Myelodysplastic syndromes (MDS) are a heterogenous group of clonal haematopoietic disorders that carry a risk of progression to acute myeloid leukaemia (AML).¹Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692. 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.¹Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692. 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.¹Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692.

Imetelstat, a novel telomerase inhibitor, has emerged as a new treatment option for lower-risk (LR) MDS patients.¹Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692. Telomere shortening and dysregulation of telomerase activity have been associated with inferior survival in MDS.¹Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692.^ Imetelstat 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).²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). All 38 patients had a high transfusion burden (≥4 units per 8 weeks), and 84% had a burden of ≥6 units per 8 weeks.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). Of all participants, 89% had received prior ESAs, and 32% had EPO levels exceeding 500U/L.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020).

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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020).

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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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).²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020). 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.²Platzbecker U. Abstract S183. Presented at the European Hematology Association 2020 (June 11-21). Available at: https://ww3.mdne.ws/3fGlVXS (Accessed 7 July 2020).

Reference

1. Bewersdorf JP, Zeidan AM. Ann Hematol. 2020 Apr;99(4):677-692.
2. 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)