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Letters to the Editor
(for whom endogenous EPO levels were not available). As shown in Figure 1A, an expected negative correlation was present between EPO and Hb levels (r=-0.64, P=0.0004). However, EPO levels in AIHA were reduced compared with expected values of controls with other types of anemia.10 Moreover, EPO levels were significant- ly reduced in transfusion dependent patients versus trans- fusion independent ones (30 U/L, range: 8-91, vs. 44 U/L, range: 10-1,328; P=0.05). Finally, bone marrow compen- satory response (BMRI) negatively correlated with EPO levels (r=-0.42, P=0.03), and positively with Hb (r=0.28, P=0.05). Regarding the efficacy of rEPO treatment (Figure 1B), the overall response rate (ORR) was 55% at 15 days, 71% at month+1, 73% at month+3, 76% at month+6, and 78% at month+12 with a progressive increase of the CR rate. The median Hb and reticulocyte increase from baseline was 24 (range: 2-83) g/L (P<0.001) and 25 (range: 0-220) x109/L at month+1; 30 (range: 0-94) g/L (P<0.001) and 33 (range: 0-352) x109/L at month+3; and 42 (9-94) g/L (P=0.01) and 21 (range: 0-218) x109/L at month+6. Hb increased independently of the AIHA type and number of previous therapy lines (see the Online Supplementary Figure S1). Response rates were greater in patients who started rEPO within the first year from AIHA diagnosis compared with patients with a longer AIHA history (85% vs. 64%, P=0.06). Likewise, a better response was observed in primary versus secondary AIHA patients (77% vs. 44%), although the difference was not statistically significant. Concerning rEPO discontinuation and outcome, 23 patients were still on EPO and 28 had discontinued treatment at the last follow-up. Reasons for discontinuation were long standing CR (n=14), subopti-
mal response (n=12, Hb increase <20 g/L or Hb<100 g/L), and AIHA relapse (n=2). During treatment, two patients experienced a thrombotic event (one thrombosis of a peripheral inserted central vein catheter and one pul- monary embolism concomitant to AIHA relapse in a splenectomized patient). The occurrence of thrombotic episodes is a concern in AIHA, being observed in up to 20% of patients,1-4,11 and associated with intravascular hemolysis, complement activation, and previous splenec- tomy.1-4 On the other hand, rEPO treatment has been associated with thrombotic diathesis although in our patients, other risk factors were also present.
In summary, EPO therapy was able to increase Hb lev- els (median Hb increase greater than 2 g/dL) in more than 70% of patients, both frontline and in relapsed/refractory chronic disease. Most responses were complete and long- lasting, allowing EPO discontinuation in about one third of responders. Almost all responses were observed between month+1 and +3, with more than half as soon as day+15. EPO efficacy was higher in patients treated within the first year from diagnosis, suggesting that the duration of the immune-suppressive therapy is particular- ly detrimental for bone marrow responsiveness. Accordingly, a worse response was observed in second- ary forms, where both underlying condition and cytotox- ic therapy may have affected bone marrow function. Additional possible confounders of EPO efficacy may be concomitant treatments or recent therapy with ritux- imab. However, EPO was started because of persistent non-response to these agents and an early response promptly observed, suggesting a primary role of EPO stimulation.
A
B
Figure 1. Relationship between endogenous erythropoietin and hemoglobin levels and response evaluation after recombinant ery- thropoietin treatment. (A) Continuous line shows the relationship in patients with autoim- mune hemolytic anemia. Black circles repre- sent patients responding to recombinant ery- thropoietin (rEPO) and white circles non respon- ders; no significant differences were observed between these two groups. As controls, 49 aplastic anemia patients (white triangles) are shown, with the corresponding correlation (dot- ted-dashed line); dashed line represent patients with other types of anemia, including iron and vitamin deficiency [log(Epo)=4.478-
(0.284xHb)] [Bergamaschi et Haematologica 2008 Dec;93(12):1785-91]. (B) Overall response rate to rEPO at different time points. Patients were treated for a median of 7 months and received mainly epoetin α 40,000 U/week (n=17, 33%) or darbepoetin α 20-300 mcg/week (n=20, 39%); a minority of cases received epoetin z 30,000 U/week (n=6, 12%) or β 30,000 U/week (N=1, 2%). Two patients received epoetin α 4,000 U/week because of co-existent chronic kidney disease. CR: com- plete response: PR: partial response; NR: no response).
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