Case Presentation: A 54-year-old woman presented with nausea, generalized weakness, fatigue, and progressive dyspnea following treatment for sinusitis. CBC revealed a leukocyte count of 135 K/µL with anemia and thrombocytopenia. She received 3 rounds of leukapheresis for hyperviscosity and started hydroxyurea 500 mg q6h. Repeat CBC showed a leukocyte count of 39.8 K/µL (80% blasts), ANC 1.19 K/µL, hgb 8.3 g/dL and platelets 50 K/µL. Bone marrow biopsy (BMBx) showed hypercellular bone marrow (BM) with effacement by mixed-phenotype acute leukemia (MPAL). Two populations of CD34+ blasts were identified using flow cytometry (FC): CD19+ CD79a+ TdT+ B lymphoblasts and CD13+ CD33+ CD117+ HLA-DR+ myeloblasts. On IHC, the B lymphoblasts were positive for PAX5 and the myeloblasts were positive for myeloperoxidase and lysozyme. Next Generation Sequencing revealed a RUNX1 mutation and PCR positive for FLT3. She was BCR-ABL negative. The patient was induced with HyperCVAD and midostaurin. She received alternating intrathecal methotrexate and cytarabine twice weekly for CNS involvement and achieved complete remission following induction. She was consolidated with alternating hyperCVAD A and B arms. Her consolidation with hyperCVAD 3A was complicated by an NSTEMI and a right MCA stroke, delaying her progression to allogeneic stem cell transplant (ASCT). She relapsed with 11% blasts in her peripheral blood and a new BMBx showed hypercellular BM with diffuse involvement by persistent MPAL. She was started on hydroxyurea for cytoreduction followed by gilteritinib monotherapy and achieved a reduction in blasts percentage, however still had residual disease in the BM. Azacitidine was added to her gilteritinib regimen and she achieved complete remission with incomplete count recovery (CRi) with 10-15% cellularity and 3% blasts in the BM. The patient has maintained CRi with continued gilteritinib and azacitidine therapy but requires intermittent platelet transfusions. Due to a poor Karnofsky performance score, she is no longer a candidate for ASCT.

Discussion: MPAL is defined by the WHO as a group of leukemias with blasts that co-express antigens of more than 1 lineage or that have separate populations of blasts of different lineages.[1] Similar to other acute leukemias, MPAL patients present with signs of BM failure such as fatigue, infection, and bleeding,[2] but compared to AML and ALL, there is a significantly impaired overall survival.[3] Treatment guidelines are unclear, but there has been success treating MPAL with ALL directed chemotherapy regimens followed by ASCT.[4] We show a patient with relapsed FLT3-mutant MPAL who achieved remission using a combination approach that included targeted therapy.

Conclusions: MPAL is a rare form of leukemia with a non-specific presentation that carries a poor prognosis. Hospitalists may find leukocytosis with peripheral blasts, anemia, and thrombocytopenia on CBC. This should prompt a workup of BM failure, as BMBx and FC are necessary to diagnose MPAL. While subsequent testing and treatment will likely be determined by hematology/oncology, hospitalists may manage MPAL patients on a variety of different treatment protocols. This patient’s progression was complicated by infections, NSTEMI, and stroke. Hospitalists must be aware of the poor prognosis, complications, and treatment-specific side effects involved in treating patients with MPAL. While the prognosis is poor, targeted therapy may prolong survival and improve quality of life when standard approaches are not available.