Mixed Type Autoimmune Hemolytic Anemia: A Single Center Observational Study

Mixed type autoimmune hemolytic anemia (mAIHA) is a rare form of AIHA, marked by the combined positivity of warm reacting IgG autoantibodies (Ab) and cold agglutinins. The diagnosis requires second level direct antiglobulin test (DAT) with monospecific antisera, autoagglutination at 20°C and cold agglutinin titer. Treatment of mAIHA is not standardized, patients are mainly managed case by case and no trials are ongoing for this disease. Here we present a retrospective observational study of 63 mAIHA patients evaluated from Sep. 1999 until June 2024, belonging to a series of 299 AIHA patients followed at a tertiary Hematologic Center in Milan, Italy. We sistematically collected clinical and hematological features at diagnosis, therapy lines with relative responses (overall response rate (ORR) Hb > 10g/dL and increase > 2 g/dL from baseline), complications and outcome. Adverse events were graded according to CTCAE v5.0. Patients were mainly females (92%), with a median age of 54 years (9-83) and were followed for a median of 54 months (1-217) . Most patients had a severe presentation with median Hb of 7.1 g/dL (2.9-11), notably 43/63 (68%) had Hb levels < 8g/dL, and 20/63 (32%) < 6g/dL; 43% of cases required transfusion, and median LDH levels were 4.1 x ULN (1.2 - 12). Furthermore, 55% of patients displayed inadequate reticulocyte compensatory response as per Bone Marrow Responsivness Index < 121 and 11% of cases had a concomitant immune thrombocytopenia (Evans Syndrome). Patients recieved a median of 2 (1-6) therapy lines, 44/63 (70%) required more than one treatment, and 22/63 (35%) more than two. These included steroids in 58 (92%, ORR 83%), rixutimab frontline in 8 (13%, ORR 100%), rituximab further lines in 21 (33%, ORR 90%). Cytotoxic immunosuppressants were used in 26 (41%, ORR 77%) in second or further therapy lines. Finally, 11 patients (17%) undwerwent splenectomy with good response rate (ORR 91%) and 4 patients (6%) recieved erythropoietin stimulating agents. During the follow up, an infectious complication occurred in 16 of patients (25%), mainly grade 2 and thrombosis in 4 (6%). Overall, 9 patients died, 2 of which due to AIHA complications (one multiorgan failure and one sepsis in a splenectomized patient). In conclusion, mAIHAs mainly show a very severe clinical presentation, require high transfusions need, several therapy lines and display frequent infections and thrombotic complications. New therapies are under investigation for wAIHA or CAD, while therapy of relapsed/refractory mAIHA represent an unmet need.