High-Dose Imetelstat Could Offer Patients with High-Risk Myelofibrosis Improved Overall Survival


An analysis of the phase 2 study IMbark shows how imetelstat can offer patients with high-risk myelofibrosis multiple clinical benefits, setting the stage for an expanded phase 3 trial.

Patients with myelofibrosis (MF) who are relapsed after or refractory to (R/R) therapy with Janus kinase (JAK) inhibitors saw better overall survival, spleen response and symptom response with higher doses of the telomerase inhibitor imetelstat, according to an analysis of the phase 2 IMbark study presented at the 2020 ASH Annual Meeting and Exposition.

“Myelofibrosis is a serious and life-threatening myeloproliferative neoplasm. Patients who are relapsed after or refractory to JAK inhibitor therapy have a dismal overall survival that ranges between 13 and 16 months,” said John Mascarenhas, MD, an associate professor of medicine at the Icahn School of Medicine at Mount Sinai, in a presentation on the study.

The randomized, single-blinded phase 2 study evaluated the efficacy of intravenous imetelstat in two different doses of 4.7 mg/kg and 9.4 mg/kg, both every three weeks, and found clinical benefits in symptom response and improvement in overall survival (OS) in the higher-dose arm.

“No matter what clinical benefit one looks at, whether it's survival, symptom response, spleen response, progression free survival, clinical improvement, transfusion independence, reduction in bone marrow fibrosis, or reduction in the fraction of driving mutations, there was superiority at the high dose or the active arm of this treatment with imetelstat in this very advanced JAK inhibitor-failure patient population,” Mascarenhas explained.

The intent-to-treat analysis presented at ASH specifically looked at the association between overall survival and spleen response, symptom response, fibrosis improvement, as well as exploring the role that pretreatment baseline characteristics play in survival.

The co-primary endpoints of spleen response and symptom response rates were measured by spleen volume reduction (SVR) of 35% or more and a total symptom score (TSS) reduction of 50% or more at Week 24, respectively. OS was a key secondary endpoint, the analysis of which was performed based on a database lock in April 2020, and the median follow-up was 41.7 months. Bone marrow fibrosis was assessed by central pathologist.

As of February 2020, median OS was 28.1 months in the higher dose arm, and 19.9 months in the lower dose arm. At 24 months, 57.9% of patients were alive in the high-dose arm, compared to 42% in the low-dose arm.

Lower risk of death was also found to significantly correlate with improved bone marrow fibrosis in the high-dose arm, according to Mascarenhas. Patients who achieved symptom response also exhibited a trend of longer OS compared to patients who did not achieve symptom response or who had no assessment. Thirty-two percent of patients in the high-dose arm had a total symptom score reduction of 50% or more, compared to 6.3% in the low-dose arm.

A similar trend was seen for patients who achieved spleen response at Week 24. “If you look at patients who had even a 10% or greater reduction in spleen volume with imetelstat treatment at the 9.4 milligram per kilogram arm, half the patients attained this, versus 19% in the low dose arm,” Mascarenhas said.

Patients who saw bone marrow fibrosis improvement also saw significantly longer OS than those with worsening bone marrow fibrosis.

Finally, Mascarenhas and his colleagues identified several baseline disease characteristic factors as prognostic for survival, including ECOG performance status, transfusion dependency, higher baseline neutrophils, and platelet values, all of which correlated with an increased risk of death.

In conclusion, these data show dose-related improvement in OS in this patient population, highlighting the need for further clinical studies, which Mascarenhas hinted at with a look at the upcoming phase three IMpact study, which is expected to be open for screening and enrollment in early 2021.

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