Imetelstat Has Disease-Modifying Activity in Relapsed/Refractory Myelofibrosis, as Shown by Effect on Telomerase Activity

John Mascarenhas, MD

Imetelstat exhibited dose-dependent inhibition of the telomerase target, as evaluated by reductions in telomerase activity, human reverse transcriptase (hTERT) levels, and telomere length, in patients with relapsed/refractory myelofibrosis (MF) who were enrolled in the phase 2 IMbark trial.¹

Analyses of the biomarker data correlated with clinical responses and longer overall survival (OS). In addition, dose-dependent reduction in variant allele frequency (VAF) of driver mutations was observed, “indicating that imetelstat has disease-modifying activity by targeting underlying malignant MF clones,” reported lead study author John Mascarenhas, MD, in a presentation during the virtual 2020 ASH Annual Meeting and Exposition.

In this latest IMbark analysis, dose-dependent and exposure-dependent pharmacodynamic (PD) effects of imetelstat were observed. A significantly higher percentage of patients in the high-dose arm (9.4 mg/kg) achieved optimal PD effect compared with the low-dose arm (4.7 mg/kg)—57.5% versus 30.3%, respectively, achieved a 50% or greater reduction in telomerase activity (P = .033) and 62.5% versus 41.7% achieved a 50% or higher reduction in hTERT (P = .049).

Similarly, a significantly higher percentage of patients with higher imetelstat exposure achieved at least a 50% reduction in hTERT expression, “therefore linking both the PD and pharmacokinetic effect of this drug with activity,” said Mascarenhas, an associate professor of medicine, hematology, and medical oncology, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Health System.

“The optimal PD effect also correlated with clinical responses and longer OS,” he said. One hundred percent of patients who had a spleen response achieved an optimal PD effect compared with 76.1% who did not have a spleen response. In addition, 93.8% who had a symptom response achieved the optimal PD effect compared with 72.7% who did not have a symptom response.

Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in patients with myelodysplastic syndromes across all disease stages, said Mascarenhas.

IMbark is a randomized, multicenter, phase 2 trial of 2 dose levels of imetelstat in 107 patients with advanced myelofibrosis who were refractory to ruxolitinib (Jakafi). The main analysis showed that clinical benefit was achieved, more so in patients who were treated with 9.4 mg/kg versus 4.7 mg/kg. The median OS in the high-dose arm was 28.1 months versus 19.9 months in the low-dose arm.² Superiority in terms of symptom response, spleen response, median progression-free survival, clinical improvement, transfusion independence, reduction in bone marrow fibrosis, and at least a 25% reduction in VAF of driver mutations was seen in the high-dose arm versus the low-dose arm.

Results of this analysis presented at the 2020 ASH Annual Meeting and Exposition showed that, of those who achieved an optimal PD effect, the median OS was 27.2 months compared with 18.3 months among the patients who did not achieve an optimal PD effect (HR, 0.54; 95% CI, 0.28-1.06).

Dose-dependent reductions in VAF of JAK2-V617F, CALR, and MPL mutations were observed with imetelstat. In total, 42.1% of patients receiving high-dose imetelstat had at least a 25% reduction of VAF in any of the 3 driver genes compared with 5.6% of those who received low-dose imetelstat (P = .019).

Shorter baseline telomere length was associated with clinical responses for 9.4 mg/kg of imetelstat. Patients with shorter telomere length at baseline who were treated with high-dose imetelstat were more likely than those with longer telomere length to have a spleen response (17.3 vs 4.2%), as well as symptom response (37.9 vs 25.0%).

A correlation was also observed between shorter telomere length and longer survival. At 9.4 mg/kg of imetelstat, the median OS was 30.1 months for those with shorter telomere length versus 27.1 months in those with longer telomere length (HR, 0.70; 95% CI, 0.35-1.41).

A higher baseline hTERT level was associated with clinical responses to 9.4 mg/kg of imetelstat. Patients with higher hTERT had superior spleen response and symptom response compared with lower hTERT level expression at both doses of imetelstat, with responses more likely at the 9.4-mg/kg dose of imetelstat.

References

1. Mascarenhas J, Komrokji RS, Cavo M, et al. Telomerase activity, telomere length and hTERT expression correlate with clinical outcomes in higher-risk myelofibrosis (MF) relapsed/refractory (R/R) to Janus Kinase Inhibitor treated with imetelstat. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-9, 2020. Abstract 347.
2. Mascarenhas J, Komrokji RS, Cavo M, et al. Imetelstat is effective treatment for patients with intermediate-2 or high-risk myelofibrosis who have relapsed on or are refractory to Janus Kinase Inhibitor therapy: results of phase 2 randomized study of two dose levels. Blood. 2018;132(suppl 1):685. doi:10.1182/blood-2018-99-115163