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

Background:Autoimmune hemolytic anemia (AIHA) is greatly heterogeneous, from mild/compensated to life-threatening, due to autoantibody class/thermal amplitude, efficiency in activating complement, activity of the reticuloendothelial system, and efficacy of bone marrow compensatory response. Aims: Here we analysed predictors of first relapse, complications, and fatality in a large AIHA series. Methods: We retrospectively studied 378 patients (135m and 243 F, median age 61 yrs, range 19-100) from 10 sites, followed-up for 4.3 yrs (range 0.5- 27). Patients were 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). Cases were also grouped in very severe (Hb<6 g/dl), severe (Hb 6-8 g/dl), moderate (Hb 8-10 g/dl) and mild (Hb>10 g/dl). LDH was expressed as fold increase upper the limit of normality (ULN), and reticulocytes as absolute count and reticulocyte index. The following therapy lines were considered a) steroids +/-IvIg, b) rituximab c) splenectomy, d) immunosuppressive drugs (azathioprine, cyclophosphamyde, cyclosporin), and e) transfusions, plasma exchange, erythropoietinResults: Table 1 shows clinical and laboratory characteristics of AIHA cases at onset and distribution of thermal types. Hb values were significantly 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). Absolute reticulocytes were reduced in CAD, mixed and IgG+C wAIHA (p<0.001) together with inadequate reticulocytosis (p=0.01). Moreover, the reticulocyte index was lower in cases with Hb<6 g/dL (65 vs 98, p<0.001), along with more frequent inadequate reticulocytosis (87 vs 70%, p=0.01). First line therapy was administered in almost all cases but 25 CAD. A second therapy line was mostly required in IgG+C wAIHA, mixed, and to a lesser extent in CAD (p=0.005). The ultra-refractory cases requiring 4 or more lines of therapy were mainly mixed, atypical and CAD. Considering anemia severity, patients with Hb<8 g/dL more frequently required treatment after first-line (51 vs 33%, p=0.004; p=0.03), or even 3 or more therapy lines (52/71, 73% vs 19/71, 26%, p<0.001). The following hazard ratios (HR) emerged from multivariate Cox regression analysis: HR 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, respectivelyAs regards complications, infections were observed in 14% of cases, mostly mixed AIHA (p=0.02); thrombosis occurred in 10% and acute renal failure in 3% of patients, with no relationship with AIHA type/Hb values. Evans’ syndrome was more frequent in mixed or atypical cases (p=0.04) and in severe forms (74% with Hb<8 g/dL vs 26%, p=0.005), and was associated with higher relapse risk (HR 2.3, 95% CI 1.4-3.9). Seventy patients died during the followup, and 12 because of AIHA-related acute complications. Higher mortality was observed for infections (HR 5.8, 95% CI), acute renal failure (HR 7.6, 95% CI) and Evans’ syndrome (HR 8.3, 95% CI).Summary/Conclusions: In conclusion, we found that severity of anemia 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