Imetelstat Versus Best Available Therapy in Patients with Intermediate-2 or High-Risk Myelofibrosis Relapsed or Refractory to Janus Kinase Inhibitor in IMpactMF, a Randomized, Open-Label, Phase 3 Trial

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm with limited disease-modifying treatment options. For patients (pt) who are relapsed or refractory (R/R) to Janus kinase inhibitors (JAKi), clinical outcomes are poor with a median overall survival (OS) of ≈1 year (Kuykendall 2018), indicating a need for additional treatment options in this pt population.

Imetelstat is a first-in-class telomerase inhibitor approved in 2024 for the treatment of pts with transfusion-dependent lower-risk myelodysplastic syndromes who are R/R/ineligible for erythropoiesis-stimulating agents. In the phase 2 IMbark trial (NCT02426086; Mascarenhas 2021), pts were randomly assigned to receive 9.4 mg/kg or 4.7 mg/kg imetelstat sodium (equivalent to 8.9 mg/kg and 4.4 mg/kg imetelstat active doses), respectively. In pts with JAKi R/R intermediate-2 (Int2) or high-risk (HR) MF, imetelstat at 9.4 mg/kg once every 3 weeks demonstrated meaningful clinical improvement. Symptom response (total symptom score [TSS] reduction ≥50% per the modified Myelofibrosis Symptom Assessment Form) was observed in 32% (19/59) of pts at week 24. Spleen response (spleen volume reduction ≥35%) was observed in 10% (6/59) of pts at week 24. Median OS was 29.9 months after median study follow-up of 27.4 months. Imetelstat treatment improved bone marrow (BM) fibrosis and reduced variant allele frequency (VAF) of MF driver mutations in a dose-dependent manner. BM fibrosis improvement and VAF reduction correlated with improved OS. The most common grade ≥3 adverse events with imetelstat were thrombocytopenia, anemia, and neutropenia, which were generally manageable, short-lived, and resolved to grade ≤2 in <4 weeks with minimal severe clinical consequences. These results support continued evaluation of imetelstat sodium 9.4 mg/kg in a phase 3, randomized controlled trial.

Methods: IMpactMF (MYF3001; NCT04576156) is a phase 3, open-label, multicenter, randomized (2:1) trial of imetelstat versus best available therapy (BAT) in ≈320 adults with JAKi R/R Int2 or HR MF who are ineligible for allogeneic stem cell transplantation or further JAKi treatment. Relapsed disease is defined as increases in spleen volume after a period of response, and refractory disease is defined as absence of spleen and/or symptom responses after ≥3 months of JAKi therapy. Randomization is to imetelstat sodium 9.4 mg/kg (8.9 mg/kg active dose) intravenously every 21 days or investigator-selected BAT (eg, hypomethylating agents, hydroxyurea, interferon, thalidomide, danazol, chemotherapy, or other non–JAKi-containing therapy). BAT options do not include hematopoietic stem cell transplantation or splenectomy. Eligibility criteria include peripheral blood and marrow blast counts <10% and Eastern Cooperative Oncology Group performance status of 0-2. Chronic liver disease unrelated to underlying MF, active systemic hepatitis infection, or clinically significant cardiovascular disease are not permitted. Pts are stratified at randomization based on Int2 or HR MF per the Dynamic International Prognostic Scoring System and baseline platelet count (platelets ≥75 to <150 × 10⁹/L vs ≥150 × 10⁹/L). Crossover to imetelstat may be permitted for pts who meet progressive disease criteria if they demonstrate a ≥25% increase in spleen volume from baseline during the study or a palpable increase in splenomegaly after 6 months of BAT.

OS, defined as the time interval from randomization date to date of death from any cause, is the primary endpoint of the study. An interim analysis is planned when ≈35% of pts planned to be enrolled have died. Secondary endpoints include week 24 symptom and spleen response rates, progression-free survival, clinical response assessments per modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria, time to and duration of response, reduction in degree of BM fibrosis, safety, pharmacokinetics, and pt-reported outcomes. Biomarkers and mutation analyses will be performed.

As of July 1, 2024, 171 sites are enrolling pts in North and South America, Europe, Middle East, Australia, and Asia. The study is actively enrolling, with 212 pts currently enrolled. An Independent Data Monitoring Committee and Independent Hepatic Expert Committee continue to periodically review the ongoing study. The planned interim analysis is expected in early 2026 and final analysis in early 2027.