Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion–Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study

Abstract

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

High-dose regimens of hypomethylating agents promote transfusion independence in IPSS lower-risk myelodysplastic syndromes: a meta-analysis of prospective studies

“…The pooled TI rate in our study was 30.5%, which is higher than that achieved by most treatments after failure on ESAs [ 29 ]. Interestingly, this rate was similar to that of newly reported agents such as luspatercept (38% in a phase 3 trial) [ 30 ] and imetelstat (37% in a phase 2 trial) [ 31 ], which are costly and not available in many parts of the world.…”

Myelodysplastic syndromes with ring sideroblasts (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T) – “2021 update on diagnosis, risk‐stratification, and management”

“…Amongst 13 patients with pre‐ and post‐treatment mutation analysis, 11 patients had baseline SF3B1 mutations and 10 had a reduction in SF3B1 VAF from baseline. Myelosuppression remains the main side effect of this drug, with ≥grade 3 anemia, neutropenia and thrombocytopenia being seen in 23%, 67% and 61% of patients, respectively 60 . Phase III studies with this agent are being planned.…”

Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

“…Imetelstat is a novel, first-in-class telomerase inhibitor, targeting selectively cells with short telomere length, binding selectively the telomerase RNA component (TERC) subunit, resulting in direct, competitive inhibition of telomerase enzymatic activity [157]. Data from a phase II/III study show a reduction in disease burden in low risk patients refractory or relapsed after ESA usage, [158] The phase III part of the study is still ongoing (NCT02598661) and meanwhile Imetelstat has been granted a Fast Track designation FDA for non-del(5q) lower risk MDS refractory or resistant to ESAs.…”