Treatment of Older Patients With ALL

Older patients with ALL often have high-risk disease characterized by adverse-risk cytogenetic and molecular abnormalities, as well as Philadelphia chromosome (Ph)-positive and Ph-like phenotypes. They often have comorbidities resulting in poor tolerance to chemotherapy and are at risk of developing therapy-related myeloid neoplasms (t-MNs). In Ph-negative ALL, the duration and intensity of chemotherapy was reduced, and outcomes improved with the addition of inotuzumab ozogamicin (InO) and blinatumomab into the frontline setting. However, t-MNs are still being observed, prompting the development of chemotherapy-free regimens with InO and blinatumomab as well as chimeric antigen receptor (CAR) T-cell therapies in high-risk disease. In Ph-positive ALL, chemotherapy and allogeneic hematopoietic stem-cell transplantation (HSCT) were historically considered a standard of care. However, the introduction of blinatumomab and newer-generation BCR::ABL1 tyrosine kinase inhibitors (TKIs) into the frontline setting significantly improved outcomes. The combination of blinatumomab and ponatinib induced high rates of complete molecular responses and excellent survival, without reliance on HSCT. A subset of patients with elevated WBC count at diagnosis are at particular risk of CNS and systemic relapse and may require additional strategies such as incorporating one to two cycles of high-dose methotrexate/cytarabine into consolidation, and potentially CAR T cells. In T-cell ALL, adding venetoclax into the frontline setting has improved outcomes. In early T-cell precursor ALL, HSCT is still needed. To further improve outcomes in older patients, novel agents such as subcutaneous blinatumomab, CAR T cells, newer-generation TKIs, and menin inhibitors should be investigated in the frontline setting.