Paper Details

ABSTRACT

Introduction: In the phase 2 IMbark trial (NCT02426086), imetelstat (IME) treatment was associated with prolonged survival and disease-modifying activity in myelofibrosis (MF). Preclinical investigations further showed that combining IME with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) achieved greater suppression of disease burden than either agent alone. The ongoing open-label, single-arm, phase 1/1b IMproveMF study (NCT05371964) is assessing the efficacy and safety of IME in combination with RUX in patients (pts) with Dynamic International Prognostic Scoring System intermediate (INT)-1, INT-2, or high-risk (HR) MF. Here, we provide updated safety data for phase 1 pts and phase 1b cohorts A and B.

Methods: In phase 1 (dose finding) of IMproveMF, RUX treatment for ≥12 weeks, including ≥4 weeks at a stable dose, was required immediately before IME intravenous (IV) infusion every 4 weeks at active doses 4.4, 5.6, 7.1, and 8.9 mg/kg. IME 8.9 mg/kg was identified as the recommended phase 2 dose (RP2D), and no dose-limiting toxicities were observed at this dose. Phase 1b (dose confirmation and expansion) enrolled adult pts with INT-1/INT-2/HR MF, an Eastern Cooperative Oncology Group performance status ≤2, peripheral blood and bone marrow blasts <10%, ≥2 active symptoms with a score of ≥3 or a total score of ≥10 on the MF Symptom Assessment Form v4.0, an absolute neutrophil count of ≥1.5×10⁹/L independent of growth factor support, a platelet count of ≥75×10⁹/L (updated criterion), no active systemic hepatitis infection, no acute or chronic liver disease unrelated to underlying MF, and no prior history of hematopoietic stem cell transplantation.

Phase 1b comprises 2 cohorts. In cohort A (JAKi-naive pts), upon enrollment, pts started RUX for ≥12 weeks (maximum 24 weeks); once the RUX dose was stable for 4 weeks, 8.9 mg/kg IME IV every 4 weeks was added. Per the updated protocol (November 2025), the study is no longer recruiting pts into cohort A; existing enrollees will continue in the study per protocol. In cohort B, eligible pts receiving first-line RUX per standard of care for ≥12 weeks and a stable dose for ≥4 weeks will begin 8.9 mg/kg IME IV every 4 weeks after enrollment. Treatment continues until unacceptable toxicity, disease progression, or withdrawal. The primary endpoints are safety and symptom response rate at week 24 (proportion of pts with ≥50% reduction in total symptom score [TSS] at week 24 from the start of IME+RUX treatment). Secondary endpoints include absolute change in TSS at week 24, average absolute change in TSS over 24 weeks, spleen response (≥35% spleen volume reduction) at week 24, and progression-free survival.

Results: As of 07/01/2026, 5 of 19 pts enrolled in phase 1 are still undergoing treatment (3 pts receiving IME 8.9 mg/kg and 1 pt each receiving 4.4 mg/kg and 5.6 mg/kg); only 2/19 pts discontinued due to a treatment-emergent adverse event (TEAE) (none in the 8.9 mg/kg group). No pts in the IME 8.9 mg/kg group had a dose reduction due to a TEAE. The median duration of IME exposure in the 8.9 mg/kg group was 38.3 weeks (range: 20.3-80.1).

By the data cutoff date, phase 1b (IME 8.9 mg/kg) enrolled 10 pts (cohort A, n=2; cohort B, n=8) with 9 pts still receiving treatment (1 pt withdrew from cohort A). The median duration of IME exposure was 28.2 weeks (range: 8.1-48.3) in cohort A and 6.1 weeks (range: 0.1-16.1) in cohort B. Hemoglobin values remained stable over time for all pts in both cohorts. Additional efficacy information will be provided if available. In the pts who received IME + RUX combination treatment (N=10) in phase 1b, no TEAEs were reported in ≥15% of pts. Among the 2 pts in cohort A, only 1 TEAE was reported, and it occurred during the single-RUX period (no TEAEs occurred during the combination treatment period). Among the 8 pts in cohort B, 2 TEAEs were reported in 1 pt each (12.5%); 3 pts reported grade 3 TEAEs (n=1 each: anemia, oral hemorrhage, sepsis) and there were no grade 4/5 events.