Imetelstat Plus Ruxolitinib Demonstrates Tolerable Safety Profile in Myelofibrosis

The safety profile of imetelstat (Rytelo) in combination with ruxolitinib (Jakafi) for the treatment of patients with myelofibrosis was consistent with that observed in other clinical trials of imetelstat with suggestions of tolerability and dose-dependent preliminary efficacy, according to findings from the phase 1/1b IMproveMF trial (NCT05371964) presented during the 2024 ASH Annual Meeting and Exposition.1

Patients who received the combination at any imetelstat dose level (n = 17) experienced no dose-limiting toxicities (DLTs) within the first 28 days of cycle 1. Eighty-eight percent of patients experienced any-grade treatment-emergent adverse effects (TEAEs), including extremity pain (41%), nausea (35%), increased alanine aminotransferase levels (29%), anemia (29%), thrombocytopenia (24%), fatigue (24%), increased aspartate aminotransferase levels (18%), and neutropenia (18%). Grade 3 TEAEs included anemia (24%), neutropenia (18%), leukopenia (12%), abdominal pain (6%), fatigue (6%), pneumonia (6%), and epistaxis (6%); 47% of patients experienced a grade 3 TEAE. There were no grade 4 or 5 TEAEs reported.

“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,” John O. Mascarenhas, MD, said during the presentation. “This is an early phase study that is [examining the] safety, pharmacokinetics, and early clinical activity of [adding] imetelstat to [to treatment for] patients who are already on ruxolitinib who are having an inadequate response as defined by the investigator.”

Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai, the director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute. He is also the director of the Adult Leukemia Program and lead of clinical investigation within the Myeloproliferative Disorders Program at Mount Sinai in New York, New York.

IMproveMF is an ongoing, open-label, single-arm, multicenter study that is enrolling adult patients with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk myelofibrosis with an ECOG performance status of 0 to 2. In phase 1, patients are required to have received ruxolitinib for at least 12 weeks with at least 4 weeks immediately preceding enrollment at a stable dose; patients treated in phase 1b are JAK inhibitor naive. All patients needed to have peripheral blood blast counts of 10% or less as well as bone marrow blast counts no higher than 10%.

In the phase 1 dose escalation portion, patients received oral ruxolitinib at a dose ranging from 5 mg to 25 mg twice daily. Patients also received intravenous imetelstat every 28 days at a dose 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).

In phase 1b, patients will receive ruxolitinib for at least 12 weeks for a maximum of 24 weeks, including 4 weeks at a stable dose. Subsequently, they will receive ruxolitinib at the same dosing range as phase 1 in combination with intravenous imetelstat at the recommended phase 2 dose every 28 days. Patients in both phases will have an end-of-treatment visit within 30 days after the last dose and post-treatment follow-up every 12 weeks.

The primary end points were the incidence and severity of adverse effects and symptom response rate at week 24.1 Secondary end points 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.2

At baseline, the median time from initial diagnosis of myelofibrosis in the overall population was 36.8 months (range, 5.4-114.5).1 Most patients were male (71%), had primary myelofibrosis (53%), DIPSS intermediate-2 disease (53%), and had less than 1% bone marrow blasts (65%). The median time on ruxolitinib prior to enrolment was 18.8 months (range, 3.4-86.2) and the median ruxolitinib dose level at enrollment was 15 mg (range, 10-25). The baseline spleen volume and total symptom score (TSS) values were 1312.5 cm3 (range, 196.5-3784.3) and 11.0 (range, 0.3-31.5), respectively.

Additional findings from IMproveMF showed that the median change in spleen volume at week 24 across dose levels was 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, the median baseline hemoglobin, leukocyte, neutrophil, and platelet counts were 112.0 g/L (range, 97.0-126.0), 7.8 x 109/L (range, 3.4 x 109/L to 51.1 x 109/L), 4.4 x 109/L (range, 2.5 x 109/L to 32.7 x 109/L), and 192.0 x 109/L (range, 143.0 x 109/L to 364.0 x 109/L), respectively. The median imetelstat treatment duration was 12.1 weeks (range, 4.1-20.9), the median number of cycles was 4 (range, 2-6), and the median ruxolitinib treatment duration was 21.7 weeks (range, 13.1-32.3); no patients in this group required dose reductions.

Among 11 patients with a baseline mutation in the total population, patients displayed variable allele frequency mutation reductions in JAK2 (45%), CALR (45%), MPL (18%), and high molecular risk mutation (55%). Notably, among patients with baseline mutations treated at the 9.4-mg/kg dose (n = 2), 100% experienced reductions in JAK2 mutations and 50% experienced reductions in MPL mutations.

Mascarenhas noted that the pharmacokinetic profile of imetelstat was consistent with what was reported in previous studies. Dose-dependent exposure was reported at day 1 of cycle 1, with maximum plasma concentration (Cmax) being reached at the end of the 2-hour infusion. A similar Cmax was reported across treatment cycles for each dose level, indicating there was no accumulation of the agent.

At the November 4, 2024, data cutoff 12 patients were still receiving treatment with imetelstat. One patient discontinued treatment at the 4.7 mg/kg dose due to withdrawal; 2 discontinued treatment at the 6.0 mg/kg dose due to physician decision and entering another trial; and 2 discontinued treatment at the 7.5 mg/kg dose due to withdrawal and physician decision. 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.

“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 said in conclusion. “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.”

Disclosures: Dr Mascarenhas reported travel support from Novartis and Celgene; research funding from AbbVie, PharmaEssentia, Novartis, Kartos, Geron, Pfizer, Ajax, Bristol Myers Squibb; NS Pharma, CTI BioPharma/SOBI, and Astellas; consultancy with AbbVie, Merck, Blueprint Medicines, PharmaEssentia, Celgene, Karyopharm, Novartis, MorphoSys, Kartos, Geron, Sumitomo, GSK, Keros, Disc, Roche, CTI BioPharma/SOBI, and Incyte; and is on the speakers bureau of Celgene, Novartis, Ariad, and Incyte.

References

1. Mascarenhas JO, Otoukesh S, Bradley T, et al. Trial update from IMproveMF, an ongoing, open-label, dose-escalation and -expansion, phase 1/1b trial to evaluate the safety, pharmacokinetics, and clinical activity of the novel combination of imetelstat with ruxolitinib in patients with intermediate-1, intermediate-2, or high-risk myelofibrosis (MF). Blood. 2024;144(suppl 1):998. doi:10.1182/blood-2024-203800
2. A study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat in combination with ruxolitinib in participants with myelofibrosis. ClinicalTrials.gov. Updated June 4, 2024. Accessed January 3, 2025. https://clinicaltrials.gov/study/NCT05371964