This pilot trial assesses the effect of the combination of blinatumomab with dasatinib or imatinib and standard chemotherapy for treating patients with Philadelphia chromosome positive (Ph+) or ABL-class Philadelphia chromosome-like (Ph-like) B-Cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a bispecific antibody that binds to two different proteins-one on the surface of cancer cells and one on the surface of cells in the immune system. An antibody is a protein made by the immune system to help fight infections and other harmful processes/cells/molecules. Blinatumomab may bind to the cancer cell and a T cell (which plays a key role in the immune system's fighting response) at the same time. Blinatumomab may strengthen the immune system's ability to fight cancer cells by activating the body's own immune cells to destroy the tumor. Dasatinib and imatinib are in a class of medications called tyrosine kinase inhibitors. They work by blocking the action of an abnormal protein that signals cancer cells to multiply, which may help keep cancer cells from growing. Giving blinatumomab and dasatinib or imatinib in combination with standard chemotherapy may work better in treating patients with Ph+ or Ph-like ABL-class B-ALL than dasatinib or imatinib with chemotherapy.
Patients must be > 365 days and < 18 years (for AIEOP-BFM), > 365 days and < 22 years (for Children's Oncology Group [COG]) and > 365 days and < 46 years (for ALLTogether sites) at the time of enrollment
Newly-diagnosed Ph+ or ABL-class Ph-like B-ALL. Leukemic blasts must express CD19. ABL-class fusions are defined as rearrangements involving the following genes predicted to be sensitive to imatinib and/or dasatinib: ABL1, ABL2, CSF1R, and PDGFRB
Evidence of BCR::ABL1 should be documented by a clinically-validated assay prior to study entry on day 15 from the first dose of vinCRIStine during Induction therapy. ABL-class Ph-like B-ALL gene rearrangements should be documented by a clinically-validated assay and enrolled on study by day 1 of Blinatumomab Block 1. Accepted methods of detection include fluorescence in situ hybridization (FISH) using break-apart of colocalization signal probes, singleplex or multiplex reverse-transcription polymerase chain reaction (RT-PCR), whole-transcriptome or panel-based ribonucleic acid (RNA) sequencing (e.g., Hematologic Cancer Fusion Analysis, TruSight RNA Pan-Cancer Panel or equivalent). Confirmation of 5' fusion partner genes is not required for study enrollment
Patients with Ph+ B-ALL must have previously started Induction therapy, which includes vinCRIStine, a corticosteroid, pegaspargase or calaspargase pegol, with or without anthracycline, and/or other standard cytotoxic chemotherapy
Known history of chronic myeloid leukemia (CML)
ABL-class Ph-like B-ALL who are CNS2 or CNS3 at end of Induction phase
ALL developing after a previous cancer treated with cytotoxic chemotherapy
Active, uncontrolled infection or active systemic illness that requires ongoing vasopressor support or mechanical ventilation
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood and CSF sample collection
Blinatumomab
Biological/VaccineReceive IV
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Calaspargase Pegol
DrugReceive IV
Cyclophosphamide
DrugReceive IV
Cytarabine
DrugReceive IV or subcutaneously
Dasatinib
DrugReceive PO
Daunorubicin
DrugReceive IV
Doxorubicin
DrugReceive IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Imatinib
DrugGiven PO
Leucovorin
DrugReceive PO or IV
Mercaptopurine
DrugReceive PO
Methotrexate
DrugReceive IT or IV or PO
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Pegaspargase
DrugReceive IV or intramuscularly
Prednisolone
DrugReceive PO
Prednisone
DrugReceive PO
Radiation Therapy
RadiationUndergo radiation therapy
Thioguanine
DrugReceive PO
Vincristine
DrugReceive IV
Philadelphia chromosome-positive (Ph+) (BCR::ABL1-rearranged) 3-year event free survival (EFS)
Will be assessed in children, adolescents, and young adults \<25 years old with newly-diagnosed Ph+ (BCR::ABL1-rearranged) B acute lymphoblastic leukemia (B-ALL) who are treated with a modified Berlin-Frankfurt-Münster (mBFM) chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous dasatinib. Will be estimated using the Kaplan-Meier method with standard errors of Peto.
ABL-class Ph-like B-ALL 3-year event free survival (EFS)
Will be assessed in children, adolescents, and young adults \<25 years old with newly-diagnosed ABL-class Ph-like B-ALL who are treated with a modified BFM chemotherapy backbone that incorporates three cycles of blinatumomab without traditional consolidation chemotherapy in combination with continuous imatinib for those with PDGFRB gene fusions or dasatinib for those without PDGFRB gene fusions. Will be estimated using the Kaplan-Meier method with standard errors of Peto.
Incidence of adverse events
Will assess the safety and toxicity profile (infections, mucositis, neurotoxicity, cytokine release syndrome, hypogammaglobulinemia, therapy delays \> 14 days, and treatment-related mortality) for patients with Ph+ or ABL-class Ph-like B-ALL treated on this novel chemo-immunotherapy backbone with continuous tyrosine kinase inhibitor (TKI). Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.
3-year overall survival (OS)
Will be assessed in patients with Ph+ and ABL-class Ph-like B-ALL, respectively. Will be estimated using the Kaplan-Meier method with standard errors of Peto.
3-year EFS
Will be estimated using the Kaplan-Meier method with standard errors of Peto.
3-year disease free survival
Will be estimated using the Kaplan-Meier method with standard errors of Peto.
Cumulative incidence rates of relapse
Will be estimated using Gray's method.
Rates of end of induction (EOI)/timepoint 1 (TP1) bone marrow MRD negativity with the introduction of dasatinib
Defined as \<1x10-4 or \<0.01% with the introduction of the relevant TKI during Induction for patients with Ph+ B-ALL.
Outcomes of patients with Ph+ and Ph-like ABL-class B-ALL who are removed from protocol therapy due to consolidation failure
Will be collected and described. A secondary analysis will also be conducted, examining the EFS of patients in both arms of the randomization using conventional definition of consolidation failure (EOC/TP2 MRD ≥ 1%).
Percentage of patients with Ph+ and ABL-class Ph-like B-ALL who continue TKI beyond protocol-prescribed therapy and their outcomes
Will be collected and described.
Outcomes for patients with Ph+ and ABL-class Ph-like B-ALL who continue TKI beyond protocol-prescribed therapy
EFS will be estimated at 3 years.
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