Long‐term safety follow‐up of a randomized trial of darbepoetin alpha and intravenous iron following autologous hematopoietic cell transplantation

To the Editor: Anemia is quite frequent in cancer patients, due to the cancer itself, its treatment, or both. Erythropoiesis-stimulating agents (ESA) have proven effective in increasing hemoglobin levels and improving quality of life. After autologous hematopoietic cell transplantation (auto-HCT), many patients experience prolonged anemia. However, ESA use in this context remains sparse. We recently reported the efficacy of darbepoetin alpha (DA) (AranespVR ) and intravenous (IV) iron (VenoferVR ) on erythroid reconstitution following auto-HCT [1]. Although there was no short-term safety issue, longer follow-up was required as some metaanalyses suggest increased mortality on study and worsened overall survival in cancer patients receiving ESA [2,3], particularly when no concomitant chemotherapy is administered. On the other hand, some in vitro and animal studies raised a possible effect of iron on tumor growth [4], but there are no available data in cancer patients receiving IV iron. In addition, the impact of ESA and/or IV iron on long-term safety, relapse, and survival has never been examined after transplantation. Therefore, we analyzed long-term outcome to verify the safety of DA and IV iron therapy after auto-HCT. We randomized 127 patients with lymphoid malignancies [1] between no erythropoietic therapy (n 5 25), DA from day 28 post-auto-HCT (n 5 52) or DA 1 3 IV iron injections (n 5 50). Median follow-up was 1.4 year (range 89 days–9.5 years). Survival analyses were performed according to the Kaplan–Meier method. More details about patients and methods can be found in the Supporting Information. The incidence of infections between end of study (day 126) and last follow-up remained comparable: three patients in control group (12%), eight in DA group (15%), and six in DA1iron group (12%) experienced at least one infection. Numbers of infections per patient were 0.2 6 0.7, 0.2 6 0.4, and 0.1 6 0.3 in control, DA, and DA1iron groups, respectively (NS). During follow-up, 4/25 (16%) patients in control group, 13/52 (25%) in DA group, and 6/50 (12%) in DA1iron group experienced at least one other complication (NS). While three patients (two in control and one in DA1iron groups) presented a thrombosis on study, no other thrombo-embolic event (TEE) occurred during follow-up. Two patients (one in control and one in DA groups) developed a benign tumor, whereas four (three in DA and one in DA1iron groups) presented a secondary malignancy (NS). Other complications were: hypertension (one in control and one in DA groups), ischemic cardiomyopathy (three in DA group) including one myocardial infarction, four arrhythmias (one in control and three in DA groups), peripheral arteriopathy (one in DA group), diabetes (two in DA and one in DA1iron groups), radiopneumonitis (one in control group), vasculitis (one in DA group), nephritis (one in DA and one in DA1iron groups), thyroiditis (one in DA group), spondylarthritis (one in DA1iron group), osteonecrosis (one in DA and two in DA1iron groups), peripheral neuropathy (one in DA and one in DA1iron groups), sudden transient deafness (one in DA group), and sarcoidosis (one in DA1iron group). One-year overall survival were 100%, 88%, and 100% and 5-year overall survival were 86%, 78%, and 91% in control, DA, and DA1iron groups, respectively (P 5 0.43) (Fig. 1A). One-year and 5-year progression-free survival were 85% and 71% in control group, compared to 86% and 57% in DA group, and 94% and 78% in DA1iron group (P 5 0.30) (Fig. 1B). One year after auto-HCT, 15%, 12%, and 10% of patients in control, DA, and DA1iron groups, respectively, had progressed or relapsed; at five years postHCT, 29%, 42%, and 22% had progressed (P 5 0.35) (Fig. 1C). Disease progression was the major cause of death (three in control group, eight in DA group, and three in DA1iron group). The impact of ESA on survival in untreated cancer patients has been studied in several meta-analyses [2,3,5], but results differed depending on included studies and data and methods used. Glaspy [5] did not find any difference in survival or disease progression, whereas Bohlius [2] and Bennett [3] showed increased mortality in patients receiving ESA. However, there are no data about the effect of ESA on overall or progressionfree survival after transplantation, or about the impact of IV iron in cancer patients, let alone after transplantation. Although our study was not designed to establish an impact on mortality, survival was obviously not different among the groups. The mechanisms responsible for increased mortality with ESA in oncology remain unclear. Whereas some suggested that it was partly explained by TEE [2,3], in our study TEE were no more frequent in the ESA groups on study, and no TEE was observed during long-term follow-up. However, three major non-fatal cardiovascular events occurred in DA group versus none in DA1iron and control groups (NS). Another cause of worsened survival could be an effect of ESA on disease progression [6] as ESA could promote cell growth directly in tumor cells expressing erythropoietin (Epo) receptors and indirectly by stimulating angiogenesis through endothelial cells expressing Epo receptors. We did not observe impaired survival reported in untreated cancer patients receiving ESA, possibly because few patients had active disease. On the other hand, iron could also impact disease progression. In animal models, tumor growth can be favored by iron overload [4] but in these models, iron-replete animals received much larger doses of iron. In our study, iron therapy did not affect disease progression. Whereas patients with pre-transplant iron overload may develop more infections after transplantation, the rates of infection were similar in our three groups, indicating that 900 mg of IV iron post-transplant has no such deleterious effect. The other serious complications were uncommon and hardly attributable to ESA or iron treatment. In conclusion, DA and IV iron therapy following auto-HCT did not affect long-term safety, disease outcome, or survival.