A randomized phase II trial of azacitidine +/- epoetin-  in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents

Abstract

T he efficacy of azacitidine in patients with anemia and with lowerrisk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).

Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes

“…Although there were potential differences in the criteria for response assessment between our trial and previous studies, [36][37][38] luspatercept resulted in a higher percentage of patients with a response or a better safety profile (or both) than were seen with previously evaluated treatments in patients with disease that was refractory or resistant to erythropoiesis-stimulating agents who had non-del(5q) transfusion-dependent lower-risk myelodysplastic syndromes. In a randomized, placebo-controlled trial of lenalidomide in such patients, transfusion independence for 8 weeks or longer was observed in 26.9% of lenalidomidetreated patients (vs. 2.5% of those receiving placebo); among patients with ring sideroblasts (70.3% of all patients), 30.6% of patients in the lenalidomide group had a response.…”

“…37 Moreover, in a phase 2 study evaluating azacitidine with or without erythropoietin in patients with erythropoiesis-stimulating agent-resistant, transfusion-dependent, lower-risk myelodysplastic syndromes, transfusion independence for 8 weeks or longer was observed in 14.3% of patients receiving azacitidine plus erythropoietin and in 16.3% of those receiving azacitidine; myelosuppression was also observed, a finding similar to other trials of azacitidine. 38,39 Patients with lower-risk myelodysplastic syndromes with ring sideroblasts for whom erythropoiesis-stimulating agents are not effective or are not an option have limited treatment options available beyond continued transfusions. Luspatercept significantly reduced the transfusion burden in a substantial proportion of these patients and was associated with mainly low-grade toxic effects.…”

Mutations in Splicing Factor Genes in Myeloid Malignancies: Significance and Impact on Clinical Features

“…Recently, luspatercept (ACE-536), a fusion protein containing a modified extracellular domain of the human activin receptor type IIB combined with a human IgG1 Fc domain and influencing the TGF-β and SMAD family proteins, is a phase II clinical trial for MDS patients and seems to induce a better clinical response in patients with SF3B1 mutations [55]. In addition, SF3B1 mutations represent a positive factor for erythroid response in a randomized phase II clinical trial of azacitidine and epoietin-β [56].…”

How we manage adults with myelodysplastic syndrome

“…HMAs also have some activity also in LR‐MDS, where their use is approved in USA and various other countries, but not in Europe. While response rates of 35–45% have been reported in patients with several cytopenias, two European studies, possibly because they included mainly purely anaemic patients, treated after ESA failure, reported lower response rates of 20–30% (Tobiasson et al , ; Thépot et al , ). In LR‐MDS, reduced HMA schedules are often used, especially with 5 day cycles of azacitidine (Lyons et al , ) or 3 days of decitabine (Jabbour et al , ).…”