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Letters to the Editor
Efficacy of recombinant erythropoietin in autoimmune hemolytic anemia: a multicenter international study
Autoimmune hemolytic anemia (AIHA) is due to autoantibody mediated hemolysis with or without com- plement (C) activation.1,2 Increasing attention has been paid to the role of bone marrow compensation,3,4 since inadequate reticulocytosis is observed in 20-40% of cases and correlates with poor prognosis.3,5 Moreover, features resembling bone marrow failure syndromes have been described in patients with chronic and relapsed/refracto- ry AIHA, including dyserythropoiesis and fibrosis.6,7 Recombinant erythropoietin (rEPO) is an established treatment of myelodysplastic syndromes, which has been used in a limited number of AIHA cases.8,9
In this study, we systematically evaluated the safety and efficacy of EPO treatment in a multicenter, interna- tional European cohort of AIHA patients. The protocol was approved by the Ethics Committees of Human Experimentation, and patients gave informed consent in accordance with the Declaration of Helsinki. We includ- ed 51 patients with primary or secondary AIHA treated with recombinant EPO, either alone or concomitantly with other therapies. Patients were treated from June 2007 until October 2019 at nine centers in Italy, France, Norway, Austria, UK, Denmark, and the Netherlands. Efficacy of EPO was evaluated at 15 and 30 days, and then at 3, 6 and 12 months. Response was defined as complete response (CR) (hemoglobin [Hb]>12 g/dL and normalization of all hemolytic markers), partial response (PR) (Hb>10 g/dL or at least 2 g/dL increase in Hb, and no transfusion requirement). Finally, retrospective data on AIHA diagnosis and course were obtained from clinical charts. Statistical analysis was performed using Student’s t-test for continuous variables and χ2 or Fisher’s exact tests for categorical ones.
Table 1 shows the patients’ characteristics at diagnosis: 66% of cases were aged >60 years and the male to female ratio was 1. Main AIHA types (warm, cold, mixed, and direct antiglobulin test [DAT] negative) were represent- ed. Five cases were secondary to a lymphoproliferative disorder (two chronic lymphocytic leukemia, two Waldenstrom macroglobulinemia, and one marginal zone lymphoma), without active disease at the time of com- mencement of EPO. At commencement of EPO, the majority of patients (90%) had been pretreated with at least one therapy line, and the median time from diagno- sis to EPO was 24 months (range: 0.03-187 months). Sixty-seven % of cases received EPO treatment because of non-response to a concomitant therapy, including steroids (n=24), rituximab (n=9), cytotoxic immune-sup- pressor (n=8), or sutimlimab (n=1). Patients who had been treated with rituximab received this drug within a median of 1 month (range: 0-5 months) before EPO. The hematologic parameters were similar to those observed at diagnosis, with 37% of cases displaying severe anemia and 53% lactate dehydrogenase levels >1.5xU/L. Inadequate reticulocytosis was observed in the majority of patients (31of 42). Regarding bone marrow character- istics, erythroid hyperplasia was present in the majority (hypercellularity of all lineages in 53%), with dyserythro- poietic features in 40% and reticulin fibrosis in 9% of patients. A lymphoid infiltrate was demonstrated in 24 cases, being greater than 10% only in patients with underlying lymphoproliferative disease. In the primary forms, lymphoid infiltrate was polyclonal (T-cells in seven cases, B-cells in two, and mixed in six), but for five
CAD patients who showed typical monoclonal CAD- associated lymphoid cells. The median endogenous EPO was 32 U/L (9.3-1,328) greater than the normal range, but inadequate in 88% of AIHA subjects considering Hb levels. Renal function was normal in all patients but two
Table 1. Patients' characteristics at diagnosis.
Data at diagnosis
Age years, median(range)
M/F
Secondary AIHA, N(%)
Type of AIHA CAD, N(%)
WAIHA IgG, N(%) WAIHA IgG+C, N(%) MIXED, N(%)
DAT neg, N(%)
Hematologic parameters at diagnosis
Hb g/L, median(range) LDH U/L, median (range) Ret x109/L, median(range) BMRI, median(range)
Previous therapy lines Treated , N(%)
N of lines, mean+SD steroids, N(%)
rituximab, N(%) splenectomy, N(%) immunosuppressor, N(%)
Time from diagnosis to EPO, months,
median (range)
Bone marrow features
Cellularity %, median (range) Hypercellularity, N(%) Dyserythropoiesis, N(%)
Lymphoid infiltrate %, median (range) Reticulinic fibrosis MF1, N(%)
Data at EPO start
Hematologic parameters
Hb g/L, median(range) LDH U/L, median (range) Ret x109/L, median(range) BMRI, median(range)
Concomitant therapy, N(%)
Time on EPO days, median (range)
All patients (N=51)
68 (25-92)
24/27 5 (9)
21 (41) 11 (22) 15 (29) 3 (6)
1 (2)
72 (40-118) 477 (174-6,000) 137 (10-310) 77 (4-193)
46 (90) 2.3+1.4 41 (80) 35 (68)
5 (9)
23 (45) 24 (0.03-187)
N=32
50 (20-95) 17 (53) 13 (40) 5 (0-90) 3 (9) N=51
85 (37-109) 344 (193-1,030) 117 (11-310) 85 (5-222) 34 (67) 188 (11-1,550)
622
Primary autoimmune hemolytic anemia (AIHA) was defined by hemolytic anemia and positive direct antiglobulin test (DAT), in the absence of associated overt lym- phoproliferative, infectious, autoimmune, or neoplastic diseases. None of the patients had a drug-induced AIHA. Patients were classified as warm (wAIHA; DAT positive for IgG or IgG+C), cold agglutinin disease (CAD; DAT positive for C only, with high titer cold agglutinins), mixed (DAT positive for IgG+C with high titer cold agglutinins) and atypical (DAT negative, DAT positive for IgA only, warm IgM, mito- gen stimulated -DAT positive only).The efficacy of the compensatory erythroblastic response was expressed as absolute reticulocyte count as well as bone marrow responsiveness index (BMRI: absolute reticulocyte count x patient’s Hb/normal Hb)[Russo R, Gambale A, Langella C, et al. Am J Hematol. 2014;89(10):e169–e175]. M: male; F: female. Hb: hemoglobin; LDH: lacatae dehydrogenase; Ret: reticulocytes; EPO: erythropoietin.
haematologica | 2021; 106(2)