Geron : Outcomes of Imetelstat Therapy In Patients with Ring Sideroblast-Negative Lower-Risk Myelodysplastic Syndromes From The Pooled Imerge Study Populations

Published: 2025-06-14 14:29:05 ET GERN

Published on 06/14/2025 at 14:29

‌Background

The majority of lower-risk myelodysplastic syndromes (LR-MDS) are in the heterogenous group of ring sideroblast (RS)-negative disease1

Current treatment options are limited in number and efficacy, particularly for patients who are either ineligible for erythropoiesis-stimulating agents (ESAs) or whose disease is relapsed or refractory to ESAs1,2

First-line luspatercept treatment demonstrated differential efficacy in RS-positive compared with RS-negative disease; a benefit in RS-positive disease was also observed with luspatercept in the second-line setting compared with placebo3,4

Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase activity approved in the United States and Europe for the treatment of certain adult patients with LR-MDS with red blood cell (RBC) transfusion-dependent (TD) anemia who were relapsed or refractory5/had unsatisfactory6 response to or ineligible for ESAs based on the results of the pivotal IMerge trial (NCT02598661)7

Overall, results showed a clinically significant benefit with imetelstat versus placebo and a generally manageable safety profile in this patient population

Of the RS-negative LR-MDS subpopulation in Phase 3 IMerge (imetelstat, n=44; placebo, n=23), higher proportions treated with imetelstat versus placebo (32% vs 9% [nominal P=.038] and 20% vs 0% [nominal P=.019]) achieved ≥8-week and ≥24-week red blood cell (RBC)-transfusion independence (TI), respectively

This post hoc analysis reports outcomes of patients with RS-negative disease from the pooled IMerge populations

Methods

IMerge was a Phase 2/3 trial with a separate ventricular repolarization substudy that was included as a double-blind, randomized 2:1, placebo-controlled assessment

IMerge included patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk, RBC-TD LR-MDS relapsed or refractory to/ineligible for ESAs

Differences between the patient populations in the QTc substudy and the Phase 3 trial are presented in Figure 1

Notably, patients in the QTc substudy could cross over from placebo to imetelstat after 2 cycles at the investigator's discretion

In each part of IMerge, adult patients were randomized to 7.1 mg/kg imetelstat active dose (equivalent to 7.5 mg/kg imetelstat sodium) or placebo, both administered as a 2-hour intravenous infusion every 4 weeks

In this post hoc analysis, imetelstat-treated patients were pooled from Phase 2, Phase 3, and the QTc substudy of IMerge and analyzed on the basis of World Health Organization (WHO) 20088 classification for RS status

Efficacy endpoints included ≥8-week and ≥24-week RBC-TI rates, and hematologic improvement-erythroid per International Working Group 2006 (transfusion reduction ≥4 U/8 weeks and hemoglobin rise ≥1.5 g/dL lasting ≥8 weeks) and 2018 (low and high transfusion burden) criteria across prior treatment subgroups

Proportion of patients with RBC-TI, and other binary endpoints, were summarized with percentage and a 2-sided 95% CI using the exact Clopper-Pearson method

Patient-reported outcomes were assessed with validated Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue9

Sustained meaningful improvement in fatigue was defined as a ≥3-point increase in FACIT-Fatigue

score for ≥2 consecutive assessments

Single-arm, open-label

Double-blind, randomized 2:1

Patient population (all treated) Patient population (ITT)

IPSS low- or INT-1-risk MDS • IPSS low- or INT-1-risk MDS

Relapsed or refractorya to ESA or • Relapsed or refractorya to ESAs or EPO >500 mU/mL EPO >500 mU/mL (ESA ineligible)

Transfusion dependent: ≥4 RBC U/ • Transfusion dependent: ≥4 RBC U/ 8 weeks over 16-week prestudy 8 weeks over 16-week prestudy period period

Inclusion of del(5q) and allowance of • Non-del(5q), no prior treatment prior LEN and HMA with LEN or HMAs

Patient population differed from that of Phase 3 IMerge as follows:

Inclusion of patients with del(5q) MDS

Allowance of prior LEN and HMA use

Option to cross over from placebo to imetelstat after 2 cycles at the investigator's discretion

Imetelstat

7.1 mg/kg active dose (equivalent to 7.5 mg/kg

imetelstat sodium)

IV every 4 weeks (n=57)

Imetelstat

7.1 mg/kg active dose (equivalent to 7.5 mg/kg

imetelstat sodium)

IV every 4 weeks (n=118)

Data cutoff date: October 13, 2023

Imetelstat

7.1 mg/kg active dose (equivalent to 7.5 mg/kg

imetelstat sodium)

IV every 4 weeks (n=35)

Crossover from placebo to imetelstat

(n=16)

Data cutoff date: October 13, 2024

Results

Baseline characteristics for the 78 patients with RS-negative MDS included in this analysis are presented in Table 1

The median RBC transfusion burden was 6.5 U/8 weeks, and most patients had prior ESA exposure

Patients with RS-negative LR-MDS in this pooled population had a median follow-up of 26 months (range, 1-87)

Median imetelstat treatment duration was 25 weeks (range, 0.1-260), and median number of cycles of imetelstat was 6.5 (range, 1-66)

Characteristic

RS negative (n=78)

Age, median (range), y

71.0 (44-86)

Sex, n (%) Female Male

29 (37)

49 (63)

Time since diagnosis, median (range), y

2.8 (0.1-12.9)

IPSS risk category, n (%)

Low Intermediate-1

47 (60)

31 (40)

Pretreatment Hb, median (range), g/dL

77 (51-101)

Prior RBC transfusion burden, median (range), RBC U/8 weeks

6.5 (4-33)

Prior RBC transfusion burden, n (%)

≤6 U/8 weeks

>6 U/8 weeks

39 (50)

Serum EPO, median (range), mU/mL

422 (16-5424)

Serum EPO level, n (%)

≤500 mU/mL

>500 mU/mL Missing

40 (51)

36 (46)

2 (3)

Prior therapies, n (%)

ESA

Luspatercept Lenalidomide HMA

62 (79)

5 (6)

8 (10)

7 (9)

Mutations at baseline, n (%)a

Missingb

37 (63)

17 (29)

7 (12)

Mutated genes, n (%)a

SF3B1 TET2 ASXL1 DNMT3A SRSF2

25 (42)

17 (29)

11 (19)

10 (17)

9 (15)

EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; RBC, red blood cell; RS, ring sideroblast.

aMutation data were available for 59 patients in the Phase 2 and Phase 3 study. bIncludes 7 patients with mutation sample available for whom mutation status at baseline was not defined.

Efficacy results are presented in Figure 2, showing clinical activity in patients with RS-negative LR-MDS

Results from the IMerge Phase 3 registration trial are shown in green overlaid lines

100

Phase 3 IMerge results7

n/N= 0

OUTCOMES OF IMETELSTAT THERAPY IN PATIENTS WITH RING SIDEROBLAST-NEGATIVE LOWER-RISK MYELODYSPLASTIC SYNDROMES FROM THE POOLED IMERGE STUDY POPULATIONS

Valeria Santini,1 Uwe Platzbecker,2 Amer M. Zeidan,3 Mikkael A. Sekeres,4 Azra Raza,5 Moshe Mittelman,6 Sylvain Thépot,7 Rena Buckstein,8 Ulrich Germing,9 Yazan F. Madanat,10 María Díez-Campelo,11 David Valcárcel,12 Anna Jonášová,13 Souria Dougherty,14 Qi Xia,14 Libo Sun,14 Shyamala Navada,14 Faye Feller,14 Michael R. Savona,15 Rami S. Komrokji,16 Pierre Fenaux17

1MDS Unit, Hematology, DMSC University of Florence, AOUC, Florence, Italy; 2National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; 3Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA; 4Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; 5Columbia University Medical Center, New York, NY, USA;

6Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; 7Centre Hospitalier Universitaire d'Angers, Angers, France; 8Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 9Clinic for Haematology, Oncology and Clinical Immunology, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany; 10Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; 11University Hospital of Salamanca, Salamanca, Spain; 12Hospital Universitario Vall d'Hebron, Barcelona, Spain; 131st Medical Department - Hematology, General Hospital, Prague, Czech Republic; 14Geron Corporation, Foster City, CA, USA; 15Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; 16Moffitt Cancer Center, Tampa, FL, USA; 17Hôpital Saint-Louis, Université de Paris 7, Paris, France

PS1622

Median length of the RBC-TI time period for ≥8-week, ≥24-week, and ≥1-year RBC-TI responders indicates durable TI beyond the outcome threshold (Figure 3, Figure 4)

n/N=

≥8-week RBC-TI 26/78

44 weeks

≥24-week RBC-TI 16/78

123 weeks

≥1-year RBC-TI 10/78

141 weeks

Time, weeks

100

120

140

160

RBC, red blood cell; TI, transfusion independence.

RBC-TI ≥8 weeks RBC transfusion Treatment ongoing

100

200

Median (range) changes in hemoglobin from baseline are shown in Figure 5

Median hemoglobin rises in the longest RBC-TI interval of ≥8-week, ≥24-week, and ≥1-year RBC-TI responders were 4.3 g/dL, 5.2 g/dL, and 5.3 g/dL, respectively

Pretreatment Hb level

Maximum Hb in longest RBC-TI interval, excluding first 2 weeks

n/N=

26/78

16/78

10/78

Patient-reported FACIT-Fatigue was an exploratory outcome analyzed for the Phase 3 part of IMerge only, as data were not available for the Phase 2 and QTc substudy parts

Of the 118 imetelstat-treated and 57 placebo-treated patients in the Phase 3 part of IMerge with evaluable data, 44 and 20, respectively, had RS-negative status

Nineteen (43%) imetelstat-treated patients and 6 (30%) placebo-treated patients reported fatigue improvement (Figure 6)

100

Imetelstat Placebo

Phase 3 IMerge results7

RS negative

FACIT, Functional Assessment of Chronic Illness Therapy; LR-MDS, lower-risk myelodysplastic syndromes; n/N, number with event/number in population; RS, ring sideroblast.

aData corresponds to Phase 3 population. The Clopper-Pearson method was used to generate 95% CIs.

In this post hoc analysis of the 3 parts of IMerge, patients with RS-negative

LR-MDS who were relapsed or refractory to or ineligible for ESAs appeared to experience clinical benefit with imetelstat treatment

A rise in hemoglobin was observed in RS-negative patients who achieved RBC-TI with imetelstat

More RS-negative patients receiving imetelstat as compared to placebo showed an improvement in fatigue in the Phase 3 portion of IMerge

These results were consistent with prior findings7,8 and support that imetelstat has clinical activity in patients with difficult-to-treat RS-negative disease

This analysis was limited by differing methodologies of the Phase 2, Phase 3, and QTc substudy parts of IMerge and by the small number of patients in some subgroups

Conclusions

Fattizzo B, et al. Front Oncol. 2022:12:795955.

Volpe VO, et al. Ther Adv Hematol. 2021;12:2040620720986641.

Della Porta MG, et al. Lancet Haematol. 2024;11(9):e646-e658.

Fenaux P, et al. N Engl J Med. 2020;382(2):140-151.

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

RYTELO® (imetelstat) summary of product characteristics. Geron Corporation; 2025.

Platzbecker U and Santini V, et al. Lancet. 2024;403(10423):249-260.

Vardiman, JW, et al. Blood. 2009; 114(5):937-951.

Yellen SB, et al. J Pain Symptom Manage. 1997;13(2):63-74.

Steensma DP, et al. J Clin Oncol. 2021;39(1):48-56.

Lennox AL, et al. Clin Translat Sci. 2025;18(2):e70169.

EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HMA, hypomethylating agent; INT, intermediate; IPSS, International Prognostic Scoring System; ITT, intention-to-treat; IV, intravenous; LEN, lenalidomide; MDS, myelodysplastic syndromes; QTc, QT correction; RBC, red blood cell.

aReceived ≥8 weeks of ESA treatment (EPO alfa ≥40,000 U, EPO beta ≥30,000 U, or darbepoetin alfa 150 µg or equivalent per week) without Hb rise ≥1.5 g/dL or decreased RBC transfusion requirement ≥4 U every 8 weeks or transfusion dependence or reduction in Hb by ≥1.5 g/dL after hematologic improvement from ≥8 weeks of ESA treatment.

≥8-week

≥24-week

≥1-year

Overall

LTBa

HTBb

Total

Transfusion reduction

≥4 U/8 weeks

Hb rise

≥1.5 g/dL/

8 weeks

RBC-TI

HI-E IWG 2018c

HI-E IWG 2006c

Hb, hemoglobin; HI-E, hematologic improvement-erythroid; HTB, high transfusion burden; IWG, International Working Group; LR-MDS, lower-risk myelodysplastic syndromes; LTB, low transfusion burden; n/N, number with event/number in population; RBC, red blood cell; RS, ring sideroblast; TI, transfusion independence.

aLTB defined as 3-7 RBC U in 16 weeks in ≥2 transfusion episodes, and a maximum of 3 in 8 weeks. bHTB defined as ≥8 RBC U in 16 weeks, or ≥4 RBC U in 8 weeks. cHb

analyses were based on a central laboratory data in the Phase 3 part of IMerge, but only local laboratory data were collected in the Phase 2 and QTc substudy parts.

≥8-week RBC-TI

≥24-week RBC-TI

≥1-year RBC-TI

Hb, hemoglobin; RBC, red blood cell; TI, transfusion independence.

Error bars represent minimum and maximum (range), and box ends represent the interquartile range.

aHb analyses were based on a central laboratory data in the Phase 3 part of IMerge, but only local laboratory data were collected in the Phase 2 and QTc substudy parts.

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. All authors contributed to and approved the presentation; writing and editorial support were provided by Jeremy J. Henriques, PhD, CMPP, of The Lockwood Group (Stamford, CT, USA), funded by Geron Corporation

Copies of this poster obtained through 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/NCT02598661

Contact information: [email protected]

Disclaimer

Geron Corporation published this content on June 14, 2025, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on June 14, 2025 at 18:28 UTC.