Publication date: Nov 01, 2025
Mixed-phenotype acute leukemia (MPAL) accounts for a fraction of de novo acute leukemias and carries a dismal prognosis, especially when adverse lesions such as monosomy 7 are present. Consensus on optimal frontline therapy remains lacking. Herein, we present a 69-year-old woman who presented with pancytopenia and 79% circulating blasts. Immunophenotyping and cytogenetics established T/myeloid MPAL with a hypodiploid clone 45, XX, dic(7;12)(p11. 2;p13)(19)/46,XX and an IDH2 R140Q mutation. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) induction achieved morphological complete remission, but measurable residual disease (MRD) persisted. Consolidation with mini-cyclophosphamide, vincristine, and dexamethasone (mini-CVD) and prednisone, vincristine, methotrexate, and 6-mercaptopurine (POMP) maintenance failed to eradicate MRD, and overt relapse occurred at month 7. Nelarabine salvage was initiated. After two nelarabine cycles (month 8. 5), bone marrow contained 85% myelomonocytic blasts. Cytogenetic evolution to 45,XX,psu dic(7;12)(p11. 2;p11. 2)/45,idem,del(16)(q12) marked transformation to acute myelomonocytic leukemia (AML-M4). Profound pancytopenia led to invasive pulmonary aspergillosis and symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. With refractory disease and escalating infectious morbidity, active therapy was discontinued; the patient died 11 months after diagnosis. This case illustrates rapid clonal evolution of T/myeloid MPAL into chemoresistant AML-M4 driven by persistent chromosome-7 loss and acquisition of del(16q). Early molecular risk stratification and deployment of targeted agents, venetoclax-based combinations, or timely allogeneic transplantation should be considered before irreversible genomic complexity emerges. Prospective studies tailored to high-risk cytogenetic subsets of MPAL are urgently needed.