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

ABSTRACT 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.