Rapid transformation from JAK2-positive PMF to acute leukemia: Therapeutic challenges and rare DIC in an aggressive disease course Free

Background:

Primary myelofibrosis (PMF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, extramedullary hematopoiesis, and constitutional symptoms. Leukemic transformation, although recognized, occurs in only 10–20% of patients and is associated with extremely poor outcomes. High-risk mutations such as RUNX1 and TP53 are linked to clonal evolution, therapeutic resistance, and rapid disease acceleration. While features like leukocytosis and cytopenias are common in transformation, spontaneous tumor lysis syndrome (TLS) and disseminated intravascular coagulation (DIC) are exceedingly rare and underreported. We present a case of JAK2 V617F-positive PMF that underwent abrupt leukemic transformation with both TLS and DIC, highlighting unique diagnostic and therapeutic challenges.

Case Presentation:

A 72-year-old man with a known history of JAK2-positive PMF presented with fatigue, early satiety, weight loss, diminished appetite, and chronic back pain. Physical exam revealed splenomegaly. Laboratory evaluation showed severe leukocytosis (WBC 145,000/μL), thrombocytopenia (platelets 41,000/μL), and mild anemia (hemoglobin 9.6 g/dL). A peripheral blood smear revealed circulating myeloblasts and immature myeloid precursors. Metabolic panel revealed renal dysfunction (BUN 95 mg/dL, creatinine 4.8 mg/dL), electrolyte derangements (hyperkalemia, hyperphosphatemia), and elevated transaminases. Coagulation studies and clinical picture were consistent with disseminated intravascular coagulation (DIC).

Within 12 hours of presentation, the patient rapidly deteriorated, developing refractory hyperkalemia, spontaneous TLS, DIC, abdominal hematoma, and a splenic infarction. Intensive management was initiated including continuous renal replacement therapy (CRRT), fresh frozen plasma (FFP), cryoprecipitate, platelet transfusions, and ATRA for coagulopathy. Emergency leukapheresis and hydroxyurea were started for cytoreduction.

Flow cytometry of peripheral blood revealed a RUNX1 mutation, confirming leukemic transformation. Subsequent bone marrow biopsy showed increased blasts and revealed a rare TP53 mutation, consistent with high-risk secondary acute myeloid leukemia (sAML) transformed from PMF. Given the aggressive phenotype, treatment with decitabine was initiated. Within 24hours, there was clinical improvement in TLS, DIC, and splenomegaly.

After stabilization, the patient was discharged and received his second cycle of decitabine as an outpatient. However, during the third cycle, he experienced rising WBC counts and 6% blasts in peripheral blood, raising concerns for relapse or treatment resistance.

The case was reviewed at a multidisciplinary leukemia tumor board. Treatment options considered included combination chemotherapy with low-dose cytarabine (Ara-C), cladribine, and venetoclax, versus a palliative approach due to the patient's declining functional status and aggressive disease biology. After a thorough discussion with the patient and family regarding the high-risk cytogenetics, poor response to therapy, and guarded prognosis, the patient opted forhospice care.

Conclusion:

This case underscores the clinical significance and poor prognosis associated with leukemic transformation of JAK2-positive PMF, particularly in the presence of high-risk mutations such as RUNX1 and TP53. These mutations not only predict an aggressive clinical course but also portend resistance to conventional hypomethylating agents. While decitabine provided initial stabilization, the early relapse highlights the limitations of current therapies in such molecularly adverse settings. The presentation of DIC at the time of leukemic transformation, an uncommon and rarely reported complication in MPNs, underscores the atypical and rapidly progressive clinical trajectory driven by adverse genetic features. Prompt identification of transformation, early cytoreduction, and supportive measures are critical. However, once leukemic transformation occurs in the context of high-risk mutations, treatment options are limited, and long-term outcomes are poor. This case illustrates the need for early referral for potential clinical trials or stem cell transplant in eligible patients, although rapid deterioration may preclude these options. Finally, multidisciplinary care and early goals-of-care discussions are essential in managing such complex and rapidly progressive hematologic malignancies.