Clinical heterogeneity of autoimmune hemolytic anemia: a gimema study of 308 patients

Background: Autoimmune haemolytic anaemia (AIHA), usually classified as warm (WAIHA), cold (CHD), mixed, and atypical forms, is a greatly heterogeneous condition both in terms of clinical presentation and response to treatment. Aims: To correlate serological characteristics and severity of anaemia with type and response to treatments, clinical outcome, and occurrence of acute complications. Methods: 308 patients from 8 Italian Centres, diagnosed between 1978 and 2013, were included in this retrospective study, and classified according to DAT-positivity and Hb levels at onset (≤6, 6.1-8, 8.1-10, >10 g/dL). The following therapy lines were recorded: steroids±IvIg, immunosuppressors, rituximab, splenectomy, plasma-exchange, and erythropoietin. Clinical outcome (recovery, relapse, death) and occurrence of infections, thrombosis, and renal failure were evaluated. Results: Patients (112 M and 196 F, median age at diagnosis 63, range 1-97) had been followed-up for a median of 33 months (range 12-372); 49% of cases were WAIHA (DAT+ for IgG), 27% CHD (DAT+ for C), 19% mixed (DAT+ for IgG and C), and 5% atypical (14 DAT- and 1 DAT+ for IgA only). Considering the degree of anemia at onset, 27% of cases had Hb levels ≤6, 37% Hb 6.1-8, 24% Hb 8.1-10, and 12% Hb>10 g/dL; mixed and atypical forms (mean Hb 6.6±1.9 and 6.5±1.7 g/dL, respectively) were more severe than WAIHA and CHD (mean Hb 7.3±2.3 and 8.6±2.2g/dL, respectively, P=0.0001). The mean reticulocytes progressively increased with the worsening of anemia (144±95, 160±122, and 242±156x109/L for Hb>10, Hb 8.1-10, and Hb 6.1-8g/dL, respectively), but not in cases with Hb<6 g/dL (192±128 x109/L, p=0.0001), possibly contributing to the clinical severity. Concerning therapy, steroids were administered in 273 cases (88%), mostly WAIHA (N=144), mixed (N=56) and atypical (N=14) (CR 43-50% and PR 27-36%); 59 CHD were treated with steroids, with lower CR (27%). As regards second line therapy, splenectomy was performed in 33 cases (11%), mostly severe warm or mixed forms (p=0.027), with a response rate of 71%; splenectomy had been performed in 3 CHD and was ineffective in 2. Cytotoxic drugs were administered in 77 patients (25%) (azathioprine 29% CR, 41% PR; cyclophosphamide 35% CR, 37% PR; cyclosporine 30% CR, 20% PR). Rituximab was administered in 55 cases (18%) (45% CR, 35% PR), more frequently in cold and mixed severe forms. Plasma-exchange was performed in 4 cases, and erythropoietin administered in 14, mostly severe forms, their efficacy being not evaluable because of concomitant therapies. Transfusions were given to 38% of patients.Summary and Conclusion: AIHAs showed a marked clinical heterogeneity, 1/3 of cases with a severe onset and 1/10 with life threatening complications. These cases are frequently mixed or atypical forms and refractory to different therapies