Primary Outcomes

Description: 5-year EFS: Kaplan-Meier estimates of EFS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.

Measure: Event-free survival of ALL patients (EFS)

Time: At 3.5 years after enrollment of the last participant

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Description: This will be a single-blind, stratified block randomized experiment. Although the investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment, treating clinicians and pharmacy staff are not. Patients will be randomized at a 1:1 ratio into two treatment groups: 1.5 mg/m^2 vs. 1 mg/m^2 vincristine (VCR) dose. Randomization will be stratified by two factors known to significantly affect neuropathy during the Continuation phase, namely, Grade 2 or higher neuropathy prior to Continuation (none, 1 episode, 2 or more episodes) and race (black, others). The proportion of patients who develop two or more episodes of Grade 2 or higher neuropathy during Continuation Treatment will be compared between the two VCR dose groups, using a Z-test for two sample proportions.

Measure: Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation

Time: At 6 months after the last randomized patient completes Continuation Treatment (Week 120).

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Description: This will be a single blind stratified block randomized experiment. The investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment. Treating clinicians and pharmacy staff will not be blinded. Patients will be randomized at a 1:1 ratio into two treatment groups at Week 49 of Continuation therapy: to vincristine + dexamethasone (VCR+DEX) pulses or to 6-mercaptopurine + methotrexate (6MP+MTX). The primary analysis will compare the cumulative incidence of the first episode of Grade 2 or higher neuropathy or neuropathic pain (the end point) by stratified Gray's test. Adverse events other than the endpoint rendering a patient drop out after Continuation Week 49 are regarded as competing events.

Measure: Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype

Time: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy

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Secondary Outcomes

Description: Kaplan-Meier estimates of OS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.

Measure: 5-year overall survival (OS) of ALL patients compared to historical controls

Time: 3.5 years after enrollment of the last patient

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Description: 5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.

Measure: EFS of LLy patients

Time: 3.5 years after enrollment of the last patient

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Description: Kaplan-Meier estimates of OS curve in patients with LLy will be computed.

Measure: 5-year OS of LLy patients

Time: 3.5 years after enrollment of the last patient

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Description: For this comparison, 40 patients will be accrued for Day 8, Day 15 and Day 42 MRD, and primarily assess the correlation and concordance between the two methods at these time points if sufficient cells are available, and secondarily analyze for Day 22 and MRD levels obtained after remission induction.

Measure: Comparison of MRD measurements between flow cytometry and sequencing

Time: From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)

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Description: The investigators will analyze the association of next-generation sequencing-determined MRD level (as a continuous variable) with the risk of relapses in bone marrow and possibly other sites (bone marrow or combined relapses). Fine-Gray regression model will be applied to estimate the hazard ratio of relapse as a function of the increase in MRD level.

Measure: Log hazard ratio of the association of low level of MRD and treatment outcome

Time: 3.5 years after enrollment of the last patient

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Description: Parametric (linear) or non-parametric (if necessary) regression models will be fitted to analyze the relationship between the MRD levels in peripheral blood by sequencing methods and MRD levels in bone marrow (by sequencing or flow cytometry). The peripheral blood MRD level corresponding to 0.01% in bone marrow is then obtained by solving the (regression) equation for the peripheral blood MRD level.

Measure: Comparison of bone marrow and peripheral blood MRD

Time: From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)

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Description: Traditional CNS2 patients with negative TdT and negative next-generation sequencing results will receive CNS1 therapy on TOT17. Risk of isolated CNS relapse in this subset of patients will be compared to that in the CNS2 patients treated on TOTXV and TOTXVI, using stratified (by protocol) Gray's test.

Measure: Isolated CNS relapse in CNS1b patients

Time: 3.5 years after enrollment of the last patient

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Description: In this study the investigators will use single-cell, cell-free, and bulk population sequencing to monitor somatic mutations in peripheral blood as patients undergo treatment, which will be correlated with clonal diversity at diagnosis, in vitro chemotherapy resistance, MRD, and patient outcome.

Measure: Level of clonal diversity and rise of leukemic clones during treatment

Time: From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)

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Description: The number and type of germline or somatic genomic variants associated with drug resistance of ALL cells to conventional and newer targeted anti-leukemic agents in a non-clinical, research setting will be given.

Measure: Number and type of germline or somatic genomic variants associated with drug resistance

Time: 3.5 years after enrollment of the last participant

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Description: To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis

Measure: Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo

Time: 5 years after enrollment of the last participant

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Description: A single-blind (psychological examiner), randomized, controlled, group sequential design will be used to evaluate the impact of computer-based cognitive intervention (Cogmed) administered during therapy, relative to the end of therapy, on neurocognitive outcomes. Patients will be randomized according to the procedure outlined in the protocol. Randomization will be stratified based on age (4-8; >9 years old) and treatment risk arm (low; standard/high) in order to roughly balance the groups on these factors. Patients will be randomized according to a 2:2:1 allocation (2 - On Therapy, 2 - End of Therapy, 1 - Control). The investigators will use a block-randomization scheme proposed by Zelen with a block size of 4. The change from pre to post intervention will be given.

Measure: Magnitude change in spatial span backward standard score (SSB)

Time: From continuation week 73 to 3-4 months after end of therapy (continuation week 120)

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Description: The primary outcome is BMD in the tibia, measured at baseline and the end of intervention. The changes from baseline to the end of the intervention between the treatment and control groups will be compared using a two-sample t-test, or Wilcoxon rank sum test if normality does not hold. Furthermore, the linear mixed model will be used to analyze the time effect, group effect and their interaction, adjusting for the factors used for stratification (gender, pubertal status, and risk group) and possible confounders (i.e., hormonal function and vitamin D metabolism, physical activity, etc.).

Measure: Change in bone mineral density (BMD) in the tibia

Time: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)

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Description: Linear mixed models will be used to evaluate this outcome. If normality does not hold, the investigators will consider transforming the outcome measures for analysis. A linear mixed effects approach will also be used to allow for potential random missingness to make use of all available data in analysis

Measure: Change in markers of bone turnover

Time: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)

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Other Outcomes

Description: The log odds ratio of pharmacogenetics predictors of treatment outcome will be given.

Measure: Log odds ratio of pharmacogenetic predictors of treatment outcome (host toxicity or in vivo efficacy)

Time: 5 years after enrollment of the last participant

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Description: The log odds ratio of pharmacokinetic predictors of treatment outcome will be given.

Measure: Log odds ratio of pharmacokinetic predictors of treatment outcome (host toxicity or in vivo efficacy)

Time: 5 years after enrollment of the last participant

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Description: The log odds ratio of pharmacodynamic predictors of treatment outcome will be given.

Measure: Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy)

Time: 5 years after enrollment of the last participant

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Description: A detailed assessment of thiopurine metabolism will be done and correlated with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.

Measure: Thiopurine metabolism

Time: 3.5 years after enrollment of the last participant

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Description: All enrolled participants will be eligible for this component. Descriptive statistics, such as frequency and proportion, will be summarized for breakthrough infections, antibiotic-resistant infections, febrile neutropenia episodes and adverse events. Cumulative incidence of breakthrough infection, febrile neutropenia and adverse events will also be explored, with competing risks and/or recurrent event appropriately adjusted.

Measure: Number of participants experiencing specific therapy-related infection events

Time: 1 year after completion of therapy for last enrolled patient (up to 3.5 years after enrollment)

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Description: Kaplan-Meier estimates of EFS curve in patients with MPAL will be computed.

Measure: 5-year EFS of MPAL patients

Time: 3.5 years after enrollment of the last patient

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Description: Kaplan-Meier estimates of OS curve in patients with MPAL will be computed.

Measure: 5-year OS of MPAL patients

Time: 3.5 years after enrollment of the last patient

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