First Philippine Report of Myeloproliferative Neoplasms with Concurrent JAK2 and BCR::ABL1 Mutations

Introduction/Background/Significance: Myeloproliferative neoplasms (MPNs) are clonal hematologic disorders categorized into BCR::ABL1-positive chronic myeloid leukemia (CML) and BCR::ABL1-negative entities such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2 V617F mutation is found in approximately 95% of PV cases and in about 50% of ET and PMF patients. Historically, the BCR::ABL1 translocation and JAK2 mutations were thought to be mutually exclusive. However, emerging evidence, including case reports and small series, has revealed rare instances of coexistent BCR::ABL1-positive CML and JAK2-mutated MPNs. This coexistence poses diagnostic and therapeutic challenges and may result in mislabeling of treatment failure or disease relapse. We present the first known case series in the Philippines involving three patients with concurrent CML and JAK2-positive MPNs.

Materials and Methods/Case Presentation/Objective: Case 1 involves a 62-year-old male diagnosed with CML in 2015, treated successfully with ponatinib. Nine years later, he developed erythrocytosis and recurrent splenomegaly, despite a sustained major molecular response. A positive JAK2 mutation assay and characteristic bone marrow morphology confirmed a diagnosis of PV.

Case 2 features a 51-year-old male initially presenting with thrombocytosis and diagnosed with CML due to the presence of BCR::ABL1 fusion genes. He failed to achieve hematologic response despite multiple TKIs. Repeat JAK2 mutation testing four years later was positive, and he was subsequently diagnosed with ET. Cytoreduction with hydroxyurea and anagrelide alongside TKI achieved platelet control.

Case 3 describes a 25-year-old male with CML diagnosed in 2012 who failed to achieve optimal molecular response with first- and second-line TKIs. After initiating ponatinib, he developed erythrocytosis, and JAK2 testing revealed positivity. A diagnosis of PV was made, and he responded well to hydroxyurea and phlebotomy.

Results/Description/Main Outcome Measures: These cases demonstrate the rare coexistence of BCR::ABL1-positive CML and JAK2-mutated MPNs. In Cases 1 and 3, JAK2-positive PV emerged several years after achieving molecular response to TKI, suggesting that TKI therapy may suppress the dominant CML clone and allow expansion of a latent JAK2-mutated clone. Case 2 presented with persistent thrombocytosis despite good molecular response, and was later confirmed to have JAK2-positive ET. This highlights the importance of re-evaluating patients with atypical disease courses.

Bone marrow morphology can aid in raising suspicion for coexisting MPNs. While CML typically shows small, hypolobated megakaryocytes, JAK2-mutated MPNs feature large, hyperlobated megakaryocytes in clusters. The emergence of such features in a CML patient warrants further molecular testing.

Treatment remains individualized, often combining TKIs with cytoreductive agents such as hydroxyurea, phlebotomy, or anagrelide. Dasatinib has shown potential benefit due to broader kinase inhibition, though data are limited. Allogeneic stem cell transplantation may offer long-term disease control in select cases, but consensus is lacking.

Conclusions: Coexistence of BCR: ABL1 and JAK2 mutations, though uncommon, is clinically relevant. In CML patients with unexpected cytoses or splenomegaly despite molecular response, testing for JAK2 mutations should be considered. Our series—the first reported in the Philippines—adds to the limited data on this overlap. We advocate for increased awareness, early recognition, and an international registry to guide future diagnostic and therapeutic standards.