Cold Agglutinin-Mediated Hemolytic Anemia Preceding the Diagnosis of Acute Myeloid Leukemia: A Case Report and Literature Review

Cold agglutinin syndrome (CAS) is a rare complement-mediated autoimmune hemolytic anemia that is usually associated with infection, autoimmune disease, or lymphoproliferative disorders and is only rarely linked to acute myeloid leukemia (AML). We report a 78-year-old woman who presented with fatigue, macrocytic anemia, reticulocytosis, elevated lactate dehydrogenase, low haptoglobin, indirect hyperbilirubinemia, a direct antiglobulin test positive for C3 and negative for IgG, and a cold agglutinin titer of 1:320. She was treated with rituximab, after which the titer declined to 1:5; however, progressive anemia developed, with hemoglobin falling to 6.5 g/dL, and peripheral blood findings evolved to show left-shifted myeloid maturation with circulating blasts. Flow cytometry demonstrated myeloblasts comprising 14% of analyzed cells, and bone marrow biopsy confirmed AML with 61% blasts and a U2AF1 mutation. Published reports of AML presenting with clearly documented cold agglutinin-mediated hemolysis are exceedingly rare. This case underscores that apparent serologic improvement in CAS does not exclude evolving marrow pathology and that worsening cytopenias, persistent macrocytosis, or new peripheral blasts should prompt timely marrow evaluation.