This phase II trial studies the effect of nivolumab in combination with blinatumomab compared to blinatumomab alone in treating patients with B-cell acute lymphoblastic leukemia (B-ALL) that has come back (relapsed). Down syndrome patients with relapsed B-ALL are included in this study. Blinatumomab is an antibody, which is a protein that identifies and targets specific molecules in the body. Blinatumomab searches for and attaches itself to the cancer cell. Once attached, an immune response occurs which may kill the cancer cell. Nivolumab is a medicine that may boost a patient's immune system. Giving nivolumab in combination with blinatumomab may cause the cancer to stop growing for a period of time, and for some patients, it may lessen the symptoms, such as pain, that are caused by the cancer.
Patients must be >= 1 and < 31 years at time of enrollment
Isolated bone marrow relapse
Isolated central nervous system (CNS) (excluding known optic nerve/retinal and CNS chloromas) and/or testicular relapse
Combined bone marrow with extramedullary relapse in the CNS (excluding known optic nerve/retinal and CNS chloromas) and/or testes
Patients with B-lymphoblastic lymphoma (B-LLy)
Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia
Patients with Philadelphia chromosome positive (Ph+) B-ALL or ABL class Ph-like B-ALL (i.e. rearrangements involving ABL1, ABL2, CSF1R or PDGFRB and predicted to be sensitive to imatinib or dasatinib)
Patients with mixed phenotype acute leukemia (MPAL)
Parallel
3-Dimensional Conformal Radiation Therapy
RadiationUndergo 3D-CRT
Asparaginase Erwinia chrysanthemi
DrugGiven IM
Biospecimen Collection
Procedure/SurgeryUndergo blood, urine and cerebrospinal fluid collection
Blinatumomab
Biological/VaccineGiven IV
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow biopsy
Calaspargase Pegol
DrugGiven IV
Cytarabine
DrugGiven IT
Dexamethasone
DrugGiven PO or IV
Hydrocortisone Sodium Succinate
DrugGiven IT
Lumbar Puncture
Procedure/SurgeryUndergo lumbar puncture
Mercaptopurine
DrugGiven PO
Methotrexate
DrugGiven IT, PO, and IV
Nivolumab
Biological/VaccineGiven IV
Pegaspargase
DrugGiven IM or IV
Vincristine Sulfate
DrugGiven IV push or via infusion
9
Treatment groupsSee each treatment group below.
Minimal residual disease (MRD) negative second remission (Rem-2) rate with blinatumomab vs with blinatumomab + nivolumab (Group 1)
MRD negative Rem-2 be defined as Rem-2 (i.e., achievement of MRD \< 1% blasts by flow cytometry and resolution of extramedullary disease (for CNS disease, requires CNS 1) ) and bone marrow with MRD \< 0.01% by flow cytometry. MRD negative Rem-2 rate between Arm A vs Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.10. Interim analysis will be conducted to monitor for futility. The futility boundaries are based on testing the alternative hypothesis at the 0.067 level.
Event-free survival post-reinduction (EFS PR) (Group 3)
Comparison of EFS post reinduction between Arm E versus Arm F will be based on a one-sided two-sample logrank test with Type I error of 0.15, to be conducted 3 years after completion of enrollment of Group 3. Interim analysis will be conducted to monitor for futility. The futility monitoring will be based on testing the alternative hypothesis at the 0.092 level. This alpha level corresponds to that which would cause futility stopping if the one-sided two-sample logrank test shows evidence of a hazard ratio \> 1.0 when half of the expected events are observed.
EFS PR (Group 4)
Comparison of EFS post reinduction between Arm H versus Arm I will be based on a one-sided two-sample logrank test with Type I error of 0.10, to be conducted 3 years after completion of enrollment of Group 3. Interim analysis will be conducted to monitor for futility. The futility monitoring will be based on testing the alternative hypothesis at the 0.092 level. This alpha level corresponds to that which would cause futility stopping if the one-sided two-sample logrank test shows evidence of a hazard ratio \> 1.0 when half of the expected events are observed.
Dose-limiting toxicity
Will be assessed using the Common Terminology Criteria for Adverse Events version 5.0.
EFS PR (Group 4)
Comparison of EFS post-reinduction between Arm C versus Arm D will be based on a one-sided two-sample logrank test with type I error of 0.15, to be conducted 2 years after completion of enrollment of Group 2. The futility monitoring will be based on testing the alternative hypothesis at the 0.092 level.
Event-free survival (Group 1)
EFS will be compared between Arm A and Arm B, and to similar patients treated on AALL1331. These analyses will be performed using logrank tests, semi-parametric or parametric survival analysis methods, as appropriate.
Event free survival (Group 4)
EFS of Arm H and Arm I will be compared to similar patients treated on AALL1331. These analyses will be performed using logrank tests, semi-parametric or parametric survival analysis methods, as appropriate. Cumulative incidence rates of each EFS event type will also be estimated and presented with cumulative incidence curves, and be compared between groups as appropriate.
Incidence of adverse events in Arm A or Arm B
The toxicities as defined by grade 3 or greater reported adverse events during the first cycle of blinatumomab or blinatumomab/nivolumab will be compared to similar patients treated with Block 1 of cytotoxic chemotherapy on AALL1331 using two-sample test of proportions.
Incidence of adverse events in Arm H or Arm I
The toxicities as defined by grade 3 or greater reported adverse events during the first cycle of blinatumomab or blinatumomab/nivolumab will be compared to similar patients treated with Block 1 of cytotoxic chemotherapy on AALL1331 using two-sample test of proportions.
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