Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor

Background: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm. Currently, there are no approved treatment options for patients who are relapsed after or refractory to (R/R) therapy with Janus kinase inhibitors (JAKi), overall survival (OS) is dismal (range, 13-16 months). Imetelstat, a telomerase inhibitor, has demonstrated clinical benefit in terms of symptom response and potential improvement in OS in IMbark, a phase 2 study in MF patients (pts) R/R to a JAKi (Mascarenhas et al ASH 2018 #685). The dose-related improvement in OS for pts treated with 9.4mg/kg imetelstat was further supported by analyses of IMbark pts with closely matched real world controls (Kuykendall et al EHA 2019 # PS1456).

Aims: Effects of imetelstat on OS were assessed in an intent-to-treat (ITT) analysis. We further evaluated associations between OS and spleen response (spleen volume reduction [SVR] by ≥35%) at Week 24, symptom response (total symptom score [TSS] reduction by ≥50%) at Week 24, and fibrosis improvement, as well as the prognostic effects of pretreatment baseline characteristic factors on OS.

Methods: IMbark (MYF2001; NCT02426086) was a 2-dose, randomized, single-blinded, phase 2 study of imetelstat in R/R intermediate-2/high-risk MF pts, who received imetelstat 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks. Primary endpoints were spleen response and symptom response rates at Week 24. OS was a key secondary endpoint, defined as the interval between the date of randomization and death. Bone marrow fibrosis was assessed by central pathologist. All correlative analyses performed were not pre-specified and are exploratory.

Results: All 107 enrolled pts (n=59 in 9.4 mg/kg arm, n=48 in 4.7 mg/kg arm) were included in the ITT analysis. As of 19 Feb 2020, with median follow-up of 41.7 months (mos), median OS was 28.1 mos in the 9.4 mg/kg arm (95% CI 22.8-31.6) and 19.9 mos in the 4.7 mg/kg arm (95% CI 17.1-33.9) (Figure 1). Similar results were observed when sensitivity analyses accounted for confounding factors of subsequent therapies, including stem cell transplantation and dose escalation from 4.7 mg/kg to 9.4 mg/kg.

Pts who achieved symptom response at Week 24 demonstrated a trend of longer OS vs pts who did not achieve symptom response or who had no assessment (HR=0.79, 95% CI 0.41-1.51). A similar trend was seen for pts who achieved spleen response at Week 24 (HR=0.46, 95% CI 0.11-1.92). Furthermore, ≥20% SVR was associated with a trend of better OS compared with ≤20% reduction (HR=0.44, 95% CI 0.19-1.04). The trend remained true with a ≥10% SVR cutoff (HR=0.69, 95% CI 0.38-1.27), consistent with published data. Among 57 pts with available bone marrow data, 19 pts (33%) had ≥1 degree of bone marrow fibrosis improvement while on study and had a significant longer OS than those who had worsening bone marrow fibrosis (HR=0.36, 95% CI 0.13-0.96 p=0.04). A similar trend was seen in 30 pts (53%) with stable vs. worsening fibrosis (HR=0.47, 95% CI 0.19-1.20).

Several baseline disease characteristic factors were identified as prognostic for survival, irrespective of treatment dose. Pretreatment DIPSS high risk, ECOG performance status, transfusion dependency, higher baseline neutrophils, lower baseline Hb and platelet values correlated with increased risk of death.

Conclusion: These data show dose-related improvement in OS with imetelstat in pts who are R/R to JAKi. The potential survival benefit observed with imetelstat was supported by the trend of correlation with other clinical benefits and warrants further clinical study.