Ph-Negative Acute Lymphoblastic Leukemia in the Older Adults: Biology, Therapeutic Strategies and Unmet Needs

Acute lymphoblastic leukaemia (ALL) in older adults represents a growing clinical challenge, driven by an ageing population, adverse disease biology, and reduced tolerance to intensive chemotherapy. Although pediatric-inspired regimens have improved outcomes in younger adults with Philadelphia chromosome (Ph)-negative ALL, survival in older patients remains poor, with high rates of treatment-related toxicity, early death, and relapse. Age-related comorbidities, impaired organ function, and unfavorable cytogenetic and molecular features, including low hypodiploidy and TP53 mutations, further compromise prognosis. In this context, monoclonal antibodies such as blinatumomab and inotuzumab ozogamicin (InO), used alone or in combination with reduced-intensity chemotherapy, have emerged as promising frontline approaches capable of deep remissions with improved tolerability. Moreover, CAR T-cell therapy is increasingly recognized as a potentially effective strategy for relapsed/refractory disease in selected older adults, particularly in the setting of low disease burden, with acceptable safety in carefully monitored cohorts. However, issues such as antigen loss, lineage switch, the management of T-cell ALL, and the optimal sequencing of immunotherapies remain unresolved. Across all treatment strategies, comprehensive geriatric assessment appears more informative than performance status alone in predicting tolerability and outcome, supporting its integration into trial design and routine decision-making. Overall, the refinement of immunotherapeutic approaches, coupled with biologically and geriatrically tailored treatment algorithms, offers the most promising avenue to improve long-term outcomes for older patients with ALL.