Early-onset CLL is characterized by enhanced microenvironment-driven metabolic fitness, increased proliferative bias, and accelerated disease progression.

Chronic lymphocytic leukemia (CLL) predominantly affects older adults; however, approximately 10% of patients are diagnosed at a younger age. Although overall survival appears comparable across age groups, emerging evidence suggests that early-onset CLL may represent a biologically distinct disease subset. Given the profound effects of aging on immune competence and tumor-host interactions, we investigated whether age at diagnosis influences leukemic cell behavior, microenvironmental responsiveness, and immune dysfunction in CLL. We first analyzed the clinical impact of age at diagnosis in a Uruguayan cohort of 462 CLL patients and subsequently explored the biological basis underlying age-associated differences. Patients were stratified according to age at diagnosis, and disease progression was assessed by time-to-first treatment (TTFT). Metabolic analysis evaluated leukemic cell responses to prototypical tumor microenvironment (TME) stimuli, including CD40L plus IL-4 and CpG-ODN plus IL-15. In parallel, we characterized proliferative and quiescent leukemic fractions in peripheral blood, assessed T-cell exhaustion profiles, and analyzed metabolic reprogramming following microenvironmental stimulation. Patients diagnosed at ≤55 years of age exhibited the shortest TTFT (median 39 months), whereas those aged ≥65 years showed a significantly longer TTFT (median 97,6) confirming the more aggressive clinical course of early-onset CLL, despite the longer overall survival as previously described. Metabolic studies revealed that leukemic cells from younger patients displayed enhanced responsiveness to TME-derived signals, characterized by increased metabolic fitness and greater metabolic reprogramming following stimulation. Moreover, early-onset CLL was enriched in proliferative leukemic fractions, whereas the frequency and distribution of exhausted T-cell subsets were comparable between age groups. Collectively, our findings indicate that age-dependent differences in CLL behavior are primarily associated with intrinsic leukemic cell properties rather than major alterations in T-cell dysfunction. Early-onset CLL is characterized by enhanced metabolic adaptability and enrichment of proliferative leukemic cells, supporting the concept that it constitutes a biologically distinct subset of the disease. Despite the absence of differences in survival between age groups, our results provide new insights into CLL heterogeneity and suggest that age-related differences in leukemic cell-microenvironment interactions may contribute to the more aggressive clinical behavior observed in younger patients.