Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma

  • STATUS
    Recruiting
  • End date
    Mar 31, 2028
  • participants needed
    1000
  • sponsor
    St. Jude Children's Research Hospital
Updated on 29 January 2021
cancer
remission
lymphoid leukemia
cyclophosphamide
tyrosine
lymphoma
methotrexate
cytarabine
flow cytometry
lymphoblastic lymphoma
dasatinib
vincristine
prednisone
minimal residual disease
adult t-cell leukemia/lymphoma
mercaptopurine
etoposide
daunorubicin
pegaspargase
residual tumor
clofarabine
blinatumomab
dexamethasone
intrathecal chemotherapy
consolidation therapy
doxorubicin
idarubicin
vorinostat
bortezomib
thioguanine

Summary

The overarching objective of this study is to use novel precision medicine strategies based on inherited and acquired 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 Day 22 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-acute lymphoblastic leukemia (B-ALL) or B-lymphoblastic lymphoma (B-LLy), and the proteasome inhibitor bortezomib for those lacking targetable lesions.
  • To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LLy) 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 and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD 0.01% at the end of induction.
  • 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 acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy).
  • To determine the tolerability of combination therapy with ruxolitinib and Early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD 5%, Day 42 MRD 1%, or LLy patients without complete response at the End of Induction and all patients with early T cell precursor leukemia.

Biological Objectives:

  • To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance.
  • To evaluate and implement deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid.
  • To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting.
  • To identify germline or somatic genomic variants associated with drug resistance of ALL cells o conventional and newer targeted anti-leukemic agents in a non- clinical, research setting.
  • 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.

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.
  • To use cell phenotyping and genomic approaches to characterize the non-tumor microenvironment and correlate with responses to conventional and immunotherapeutic approaches.
  • To estimate the treatment response and event-free survival and overall survival of children with mixed phenotype acute leukemia (MPAL) when ALL diagnostic and treatment approaches are used.

Description

Participants will be classified into one of three categories (low-, standard-, or high-risk) based on the presenting age, leukocyte count/lymphoma staging, presence or absence of CNS-3 status or testicular disease, immunophenotype, molecular genetics, DNA index, and early response to therapy.

Treatment will consist of three main phases: Remission Induction, Consolidation, and Continuation. Early Intensification therapy will be given prior to Consolidation to patients with provisional standard-risk or high-risk ALL/LLy or any provisional low-risk patients with Day 15 MRD 1% as well as provisional low-risk LLy patients who do not obtain complete response at the end of Induction. Patients with mixed phenotype acute leukemia (MPAL) are treated by using the same treatment stratification used in ALL (B/Myeloid [B/M] MPAL is treated as B-ALL and T/M MPAL is treated as ETP-ALL) although analysis is performed separately from ALL or LLy cohorts.

Brief outline of treatment plan:

Patients will be assigned to treatment based on risk group: Low-Risk, Standard-Risk and High-Risk and cell type (T or B cell).

Remission Induction initially consists of prednisone (28 days), vincristine (4 weekly doses), daunorubicin (1 to 3 weekly doses), and pegaspargase (2 doses). The second part (given over 2 weeks and overlapping with the last week of the first part of induction) consists of cyclophosphamide, cytarabine, and mercaptopurine combinations. Dasatinib will be added for patients with Ph+ and Ph-like ABL1-class fusions and bortezomib will be given to patients with no targetable lesions and Day 15 or Day 22 minimal residual disease (MRD) 5% on Days 29 and 32.

Early Intensification will be given prior to Consolidation to patients with provisional standard-risk or high-risk ALL/LLy or any provisional low-risk patients with Day 15 MRD 1% as well as provisional low-risk LLy patients who do not obtain complete response at the end of Induction. For patients with Ph-like ALL that is targetable with JAK inhibitor and Day 15 or Day 22 MRD level 5% or end of Remission Induction 1% as well as all patients with early T cell precursor (ETP) ALL, ruxolitinib will be used. This includes, but is not limited to CRLF2, JAK2, and EPOR rearrangements and sequence/structural changes in JAK1/2, TYK2, IL7R, and SH2B3. Ruxolitinib will be added in LLy patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib whose responses do not qualify complete response at the end of Remission Induction. Dasatinib will continue for patients with ABL-class fusions. Bortezomib will be added for patients with no targetable lesions and Day 15 or Day 22 MRD 5% or LLy patients without complete response at the End of Induction.

Consolidation Therapy will consist of high dose methotrexate (HDMTX) (every other week for 4 doses); daily mercaptopurine and IT chemotherapy on the same dates of HDMTX. Dasatinib will continue for patients with ABL-class fusions. Ruxolitinib will continue for patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD 5% or Day 42 MRD 1% (or for LLy patients who do not qualify complete response at the end of Remission Induction) and all cases with ETP ALL.

Immunotherapy: CAR T-cell therapy will be considered for High-risk B-ALL and B-LLy patients. Blinatumomab will be given to patients with Standard-risk B-ALL and B-LLy with residual disease at the end of induction and High-risk B-ALL and B-LLy patients who are not able to receive CAR T-cell therapy. Blinatumomab is also given to patients with the following genetic subtypes (BCR-ABL1, JAK-STAT activating mutation, hypodiploid, iAMP21, MEF2D, TCF3/HLF, and BCL2/MYC) or with Down syndrome, regardless of MRD level and/or Total 17 risk category.

Reintensification therapy will be offered to certain High-risk patients with persistent MRD after Immunotherapy (B-ALL and B-LLy) or Early Intensification (T-ALL and T-LLy), or those who cannot receive Immunotherapy.

Continuation Treatment will consist of 120 weeks of risk-directed therapy. Dasatinib will continue in patients with ABL1-class fusion. Ruxolitinib will continue in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD 5% or Day 42 MRD 1% (or for LLy patients who do not qualify complete response at the end of Remission Induction) and all cases with ETP ALL. T-ALL and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD 0.01% at the end of Induction will receive nelarabine. ALL/LLy 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/m2 or 1 mg/m2 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.

Patients with mixed phenotype acute leukemia (MPAL) are eligible and treatment is given by using the same treatment stratification used in ALL (B/Myeloid [B/M] MPAL is treated as B-ALL and T/M MPAL is treated as ETP ALL) although analysis is performed separately from ALL or LLy cohorts.

Details
Condition childhood ALL, Acute Lymphoblastic Lymphoma, Lymphocytic Leukemia, Acute, acute lymphoblastic leukemia, leukemia, acute lymphoblastic, acute lymphoid leukaemia, acute lymphocytic leukemia, acute lymphoblastic leukemia (all)
Treatment Rituximab, cyclophosphamide, methotrexate, cytarabine, etoposide, prednisone, Ruxolitinib, Dexamethasone, vincristine, doxorubicin, Pegaspargase, Bortezomib, Vorinostat, Mercaptopurine, Idarubicin, Clofarabine, Daunorubicin, Thioguanine, dasatinib, Blinatumomab, Nelarabine, Erwinase®
Clinical Study IdentifierNCT03117751
SponsorSt. Jude Children's Research Hospital
Last Modified on29 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Diagnosis of B- or T-ALL or LLy by immunophenotyping
LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by morphology and flow cytometry. If any of these show 25% blasts, patient will be considered to have leukemia. Patients with MPAL are eligible
Age 1-18 years (inclusive)
No prior therapy, or limited prior therapy, including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy (e.g., to the mediastinum, head and neck, orbit, etc.) and one dose of intrathecal chemotherapy
Written, informed consent and assent following Institutional Review Board (IRB), National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP) Guidelines

Exclusion Criteria

Participants who are pregnant or lactating. Males or females of reproductive potential must agree to use effective contraception for the duration of study participation
Inability or unwillingness of research participant or legal guardian/representative to give written informed consent
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