Imetelstat effective in heavily transfusion-dependent patients with lower-risk myelodysplastic syndrome

To date, there are still unmet needs for novel therapies after failure of erythropoiesis stimulating agents in red blood cell transfusion dependent lower-risk myelodysplastic syndromes (LR-MDS). Results of IMerge phase III demonstrated that imetelstat can induce statistically significant and clinically meaningful efficacy with robust 8-week, 24-week, and 1-year transfusion independence rates and durable continuous transfusion independence.

Imetelstat is a first-in-class direct and competitive inhibitor of telomerase activity that specifically targets malignant clones with abnormally high telomerase activity, enabling recovery of effective haematopoiesis. In the phase II part of the IMerge study, patients with lower-risk myelodysplastic syndrome (LR-MDS) who were heavily red blood cell (RBC) transfusion dependent, erythropoiesis stimulating agents (ESA) relapsed/refractory or ineligible, non-del(5q) and naïve to lenalidomide and hypo-methylating agents (HMA) achieved durable and continuous RBC-transfusion independence (TI) when treated with imetelstat. At EHA 2023, phase III results from IMerge in the same patient population were reported.

Study design

IMerge is a phase III, double-blind, randomised clinical trial conducted in 17 countries. Heavily RBC transfusion dependent ESA relapsed/refractory/ineligible (R/R) non-del(5q) LR-MDS patients naive to lenalidomide and HMA were randomised 2:1 to receive imetelstat 7.5 mg/kg (N= 118) or placebo (N= 60) every 4 weeks. Transfusion dependency was defined as at least 4 units of RBCs per 8 weeks over the 16-weeks pre-study. The primary endpoint was 8-week transfusion independence (TI) rate; subgroup analyses included IPSS risk, prior transfusion burden, and ring sideroblasts (RS) status. Secondary endpoints included 24-week TI rate, duration of TI, and haematologic improvement-erythroid (HI-E) rate. Change in mutation burden (variant allele frequency [VAF]) was exploratory.

Results

The primary endpoint of 8-week RBC-TI rate was significantly higher with imetelstat vs. placebo (39.8% vs. 15.0%, p< 0.001). Higher rates of longer-term duration of RBC-TI were observed with imetelstat vs. placebo, including one-year RBC-TI with additional three months follow-up (17.8% vs. 1.7%, p= 0.002), representing 66% of ≥24-week TI imetelstat responders. The rate of 8-week TI was also significantly higher with imetelstat vs. placebo across subgroups, including in RS negative patients. Median duration of RBC TI was 51.6 weeks with imetelstat vs. 13.3 weeks with placebo, HR[95%CI]: 0.23[0.09-0.57], p< 0.001. HI-E rates (2018 IWG, emphasising >16-week response) were 42.4% with imetelstat vs. 13.3% with placebo, p< 0.001. In addition, patients receiving imetelstat had a significantly higher and sustained increase in median haemoglobin rise (3.6 g/dL vs. 0.8 g/dL) and a greater reduction in mean RBC transfusion units over time than those on placebo. Reductions in VAF of genes frequently mutated in MDS were greater in patients treated with imetelstat than placebo: SF3B1 (p< 0.001), TET2 (p= 0.032), DNMT3A (p= 0.019) and ASXL1 (p= 0.146). In the imetelstat group, SF3B1 VAF ≥50% reductions were associated with durable RBC-TI rates and longer RBC-TI duration.  

Consistent with prior clinical experience, the most common adverse events (AEs) were haematologic. Grade 3-4 thrombocytopenia and neutropenia were the most frequently reported AEs, most often reported during cycles 1-3. There were no fatal haematologic AEs. Non-haematologic AEs were generally of low grade. There were no cases of Hy’s Law or drug-induced liver injury observed. Most AEs leading to dose modification were grade 3-4 neutropenia and thrombocytopenia. Although 74% of patients treated with imetelstat had dose modifications due to AEs, less than 15% of patients discontinued treatment due to treatment-emergent AEs (TEAEs). Of note, discontinuation of imetelstat due to a TEAE generally occurred late in treatment, with a median time to treatment discontinuation of 21.1 weeks.

Conclusions

Imetelstat demonstrated highly statistically significant and clinically meaningful efficacy compared with placebo in the heavily transfusion-dependent LR-MDS population in need of novel therapy. For this LR-MDS patient population, almost one fifth of imetelstat-treated patients achieved continuous TI for ≥1 year, representing substantial relief from transfusion-associated complications. Safety results of imetelstat were consistent with prior reports.

Reference

Platzbecker U, et al. Continuous tranfusion independence with imetelstat in heavily transfused non-del(5q) lower-risk myelodysplastic syndromes relapsed/refractory to erythropoiesis stimulating agents in IMerge phase 3. Presented at EHA 2023; Abstract S165.