Geron : Outcomes with Imetelstat by Serum Erythropoietin Levels In Patients with Lower-Risk Myelodysplastic Syndromes Who Were Treatment Naive or Who Had Prior Treatment with Erythropoiesis-Stimulating Agents

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

Published on 06/14/2025 at 14:29

‌Background

Erythropoiesis-stimulating agents (ESAs) are the preferred first-line treatment option for patients with non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) and anemia1,2

However, ~10% of patients with LR-MDS are ineligible for ESAs due to an elevated baseline serum erythropoietin (sEPO) level >500 mU/mL3

Current treatment options are limited in number and efficacy for patients who are ineligible for ESAs as well as for those whose disease is relapsed or refractory to ESAs2

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 anemia who were ineligible for ESAs or had relapsed or refractory/unsatisfactory response to ESAs based on results from the IMerge Phase 3 trial (NCT02598661)4-6

In IMerge, imetelstat demonstrated clinically significant benefit compared with placebo, including RBC transfusion independence (TI), and a generally manageable safety profile in this patient population

This post hoc analysis examined outcomes with imetelstat by baseline sEPO level in patients with LR-MDS pooled from the 3 parts of IMerge (Phase 2, Phase 3, and QTc substudy)

Methods

IMerge comprised the following 3 parts: Phase 2, Phase 3, and QTc substudy (Figure 1)

Patients who had del(5q) or prior therapy with lenalidomide or HMAs were excluded from Phase 3 but were allowed in Phase 2 and the QTc substudy

In the QTc substudy, patients assigned to the placebo group could cross over to receive imetelstat after 2 cycles at the investigator's discretion

In all 3 parts of IMerge, adults received 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

Outcomes for this analysis included ≥8-week, ≥24-week, and ≥1-year RBC-TI rates; hematologic improvement-erythroid (HI-E) per International Working Group (IWG) 2006 (transfusion reduction ≥4 U/8 weeks and hemoglobin rise ≥1.5 g/dL lasting

≥8 weeks) and IWG 2018 (low transfusion burden and high transfusion burden)

criteria; and duration of RBC-TI for responders

Phase 2 IMerge7

Single-arm, open-label

Phase 3 IMerge6

Double-blind, randomized 2:1

QTc Substudy of Phase 3 IMerge8

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

Transfusion dependent: ≥4 RBC U/ • Transfusion dependent: ≥4 RBCU/ 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

Imetelstat Imetelstat

7.1 mg/kg active dose 7.1 mg/kg active dose

(equivalent to 7.5 mg/kg (equivalent to 7.5 mg/kg

imetelstat sodium) imetelstat sodium)

IV every 4 weeks IV every 4 weeks (n=57) (n=118)

Data cutoff date: October 13, 2023

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=35)

Crossover from placebo to imetelstat

(n=16)

Data cutoff date: October 13, 2024

Results

At the data cutoff dates (Phase 2/3, October 13, 2023; QTc substudy, October 13, 2024), 210 imetelstat-treated patients pooled from IMerge were included in this analysis

13 patients were treatment naive (no prior ESA or other prior therapies) and had sEPO >500 mU/mL

112 patients had prior ESA and sEPO <200 mU/mL

43 patients had prior ESA and sEPO 200 to ≤500 mU/mL

42 patients had prior ESA and sEPO >500 mU/mL

Baseline characteristics for the 13 treatment-naive patients were similar to the other patient groups (Table 1)

Median age was 71 years (range, 49-81), median transfusion burden was 6 RBC U/ 8 weeks (range, 4-11), 31% of patients required >6 RBC U/8 weeks, 38% had intermediate-1-risk International Prognostic Scoring System disease, 85% had ring sideroblast-negative status, and the median time since initial diagnosis was 1 year (range, 0.1-8)

Characteristics

Treatment naive and sEPO

>500 mU/mL (n=13)

Prior ESA and sEPO

<200 mU/mL (n=112)

Prior ESA and sEPO 200 to

≤500 mU/mL

(n=43)

Prior ESA and sEPO

>500 mU/mL (n=42)a

Age, median (range), y

71.0 (49-81)

72.5 (46-87)

71.0 (50-85)

70.0 (43-86)

Male, n (%)

6 (46)

71 (63)

26 (60)

29 (69)

Time since diagnosis, median (range), y

0.9 (0.1-7.8)

3.8 (0.3-24.4)

3.5 (0.6-21.9)

3.4 (0.5-12.9)

WHO classification, n (%)

RS+

2 (15)

83 (74)

31 (72)

22 (52)

RS−

11 (85)

28 (25)

12 (28)

20 (48)

IPSS risk category, n (%)

Low

8 (62)

79 (71)

28 (65)

24 (57)

Intermediate-1

5 (38)

33 (29)

15 (35)

18 (43)

Pretreatment Hb, median (range), g/dL

75.5 (63-84)

79.4 (51-93)

78.7 (64-101)

75.0 (53-90)

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

6 (4-11)

6 (4-17)

7 (4-33)

8 (4-15)

Prior RBC transfusion burden, n (%)

≤6 RBC U/8 weeks

9 (69)

63 (56)

19 (44)

13 (31)

>6 RBC U/8 weeks

4 (31)

49 (44)

24 (56)

29 (69)

sEPO, median (range), mU/mL

749.9

(535.0-5424.0)

84.4

(6.0-196.0)

307

(200-497.3)

763.5

(509.0-4460.0)

Prior ESA, n (%)

112 (100)

43 (100)

42 (100)

Prior luspatercept, n (%)

11 (10)

10 (23)

10 (24)

Prior lenalidomide, n (%)

12 (11)

4 (9)

8 (19)

Prior HMA, n (%)

9 (8)

5 (12)

6 (14)

PS1640

SYNDROMES WHO WERE TREATMENT NAIVE OR WHO HAD PRIOR TREATMENT WITH ERYTHROPOIESIS-STIMULATING AGENTS

Rami S. Komrokji,1 Michael R. Savona,2 Valeria Santini,3 Amer M. Zeidan,4 Mikkael A. Sekeres,5 Pierre Fenaux,6 Azra Raza,7 Moshe Mittelman,8 Sylvain Thépot,9 Rena Buckstein,10 Ulrich Germing,11 María Díez-Campelo,12 David Valcárcel,13 Anna Jonášová,14 Qi Xia,15 Libo Sun,15 Shyamala Navada,15 Tymara Berry,15 Faye Feller,15 Uwe Platzbecker,16 Yazan F. Madanat17

1Moffitt Cancer Center, Tampa, FL, USA; 2Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; 3MDS Unit, Hematology, DMSC University of Florence, AOUC, Florence, Italy; 4Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA; 5Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; 6Hôpital Saint-Louis, Université de Paris 7, Paris, France; 7Columbia University Medical Center, New York, NY, USA; 8Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; 9Centre Hospitalier Universitaire d'Angers, Angers, France; 10Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 11Clinic for Haematology, Oncology and Clinical Immunology, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany; 12University Hospital of Salamanca, Salamanca, Spain; 13Hospital Universitario Vall d'Hebron, Barcelona, Spain; 141st Medical Department - Hematology, General Hospital, Prague, Czech Republic; 15Geron Corporation, Foster City, CA, USA; 16National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; 17Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

OUTCOMES WITH IMETELSTAT BY SERUM ERYTHROPOIETIN LEVELS IN PATIENTS WITH LOWER-RISK MYELODYSPLASTIC

100

Median duration of ≥8-week RBC-TI

Treatment naive (sEPO >500 mU/mL), 43 weeks Prior ESA (sEPO <200 mU/mL), 55 weeks

Prior ESA (sEPO 200 to ≤500 mU/mL), 73 weeks

Prior ESA (sEPO >500 mU/mL), 48 weeks

Treatment naive and sEPO >500 mU/mL (n=13) Prior ESA and sEPO <200 mU/mL (n=112)

Prior ESA and sEPO 200 to ≤500 mU/mL (n=43)

Prior ESA and sEPO >500 mU/mL (n=42)

n/N=

≥8-week RBC-TI

≥24-week RBC-TI

≥1-year RBC-TI

112

Patients, %

ESA, erythropoiesis-stimulating agent; n/N, number with event/number in population; RBC, red blood cell; sEPO, serum erythropoietin; TI, transfusion independence.

Among treatment-naive patients, HI-E per IWG 2006 (Figure 3) and IWG 2018 (Figure 4) was achieved by 69% and 62% with imetelstat, respectively

100

Treatment naive and sEPO >500 mU/mL (n=13) Prior ESA and sEPO <200 mU/mL (n=112)

Prior ESA and sEPO 200 to ≤500 mU/mL (n=43)

Prior ESA and sEPO >500 mU/mL (n=42)

n/N=

HI-E per IWG 2006

≥4 U RBC reduction/ 8 wk ≥1.5 g/dL Hb rise/ 8 wk

112

Patients, %

ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HI-E, hematologic improvement-erythroid; IWG, International Working Group; n/N, number with event/number in population; RBC, red blood cell; sEPO, serum erythropoietin.

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.

100

Treatment naive and sEPO >500 mU/mL (n=13) Prior ESA and sEPO <200 mU/mL (n=112)

Prior ESA and sEPO 200 to ≤500 mU/mL (n=43)

Prior ESA and sEPO >500 mU/mL (n=42)

n/N=

Total

HI-E responseb

LTBd

Major HI-E responseb Minor HI-E responsec

HTBe

112

Among imetelstat-treated patients who achieved ≥8-week RBC-TI, median hemoglobin levels increased from baseline, regardless of whether they were treatment naive or had prior ESA across baseline sEPO levels (Figure 5)

- Median hemoglobin rise in the longest RBC-TI interval was 4.2 g/dL for treatment-naive patients with sEPO >500 mU/mL, 3.8 g/dL for patients with prior ESA and sEPO <200 mU/mL, 4.0 g/dL for patients with prior ESA and sEPO 200 to ≤500 mU/mL, and 2.5 g/dL for patients with prior ESA and sEPO >500 mU/mL

Pretreatment Hb level

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

n/N= 0

7/13

56/112

14/43

9b/42

Treatment naive Prior ESA Prior ESA Prior ESA and sEPO and sEPO and sEPO 200 to and sEPO

>500 mU/mL <200 mU/mL ≤500 mU/mL >500 mU/mL

Hb, g/dL

ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; RBC, red blood cell; sEPO, serum erythropoietin; 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.

In this post hoc pooled analysis, patients with LR-MDS who were treatment naive and had a high sEPO level at baseline experienced clinical benefit with imetelstat

Additionally, patients who had prior ESA therapy experienced clinical benefit with imetelstat regardless of baseline sEPO levels, including those with

sEPO >500 mU/mL

Together, these findings support the use of imetelstat in the frontline setting in certain patients with LR-MDS with anemia who are ineligible for ESAs, and further support use in patients after ESA therapy regardless of baseline

sEPO levels

Results should be interpreted with caution given the post hoc nature of this analysis and the small sample sizes in some groups

Conclusions

bOne patient in the Phase 3 part did not have available central hemoglobin values during the longest TI period and was excluded from the Hb rise analysis.

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.

aSeven patients were missing EPO data and are not included in the study population. bReceived ≥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.

ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; RBC, red blood cell; RS, ring sideroblast; sEPO, serum erythropoietin; WHO, World Health Organization.

aNine patients with sEPO >500 mU/mL had received prior non-ESA therapies and were excluded from this analysis. Note percentages are rounded to the nearest whole value.

Median duration of imetelstat treatment included the following:

Treatment naive and sEPO >500 mU/mL: 52 weeks (range, 8-260)

Prior ESA and sEPO <200 mU/mL: 50 weeks (range, 0.1-189)

Prior ESA and sEPO 200 to ≤500 mU/mL: 30 weeks (range, 0.1-148)

Prior ESA and sEPO >500 mU/mL: 20 weeks (range, 0.1-180)

Among treatment-naive patients, 54% achieved ≥8-week RBC-TI with imetelstat (Figure 2)

The median duration of ≥8-week RBC-TI was 43 weeks

EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HI-E, hematologic improvement-erythroid; HTB, high transfusion burden; IWG, International Working Group; LTB, low transfusion burden; n/N, number with event/number in population; RBC, red blood cell; sEPO, serum erythropoietin.

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. b16-

week RBC-TI. c50% RBC U reduction/16 weeks. dDefined as 3-7 RBC U/16 weeks in ≥2 transfusion episodes, and a maximum of 3 in 8 weeks. eDefined as ≥8 RBC U/16 weeks, or

≥4 RBC U/8 weeks.

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Gabrilove J, et al. Br J Haematol. 2008;142(3):379-393.

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.

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

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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. 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

Patients, %

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.