Nonimmune Hemolytic Anemia in Myelodysplastic Neoplasms (MDS) with U2AF1 Gene Mutation at S34 Hotspot: A Rare and Challenging Case Presentation

Abstract Introduction/Objective Hemolysis is recognized but not well understood in a subset of patients with myelodysplastic Neoplasms (MDS), largely through non-immune-mediated mechanisms. Lower survival rates are observed in MDS patients experiencing hemolysis. It is important to investigate the underlying mechanism including the molecular features of these cases. We hereby present a rare and challenging case of nonimmune hemolytic anemia in MDS with U2AF1 gene mutation at S34 hotspot. Methods/Case Report The patient is a 75-year-old male with past medical history of hypertension that presented with two weeks of 20 pounds weight loss, dyspnea on exertion and a syncopal event complicated with a parietal subarachnoid hemorrhage. Patient was found to have pancytopenia with severe anemia (hemoglobin 3.6 g/dl), reticulocytosis (reticulocyte 13.29%), decreased haptoglobin, while increased indirect bilirubin and lactate dehydrogenase. Spherocytes were detected in peripheral blood smear. With Coombs test being negative, all above are consistent with nonimmune hemolytic anemia. There is no evidence of paroxysmal nocturnal hemoglobinuria. Bone marrow biopsy revealed trilineage hematopoiesis, many hypo-or mono-lobated dysplastic megakaryocytes and less than 5% blasts. Cytogenetics/FISH unveiled 5q deletion, 20q deletion and trisomy 8. Mutation in the U2AF1 gene at S34 hotpot is detected by next-generation sequencing. The overall findings are consistent with MDS with nonimmune mediated hemolysis. Results (if a Case Study enter NA) NA Conclusion Hemolysis, although uncommon in MDS, has a substantial impact on prognosis, treatment approaches and response. U2AF1 gene mutation is associated with poor outcomes in MDS patients. U2AF1 gene mutation at S34 hotpot is observed in 30% MDS patients with hemolysis in one recent report. Responses to erythropoiesis-stimulating agents and hypomethylating agents vary depending on different mutations, including U2AF1, SF3B1 and EZH2, with discrepancies across studies. Further investigation is warranted to elucidate the relationship between the molecular abnormalities and treatment response as well as prognosis in MDS patients with hemolysis.