Relapsed acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) remains a high-risk scenario with limited evidence guiding optimal salvage regimens. Pediatric-inspired protocols have improved frontline outcomes in AYA-ALL, yet their applicability in relapse remains undefined. To compare the clinical efficacy and toxicity of the pediatric-based UKALL R3 protocol versus the adult salvage fludarabine/cytarabine (FA) regimen in relapsed Philadelphia-negative AYA-ALL. A retrospective cohort study was conducted at a single tertiary care center including 77 patients aged 14–40 years with relapsed AYA-ALL. Seventeen patients received the R3 regimen and sixty received the FA protocol. Primary endpoints included complete remission (CR) rate and overall survival (OS). Secondary endpoints assessed minimal residual disease (MRD) response, transplantation rates, and treatment-related toxicities. Baseline characteristics were comparable, though the FA cohort had older patients and higher-risk cytogenetics. CR rates were 60 % in R3 versus 76.3 % in FA (p=0.1). Median follow-up of 4 years showed numerically superior OS with R3 (53 % vs. 30.8 %, p=0.8). Toxicities varied: febrile neutropenia and hepatotoxicity were more frequent with FA, while mucositis and peripheral neuropathy predominated in R3. Infection-related deaths occurred less often in R3 (12.5 % vs. 25 %). The pediatric-inspired R3 and adult-based FA regimens yielded similar survival and remission rates in relapsed AYA-ALL. Distinct toxicity profiles suggest that treatment selection should be individualized. Larger, prospective studies are warranted to validate the role of pediatric salvage protocols in this challenging population.

Immune checkpoint inhibitors have transformed the treatment of hematolymphoid malignancies by enhancing antitumor immunity. These agents are associated with immune-related adverse events (irAEs), including hematologic toxicities such as autoimmune hemolytic anemia, immune-related thrombocytopenia (irTCP), and neutropenia. Although rare, hematologic irAEs (hem-irAEs) may reflect systemic immune activation and could serve as biomarkers of treatment response. Emerging evidence, particularly from observational studies and meta-analyses, suggests that patients who experience hem-irAEs may have lower rates of disease recurrence and improved survival outcomes. This manuscript reviews the mechanisms, incidence, and prognostic implications of hem-irAEs in patients with hematolymphoid malignancies, emphasizing their hypothesis-generating potential as predictive markers that warrant prospective validation.