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Background Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by the proliferation of fibrous tissue in the bone marrow. Transformation to acute leukemia, typically acute myeloid leukemia, represents a terminal event in its natural history; however, transformation to mixed phenotype acute leukemia (MPAL) is exceedingly rare. The diagnosis and treatment of MPAL are particularly challenging, especially in elderly patients with underlying MF. The clinical characteristics, treatment response, and prognosis of such cases remain unclear and are rarely reported. Case presentation This article presents a retrospective analysis of a 75-year-old female patient who initially presented in October 2023 with splenomegaly and thrombocytopenia. Based on bone marrow morphology, biopsy (revealing Grade MF-2 fibrosis), and molecular testing (detecting a JAK2 V617F mutation with a variant allele frequency of 44.67% and an ASXL1 mutation), a diagnosis of primary myelofibrosis (PMF) was established. The patient did not receive standard targeted therapy and was subsequently lost to follow-up. Approximately two years later (September 2025), she was readmitted due to a significantly elevated white blood cell count (47.14 × 10 9 /L) with 64% blasts in the peripheral blood. A comprehensive re-evaluation using MICM (Morphology, Immunology, Cytogenetics, Molecular) classification was performed: bone marrow flow cytometry revealed that 65.73% of the blasts co-expressed CD34, CD117, and the T-lineage marker CD7. Molecular testing detected the persistence of the original JAK2 and ASXL1 mutations, with the acquisition of additional NRAS , EZH2 , and TET2 mutations. A definitive diagnosis of MPAL (T/Myeloid mixed phenotype) transformed from PMF was established. Given the patient’s advanced age and underlying MF, two cycles of a low-intensity chemotherapy regimen primarily based on the “VP regimen (Vincristine + Prednisone) combined with Azacitidine” were administered. Initial treatment resulted in a complete remission with incomplete hematologic recovery (CRi). Considering the incomplete recovery of peripheral blood platelets and the presence of minimal residual blasts detected by bone marrow flow cytometry, the patient was started on a regimen combining the VP regimen with a VA regimen chemotherapy to achieve a deep and durable complete remission. As of the latest follow-up, the patient’s relevant laboratory results remain within a safe range, with no peripheral blasts detected. Her psychological and physiological status is acceptable, she reports no specific discomfort, and her disease is well-controlled. Discussion This rare case offers several critical insights: 1) Rare Transformation Type: It clearly delineates the complete clinical and molecular evolutionary trajectory of PMF transforming into the rare MPAL, underscoring the importance of precise immunophenotyping during the blast phase of MF to identify atypical transformations. 2) Clonal Evolution Pattern: The molecular profile evolved from typical MPN driver mutations ( JAK2 , ASXL1 ) to the acquisition of additional mutations associated with leukemic transformation ( NRAS , EZH2 , TET2 ), providing a concrete example for understanding the genetic mechanisms underlying such transformations. 3) Treatment Dilemma in the Elderly: The case highlights the immense therapeutic challenges in elderly MPAL patients with concomitant persistent myelofibrosis. While low-intensity regimens may induce short-term remission, the responses are not durable. Patient tolerability to intensive chemotherapy and novel targeted agents (e.g., Venetoclax) is poor, leading to a dismal prognosis. 4) Management Implications: It emphasizes the necessity of long-term, regular follow-up and early intervention for MF patients, particularly those harboring high-risk mutations. Furthermore, it underscores the urgent need for more effective and better-tolerated novel therapies for this patient population. Conclusion Transformation of MF to MPAL is a rare event associated with an poor prognosis. This study provides the detailed report of an elderly patient with MPAL arising from JAK2 -positive PMF. This case not only serves as a unique model illustrating the complex evolution of a malignant clone but also profoundly reveals the unique therapeutic challenges and extremely poor survival outcome resulting from the convergence of advanced age, MF background, and MPAL transformation. It offers pivotal real-world evidence for the clinical management of this specific patient population and highlights the need to explore novel therapeutic strategies.