -1.5) in working memory measured by CogState will be estimated.
Incidence of Osteonecrosis (ON) Defined by Magnetic Resonance (MR) Imaging in Children, Adolescents, and Young Adults 10 Years of Age and Greater Up to 10 years Incidence of ON among patients who have submitted MRI screening data will be estimated.
The Prevalence of Cognitive Deficits Measured by CogState (Domain: Processing Speed), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy Up to 10 years The percentage of patients with abnormal results (Z ≤ -1.5) in processing speed measured by CogState will be estimated.
The Prevalence of Cognitive Deficits Measured by CogState (Domain: Visual Attention), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy Up to 10 years The percentage of patients with abnormal results (Z ≤ -1.5) in visual attention measured by CogState will be estimated.
Toxicity and Tolerability of Post-induction Age-adjusted ITT Compared to Age-adjusted IT MTX in Children With HR B-ALL Up to 10 years (Completed effective March 19, 2018) Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated for each randomized arm.
Induction Mortality in Patients With DS and HR B-ALL Treated With Modified Induction At 1 month Percentage of deaths in induction will be calculated.
5-year DFS in Patients With Down Syndrome (DS) and HR B-ALL Treated With Modified Induction and Post-Induction Therapy Regimen With MBFM-IMIDM At 5 years DFS time is defined as time from end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. 5-year DFS will be estimated using the Kaplan-Meier method.
DFS for Children and Young Adults With Ph-like B-ALL and a Predicted Tyrosine Kinase Inhibitor (TKI)-Sensitive Mutation Treated With Dasatinib Plus MBFM-IMHDM Up to 4 years DFS time is defined as time from randomization end of induction to first event (relapse, second malignant neoplasm, death) or date of last contact for patients who are event-free. 4-year DFS will be estimated using the Kaplan-Meier method.
Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm. At 4 years OS of VHR-B-ALL post-Induction patients who receive a modified MBFM-IMHDM regimen that contains a second IM (Control Arm) compared to patients receive the cyclophosphamide + etoposide containing regimen (Experimental Arm 1). OS time is defined as time from enrollment to death or date of last contact for patients who are alive. 4-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.
The Prevalence of Cognitive Deficits Measured by CogState (Domain: Executive Function), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy Up to 10 years The percentage of patients with abnormal results (Z ≤ -1.5) in executive function measured by CogState will be estimated.
The Prevalence of Cognitive Deficits Measured by CogState (Domain: Visual Learning), in Children (Ages 6 to < 13 Years) With HR- and VHR B-ALL at 1 Year Off Therapy Up to 10 years The percentage of patients with abnormal results (Z ≤ -1.5) in visual learning measured by CogState will be estimated.
Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL Up to 10 years Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated for each randomized arm. (Closed effective February 15, 2017)
Toxicity and Tolerability of MBFM-interim Maintenance Intermediate Dose Methotrexate (IMIDM) in Children With Down Syndrome Up to 10 years Percentage of patients who experienced Grade 3 or higher Toxicity Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, will be estimated.
Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm At 5 years OS time is defined as time from enrollment to death or date of last contact for patients who are alive. 5-year OS will be estimated for the two randomized arms using the Kaplan-Meier method.
Trial Locations
- Locations (239)
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
Children's Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Nemours Children's Clinic - Orlando
🇺🇸Orlando, Florida, United States
Nemours Children's Hospital
🇺🇸Orlando, Florida, United States
Albany Medical Center
🇺🇸Albany, New York, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Legacy Emanuel Children's Hospital
🇺🇸Portland, Oregon, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Covenant Children's Hospital
🇺🇸Lubbock, Texas, United States
UMC Cancer Center / UMC Health System
🇺🇸Lubbock, Texas, United States
Vannie Cook Children's Clinic
🇺🇸McAllen, Texas, United States
Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
Carilion Children's
🇺🇸Roanoke, Virginia, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Kingston Health Sciences Centre
🇨🇦Kingston, Ontario, Canada
Children's Hospital
🇨🇦London, Ontario, Canada
University of Alabama at Birmingham Cancer Center
🇺🇸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
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
University of Arkansas for Medical Sciences
🇺🇸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-Parnassus
🇺🇸San Francisco, 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
Lee Memorial Health System
🇺🇸Fort Myers, Florida, United States
Golisano Children's Hospital of Southwest Florida
🇺🇸Fort Myers, Florida, United States
University of Florida Health Science Center - Gainesville
🇺🇸Gainesville, Florida, United States
Memorial Regional Hospital/Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nemours Children's Clinic-Jacksonville
🇺🇸Jacksonville, Florida, United States
Palms West Radiation Therapy
🇺🇸Loxahatchee Groves, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Arnold Palmer Hospital for Children
🇺🇸Orlando, Florida, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
Nemours Children's Clinic - Pensacola
🇺🇸Pensacola, Florida, United States
Johns Hopkins All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
Tampa General Hospital
🇺🇸Tampa, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Saint Mary's Medical Center
🇺🇸West Palm Beach, Florida, United States
Children's Healthcare of Atlanta - Arthur M Blank Hospital
🇺🇸Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
Memorial Health University Medical Center
🇺🇸Savannah, Georgia, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, 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
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
Saint Jude Midwest Affiliate
🇺🇸Peoria, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Ascension Saint Vincent Indianapolis Hospital
🇺🇸Indianapolis, Indiana, United States
Blank Children's Hospital
🇺🇸Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸Iowa City, Iowa, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Norton Children's Hospital
🇺🇸Louisville, Kentucky, United States
Tulane University School of Medicine
🇺🇸New Orleans, Louisiana, 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
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
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Henry Ford Health Saint John Hospital
🇺🇸Detroit, Michigan, United States
Michigan State University Clinical Center
🇺🇸East Lansing, Michigan, United States
Hurley Medical Center
🇺🇸Flint, 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
Corewell Health William Beaumont University Hospital
🇺🇸Royal Oak, Michigan, United States
Children's Hospitals and Clinics of Minnesota - Minneapolis
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
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
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Morristown Medical Center
🇺🇸Morristown, 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
Overlook Hospital
🇺🇸Summit, New Jersey, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
NYU Langone Hospital - Long Island
🇺🇸Mineola, New York, United States
The Steven and Alexandra Cohen Children's Medical Center of New York
🇺🇸New Hyde Park, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
NYP/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
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
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
Natalie Warren Bryant Cancer Center at Saint Francis
🇺🇸Tulsa, Oklahoma, United States
Dayton Children's Hospital
🇺🇸Dayton, Ohio, United States
ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital
🇺🇸Toledo, Ohio, United States
Mercy Children's Hospital
🇺🇸Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Lehigh Valley Hospital-Cedar Crest
🇺🇸Allentown, Pennsylvania, United States
Lehigh Valley Hospital - Muhlenberg
🇺🇸Bethlehem, 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
Greenville Cancer Treatment 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
Saint Jude Children's Research Hospital
🇺🇸Memphis, Tennessee, United States
The Children's Hospital at TriStar Centennial
🇺🇸Nashville, Tennessee, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Texas Tech University Health Sciences Center-Amarillo
🇺🇸Amarillo, Texas, United States
Dell Children's Medical Center of Central Texas
🇺🇸Austin, Texas, United States
Driscoll Children's Hospital
🇺🇸Corpus Christi, Texas, United States
Medical City Dallas Hospital
🇺🇸Dallas, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
El Paso Children's Hospital
🇺🇸El Paso, Texas, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸Houston, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
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
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
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
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
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Royal Children's Hospital-Brisbane
🇦🇺Herston, Queensland, 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
Princess Margaret Hospital for Children
🇦🇺Perth, Western Australia, Australia
Perth Children's Hospital
🇦🇺Perth, Western Australia, Australia
Alberta Children's Hospital
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital
🇨🇦Edmonton, Alberta, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Janeway Child Health Centre
🇨🇦Saint John's, Newfoundland and Labrador, Canada
IWK Health Centre
🇨🇦Halifax, Nova Scotia, Canada
McMaster Children's Hospital at Hamilton Health Sciences
🇨🇦Hamilton, Ontario, Canada
Children's Hospital of Eastern Ontario
🇨🇦Ottawa, Ontario, Canada
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
The Montreal Children's Hospital of the MUHC
🇨🇦Montreal, Quebec, Canada
Allan Blair Cancer Centre
🇨🇦Regina, Saskatchewan, Canada
Saskatoon Cancer Centre
🇨🇦Saskatoon, Saskatchewan, Canada
Our Lady's Children's Hospital
🇮🇪Dublin, Co Dublin, Ireland
Starship Children's Hospital
🇳🇿Grafton, Auckland, New Zealand
Christchurch Hospital
🇳🇿Christchurch, New Zealand
San Jorge Children's Hospital
🇵🇷San Juan, Puerto Rico
University Pediatric Hospital
🇵🇷San Juan, Puerto Rico
Swiss Pediatric Oncology Group - Geneva
🇨🇭Geneva, Switzerland
Swiss Pediatric Oncology Group - Lausanne
🇨🇭Lausanne, Switzerland