Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND

Unmet medical needs remain in patients with red blood cell transfusion-dependent (RBC-TD) lower-risk myelodysplastic syndromes (LR-MDS) who are not responding to or are ineligible for erythropoiesis-stimulating agents (ESAs). Imetelstat, a competitive telomerase inhibitor, showed promising results in a phase 2 trial. We aimed to compare the RBC transfusion independence (RBC-TI) rate with imetelstat versus placebo in patients with RBC-TD LR-MDS.

METHODS

In phase 3 of IMerge, a double-blind, placebo-controlled trial conducted in 118 sites including university hospitals, cancer centres, and outpatient clinics in 17 countries, patients (aged ≥18 years) with ESA-relapsed, ESA-refractory, or ESA-ineligible LR-MDS (low or intermediate-1 risk disease as per International Prognostic Scoring System [IPSS] criteria) were randomly assigned via a computer-generated schedule (2:1) to receive imetelstat 7·5 mg/kg or placebo, administered as a 2-h intravenous infusion, every 4 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent. Randomisation was stratified by previous RBC transfusion burden and IPSS risk group. Patients, investigators, and those analysing the data were masked to group assignment. The primary endpoint was 8-week RBC-TI, defined as the proportion of patients without RBC transfusions for at least 8 consecutive weeks starting on the day of randomisation until subsequent anti-cancer therapy, if any. Primary efficacy analyses were performed in the intention-to-treat population, and safety analyses were conducted in patients who received at least one dose of trial medication or placebo. This trial is registered with ClinicalTrials.gov (NCT02598661; substudy active and recruiting).

FINDINGS

Between Sept 11, 2019, and Oct 13, 2021, 178 patients were enrolled and randomly assigned (118 to imetelstat and 60 to placebo). 111 (62%) were male and 67 (38%) were female. 91 (77%) of 118 patients had discontinued treatment by data cutoff in the imetelstat group versus 45 (75%) in the placebo group; a further one patient in the placebo group did not receive treatment. Median follow-up was 19·5 months (IQR 12·0-23·4) in the imetelstat group and 17·5 months (12·1-22·7) in the placebo group. In the imetelstat group, 47 (40% [95% CI 30·9-49·3]) patients had an RBC-TI of at least 8 weeks versus nine (15% [7·1-26·6]) in the placebo group (rate difference 25% [9·9 to 36·9]; p=0·0008). Overall, 107 (91%) of 118 patients receiving imetelstat and 28 (47%) of 59 patients receiving placebo had grade 3-4 treatment-emergent adverse events. The most common treatment-emergent grade 3-4 adverse events in patients taking imetelstat were neutropenia (80 [68%] patients who received imetelstat vs two [3%] who received placebo) and thrombocytopenia (73 [62%] vs five [8%]). No treatment-related deaths were reported.

INTERPRETATION

Imetelstat offers a novel mechanism of action with durable transfusion independence (approximately 1 year) and disease-modifying activity for heavily transfused patients with LR-MDS who are not responding to or are ineligible for ESAs.

FUNDING

Janssen Research & Development before April 18, 2019, and Geron Corporation thereafter.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests UP received honoraria consultancy fees and research funding from Geron Corporation, BMS/Celgene, AbbVie, Jazz, Janssen, Syros, Servier, Silence Therapeutics, and Takeda. VS served on advisory boards with AbbVie, CTI, Geron Corporation, Gilead, BMS/Celgene, Novartis, Otsuka, Servier, and Syros, and received a travel grant from Janssen. PF received consultancy fees, research funding, and honoraria from BMS/Celgene, and honoraria and research funding from Celgene. MAS received advisory board fees from Geron Corporation, BMS/Celgene, Novartis, and Kurome. MRS received research funding from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; consults or serves on advisory or data safety monitoring boards for AbbVie, BMS/Celgene, Forma, Geron Corporation, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, and TG Therapeutics; and has equity in Karyopharm and Ryvu. YFM received honoraria or consulting fees from Blueprint Medicines, Geron Corporation, and OncLive; participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, and Novartis; and received travel reimbursement from Blueprint Medicines and Morphosys. MD-C consulted or participated in an advisory role with BMS/Celgene, Novartis, GlaxoSmithKline, and Blueprint Medicines; received travel and accommodation expenses from Gilead Sciences; and received honoraria from BMS/Celgene and Novartis. DV consulted or participated in an advisory role with BMS/Celgene, Amgen, GlaxoSmithKline, Novartis, Takeda, Pfizer, BMS/Celgene, Sanofi, Jazz Pharmaceuticals, and SOBI; participated in speakers' bureau at Agios, Novartis, Amgen, GlaxoSmithKline, Astellas Pharma, Pfizer, Jazz Pharmaceuticals, Sanofi/Aventis, BMS/Celgene, Astellas Pharma, Kyte, and Gebro Pharma; and received travel, accommodations, and expenses from BMS/Celgene, Amgen, Pfizer, GlaxoSmithKline, and Jazz Pharmaceuticals. TI consulted or participated in an advisory role at Novartis, AstraZeneca, and AbbVie. AJ consulted or participated in an advisory role at AbbVie, BMS/Celgene, and Novartis; and received travel, accommodations, and expenses from AbbVie and BMS/Celgene. RSK participated on a speaker bureau with Jazz, Servier, AbbVie, CTI, and PharmaEssentia; received advisory board fees or honoraria from BMS/Celgene, Novartis, AbbVie, Jazz, Servier, PharmaEssentia, Taiho, Takeda, Geron Corporation, Gilead/Forty Seven, and CTI; received travel, accommodations, expenses from Jazz, BMS/Celgene, and PharmaEssentia; has stock and other ownership interests in AbbVie; and received research funding from BMS/Celgene. AMZ received research funding (institutional) from BMS/Celgene, AbbVie, Astex, Pfizer, Kura, Medimmune/AstraZeneca, Boehringer Ingelheim, Incyte, Takeda, Novartis, Shattuck Labs, Geron Corporation, Foran, and Aprea; participated in advisory boards, had a consultancy with, or received honoraria from AbbVie, Pfizer, BMS/Celgene, Jazz, Incyte, Agios, Servier, Boehringer Ingelheim, Novartis, Astellas, Daiichi Sankyo, Geron Corporation, Taiho, Seattle Genetics, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Zentalis, Schrodinger, Regeneron, Syros, Schrodinger, and Tyme; and served on clinical trial committees for Novartis, AbbVie, Gilead, Syros, BioCryst, ALX Oncology, Kura, Geron Corporation, and BMS/Celgene. LS, TB, SD, SS, QX, LJS, YW, FH, AI, SN, and FF are employees of Geron Corporation. PB declares no competing interests.