Lower-risk MDS patients benefit from novel drug, imetelstat

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Myelodysplastic syndromes (MDS) are a heterogenous group of clonal haematopoietic disorders that carry a risk of progression to acute myeloid leukaemia (AML).¹ Patients are stratified into risk groups due to the heterogeneity of the disease, which is also exemplified by median overall survival (OS) of 8.8 years for very low risk, and 0.8 years for very high risk patients.¹ Due to symptoms such as anaemia, supportive red blood cell (RBC) transfusions are needed in 80-90% of patients during their disease course and RBC dependence is shown to be an adverse prognostic marker.¹

Imetelstat, a novel telomerase inhibitor, has emerged as a new treatment option for lower-risk (LR) MDS patients.¹ Telomere shortening and dysregulation of telomerase activity have been associated with inferior survival in MDS.¹Imetelstat is currently being investigated in IMerge, a phase 2/3 global study, for transfusion-dependent patients with LR MDS and relapsed or refractory to erythropoietin stimulating agents (ESA R/R).² The long-term efficacy and safety results of this trial were reported at the European Hematology Association 25^th Annual Congress in 2020.

Patients received imetelstat 7.5mg/kg IV Q4W, and 38 LR non-del(5q) transfusion-dependent ESA R/R MDS patients were followed for a median of 24 months.² Long-term efficacy outcomes included ≥8-week, ≥24-week, and ≥1-year RBC transfusion-independence (TI) rates, longest and cumulative duration of ≥8-week TI, duration of haematologic improvement-erythroid, and major/minor response according to updated International Working Group (IWG) 2018 guidelines.² All 38 patients had a high transfusion burden (≥4 units per 8 weeks), and 84% had a burden of ≥6 units per 8 weeks.² Of all participants, 89% had received prior ESAs, and 32% had EPO levels exceeding 500U/L.²

In these 38 patients, 42% had ≥8-week TI, 32% achieved ≥24-week TI, and 29% with a median transfusion burden of 6 units per 8 weeks were transfusion-free for over 1-year.² Clinically meaningful major and minor responses (16-week TI and 50% transfusion reduction/16 weeks) were achieved by 37% and 55% of patients, per IWG guidelines.² The 42% 8-week TI rate is the longest reported with any agent in non-del(5q) LR-MDS patients. Grade ≥3 cytopenias were the most frequently reported adverse events but were manageable and reversible.²

Over 50% reduction of telomerase activity and human telomerase reverse transcriptase (hTERT) RNA levels post-imetelstat dosing were used to demonstrate on-target imetelstat activity, which was observed in 23.1% and 54.3% of patients, respectively.² A significantly higher proportion of patients had ≥50% hTERT expression reduction when achieving ≥8-week TI compared with patients without TI (80% vs. 35%; p=0.0155).² This was also seen in patients achieving ≥24-week TI vs. patients without TI (91.7% vs. 34.8%; p=0.0016). This indicates there may be a correlation between telomerase inhibition and clinical benefit.²

Reference

Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692.

Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020)

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This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).