John Mascarenhas, MD of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute speaks about the ASH 2020 Abstract – 53 Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor.
Context:
Myelofibrosis (MF) is a myeloproliferative neoplasm that is extreme and life-threatening. There are currently no accepted treatment options for patients who have relapsed or are refractory to (R/R) Janus kinase inhibitor (JAKi) therapy, and overall survival (OS) is dismal (range, 13-16 months). Imetelstat, a telomerase inhibitor, has shown clinical benefit in IMbark, a phase 2 study in MF patients (pts) R/R to JAKi (Mascarenhas et al ASH 2018 #685), in terms of symptom response and possible improvement in OS. Analyses of IMbark pts with closely matched real-world controls (Kuykendall et al EHA 2019 # PS1456) further confirmed the dose-related increase in OS for pts treated with 9.4mg/kg imetelstat.
Targets:
In an intent-to-treat (ITT) study, the effects of imetelstat on OS were assessed. The associations between OS and spleen response (spleen volume reduction [SVR] by ⇠35 percent) at Week 24, symptom response (total symptom score [TSS] reduction by ⇠50 percent) at Week 24, and improvement in fibrosis, as well as the prognostic effects on OS of pretreatment baseline characteristic variables, were further evaluated.
Methodology:
IMbark (MYF2001; NCT02426086) was a 2-dose, randomized, single-blind phase 2 imetelstat study in R/R intermediate-2/high-risk MF pts that received 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks with imetelstat. In Week 24, spleen response and symptom response rates were the primary endpoints. A main secondary endpoint, defined as the interval between the randomization date and death, was OS. Fibrosis of the bone marrow was examined by the central pathologist. Not all correlative analyses conducted have been pre-specified and are exploratory.
Outcomes:
The ITT review included all of the 107 enrolled pts (n=59 in the 9.4 mg/kg arm, n=48 in the 4.7 mg/kg arm). As of 19 Feb 2020, the 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) with a median follow-up of 41.7 months (mos) as of 19 Feb 2020 (Figure 1). Similar findings were obtained when sensitivity analyses, including stem cell transplantation and dose escalation from 4.7 mg/kg to 9.4 mg/kg, accounted for confounding variables of subsequent therapies.
A pattern 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) was shown by pts who achieved symptom response at Week 24. For pts that achieved spleen reaction at week 24 (HR= 0.46, 95 percent CI 0.11-1.92), a similar pattern was observed. In addition, a pattern of better OS was correlated with about 20 percent SVR compared to about 20 percent reduction (HR=0.44, 95 percent CI 0.19-1.04). With a ~10 percent SVR cutoff (HR=0.69, 95 percent CI 0.38-1.27), consistent with published data, the pattern remained real. 19 pts (33 percent) of 57 pts with available bone marrow data had ~1 degree of improvement in bone marrow fibrosis during the study and had a slightly longer OS than those with deteriorating bone marrow fibrosis (HR=0.36, 95 percent CI 0.13-0.96 p=0.04). 30 pts (53 percent) with stable vs. deteriorating fibrosis (HR=0.47, 95 percent CI 0.19-1.20) showed a similar pattern.
Several characteristic factors of baseline disease have been established as prognostic for survival, irrespective of the dose of care. High-risk pretreatment DIPSS, ECOG output status, transfusion dependence, higher baseline neutrophils, lower baseline Hb and increased risk of death associated with platelet values.
The Conclusion:
These data indicate a dose-related increase in OS in pts that are R/R to JAKi with imetelstat. The pattern of association with other therapeutic advantages has confirmed the possible survival gain observed with imetelstat and warrants further clinical research.