Some patients with myelodysplastic syndrome (MDS) who were heavily dependent on red blood cell (RBC) transfusions were able to stop transfusions altogether after treatment with the experimental agent imetelstat (Geron Pharmaceuticals), a first-in-class telomerase inhibitor.
"We found high rates of transfusion independence across multiple patient subtypes, including those with relapsed or refractory to erythropoiesis-stimulating agents (ESA) and who had a high or very high transfusion burden," said first author Uwe Platzbecker, MD, of the Department of Hematology and Cell Therapy, University Clinic Leipzig, Germany.
The 8-week RBC transfusion independence rate of 42%, achieved for a median duration of 20 months, is "the longest so far reported with any agent in non-del 5q lower-risk MDS," Platzbecker noted.
He was presenting the latest findings from the open-label IMerge phase 2/3 clinical trial as part of the virtual European Hematology Association 25th Annual Congress (EHA) 2020.
Patients with low-risk MDS who experience relapse or whose condition is refractory to ESA can be heavily dependent on RBC transfusions, with limited treatment options, he explained.
Patients across all MDS disease stages tend to have short telomeres. Imetelstat, which targets cells with short telomeres and active telomerase, has attracted interest and has shown encouraging effects in earlier studies.
Platzbecker was reporting long-term efficacy and safety from 38 patients who have been treated on an outpatient basis with intravenous imetelstat 7.5 mg/kg every 4 weeks.
Transfusion dependence was defined as requiring at least four RBC units within 8 weeks. All of these patients were considered to have a high transfusion burden; 84% required six or more units per 8 weeks (median, eight units over 8 weeks).
Most patients (89%) had received prior ESA. For 32%, the erythropoietin (EPO) level was >500 U/L. The median age of the patients was 70.1 years.
Over a median follow-up of 24 months, 16 patients (42%) achieved transfusion independence. For 12 of those patients, hemoglobin increased by 3.0 g/dL or more from the pretreatment period to the transfusion-free period.
Twelve patients (32%) achieved transfusion independence for 24 weeks or longer, and 11 (29%) whose transfusion burden was six units per 8 weeks were transfusion free for 1 year or longer.
The median period of transfusion independence was 88 weeks (20 months); the longest period was 2.7 years.
For 37% of patients, the improvements represented clinically meaningful major response (transfusion independence for 16 weeks), according to International Working Group criteria. The response was minor (50% transfusion reduction by 16 weeks) for 55% of patients.
Importantly, there were no significant differences in clinical benefit among subgroups, including those with a high (four to six units) or very high (more than six units) transfusion burden and serum EPO level of 500 mU/mL, nor those with EPO level <500 mU/mL and those with EPO level >500 mU/mL.
"It was a surprise to see no differences in response according to subgroup, particularly in those with a very high EPO level," Platzbecker told Medscape Medical News.
Hematologic improvement–erythroid (HI-E) was achieved by 26 patients (68%) over a median duration of 21 months. Reductions in telomerase activity and hTERT expression correlated with the treatment, demonstrating the drug's disease-modifying activity, Platzbecker said.
In terms of safety, the most frequent adverse event was cytopenia of grade 3 or higher, but these cases were manageable and reversible, he said. Of note, 5% of patients had neutropenia.
Other adverse events were mostly lower than grade 4 and were reversible, Platzbecker noted.
"We saw no new safety signals, and the potential disease-modifying activity of this agent was shown by the magnitude of the response, with a strong increase in hemoglobin compared to pretreatment and a reduction of the SF381mutation, which correlated with a shorter onset time to achieve a response," he concluded.
Platzbecker said a phase 3 trial of the therapy is getting underway, with 115 patients and 55 control persons.
"We are thrilled that the phase 3 double-blind randomized controlled trail is ongoing with a 2:1 randomization, which will hopefully pave the way for the registration of this drug in lower-risk MDS patients," he said.
Approached for comment on this study, Raphael Itzykson, MD, of the Service Hématologie Adultes Hopital Saint-Louis, in Paris, France, said the findings shed important light on the effects of imetelstat in MDS.
"These results are indeed very interesting," he told Medscape Medical News. They can "be compared with the MDS-005 study of lenalidomide in a similar population."
In that randomized, phase 3 study, lenalidomide-induced RBC transfusion independence was achieved in 27% of transfusion-dependent patients with lower-risk non-del(5q) MDS in at least 8 weeks. The median onset of transfusion independence was 10.1 weeks. The response was also associated with quality-of-life improvements.
The study was sponsored by Geron. Platzbecker has financial relationships with BMS, Amgen, Novartis, Jazz, and Geron. Itzykson has received research funding from Janssen, Novartis, and Oncoethix (now Merck); honoraria from Sanofi, BMS, and Celgene; and consulting fees from Novartis, Otsuka Pharma, Jazz Pharmaceuticals, Karyopharm, StemLine Therapeutics, and AbbVie.
European Hematology Association 25th Annual Congress (EHA) 2020. Abstract S183
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