Alessandra Vatteroni

Extramedullary relapse (EMR) of acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) represents a clinically and biologically distinct entity compared with medullary relapse, characterized by marked heterogeneity, compartmental immune escape mechanisms, and generally poor prognosis. EMR arises at the intersection of clonal resistance, evolutionary disease adaptation, and heterogeneous distribution of the graft-versus-leukemia effect, resulting in evolutionary trajectories that are often dissociated between medullary and extramedullary compartments. In the absence of prospectively validated therapeutic algorithms, EMR management requires a structured and adaptive approach based on multidimensional assessment integrating leukemia biology, disease burden and anatomical distribution, bone marrow minimal residual disease (MRD) status, and immune reconstitution. Therapeutic strategies include local treatments, targeted agents, immunotherapies, and immunomodulatory interventions, applied within a dynamic sequence tailored to treatment response. Follow-up plays a central role as an active tool for prognostic stratification and clinical decision-making, enabling early detection of systemic progression and optimization of the timing of consolidative strategies, including second Allo-HSCT in selected patients. An integrated and biologically driven management of post-Allo-HSCT EMR is essential to improve outcomes in this high-risk clinical setting.