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Patients receive induction, consolidation, interim maintenance, delayed intensification, interim maintenance and maintenance therapies.

See outline for details.

Patients receive induction, consolidation, interim maintenance, delayed intensification and maintenance therapies.

See outline for details.

Patients receive consolidation, interim maintenance, delayed intensification and maintenance therapies.

See outline for details.

Daunorubicin Hydrochloride

Doxorubicin Hydrochloride

Hydrocortisone Sodium Succinate

Laboratory Biomarker Analysis

Leucovorin Calcium

Radiation Therapy

Vincristine Sulfate

Michael J Burke

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.

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.

Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations

A Phase III Randomized Trial for Newly Diagnosed High Risk B-Lymphoblastic Leukemia (B-ALL) Including a Stratum Evaluating Dasatinib (NSC#732517) in Patients With Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations

(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.

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)

(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%.

(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.

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)

Percentage of deaths in induction will be calculated.

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 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.

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.

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.

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.

Incidence of ON among patients who have submitted MRI screening data will be estimated.

The percentage of patients with abnormal results (Z ≤ -1.5) in working memory measured by CogState will be estimated.

The percentage of patients with abnormal results (Z ≤ -1.5) in executive function measured by CogState will be estimated.

The percentage of patients with abnormal results (Z ≤ -1.5) in visual learning measured by CogState will be estimated.

The percentage of patients with abnormal results (Z ≤ -1.5) in processing speed measured by CogState will be estimated.

The percentage of patients with abnormal results (Z ≤ -1.5) in visual attention measured by CogState will be estimated.

National Cancer Institute (NCI)

Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.

Patients without Down syndrome receive induction chemotherapy

Non-DS B-ALL

Patients with Down syndrome receive induction chemotherapy

DS B-ALL

Patients from AALL0932 enroll on this study at the end of Induction

Patients Transferred From AALL0932

Non-DS HR patients receive post induction age-adjusted intrathecal (IT) methotrexate (MTX)

Non-DS HR B-ALL Arm A

Non-DS HR patients receive post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone

Non-DS HR B-ALL Arm B

Non-DS HR patients transferred from AALL0932 receive post induction age-adjusted intrathecal (IT) methotrexate (MTX)

Non-DS HR B-ALL From AALL0932 Arm A

Non-DS HR patients transferred from AALL0932 receive post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone

Non-DS HR B-ALL From AALL0932 Arm B

Non-DS VHR patients receive a modified MBFM-IMHDM regimen that contains a second IM (Control Arm)

Non-DS VHR B-ALL Control Arm

Non-DS VHR patients receive cyclophosphamide + etoposide containing regimen (Experimental Arm 1)

Non-DS VHR B-ALL Experimental Arm 1

Non-DS VHR patients receive clofarabine+ cyclophosphamide + etoposide containing regimen (Experimental Arm 2)

Non-DS VHR B-ALL Experimental Arm 2

Non-DS VHR patients transferred from AALL0932 receive a modified MBFM-IMHDM regimen that contains a second IM (Control Arm)

Non-DS VHR B-ALL From AALL0932 Control Arm

Non-DS VHR patients transferred from AALL0932 receive cyclophosphamide + etoposide containing regimen (Experimental Arm 1)

Non-DS HR B-ALL From AALL0932 Experimental Arm 1

Non-DS VHR patients transferred from AALL0932 receive clofarabine+ cyclophosphamide + etoposide containing regimen (Experimental Arm 2)

Non-DS HR B-ALL From AALL0932 Experimental Arm 2

Patients with Philadelphia chromosome (Ph)-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus MBFM-IMHDM

Non-DS Ph-like Pred TKI Sensitive Kinase Dasatinib Arm

Down Syndrome HR patients receive post-Induction therapy regimen

DS HR B-ALL

Down Syndrome HR patients transferred from AALL0932 receive post-Induction therapy regimen

DS HR B-ALL From AALL0932

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Pre-specified in protocol to collect baseline data by induction arms (Non-DS B-ALL and DS B-ALL) and AALL0932 participants as a single arm/group.

Results Reporting Coordinator

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.

Non-DS HR B-ALL patients with post induction therapies (includes patients from AALL0932). Inevaluable patients were excluded from analysis.

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

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.

Non-DS VHR B-ALL Exp Arm1

Non-DS VHR B-ALL patients with post induction therapies (includes patients from AALL0932). Inevaluable patients were excluded from analysis.

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)

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.

Toxicity and Tolerability of Post-induction Age-adjusted ITT Compared to Age-adjusted IT MTX in Children With HR B-ALL

(includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.

Toxicity and Tolerability of Experimental Arm 1 and Control Arm in Patients With VHR B-ALL

DS HR B-ALL (Induction)

Patients with DS and HR B-ALL treated with modified Induction

Induction Mortality in Patients With DS and HR B-ALL Treated With Modified Induction

Patients with DS and HR B-ALL treated with modified Induction and post induction therapy with MBFM-IMIDM. Inevaluable patients were excluded from analysis

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

Patients with Ph-like B-ALL and a predicted tyrosine kinase inhibitor (TKI)-sensitive mutation treated with dasatinib plus MBFM-IMHDM

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

DS patients received MBFM-interim maintenance intermediate dose methotrexate (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.

Toxicity and Tolerability of MBFM-interim Maintenance Intermediate Dose Methotrexate (IMIDM) in Children With Down Syndrome

Non-DS HR B-ALL Overall

Total HR B-ALL patients (includes patients from AALL0932). Inevaluable and ineligible patients were excluded from analysis.

Overall Survival (OS) Rate for HR B-ALL Patients, Overall and by Randomized Arm

Non-DS VHR B-ALL Overall

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.

Overall Survival (OS) Rate for VHR B-ALL Patients, Overall and by Randomized Arm.

HR and VHR B-ALL patients, 10 years or older with submitted MRI screening data

HR and VHR B-ALL Patients (10 Years or Older)

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.

Incidence of Osteonecrosis (ON) Defined by Magnetic Resonance (MR) Imaging in Children, Adolescents, and Young Adults 10 Years of Age and Greater

HR and VHR B-ALL patients, age 6 to \<13 years who consented to participate in the CogState assessments.

HR and VHR B-ALL Patients (6 to <13 Years Old)

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.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations	NCT02883049	B Acute Lymphob... B Acute Lymphob... Central Nervous... Testicular Leuk...	Clofarabine Cyclophosphamid... Cytarabine Dasatinib Daunorubicin Hy... Dexamethasone Doxorubicin Hyd... Etoposide Hydrocortisone ... Laboratory Biom... Leucovorin Calc... Mercaptopurine Methotrexate Pegaspargase Prednisone Radiation Thera... Thioguanine Vincristine Sul...	1 Year - 31 Years	National Cancer Institute (NCI)
Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations	NCT02883049	B Acute Lymphob... B Acute Lymphob... Central Nervous... Testicular Leuk...	Clofarabine Cyclophosphamid... Cytarabine Dasatinib Daunorubicin Hy... Dexamethasone Doxorubicin Hyd... Etoposide Hydrocortisone ... Laboratory Biom... Leucovorin Calc... Mercaptopurine Methotrexate Pegaspargase Prednisone Radiation Thera... Thioguanine Vincristine Sul...	1 Year - 31 Years	National Cancer Institute (NCI)
Inotuzumab Ozogamicin and Post-Induction Chemotherapy in Treating Patients With High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and B-LLy	NCT03959085	B Acute Lymphob... B Lymphoblastic... Central Nervous... Mixed Phenotype... Testicular Leuk...	Biospecimen Col... Bone Marrow Asp... Bone Marrow Bio... Bone Scan Calaspargase Pe... Computed Tomogr... Cyclophosphamid... Cytarabine Daunorubicin Hy... Dexamethasone Doxorubicin Hyd... Inotuzumab Ozog... Leucovorin Calc... Magnetic Resona... Mercaptopurine Methotrexate Pegaspargase Positron Emissi... Prednisolone Questionnaire A... Radiation Thera... Radiation Thera... Thioguanine Vincristine Sul...	1 Year - 25 Years	Children's Oncology Group

Spots Global Cancer Trial Database for central nervous system leukemia