New approaches to the treatment of older adults with acute lymphoblastic leukemia

Outcomes for older adults (defined here as ≥55-65 years old) with acute lymphoblastic leukemia (ALL) are poor, with long-term survival less than 20%. Pediatric chemotherapy regimens produce long-term cure rates of 80% to 90% in children and 60% to 70% in adolescents and young adults with Ph-negative ALL, however, tolerability of intensive chemotherapy becomes problematic with advanced age due to comorbidities and reduced tolerability of chemotherapy leading to high rates of treatment-related mortality. For older adults with Ph-positive ALL, BCR-ABL1-directed tyrosine kinase inhibitors in combination with corticosteroids or chemotherapy produce deep remissions with low treatment-related toxicity but optimal postremission therapy is not known. New therapeutic approaches for older adults with ALL involve integration of the novel targeted agents including monoclonal antibody-based therapy with blinatumomab and inotuzumab ozogamicin in the frontline. Ongoing studies will ideally define optimal combinations and sequencing of novel agents with or without chemotherapy, tyrosine kinase inhibitors, and/or corticosteroids to maximize efficacy while avoiding treatment-related death. Anti-CD19 chimeric antigen receptor modified T cells are a promising modality, with high rates of remission and minimal residual disease negativity achieved in early phase trials for adults with relapsed/refractory B-cell ALL but the tolerability of chimeric antigen receptor modified T cell therapies in older adults is yet to be well defined. Advances in minimal residual disease detection have helped to effectively stratify adults in complete response in terms of relapse risk and predicted relative benefit for allogeneic hematopoietic cell transplant. For older adults with ALL in complete response at high risk for relapse for whom myeloablative conditioning is predicted to result in excessive transplant-related mortality, reduced-intensity conditioning allogeneic hematopoietic cell transplant is a less toxic approach for providing a graft-versus-leukemia effect and long-term disease control.