Erythropoietin therapy after allogeneic hematopoietic cell transplantation has no impact on long‐term survival
Authors: Aurélie Jaspers, Frédéric Baron, Sophie Servais, Marie Lejeune, Évelyne Willems, Laurence Seidel, Kaoutar Hafraoui, Christophe Bonnet, Yves Beguin
Journal: American Journal of Hematology (2015)

To the Editor: Most cancer patients experience anemia, caused either by the cancer itself (chronic inflammation, inadequate erythropoietin production), its treatment, or both. Erythropoiesis-stimulating agents (ESA) proved in many clinical trials to be efficient to increase hemoglobin levels and decrease red blood cell (RBC) transfusion requirements, improving quality of life. However, some meta-analyses suggest increased mortality in cancer patients receiving ESA 1, 2, specifically when no concomitant chemotherapy is administered. The reasons remain unclear; this is possibly due to a higher incidence of fatal thrombo-embolic (TE) 2 or cardio-vascular (CV) events 3 or to a higher incidence of tumor progression in untreated cancer patients 3. Following allogeneic hematopoietic cell transplantation (allo-HCT), anemia may persist for months. However, there is no consensus about the ESA use after transplantation in evidence-based ESA guidelines. We have recently published a prospective randomized trial on the efficacy of erythropoietin therapy on erythroid reconstitution and transfusion requirements in patients undergoing allo-HCT 4. There are no data about a possible survival impact of ESA use after allo-HCT. Therefore, even though short-term overall and progression-free survivals were not affected by erythropoietin therapy, we assessed long-term follow-up of patients included in the study. In this trial, 131 patients given allo-HCT were randomized between the control arm (no erythropoietic therapy) and the erythropoietin (EPO) arm. Patient characteristics and methods have been previously reported 4. Patients received an average of 12.6 ± 4.6 EPO injections until day 126 (D126). After D126, 19 patients received maintenance therapy with the lowest possible EPO dose. Two patients in EPO arm did not receive it 4, so 129 patients were evaluable for safety analyses. For long-term analyses, patients given a subsequent transplant were censored at that time. After a median follow-up of 1.3 years (5.4 years in survivors, up to 8.8 years), we did not observe any fatal TE or CV event and one patient in each arm died of an unknown cause. While two patients (one in each arm) presented a thrombosis on study, six thrombo-embolic events (TEEs) occurred during follow-up (two in control and four in EPO arms) (NS). Four patients (two in each arm) developed a benign tumor, whereas 12 (three in control and nine in EPO arms) presented a secondary malignancy (NS). The incidences of acute and chronic graft-versus-host disease were not different in the two arms. Other complications were: hypertension (defined as introduction of anti-hypertensive drug or increase of anti-hypertensive treatment after inclusion; on study: five in control and nine in EPO arms, later during follow-up: three in control and five in EPO arms), ischemic cardiomyopathy (three in control and four in EPO arms), arrhythmia (three in control and four in EPO arms). The overall incidence combining all these events, as well as incidences of polyneuropathy, pericarditis, esophagitis/gastritis, encephalopathy, pancreatitis, glomerulonephritis, non-infectious pneumopathy and vasculitis was not significantly different in the two arms. Infection rates between study end (D126) and last follow-up remained comparable in the two arms (Fig. 1A).There was no difference in overall survival (OS) between the two arms. Thus, 1-year and 5-year OS were 67% and 43% in EPO arm and 61% and 40% in control arm (P = 0.33) (Fig. 1B). Moreover, when we looked separately at patients in complete remission (CR) and those who were not in CR before transplantation, the OS curves were also similar in EPO and control arms. Causes of death were disease (20 in control and 18 in EPO arms), infection (13 in control and 7 in EPO arms), GVHD (5 in control and 4 in EPO arms), other neoplasia (1 in each arm), undetermined (1 in each arm) and other (1 in control and 3 in EPO arms). Progression-free survival (PFS) was also similar in the two arms: 1-year and 5-year PFS were 50% and 34% in control arm and 57% and 33% in EPO arm (P = 0.80) (Fig. 1C). Like OS, PFS was not different whether the patients were in CR before HCT or not. Finally, we observed similar relapse/progression rates in the two arms: 25% in control and 29% in EPO arms at 1 year and 32% in control and 35% in EPO arms at 5 years (P = 0.45) (Fig. 1D). In multivariate analyses with rhEPO use, conditioning (MA vs. NMA), EBMT risk score, and disease risk index, only the disease risk index was significantly associated with a worsened survival, and with a trend for more relapse/progression (Fig. 1E,F). On the other hand, rhEPO therapy does not significantly affect OS, PFS, or relapse/progression rates. A: Infections; (B) OS; (C) PFS; (D) relapse/progression after allo-HCT (control arm in solid line and EPO arm in dotted line). E: Multivariate analyses for OS (NMA: non-myeloablative). F: Multivariate analyses for relapse/progression. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Several meta-analyses addressed the question of the survival of cancer patients with anemia, treated with ESA 1, 2, 5. However, according to included studies and data included and method used, conclusions may be different. Glaspy et al. 5 demonstrated the absence of any deleterious effect of ESA therapy on progression or survival, whereas Bohlius et al. 1 and Bennett et al. 2 found an increased mortality in patients receiving ESA. However, there are no data about the effect of ESA use on OS or PFS after transplantation, except for our trial on ESA ± intravenous iron therapy following autologous transplantation 6. Although our study was not powered for survival as an endpoint, OS was not different between the two arms. Several reasons may explain the difference between our results and those observed in the anemia of cancer. First, although some authors attributed increased mortality to cancer progression 3, PFS and relapse were superimposable in the two groups. This is in accordance with our results in another study on ESA use following autologous HCT for lymphoid malignancies where short-term and long-term disease progression was not increased by ESA or iron therapy 6. Then, TE rates were very low in our patients and similar in the two arms. Besides, in contrast with other studies (included in meta-analyses) in untreated cancer patients with active malignancies, most patients in our study were in complete remission before transplantation (n = 60) or achieved it rapidly afterwards (n = 30). In multivariate analyses, rhEPO administration, contrarily to the disease risk index, had no impact on OS and relapse/progression rates. Finally, rhEPO treatment was not associated with any particular side effect. In conclusion, in our study, ESA treatment following allo-HCT did not affect survival in long-term analyses since we observed no difference in OS, PFS, relapse/progression rate and TE events. Aurélie Jaspers1, Frédéric Baron1, Sophie Servais1, Marie Lejeune1, Évelyne Willems1, Laurence Seidel2, Kaoutar Hafraoui1, Christophe Bonnet1, Yves Beguin1* 1Division of Hematology, Department of Medicine, CHU of Liège and University of Liège, Liège, Belgium; 2Department of Statistics, SIME, CHU of Liège, Liège, Belgium