Biosimilar drugs are similar, but not identical, versions of biological medicines that have already been approved. ‘Biosimilar’ is a regulatory term used to indicate a biopharmaceutical product that has been approved under a well-defined regulatory pathway, such as the one established by the European Medicines Agency (EMA). Several biosimilar versions of recombinant human erythropoietin are currently approved for use in Europe, including a biosimilar epoetin-α (HX757). HX575 is a biosimilar version of human recombinant erythropoietin (epoetin-α) that was approved for use in Europe in 2007 under the EMA biosimilar approval pathway. HX575 was approved by the EMA in Europe after it exhibited similarity/comparability to originator epoetin-α in terms of protein structure, equivalence with respect to pharmacokinetic and pharmacodynamic profiles and comparable clinical efficacy and safety profiles in studies (1–3). Although the use of erythropoiesis-stimulating agents (ESAs) for low-risk patients with myelodysplastic syndromes (MDS) is currently supported by all major MDS treatment guidelines regarding hematopoietic growth factors (4–8), data on the use of biosimilar ESAs in this population are lacking. The aim of this study was to determine whether HX575 is similar in terms of efficacy, safety and cost to originator epoetin-α for the treatment of refractory anemia in patients with MDS.

It has been demonstrated that Hb levels may be increased with epoetin-α treatment in patients with MDS and other conditions characterized by bone marrow failure (10–14). However, data regarding the use of HX757 in MDS are currently lacking.

ESA monotherapy typically results in erythropoietic response rates of 20–30% in the general MDS population. Response rates are higher when patients are carefully selected based on pretreatment serum erythropoietin level or other factors. The median duration of ESA response is ~2 years and is, on average, longer among patients who achieve a larger treatment-associated Hb increment compared with those who experience only a minor Hb increase (15,16).

In 1995, Hellström-Lindberg (17) reviewed 205 patients with MDS treated with ESAs in 17 small studies and identified three major factors as predictive of a Hb response, namely pretreatment serum erythropoietin level <200 U/l, a form of MDS other than refractory anemia with ringed sideroblasts and absence of a red blood cell transfusion requirement. A total of 4 patients in groups A and B (2 per group) succumbed due to disease progression to leukemia. Based on currently available evidence, progression to leukemia is unlikely to be the result of epoetin treatment. A prospective clinical trial of ESAs in MDS (ECOG E1996 trial) evaluated the efficacy and long-term safety of epoetin, with or without granulocyte colony-stimulating factor plus supportive care (SC; n=53) vs. SC alone (n=57) for the treatment of anemic patients with lower-risk MDS (18). The presence of older patients with more comorbidities and the lack of data regarding basal serum epoetin level may explain the marginally worse time-to-response to epoetin and the most frequent administration of maintenance epoetin dose in group A. In fact, older age was identified as an adverse prognostic factor in a number of different MDS prognostic scoring systems (19–21). A subsequent study demonstrated that only a limited number of patients with pretreatment serum erythropoietin levels >500 U/l respond to ESA therapy (22).

The proportion of patients in our study responding to epoetin was similar between the originator and biosimilar epoetin-α groups. Overall, 43 of the 92 patients (47%) exhibited a response to epoetin; this proportion was higher compared with that reported in the literature (23), although the lack of data regarding endogenous erythropoietin level for some patients and the low number of patients included make it difficult to draw meaningful conclusions based on response rate.

With prolonged follow-up (median, 5.8 years), no differences were observed in the overall survival of patients in the epoetin vs. SC arms (median, 3.1 vs. 2.6 years, respectively) or in the incidence of transformation to acute myeloid leukemia (7.5 and 10.5% of the patients, respectively). Other adverse effects, such as headache and small increases in blood pressure, occurred with a similar incidence in the two treatment groups and are not considered clinically relevant.

The cost analysis in our study suggested lower overall costs in the group who received biosimilar epoetin-α compared with that in the group that received originator epoetin-α, although these findings require confirmation using more robust measures of cost-effectiveness, such as quality-adjusted life years.

The rationale behind the use of liposomal iron is that patients with MDS frequently exhibit a functional deficit of iron, with elevated ferritin levels and low transferrin saturation (<20%). In these patients, an increase in the level of the protein hepcidin is observed, which inhibits intestinal iron absorption and iron release from tissue macrophages (24). In patients with functional iron deficiency, intravenous (i.v.) iron may be effective in supporting erythropoiesis, although several studies have demonstrated oral iron to be ineffective (25–28). However, the results of preliminary studies indicate that oral liposomal iron may be as effective as i.v. iron in myelodysplastic and neoplastic patients (29–31). For this reason, the patients in our study received oral liposomal instead of i.v. iron. Our study had several limitations, including its retrospective nature, the absence of data regarding basal serum endogenous erythropoietin for all the patients and the limited number of patients (responders) evaluated (43/92). However, despite these limitations, biosimilar epoetin-α appears to be as safe and effective and potentially more cost-effective compared with originator epoetin-α for the treatment of MDS patients with refractory anemia.