B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, BCR-ABL1-Like, Central Nervous System Leukemia, Testicular Leukemia
Conditions
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.
Interventions
DRUGClofarabine
Given IV
DRUGCyclophosphamide
Given IV
DRUGCytarabine
Given IT, IV, or SC
DRUGDasatinib
Given PO
DRUGDaunorubicin Hydrochloride
Given IV
DRUGDexamethasone
PO or IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
Given IT
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLeucovorin Calcium
Given PO or IV
DRUGMercaptopurine
Given PO
DRUGMethotrexate
Given IT and IV
DRUGPegaspargase
Given IV
DRUGPrednisone
Given PO or IV
RADIATIONRadiation Therapy
Undergo radiation therapy
DRUGThioguanine
Given PO
DRUGVincristine Sulfate
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 31 Years
Healthy volunteers
No
Inclusion criteria
* 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 * 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 * 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) * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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%. |
| 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| 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. |
| 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: 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| The Reduction in MRD From End-Induction (EOI) to End-Consolidation (EOC) for Children, Adolescents, and Young Adults With VHR B-ALL Receiving Experimental Arms 1 Compared to the Control Arm | Up to 90 days | (Closed effective Amendment 6) Mean change in MRD from EOI to EOC will be calculated for VHR patients on Experimental Arm 1 and Control Arm. |
Countries
Australia, Canada, Ireland, New Zealand, Puerto Rico, Switzerland, United States
Participant flow
Pre-assignment details
For Induction, 4,973 patients were stratified between Down Syndrome and Non-Down Syndrome. For Post Induction, 2,000 of the Down Syndrome and Non-Down Syndrome patients and an additional 974 patients transferred from AALL0932 were stratum assigned and received treatment based upon the patient's response. 2 patients from AALL0932 were deemed ineligible and not stratum assigned Post Induction
Participants by arm
| Arm | Count |
|---|---|
| Non-DS B-ALL Patients without Down syndrome receive induction chemotherapy | 4,749 |
| DS B-ALL Patients with Down syndrome receive induction chemotherapy | 224 |
| Patients Transferred From AALL0932 Patients from AALL0932 enroll on this study at the end of Induction | 976 |
| Total | 5,949 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Induction | Adverse Event | 52 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Death | 76 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Developed SMN | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Enrolled onto another COG study | 72 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Identified as HR patients | 165 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Identified as Ph+ patients | 279 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Identified as VHR at end of Induction | 244 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Incomplete induction data | 17 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Ineligible | 35 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Inevaluable | 33 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Lost to Follow-up | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | M3 Marrow at Day29 | 8 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Moved to another non-COG institution | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | MRD negative | 36 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Physician Decision | 1,407 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Protocol Violation | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Randomization closed | 41 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Refusal of further protocol therapy | 466 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Induction | Withdrawal by Subject | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post Induction | Adverse Event | 0 | 0 | 0 | 7 | 8 | 3 | 4 | 5 | 6 | 7 | 2 | 2 | 0 | 0 | 5 | 2 |
| Post Induction | Death | 0 | 0 | 0 | 9 | 9 | 0 | 1 | 6 | 5 | 3 | 1 | 0 | 1 | 1 | 10 | 2 |
| Post Induction | Developed SMN | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 |
| Post Induction | Enrolled onto another COG study | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 4 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
| Post Induction | Induction Failure | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Post Induction | Ineligible | 0 | 0 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Post Induction | Inevaluable | 0 | 0 | 0 | 1 | 1 | 2 | 7 | 6 | 4 | 4 | 1 | 1 | 2 | 0 | 0 | 1 |
| Post Induction | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Post Induction | Moved to another non-COG institution | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Post Induction | MRD negative | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 11 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post Induction | Physician Decision | 0 | 0 | 0 | 27 | 27 | 23 | 30 | 56 | 85 | 12 | 5 | 14 | 1 | 11 | 19 | 5 |
| Post Induction | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post Induction | Randomization closed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post Induction | Recurrent leukemia | 0 | 0 | 0 | 17 | 12 | 4 | 1 | 13 | 27 | 5 | 3 | 12 | 1 | 1 | 9 | 3 |
| Post Induction | Refusal of further protocol therapy | 0 | 0 | 0 | 11 | 15 | 9 | 13 | 5 | 21 | 7 | 0 | 7 | 3 | 0 | 4 | 1 |
| Post Induction | Withdrawal by Subject | 0 | 0 | 0 | 5 | 2 | 1 | 0 | 0 | 2 | 0 | 1 | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Non-DS B-ALL | DS B-ALL | Patients Transferred From AALL0932 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 4237 Participants | 183 Participants | 976 Participants | 5396 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 512 Participants | 41 Participants | 0 Participants | 553 Participants |
| Age, Continuous | 11.36 years STANDARD_DEVIATION 6.01 | 12.64 years STANDARD_DEVIATION 6.27 | 4.74 years STANDARD_DEVIATION 2.19 | 10.32 years STANDARD_DEVIATION 6.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1428 Participants | 86 Participants | 241 Participants | 1755 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3068 Participants | 132 Participants | 692 Participants | 3892 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 253 Participants | 6 Participants | 43 Participants | 302 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 41 Participants | 3 Participants | 11 Participants | 55 Participants |
| Race (NIH/OMB) Asian | 210 Participants | 4 Participants | 40 Participants | 254 Participants |
| Race (NIH/OMB) Black or African American | 288 Participants | 8 Participants | 48 Participants | 344 Participants |
| Race (NIH/OMB) More than one race | 34 Participants | 1 Participants | 6 Participants | 41 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 35 Participants | 1 Participants | 4 Participants | 40 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 750 Participants | 29 Participants | 134 Participants | 913 Participants |
| Race (NIH/OMB) White | 3391 Participants | 178 Participants | 733 Participants | 4302 Participants |
| Sex: Female, Male Female | 2082 Participants | 105 Participants | 432 Participants | 2619 Participants |
| Sex: Female, Male Male | 2667 Participants | 119 Participants | 544 Participants | 3330 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 78 / 4,714 | 8 / 223 | 0 / 0 | 23 / 526 | 24 / 528 | 6 / 348 | 11 / 345 | 48 / 282 | 57 / 369 | 15 / 73 | 4 / 61 | 12 / 131 | 1 / 28 | 4 / 23 | 36 / 199 | 7 / 58 |
| other Total, other adverse events | 1,175 / 4,714 | 130 / 223 | 0 / 0 | 332 / 526 | 338 / 528 | 210 / 348 | 207 / 345 | 148 / 282 | 257 / 369 | 56 / 73 | 37 / 61 | 79 / 131 | 21 / 28 | 12 / 23 | 182 / 199 | 55 / 58 |
| serious Total, serious adverse events | 212 / 4,714 | 19 / 223 | 0 / 0 | 46 / 526 | 45 / 528 | 18 / 348 | 30 / 345 | 55 / 282 | 72 / 369 | 45 / 73 | 5 / 61 | 18 / 131 | 16 / 28 | 18 / 23 | 49 / 199 | 13 / 58 |
Outcome results
Primary
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
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)
Time frame: At 5 years
Population: Non-DS HR B-ALL patients with post induction therapies (includes patients from AALL0932). Inevaluable patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 92.48 Percentage of patients |
| Non-DS HR B-ALL Arm B | 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 | 92.33 Percentage of patients |
Comparison: To compare the DFS of the randomized patients on HR B-ALL Arm A vs Arm B. With a total of 1800 patients accrued over 5 years with minimum follow up of 2 years, randomized 1:1 to the 2 arms, we will be able to detect an improvement in 5-year DFS from 90% to 94 (HR=0.5873) between IT MTX and ITT based regimens (2-sided log rank test, alpha=5%), with 84.2% power.p-value: 0.89395% CI: [0.74, 1.413]Log Rank
Primary
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)
(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%.
Time frame: At 4 years
Population: Non-DS VHR B-ALL patients with post induction therapies (includes patients from AALL0932). Inevaluable patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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) | 77.11 Percentage of patients |
| Non-DS HR B-ALL Arm B | 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) | 76.75 Percentage of patients |
Comparison: To compare the DFS of the randomized patients on Control Arm vs. Experimental Arm 1. This study design will have 86.8% power (1-sided log rank test, adjusted alpha=0.025 for multiple comparisons) to detect an improvement in 4-year DFS from 70% to 79% (HR=0.661) between the control arm and the experimental arm.p-value: 0.556Log Rank
Secondary
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
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.
Time frame: At 5 years
Population: Patients with DS and HR B-ALL treated with modified Induction and post induction therapy with MBFM-IMIDM. Inevaluable patients were excluded from analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 71.78 Percentage of patients |
Secondary
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
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.
Time frame: Up to 4 years
Population: Patients with Ph-like B-ALL and a predicted tyrosine kinase inhibitor (TKI)-sensitive mutation treated with dasatinib plus MBFM-IMHDM
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 55.56 Percentage of patients |
Secondary
Incidence of Osteonecrosis (ON) Defined by Magnetic Resonance (MR) Imaging in Children, Adolescents, and Young Adults 10 Years of Age and Greater
Incidence of ON among patients who have submitted MRI screening data will be estimated.
Time frame: Up to 10 years
Population: HR and VHR patients that are 10 years or older with submitted MRI screening data. It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim. Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Incidence of Osteonecrosis (ON) Defined by Magnetic Resonance (MR) Imaging in Children, Adolescents, and Young Adults 10 Years of Age and Greater | 25 Percentage of patients |
Secondary
Induction Mortality in Patients With DS and HR B-ALL Treated With Modified Induction
Percentage of deaths in induction will be calculated.
Time frame: At 1 month
Population: Patients with DS and HR B-ALL treated with modified Induction
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Induction Mortality in Patients With DS and HR B-ALL Treated With Modified Induction | 3.57 Percentage of patients |
Secondary
Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm
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.
Time frame: At 5 years
Population: Total HR B-ALL patients (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm | 96.65 Percentage of patients |
| Non-DS HR B-ALL Arm B | Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm | 97.05 Percentage of patients |
| Non-DS HR B-ALL Arm B | Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm | 96.25 Percentage of patients |
Secondary
Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm.
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.
Time frame: At 4 years
Population: VHR B-ALL patients with post induction therapies (includes patients from AALL0932). Experimental Arm 2 was closed early in the study due to excessive toxicities. The objectives and study design for VHR patients was modified to be limited to the two arms (Control vs Experimental Arm 1). Inevaluable and ineligible patients were also excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm. | 87.87 Percentage of patients |
| Non-DS HR B-ALL Arm B | Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm. | 87.31 Percentage of patients |
| Non-DS HR B-ALL Arm B | Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm. | 88.50 Percentage of patients |
Secondary
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
The percentage of patients with abnormal results (Z ≤ -1.5) in executive function measured by CogState will be estimated.
Time frame: Up to 10 years
Population: It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim . Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 5.28 percentage of participants |
Secondary
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
The percentage of patients with abnormal results (Z ≤ -1.5) in processing speed measured by CogState will be estimated.
Time frame: Up to 10 years
Population: It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim. Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 17.40 percentage of participants |
Secondary
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
The percentage of patients with abnormal results (Z ≤ -1.5) in visual attention measured by CogState will be estimated.
Time frame: Up to 10 years
Population: It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim. Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 17.49 percentage of participants |
Secondary
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
The percentage of patients with abnormal results (Z ≤ -1.5) in visual learning measured by CogState will be estimated.
Time frame: Up to 10 years
Population: It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim. Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 8.47 percentage of participants |
Secondary
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
The percentage of patients with abnormal results (Z ≤ -1.5) in working memory measured by CogState will be estimated.
Time frame: Up to 10 years
Population: It was pre-specified in Study Protocol to collect and report data as a single Arm/Group for patients who met eligibility criteria for this correlative aim. Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | 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 | 19.11 percentage of participants |
Secondary
Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL
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)
Time frame: Up to 10 years
Population: (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL | 66.27 Percentage of patients |
| Non-DS HR B-ALL Arm B | Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL | 73.16 Percentage of patients |
Secondary
Toxicity and Tolerability of MBFM-interim Maintenance Intermediate Dose Methotrexate (IMIDM) in Children With Down Syndrome
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.
Time frame: Up to 10 years
Population: DS patients received MBFM-interim maintenance intermediate dose methotrexate (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Toxicity and Tolerability of MBFM-interim Maintenance Intermediate Dose Methotrexate (IMIDM) in Children With Down Syndrome | 50 Percentage of patients |
Secondary
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) 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.
Time frame: Up to 10 years
Population: Patients risk assigned as HR B-ALL and randomized to the two post induction therapies (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Non-DS HR B-ALL Arm A | Toxicity and Tolerability of Post-induction Age-adjusted ITT Compared to Age-adjusted IT MTX in Children With HR B-ALL | 62.44 Percentage of patients |
| Non-DS HR B-ALL Arm B | Toxicity and Tolerability of Post-induction Age-adjusted ITT Compared to Age-adjusted IT MTX in Children With HR B-ALL | 63.39 Percentage of patients |
Other Pre-specified
The Reduction in MRD From End-Induction (EOI) to End-Consolidation (EOC) for Children, Adolescents, and Young Adults With VHR B-ALL Receiving Experimental Arms 1 Compared to the Control Arm
(Closed effective Amendment 6) Mean change in MRD from EOI to EOC will be calculated for VHR patients on Experimental Arm 1 and Control Arm.
Time frame: Up to 90 days