CD30-directed therapy, JAK/STAT inhibition, and checkpoint blockade offer potential options for ALK-negative anaplastic large cell lymphomaNewer treatment paths for young people with a rare lymphoma

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a rare and diagnostically challenging entity in children, adolescents, and young adults. Although ALCL accounts for a meaningful subset of young patients diagnosed with non-Hodgkin lymphoma, the vast majority of cases are ALK-positive, while ALK-negative disease is seen predominantly in older adults. As a result, pediatric-specific data are limited to small series and case reports, with treatment strategies often extrapolated from adult peripheral T-cell lymphoma or pediatric ALK-positive ALCL clinical trials. Despite morphologic overlap with ALK-positive ALCL, ALK-negative ALCL is biologically heterogeneous, with recurrent alterations involving DUSP22, TP63, JAK/STAT pathway genes, TYK2, ROS1, ERBB4, and other potential molecular drivers. These alterations may have prognostic and therapeutic implications, but their frequency and significance in children and adolescents remain incompletely defined. Accurate diagnosis of ALK-negative ALCL requires expert hematopathology review, with integration of morphology, immunophenotype, and molecular testing. Emerging therapeutic approaches include CD30-directed therapy, JAK/STAT pathway inhibition, and checkpoint blockade. This review summarizes the diagnostic, biologic, and therapeutic challenges affecting young patients with ALK-negative ALCL and the healthcare teams that care for them. We highlight the need for further collaborative and multidisciplinary work, systematic molecular profiling, and consideration of this group in future clinical trials to ultimately advance care for this group of pediatric and adolescent cancer patients.