Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR-ABL1 fusion oncogene. While thrombocytosis is common, extreme thrombocytosis at presentation is atypical. Co-occurrence of BCR-ABL1 and JAK2 mutations in CML appears rare.

A 63-year-old male office worker was admitted emergently after routine occupational testing revealed extreme thrombocytosis. He was asymptomatic with no visceromegaly on exam. Bloodwork showed leukocytosis (WBC 45.02 K/µL) with 60% neutrophils, 9% basophils, 2% metamyelocytes/myelocytes, hemoglobin 13.5 g/dL, and platelets 2,545 K/µL. The peripheral smear demonstrated leukocytosis with maturing granulocytes, eosinophilia, <5% blasts, and marked thrombocytosis. Coagulation, hepatic, and renal profiles were normal apart from LDH 335 IU/L. He was admitted for further evaluation, with plans to start hydroxyurea cytoreduction pending confirmatory studies for definitive treatment. Bone marrow biopsy revealed 95% cellularity, markedly increased myeloid/megakaryocytic series, decreased erythroid series, and immunohistochemistry consistent with myeloproliferative neoplasm. Quantitative RT-PCR detected BCR-ABL1 p210 at 57% and JAK2 V617F mutation. Cytogenetics confirmed t(9;22) in all 20 metaphases analyzed. Imaging showed mild splenomegaly without lymphadenopathy/masses. CML in chronic phase was diagnosed. Imatinib 400 mg daily was initiated with excellent response, and JAK2 V617F persistence was confirmed on re-testing.

We present a rare case of chronic myeloid leukemia with extreme thrombocytosis at diagnosis, compounded by the infrequent co-occurrence of BCR-ABL1 and JAK2 V617F mutations. While the patient achieved deep molecular response on imatinib, the precise role this mutational interplay exerts on CML&apos;s clinical phenotype and molecular behavior remains incompletely characterized. Further study of such compound mutant cases is warranted to understand how these genetic lesions may modify disease manifestations and outcomes when co-occurring versus their isolated molecular subtypes. This report highlights the importance of comprehensive mutation profiling in myeloproliferative disorders to uncover unexpected findings with potential diagnostic, prognostic, and therapeutic implications.