Overall Survival in High-Risk Myelofibrosis Improved With High-Dose Imetelstat

John Mascarenhas, MD

Higher doses of telomerase inhibitor imetelstat demonstrated better overall survival, spleen response, and symptom response in patients with myelofibrosis (MF) who are relapsed after or refractory to (R/R) therapy with Janus kinase (JAK) inhibitors in the phase 2 IMbark study (MYF2001; NCT02426086), according to findings presented at the 2020 American Society of Hematology Annual Meeting.

The randomized, single-blinded study evaluated the efficacy of 2 doses of intravenous imetelstat: 4.7 mg/kg compared to 9.4 mg/kg, both every 3 weeks, and found dose-related 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,” said John Mascarenhas, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, in a presentation on the study at ASH.

The dose-related improvement in OS in the higher dose arm was further supported by analyses of IMbark with closely matched real world controls (Kuykendall et al EHA 2019 # PS1456).

The intent-to-treat (ITT) analysis Mascarenhas presented at ASH specifically evaluated the association between overall survival and spleen response, symptom response, and fibrosis improvement, and set out to explore the prognostic pretreatment baseline characteristic factors on 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, and analysis of OS was performed based on a database lock in April 2020, and the median follow-up was 41.7 months (range 0.2, 49.2). Bone marrow fibrosis was assessed by central pathologist.

All 107 enrolled patients (59 in 9.4 mg/kg arm, n=48 in 4.7 mg/kg arm) were included in the ITT analysis.

As of February 2020, median OS was 28.1 months in the 9.4 mg/kg arm (95% CI 22.8-31.6) and 19.9 months in the 4.7 mg/kg arm (95% CI 17.1-33.9). 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. 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. “Bone marrow fibrosis reduction of at least one grade was associated with the hazard ratio of .37 for death, suggesting a reduction in risk of death and improvement in survival for patients who had an associated survival in patients who had an associated improvement in bone marrow fibrosis, and this also trended for patients who had stability in bone marrow fibrosis over the treatment period.”

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 (HR=0.79, 95% CI 0.41-1.51). 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 (HR=0.46, 95% CI 0.11-1.92). “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.

Of the 57 patients with available bone marrow data, 19 (33%) had ≥1 degree of bone marrow fibrosis improvement, and saw significantly longer OS than those who had worsening bone marrow fibrosis (HR=0.36, 95% CI 0.13-0.96 p=0.04.

Irrespective of treatment dose, Mascarenhas and his colleagues identified several baseline disease characteristic factors as prognostic for survival. Pretreatment DIPSS high risk, ECOG performance status, transfusion dependency, higher baseline neutrophils, lower baseline Hb and platelet values all correlated with an increased risk of death according to the researchers.

“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,” Mascarenhas explained.

These data, however, 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 (IMpactMF, NCT04576156) which is expected to be open for screening and enrollment in the first quarter of 2021.

_References

_{Wang M, Rossi JM, Munoz J, et al. Favorable Overall Survival with Imetelstat Treatment Correlates with Other Clinical Benefits in Intermediate 2 or High-Risk Myelofibrosis Relapsed/Refractory to Janus Kinase Inhibitor. Presented at: 2020 ASH Annual Meeting and Exposition. Abstract 53.}