The combination of imetelstat (Rytelo) and ruxolitinib (Jakafi) shows a tolerable safety profile in patients with myelofibrosis, according to the phase 1/1b IMproveMF trial (NCT05371964) presented at the 2024 ASH Annual Meeting and Exposition. The study suggests potential tolerability and dose-dependent preliminary efficacy of the combination therapy.
Safety and Tolerability
In the study, 17 patients received the combination at various imetelstat dose levels without experiencing any dose-limiting toxicities (DLTs) within the first 28 days of cycle 1. Eighty-eight percent of patients experienced treatment-emergent adverse effects (TEAEs) of any grade. Common TEAEs included extremity pain (41%), nausea (35%), and increased alanine aminotransferase levels (29%). Grade 3 TEAEs included anemia (24%) and neutropenia (18%). No grade 4 or 5 TEAEs were reported.
Investigator Comments
Dr. John O. Mascarenhas, MD, from the Icahn School of Medicine at Mount Sinai, noted, "Ruxolitinib is a very effective drug in improving spleen [response] and symptoms, but it does not reliably affect the natural history of the disease. Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase [and is] now approved for the treatment of transfusion-dependent, lower-risk patients with myelodysplastic syndrome." He added that this early-phase study examines the safety, pharmacokinetics, and early clinical activity of adding imetelstat to ruxolitinib in patients with an inadequate response to ruxolitinib alone.
Study Design and Patient Population
The IMproveMF trial is an ongoing, open-label, single-arm, multicenter study involving adult patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk myelofibrosis. Patients had an ECOG performance status of 0 to 2. In phase 1, patients must have received ruxolitinib for at least 12 weeks, with a stable dose for at least 4 weeks before enrollment. Phase 1b included JAK inhibitor-naive patients. All patients had peripheral blood blast counts of 10% or less and bone marrow blast counts no higher than 10%.
During the phase 1 dose escalation, patients received oral ruxolitinib (5 mg to 25 mg twice daily) and intravenous imetelstat every 28 days at doses of 4.7 mg/kg (n = 3), 6.0 mg/kg (n = 3), 7.5 mg/kg (n = 4), or 9.4 mg/kg (n = 7). Phase 1b involves ruxolitinib for at least 12 weeks (up to 24 weeks), followed by combination therapy with intravenous imetelstat at the recommended phase 2 dose every 28 days.
The primary endpoint was the incidence and severity of adverse effects and symptom response rate at week 24. Secondary endpoints included pharmacokinetic outcomes, progression-free survival, spleen response at week 24, time to response, duration of response, response rate, and reduction of bone marrow fibrosis.
Baseline Characteristics and Efficacy Signals
The median time from initial myelofibrosis diagnosis was 36.8 months. Most patients were male (71%), had primary myelofibrosis (53%), DIPSS intermediate-2 disease (53%), and less than 1% bone marrow blasts (65%). The median time on ruxolitinib before enrollment was 18.8 months, with a median ruxolitinib dose of 15 mg. Baseline spleen volume was 1312.5 cm3, and the total symptom score (TSS) was 11.0.
Additional findings showed a median change in spleen volume at week 24 of 2.8%. The median absolute change from baseline in TSS over week 12 and the median maximum absolute reduction from baseline TSS up to week 24 were both -5.
In the 9.4-mg/kg dose group, median baseline hemoglobin, leukocyte, neutrophil, and platelet counts were 112.0 g/L, 7.8 x 109/L, 4.4 x 109/L, and 192.0 x 109/L, respectively. The median imetelstat treatment duration was 12.1 weeks, with a median of 4 cycles. The median ruxolitinib treatment duration was 21.7 weeks; no patients in this group required dose reductions.
Among 11 patients with a baseline mutation, variable allele frequency mutation reductions were observed in JAK2 (45%), CALR (45%), MPL (18%), and high molecular risk mutations (55%). In patients treated at the 9.4-mg/kg dose (n = 2), 100% experienced reductions in JAK2 mutations and 50% in MPL mutations.
Pharmacokinetic Profile and Study Status
The pharmacokinetic profile of imetelstat was consistent with previous studies, showing dose-dependent exposure at day 1 of cycle 1, with maximum plasma concentration (Cmax) reached at the end of the 2-hour infusion. Similar Cmax values were reported across treatment cycles, indicating no agent accumulation.
As of the November 4, 2024, data cutoff, 12 patients were still receiving imetelstat. IMproveMF is currently enrolling patients at the 9.4 mg/kg dose of imetelstat for the phase 1b dose confirmation and expansion portion of the study.
Conclusion
"This was a well-tolerated combination with no DLTs in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis who were already on ruxolitinib," Mascarenhas concluded. "The 2 drugs in combination did not affect each other’s pharmacokinetic profiles, and there is some early evidence of efficacy in terms of spleen, symptom, and [possibly] mutational changes."
