Abstract 2832Co-occurrence of a JAK2 V617F-positive myeloproliferative neoplasm (MPN) with BCR-ABL-positive chronic myelogenous leukemia (CML) in a single patient is rare. Previous reports have suggested that the two disorders may arise independently or within the same clone, but definitive clonal analysis has never been performed. While ABL inhibitors are widely available, specific inhibitors of JAK2 have only recently become available. We report a patient with concomitant polycythemia vera (PV) and CML treated with both ruxolitinib and dasatinib.A 55 year-old woman was first diagnosed with PV when she presented with a hemoglobin (Hb) of 20.0 g/dL. Over the ensuing ten years, the patient was treated with aspirin and intermittent hydroxyurea and anagrelide, with poor compliance. Ten years after initial PV diagnosis, she presented with worsening fatigue, weight loss, and splenomegaly, and was found to have leukocytosis (WBC 45 × 109/L) with rare circulating blasts (3%), anemia (Hb 9.5 g/dL), and leukoerythroblastosis. A bone marrow biopsy showed hypercellularity with granulocytic and megakaryocytic hyperplasia and atypia. Marrow blasts were not increased. Reticulin staining revealed moderate fibrosis. Cytogenetics were not performed. Clinically, the picture was consistent with post-PV myelofibrosis (MF). Quantitative JAK2 V617F testing revealed a mutant allele burden of 6%. However, testing for the BCR-ABL fusion was also positive (92.5% by FISH). Therefore, it appeared that the patient had developed CML with relative clonal dominance over PV.Treatment with dasatinib was initiated two months after CML diagnosis. Within a month, the patient’s leukocytosis and anemia had largely resolved. Shortly thereafter, however, her WBC and platelet count began to rise dramatically. Three months after starting dasatinib, the patient’s WBC count was 42 × 109/L, Hb 12.3 g/dL, and platelet count 799 × 109/L. FISH for BCR-ABL had decreased to 4.0%. Treatment with hydroxyurea was initiated, but the patient had difficulty tolerating the medication. Five months after starting dasatinib, the patient’s WBC was 38 × 109/L, Hb 12.5 g/dL, and platelet count 799 × 109/L. Although FISH for BCR-ABL had decreased further to 0.5%, the JAK2 V617F allele burden had increased to 83%.Since initiation of dasatinib, the patient continued to report fatigue and poor appetite, progressive weight loss of 15 pounds, and persistent splenomegaly. A bone marrow biopsy performed one year after CML diagnosis appeared morphologically similar to the prior study, but with more severe fibrosis. FISH for BCR-ABL demonstrated a complete cytogenetic response.Due to the progressive increase in counts, ongoing constitutional symptoms, and poor tolerance of hydroxyurea, treatment with ruxolitinib was initiated. Six weeks later, the patient’s WBC was 11.9 × 109/L, Hb 11.9 g/dL, and platelet count 297 × 109/L. The JAK2 V617F allele burden had decreased to 43%. The patient reported moderate improvement in her fatigue and appetite, and was tolerating the ruxolitinib well. Two months after starting ruxolitinib, she remains on treatment with both tyrosine kinase inhibitors (TKIs).In this case, serial quantitative measurements of BCR-ABL and JAK2 V617F strongly suggest that the two disorders arose in independent clones. In preliminary experiments, genotyping studies of individual progenitor colonies are consistent with this notion. To our knowledge, this represents the first case of a BCR-ABL- and JAK2 V617F-positive MPN treated with tandem targeted therapy. The optimal schedule of treatment for such patients (e.g. simultaneous, sequential, or syncopated TKI regimens) can potentially be guided by molecular monitoring and biologic correlative analyses, but may ultimately be determined by the kinetic dynamics of each clone and the tolerability of combining TKIs. Disclosures:No relevant conflicts of interest to declare.