Clonal Evolution and Lineage Switch from T-Cell Acute Lymphoblastic Leukemia to Acute Myeloid Leukemia in Therapy-Resistant PICALM::MLLT10 Leukemia.

Background: PICALM::MLLT10-positive T-ALL is rare and associated with poor prognosis. Lineage switch to AML is exceptionally uncommon, particularly after long-term remission. Case Presentation: We report an adolescent PICALM::MLLT10-positive T-ALL with a cortical thymocyte, non-ETP phenotype. The patient achieved complete remission but relapsed as AML 6 years later. Cytogenetics revealed del(5q), del(17p), and 17q gain. Mutational profiling demonstrated mutations with LOH in NF1 and EZH2, a hemizygous SMC1A mutation, and a hemizygous PHF6 mutation detected only after subsequent therapy. Conclusion: This case illustrates that therapy-resistant PICALM::MLLT10 progenitors can persist during remission and re-emerge as AML through lineage switch. The sequential acquisition of cooperating genetic lesions supports clonal evolution and highlights the need for molecular monitoring and novel therapeutic strategies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.