Imetelstat Sustains Significant Survival Benefit in R/R Myelofibrosis

An updated post hoc analysis from the phase 2 IMbark trial (NCT02426086) has reaffirmed that the telomerase inhibitor imetelstat delivers a clinically meaningful and statistically significant overall survival (OS) benefit compared with best available therapy (BAT) in patients with JAK inhibitor (JAKi)–relapsed or refractory (R/R) intermediate-2– or high-risk myelofibrosis (MF), even as real-world outcomes in this population have improved substantially over the past decade.¹

The comparative OS analysis, which will be presented at the 2026 ASCO Annual Meeting, included 59 IMbark patients and 54 closely matched real-world patients. At a median follow-up of 46.2 months for IMbark patients and 48.2 months for real-world patients, median OS (mOS) with imetelstat was 30.7 months (95% CI, 25.5-36.9) versus 15.4 months (95% CI, 13.1-30.5) with BAT, an approximate doubling of survival (HR, 0.512; P = .003) in the unweighted analysis.

Propensity-weighted sensitivity analyses using both average treatment effect for the overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) produced consistent results, confirming the survival difference was not attributable to baseline imbalances between cohorts.

These updated findings are consistent with the previously published primary analysis by Kuykendall et al and, with nearly 4 years of follow-up now available in both cohorts, strengthen the evidence base for imetelstat's benefit in this high-risk, post-ruxolitinib population.

A Shifting Real-World Landscape

The broader real-world treatment pattern assessment, which encompassing 96 patients, revealed striking temporal improvements in survival. Patients diagnosed after 2016 achieved an mOS of 34.2 months (95% CI, 24.2-not available) compared with 15.4 months (95% CI, 13.1-30.5) for those diagnosed before 2016. Stratifying around 2019 showed an even larger gap: 39.8 months (95% CI, 34.2-not available) versus 16.6 months (95% CI, 14.2-30.0).

These gains appear driven by changes in how ruxolitinib is used. Mean time from MF diagnosis to ruxolitinib initiation dropped from 46.7 months in the pre-2016 cohort to 10.5 months post-2016, and from 39.7 months to 8.2 months comparing pre- and post-2019 groups. Mean ruxolitinib duration similarly declined, from 30.4 to 13.5 months (pre- vs. post-2016) and from 26.1 to 15.0 months (pre- vs. post-2019). This reflects earlier pivots to next-line therapy or clinical trial enrollment. Transplant rates were stable across eras, ranging from 5.6% to 9.5%, indicating that transplant utilization alone does not account for improved outcomes.

IMbark Study Design and Patient Population

The real-world dataset was expanded to 126 patients who discontinued ruxolitinib and received BAT at Moffitt Cancer Center between 2010 and 2025. For the head-to-head OS comparison, IMbark eligibility criteria were applied to the real-world population to identify a closely matched cohort—restricted to patients diagnosed before 2016 who had received ruxolitinib but were relapsed or refractory—minimizing temporal confounding from more recently diagnosed patients with inherently better outcomes. OS was measured from JAK inhibitor discontinuation to death or last follow-up, and ATO and sIPTW propensity score methods were used to adjust for prognostic covariates.

The investigators acknowledged the limitations inherent to non-randomized comparisons, including potential residual confounding. Nevertheless, the consistency of results across analytical approaches and the magnitude of the OS difference support the validity of the findings.

Implications for Clinical Practice

As real-world MF outcomes continue to improve through earlier treatment initiation and more timely therapy transitions, the benchmark against which new agents are evaluated is rising. The investigators emphasize that these evolving patterns are key considerations when contextualizing outcomes in future trials, particularly those using historical or real-world comparators. For imetelstat specifically, this updated analysis confirms a durable and robust OS advantage in a setting where effective options remain limited.

REFERENCES

1. Kuykendall AT, et al. Updated overall survival analysis of imetelstat versus real-world best available therapy in patients with JAK inhibitor–relapsed/refractory myelofibrosis: IMbark trial and Moffitt Cancer Center real-world cohort comparison. To be presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2026; Chicago, IL.