There is one clinical trial.
The overarching objective of this study is to use novel precision medicine strategies based on inherited and leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy). Primary Therapeutic Objectives: - To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) ≥ 5% at Day 15 or ≥1% at the end of Remission Induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cell / blinatumomab for refractory B-ALL, and the proteasome inhibitor bortezomib for those lacking targetable lesions. - To improve overall treatment outcome of T-ALL by optimizing pegaspargase and cyclophosphamide treatment and by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction. - To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early Remission Induction therapy decreases allergic reactions to pegaspargase. - To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype. Secondary Therapeutic Objectives: - To estimate the event-free survival and overall survival of children with ALL and LLy. - To examine whether the administration of two doses of rituximab can lower the minimal residual disease (MRD) levels. - To determine the tolerability of combination therapy with ruxolitinib. Biological Objectives: - To use data from clinical genomic sequencing and sequencing-based MRD in bone marrow, blood and cerebrospinal fluid. - To assess clonal diversity and evolution of pre-leukemic and leukemic populations. - To identify germline or somatic genomic variants associated with drug resistance of ALL cells. - To compare drug sensitivity of ALL cells from diagnosis to relapse. Supportive Care Objectives - To conduct serial neurocognitive monitoring of patients and to evaluate the benefits of a computer-based cognitive intervention. - To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. Exploratory Objectives: - To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome. - To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome. - To establish xenografts of representative subtypes of ALL. - To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics.
ALL patients with the CEP72 rs904627T/T genotype (16% of patients) will be randomized (unblinded design except those who evaluate neuropathies) to receive either 1.5 mg/m^2 or 1 mg/m^2 of vincristine after Continuation Week 1. Patients with either a CEP72 rs904627 C/T or C/C genotype (84% of patients) will be randomized to receive vincristine and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment.
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
Description: This study will use un-blinded stratified randomization, and analysis be reported by group. All B-ALL patients will be randomized before Day 3 of Remission Induction, at a 1:1 ratio into two groups, in one of which rituximab will be administered, and no rituximab in the other. The randomization will be stratified by diagnostic WBC levels (<50 x 10^9/L vs. ≥50 x 10^9/L) and CD20 expression (positive vs. negative) because these are factors known to affect rituximab effect. In the final analysis the investigators will also compare the allergic reaction rate between the two groups by logistic regression, accounting for potential confounding factors, such as Day 15 MRD status (>5% vs. not), risk and subtypes that affect treatment intensityMeasure: Rate of allergic reactions to pegaspargase in B-ALL patients Time: At 6 months after the last randomized patient completes Reinduction II
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).
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
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
Description: 5-year EFS: Although the lymphoblastic lymphoma (LLy) patients will receive essentially the same treatment as the ALL patients, these two cohorts of patients will be analyzed and reported separately. 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
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
Description: The 85th percentile of the MRD distribution in the rituximab group vs. that in the control group will be compared by the percentile ratio method.Measure: Comparison of minimum residual disease (MRD) in B-ALL patients Time: Day 15 through Day 42 during Remission induction therapy (At 6 months after enrollment of the last patient)
Description: Any participant who experiences a DLT at any time during Early Intensification therapy is considered evaluable for toxicity. For dose escalation phase, Early Intensification therapy is 28 days (49 days for evaluation of hematologic toxicity).Measure: Number of patients with dose-limiting toxicities (DLT) of ruxolitinib in patients with early T cell precursor leukemia Time: Through up to 49 days after start of Early Intensification therapy of last evaluable patient
Description: The MTD is empirically defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT. The rolling-6 design will be used to determine dose escalation and reduction within each stratum separately.Measure: Maximum tolerated dose (MTD) of ruxolitinib Time: Through up to 49 days after start of Early Intensification therapy of last evaluable patient
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)
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
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)
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
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)
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
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 diagnosisMeasure: 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
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)
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)
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 analysisMeasure: 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)
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
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
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
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
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)