Perlmutter Cancer Center

While outcomes in Standard Risk (SR) B-lymphoblastic leukemia (B-ALL) have improved significantly, this population still accounts for approximately half of the overall burden of relapse among children with ALL. Despite contemporary intensive chemotherapy, the outcomes for children with relapsed ALL remain dismal, with 5-year overall survival (OS) of approximately 38%. Interventions that further reduce the number of SR ALL relapses will therefore significantly improve the long-term survival of the overall ALL population. AALL1731 is a group-wide risk-stratified trial for children with newly diagnosed B-ALL and localized B-lymphoblastic lymphoma (B-LLy) that will test if the addition of blinatumomab to standard chemotherapy in patients with NCI SR B-ALL at highest risk for relapse will improve disease-free survival (DFS). Risk stratification will be determined by traditional prognosticators (tumor genetics, extent of extramedullary involvement, early response to therapy as determined by flow cytometry) combined with the new DNA-based MRD detection technology of high throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH). A subset of NCI SR B-ALL children with outstanding outcomes (SR-Favorable) will be identified in whom no new randomized intervention will be tested. Similarly, patients with localized (Murphy stage I/II) B-LLy will receive non-randomized standard risk ALL therapy. NCI SR B-ALL patients without specific adverse clinical features (CNS3, testicular leukemia) and a positive end of Induction (EOI) bone marrow MRD within the context of a genotype-specific threshold will be classified as Standard Risk-Average (SR-Avg) post-Induction. EOI MRD detection by HTS will identify an additional subgroup of these patients with outstanding outcomes (EOI HTS-MRD negative) who will be treated with standard chemotherapy alone, while the remaining SR-Avg patients will be eligible for randomization to either standard chemotherapy alone or standard chemotherapy plus blinatumomab. NCI SR patients with poor prognostic features, such as unfavorable tumor genetics or EOI bone marrow MRD above a genotype specific threshold (>0.1% for those with double trisomies of chromosomes 4 and 10; =0.01% for all others), will be classified as Standard Risk-High post-Induction and will be eligible for randomization to augmented Berlin-Frankfurt-Münster (aBFM)-based chemotherapy post-Induction with or without blinatumomab. This trial will also test whether patients can be treated with a uniform duration of therapy (2 years from the start of Interim Maintenance 1) regardless of sex, substantially reducing the burden of therapy for males. We will also investigate the role of immunotherapy in children with Down Syndrome (DS) and B-ALL, a population traditionally excluded from studies of novel agents, and for which intensification of standard cytotoxic chemotherapy is not feasible due to their significantly increased risk of non-relapse morbidity and mortality. Patients with DS and B-ALL with high-risk features (DS-High) will be non-randomly assigned to receive blinatumomab added to a chemotherapy backbone that omits intensive elements of therapy. Patients with DS lacking high-risk features will be risk stratified in the same fashion as non-DS NCI SR B-ALL patients, including eligibility for randomization to chemotherapy with or without blinatumomab. DS patients with localized B-LLy are eligible for AALL1731 and will non-randomly be assigned to receive standard risk chemotherapy. AALL1731 also includes studies to identify the effects of household material hardship (HMH) on neurocognitive functioning during treatment, determine the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms, and explore new applications of the HTS-MRD assay in B-ALL. Additional correlative aims will explore the impact of ALL therapy and its effects on neurocognitive, functional and quality of life outcomes in children with DS, and will identify immune defects underlying the high rates of life-threatening infectious toxicities in patients with DS. This trial will also define the prevalence of minimal marrow disease (MMD) in B-LLy and correlate MMD at diagnosis with outcomes.