Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

Incidence of dose-limiting toxicities (DLTs) (safety phase)

For the safety phase, DLTs of the induction + venetoclax cycle of KMT2A-rearranged (R) patients will be assessed.

Incidence of DLTs (expansion phase)

For the expansion phase, DLTs of Arm B will be assessed and monitored for the cycles that contain venetoclax (induction, consolidation, and MARMA cycles of Arm B).

Minimal residual disease (MRD)-negative remission rate

The end of induction MRD-negative remission rate will be compared between Arm A and Arm B. MRD negativity is defined as achievement of complete remission and MRD \< 0.01% by flow cytometry. The MRD-negative remission rate at the end of induction between Arm A and Arm B will be compared using a one-sided Z test of proportions with Type I error of 0.15.

MRD-negative remission rate

MRD-negative remission rate at the end of induction and the standard error or 95% confidence interval will be estimated among infants with KMT2A-R acute lymphoblastic leukemia (ALL) treated with venetoclax at the RP2D. This analysis will include eligible KMT2A-R patients treated with venetoclax at the RP2D in the safety phase, as well as patients randomized to Arm B and treated with venetoclax in the expansion phase. MRD negativity is defined as \< 0.01% by flow cytometry.

Event free survival (EFS) rates of infants with KMT2A-R ALL

The EFS rates from date of randomization of Arm B will be compared to Arm A. Comparison of EFS rates between Arm A and Arm B will be based on a one-sided logrank test with Type I error of 0.15. In addition, EFS rates will be estimated using the Kaplan-Meier method with Greenwood standard errors. Hazard ratios and confidence intervals will be estimated based on Cox regression models as appropriate. Cumulative incidence rates of each EFS event type (relapse, treatment failure, secondary malignant neoplasm and death) will also be estimated and presented with cumulative incidence curves and compared between arms as appropriate.

3-year EFS of infants with KMT2A-R ALL

For Arm A, the 3-year EFS rate (representing a plateau rate based on the shape of EFS curves of historical data in this patient population) from the date of randomization will be compared to the stable historical 3-year EFS rate of 35% observed in AALL0631 and other international trials.

Proportion of KMT2A-germline (G) patients in Arm C who are able to receive all treatment cycles before maintenance

The feasibility of treating KMT2A-G patients with a high-risk ALL backbone and two cycles of blinatumomab (Arm C) will be assessed. Arm C treatment will be considered feasible for KMT2A-G patients if the proportion of KMT2A-G patients in Arm C who are able to receive all treatment cycles before maintenance (i.e., up to interim maintenance 2) is more than 76.8%. The proportion of patients receiving all cycles before Maintenance will be compared to 76.8% with a one-sample exact test of proportion with Type I error of 0.15.

3-year EFS of infants with KMT2A-R ALL treated on Arm B

Arm B, the 3-year EFS rate from date of randomization will be estimated, and will be compared to Arm A as described in the secondary objective, and to historical 3-year EFS. Comparison to historical rate will be based on a one-sample test of proportion with one-sided Type I error of 0.15.

Use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry

Pre-treatment HTS clonality and HTS MRD tracking results will be collected and compared to the required centralized flow cytometry-based MRD data to evaluate the feasibility and prognostic utility of HTS MRD evaluation in the infant ALL population.

PK of calaspargase pegol in infants with ALL

PK of calaspargase pegol will be analyzed by monitoring asparaginase activity levels. Once a PK model is developed for calaspargase pegol, standard regression analysis will be used to describe the relationship between drug exposure and asparaginase activity. Additionally, asparaginase-associated toxicities will be described for the entire study population and correlated with activity levels when possible. The result of this analysis will be an estimation of potential optimal exposure expected to yield the maximum efficacy while limiting toxicity. These analyses will be exploratory and descriptive.

Incidence of CD19-negative relapse and myeloid switch relapse with protocol therapy

For patients who experience relapse, will collect information regarding the immunophenotype of the leukemic blasts at time of relapse. Will report on the rate of CD19 negative relapse as well as myeloid switch relapse for all patients enrolled on study. This analysis will be exploratory and descriptive.