Geron : IMpactMF, Randomized, Open-Label, Phase 3 Trial of Imetelstat Versus Best Available Therapy In Patients with Intermediate-2 or High-Risk Myelofibrosis Relapsed or Refractory to Janus Kinase Inhibitors

Published: 2025-06-13 13:46:06 ET GERN

Published on 06/13/2025 at 13:46

IMPACTMF, RANDOMIZED, OPEN-LABEL, PHASE 3 TRIAL OF IMETELSTAT VERSUS BEST AVAILABLE THERAPY IN PATIENTS WITH INTERMEDIATE-2 OR HIGH-RISK MYELOFIBROSIS RELAPSED OR REFRACTORY TO JANUS KINASE INHIBITORS

John O. Mascarenhas,1 Claire Harrison,2 Prithviraj Bose,3 Jean-Jacques Kiladjian,4 Alessandro Lucchesi,5 Alessandro M. Vannucchi,6 Michelle Mudge-Riley,7 Jennifer Riggs,7 Lixian Peng,7 Fei Huang,7 Ying Wan,7 Vivian Rodolf,7 Judy Ho,7 Shyamala Navada,7 Rami S. Komrokji8

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Guy's and St Thomas' National Health Service Foundation Trust, London, UK; 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France; 5Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy; 6University of Florence, Florence, Italy; 7Geron Corporation, Foster City, CA, USA; 8H. Lee Moffitt Cancer Center, Tampa, FL, USA

PF841

‌Introduction

Myelofibrosis (MF) is a progressive, life-threatening myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, constitutional symptoms, cytopenias, and potential leukemic transformation1-3

While Janus kinase inhibitors (JAKi) have transformed therapy in MF, ultimately patients either relapse or become refractory to JAKi and have poor survival rates (median overall survival [OS] ≈1 year), highlighting the need for novel treatment options with distinct mechanisms of action4

Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase enzymatic activity approved in the United States and Europe for the treatment of certain adult patients with lower-risk myelodysplastic syndromes with red blood cell transfusion-dependent anemia who were ineligible for erythropoiesis-stimulating agents (ESAs) or had relapsed or refractory (R/R)/unsatisfactory response to ESAs based on results from the IMerge Phase 3 trial (NCT02598661)5,6

In the Phase 2 IMbark trial (NCT02426086), patients with intermediate-2 (INT-2) or high-risk (HR) MF R/R to JAKi were randomized to receive 4.4 mg/kg or 8.9 mg/kg imetelstat active doses (equivalent to 4.7 mg/kg and 9.4 mg/kg imetelstat sodium, respectively) as an intravenous infusion every

21 days (Table)7

Imetelstat 8.9 mg/kg demonstrated clinically meaningful improvement in symptom response and improved OS compared with the 4.4-mg/kg dose

Imetelstat improved bone marrow (BM) fibrosis and reduced variant allele frequency of MF driver mutations compared with baseline in a dose-dependent manner; these outcomes correlated with the improvement in OS

Patients who had ≥1 grade improvement in BM fibrosis with imetelstat had longer OS than those without fibrosis improvement (median OS, 31.6 months vs 24.6 months; hazard ratio, 0.54 [95% CI, 0.23-1.29])

Grade ≥3 adverse events were generally manageable, of short duration, and resolved to grade ≤2 in

<4 weeks with minimal severe clinical complications

Patients who received 8.9 mg/kg imetelstat in IMbark had a significantly lower risk of death compared with a closely matched cohort of real-world patients with MF who had discontinued ruxolitinib due to lack/loss of response and subsequently received best available therapy (hazard ratio, 0.35; P=.0019)8

The results of IMbark support the continued clinical evaluation of 8.9 mg/kg imetelstat in patients with R/R MF in the Phase 3 IMpactMF trial

Imetelstat

4.4 mg/kg (n=48)

Imetelstat

8.9 mg/kg (n=59)

Symptom responsea at week 24, n (%) [95% CI]

3 (6)

[1-17]

19 (32)

[21-46]

Spleen responseb at week 24, n (%) [95% CI]

0

6 (10)

[4-21]

OS,c median (95% CI) months

19.9 (17.1-NE)

29.9 (22.8-NE)

Improvement in BM fibrosis,d n (%)

4 (20) of 20

evaluable patients

15 (41) of 37

evaluable patients

Grade ≥3 AEs, n (%)

39 (81)

52 (88)

Most common grade ≥3 AEs, n (%)

Thrombocytopenia

11 (23)

24 (41)

Anemia

15 (31)

23 (39)

Neutropenia

5 (10)

19 (32)

Methods

Approximately 320 patients will be randomized as follows: ≈214 to Arm A (imetelstat) and ≈106 to Arm B (BAT)

IMpactMF Phase 3 Study Design

May require Continues until disease progression, tapering off +14-day unacceptable toxicity, or consent

washout from all prior therapy, including JAKi treatment

withdrawal

Continues until death, loss to follow-up, withdrawal of consent, or study end

R/R to JAKi

(N≈320)

Arm A

Imetelstat

8.9 mg/kg imetelstat active dose

(equivalent to 9.4 mg/kg imetelstat sodium)

IV every 21 days

2:1

Within 30 days after the last dose

Investigator-selected, non-JAKi therapya

thalidomide or an to cross over

analog of thalidomide, to imetelstat

interferon, danazol, HMA, chemotherapy, or combination

of treatments)

Key Eligibility Criteria

Adults with diagnosis of primary MF per the revised WHO criteria; or post-essential thrombocythemia MF or post-polycythemia vera MF per the IWG-MRT

INT-2 or HR MF (per DIPSS)

ECOG PS ≤2

R/R to JAKi treatment as defined as:

Treatment with JAKi for ≥6 months, including ≥2 months at an optimal dose as assessed by the

investigator and ≥1 of the following:

No decrease in spleen volume (<10% by MRI or CT) from the start of treatment with JAKi

No decrease in spleen size (<30% by palpation or length by imaging) from start of treatment with JAKi

No decrease in symptoms (<20% by MFSAF v4.0/myeloproliferative neoplasm SAF) from start of treatment with JAKi

Score of ≥15 on TSS, assessed using the MFSAF v4.0 during screening

Treatment with JAKi for ≥3 months with maximal doses (eg, 20-25 mg twice daily ruxolitinib) without a spleen or symptom response and would not benefit from remaining on treatment for 6 months

Following maximum tolerated doses of JAKi for ≥3 months duration, having documented

relapsed disease defined as either:

o increase in spleen volume from time of best response by 25% measured by MRI or CT, or

o increase in spleen size by palpation, CT, or ultrasound

And not a candidate for further JAKi therapy

Measurable splenomegaly demonstrated by palpable spleen measuring ≥5 cm below the left costal margin or a spleen volume ≥450 cm3 by MRI or CT

Absolute neutrophil count ≥1.5×109/L and platelets ≥75×109/L

Peripheral blood blast count <10%

Bone marrow blast count <10%

Active symptoms of MF on the MFSAF v4.0: symptom score of ≥5 points (on a 0-10 scale) on ≥1 symptoms or a score of ≥3 on ≥2 of the following symptoms: fatigue, night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain

Eligible patients will be stratified based on (a) INT-2 or HR per Dynamic International Prognostic Scoring System, and (b) platelet count at study entry (platelets ≥75×109/L and <150×109/L vs ≥150×109/L)

Study Endpoints

PRIMARY ENDPOINT

Overall survival

AE, adverse event; BM, bone marrow; MF, myelofibrosis; MFSAF, Myelofibrosis Symptom Assessment Form; NE, not estimable; OS, overall survival; R/R, relapsed or refractory.

aDefined as ≥50% total symptom score reduction per the modified MFSAF v4.0. bDefined as spleen volume reduction ≥35%. cMedian follow-up = 27.4 months; clinical cutoff was October 22, 2018. dDefined as ≥1

grade improvement on central assessment.

CT, computed tomography; DIPSS, Dynamic International Prognostic Scoring System; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, high risk; INT, intermediate; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; JAKi, Janus kinase inhibitor; MF, myelofibrosis; MFSAF, Myelofibrosis Symptom Assessment Form; IV, intravenous; MRI, magnetic resonance imaging; R/R, relapsed or refractory; SAF, Symptom Assessment Form; TSS, total symptom score; WHO, World Health Organization.

An interim analysis is planned when ≈35% of the planned enrolled patients have died; the final analysis

is planned when >50% of the planned enrolled patients have died

Efficacy analyses will be performed based on the intent-to-treat population

Kaplan-Meier method will be used to estimate the OS distribution for each treatment; treatment effect (hazard ratio) and its 2-sided 95% CI will be estimated using a stratified Cox regression model with treatment as the explanatory variable

- To evaluate the confounding effect of crossover and subsequent therapy, proportional hazard assumptions will be evaluated, and sensitivity analysis of OS will be explored

Symptom response rate at week 24, spleen response rate at week 24, complete response, partial response, and clinical improvement per modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria will be summarized with frequency and percentage along with a 2-sided 95% exact CI by treatment arm

A sequential gate-keeping procedure and Hochberg procedure will be implemented to ensure that the overall type I error rate for the secondary endpoints is controlled

Here, we present the methodology of IMpactMF (MYF3001; NCT04576156), a randomized, open-label, Phase 3 study evaluating the efficacy and safety of imetelstat versus best available therapy (BAT) in patients with INT-2 or HR MF R/R to JAKi who are ineligible for allogeneic stem cell transplantation or further JAKi treatment

For the pharmacokinetic analysis, all plasma concentrations below the lowest quantifiable

BAT, best available therapy; HMA, hypomethylating agent; HR, high risk; INT, intermediate; IV, intravenous; JAKi, Janus kinase inhibitor; MF, myelofibrosis; PD, progressive disease; R/R, relapsed or refractory.

SECONDARY ENDPOINT

Symptom response rate at week 24 (≥50% reduction in TSS measured by MFSAF v4.0)

PFS

Spleen response rate at week 24 (≥35% spleen volume reduction by MRI or CT)

Complete remission, partial remission, clinical improvement, spleen response, symptom response, and anemia response per modified 2013 IWG-MRT criteria

Time to and duration of responses

Reduction in the degree of bone marrow fibrosis

Safety

PK and immunogenicity of imetelstat

PROs as measured by the EORTC QLQ-C30 and EuroQol-EQ-5D (EQ-5D-5L) questionnaires

aHematopoietic stem cell transplantation or splenectomy are not be permitted as BAT. bMust demonstrate ≥25% increase in spleen volume from baseline during the study or a palpable increase in splenomegaly after

6 months of BAT.

Study Status

IMpactMF is actively recruiting patients

As of February 2025, 172 sites in North and South America, Europe, the Middle East, Australia, and Asia

have enrolled ≈80% of patients

The planned interim analysis (when ≈35% of patients planned to be enrolled have died) is expected in the second half of 2026 and final analysis (when >50% of the planned enrolled patients have died) is expected in the second half of 2028

EXPLORATORY ENDPOINTS

Association between baseline cytogenetic and mutational status and clinical responses; change in mutant allele burden (molecular response)

Correlation between baseline TA, TL, or hTERT and OS, symptom response, or spleen response

BAT, best available therapy; CT, computed tomography; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items; hTERT, human telomerase reverse transcriptase; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; MFSAF, Myelofibrosis Symptom Assessment Form; MRI, magnetic resonance imaging; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; PRO, patient-reported outcome; TA, telomerase activity; TL, telomere length; TSS, total symptom score.

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Kuykendall AT, et al. Ann Hematol. 2018;97(3):435-441.

RYTELO® (imetelstat) for injection, for intravenous use. Package insert. Geron Corporation; 2024.

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The authors thank all the patients and caregivers for their participation in this study and acknowledge the collaboration and commitment of all investigators and their research support staff

This study was funded by Geron Corporation

Copies of this poster obtained through

concentration or missing data will be labeled as such in the concentration data presentation and will be excluded in the calculation of summary statistics

Descriptive statistics will be used for safety parameters and patient-reported outcome measures

All authors contributed to and approved the presentation; writing

and editorial support were provided by Meredith Rogers, MS, CMPP, of The Lockwood Group (Stamford, CT, USA), funded by Geron Corporation

the Quick Response (QR) code are for personal use only and may not be reproduced without permission from the author of this poster.

Presented at the 30th European Hematology Association Annual Congress; June 12-15, 2025; Milan, Italy

ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04576156

Contact information: [email protected]

Disclaimer

Geron Corporation published this content on June 13, 2025, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on June 13, 2025 at 17:45 UTC.