Clinical follow-up of 378 patients with autoimmune hemolytic anemia: prognostic impact of hemoglobin levels, autoantibody class, and reticulocytopenia at onset on the relapse risk and outcome

Abstract

Autoimmune hemolytic anemia (AIHA) is greatly heterogeneous, from mild/compensated to life-threatening, due to autoantibody class/thermal amplitude and bone marrow compensatory response. Here we studied 378 patients (135 M and 243 F, median age 61 yrs, range 19-100), followed-up for 4.3 yrs (range 0.5-27), classified in warm (w)AIHA (DAT positive for IgG and IgG+C), cold agglutinin disease, CAD (C), mixed (IgG+C with high titer cold agglutinins) and atypical (DAT-, IgA+, wIgM). Anemia was categorized in Hb<6, 6-8, 8-10 and >10 g/dl, LDH expressed as fold upper the limit of normality (ULN) and reticulocytes as absolute count and index. The therapy lines were: steroids, rituximab, splenectomy, immunosuppressors, and transfusions/plasma exchange/erythropoietin. Hb was lower in IgG+C wAIHA and atypical cases (p<0.001), LDH higher in IgG+C wAIHA, mixed and atypical forms (p=0.01), and Hb and LDH values were negatively correlated (r=-0.25,p<0.001)[Table1]. Reticulocytes were lowerin CAD, mixed and IgG+C wAIHA (p<0.001) with inadequate reticulocytosis (p=0.01). Moreover, reticulocyte index was lower in cases with Hb<6 g/dL (p<0.001), with inadequate reticulocytosis (87 vs 70%,p=0.01).1st line therapy was administered in all cases but 25 CAD. 2nd line was mostly required in IgG+C wAIHA, mixed, and CAD (p=0.005). Ultra-refractory cases requiring 4 or> lines were mixed, atypical, and CAD. Patients with Hb<8 g/dL frequently required a 2nd line (51 vs 33%, p=0.004; p=0.03), or 3 or > lines (73% vs 26%, p<0.001). The following hazard ratios (HR) emerged from multivariate analysis: 3.2 (95% CI 1.4-7), 2.9 (1.4-6.2), 3.4 (1.6-7.5), for Hb<6, 6-8, and 8-10 g/dL compared to patients with Hb>10. Infections occurred in 14% of cases (mostly mixed AIHA, p=0.02), thrombosis in 10%, and acute renal failure (ARF) in 3% with no relationship with AIHA type/Hb. Evans\u2019 syndrome was frequent in mixed or atypical (p=0.04) and in severe forms (74% with Hb<8 g/dL vs 26%, p=0.005), and associated with higher relapse risk (HR 2.3, 95% CI 1.4-3.9). Seventy patients died, 12 because of AIHA complications. Mortality correlated with infections (HR 5.8),ARF (HR 7.6) and Evans\u2019 syndrome (HR 8.3). In conclusion, we found that anemia severity at onset was the major determinant of relapse risk. The lowest Hb levels were observed in patients with IgG+C WAIHA and atypical cases along with higher LDH levels and inadequate reticulocytosis, advising strict clinical observation in these patients