Geron : Increased Duration Of Time Without Transfusion Reliance (TWITR) For Patients With Lower-Risk Myelodysplastic Syndromes Treated With Imetelstat Versus Placebo In the Imerge Trial

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

Published on 06/13/2025 at 13:46

‌Background

For patients with lower-risk myelodysplastic syndromes (LR-MDS), the need for frequent red blood cell (RBC) transfusions negatively affects quality of life (QOL), is costly, and is associated with additional risks, including iron overload and alloimmunization1

Imetelstat is a first-in-class, oligonucleotide inhibitor of telomerase activity recently approved in the United States and Europe for certain adult patients with LR-MDS with RBC transfusion-dependent (TD) anemia who have relapsed or refractory/unsatisfactory response to or ineligible for erythropoiesis-stimulating agents (ESAs), based on the pivotal, Phase 3 IMerge trial (NCT02598661)2-4

The Phase 3 primary analysis of IMerge found higher rates of ≥8-week, ≥24-week, and ≥1-year RBC transfusion independence (TI) with imetelstat (n=118) versus placebo (n=60) in the intention-to-treat population: 39.8% versus 15.0% (P=.0008), 28.0% versus 3.3% (P=.0001), and 17.8% versus 1.7% (nominal P=.0023), respectively

The most common adverse events were neutropenia and thrombocytopenia, which were generally reversible and manageable with dose modifications

Based on exploratory analysis, more imetelstat-treated patients experienced maintenance of QOL and MDS-related symptoms (eg, anemia) compared with worsening with placebo5

Commonly used QOL measures have limitations, such as the inability to distinguish between improvement of anemia symptoms from treatment versus continued RBC transfusions; this has prompted the development of alternative measures such as time without transfusion reliance (TWiTR)

Here, we present results from a post hoc TWiTR analysis comparing imetelstat and placebo arms in the intention-to-treat population of the Phase 3 IMerge trial

Methods

In IMerge, patients with RBC-TD LR-MDS who provided informed consent were randomized to

7.1 mg/kg imetelstat active dose (equivalent to 7.5 mg/kg imetelstat sodium) or placebo

administered as 2-hour intravenous infusions every 4 weeks (Figure 1)

Phase 3

Double- domized

blind, ran

7.1 mg/kg IV every 4

Imetelstat

weeks

118 clinical sites in 17 countries

Patient population (ITT): N=178

IPSS low-risk or intermediate-1-risk MDS

R/Ra to ESAs or EPO >500 mU/mL

(ESA ineligible)

RBC-TD: ≥4 U RBCs every 8 weeks over 16-week prestudy

Non-del(5q)

No prior treatment with lenalidomide or HMAs

(n=118)

Stratification

Transfusion burden (4-6 U vs >6 U)

IPSS risk category (low vs intermediate-1)

2:1 Supportive care, including RBC and platelet transfusions, myeloid growth factors

(eg, G-CSF), and iron chelation therapy administered as needed on-study per investigator discretion

Primary endpoint

≥8-week RBC-TIb

Key secondary endpoints

≥24-week RBC-TI,c duration of RBC-TI, HI-E, safety

Other secondary endpoints

OS, PFS, time to progression to AML

Key exploratory endpoints

Changes in VAF of somatic mutations, cytogenetic response, PROs

Placebo

(n=60)

Post hoc TWiTR analysis

AML, acute myeloid leukemia; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, hemoglobin; HI-E, hematologic improvement-erythroid;

HMA, hypomethylating agent; IPSS, International Prognostic Scoring System; ITT, intention-to-treat; IV, intravenous; MDS, myelodysplastic syndromes; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcome; R, randomized; RBC, red blood cell; R/R, relapsed or refractory; TD, transfusion dependent; TI, transfusion independence; TWiTR, time without transfusion reliance; VAF, variant allele frequency. aReceived ≥8 weeks of ESA treatment (epoetin alfa ≥40,000 U, epoetin 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 RBC-TD or reduction in Hb by ≥1.5 g/dL after hematologic improvement from ≥8 weeks of ESA treatment. bProportion of patients without any RBC transfusion for ≥8 consecutive weeks since entry to the trial (≥8-week RBC-TI). cProportion of patients without any RBC transfusion for ≥24 consecutive weeks since entry to the trial (≥24-week RBC-TI).

In the post hoc TWiTR analysis, 3 health states were defined as follows:

TD state

REL state

TWiTR state

Sum of all TD periods experienced by the patient, ending at disease progression, death, or censoring for progression (eg, PFS analysis)

Time between disease progression and death or OS censoring

Calculated as OS minus PFS

Time without TD or REL

Calculated as PFS minus TD

OS, overall survival; PFS, progression-free survival; REL, relapse; TD, transfusion dependent; TWiTR, time without transfusion reliance.

An example of how the states for the TWiTR analysis were assigned is shown in Figure 2

Death

No transfusions for

≥8 weeks

No transfusions for

<8 weeks

D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1 8 15 22 D1

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7

RBC-TD at baseline RBC-TD

28 days

RBC-TI 105 days

RBC-TD 78 days

= Transfusion

Cycle 8 Cycle 9 Cycle 10

REL 55 days PFS=211 days

OS=266 days

TWiTR = PFS ‒ TD = 105 days

Units transfused, n

Results

A total of 178 patients (imetelstat, n=118; placebo, n=60) in the intention-to-treat population from the final data analysis of IMerge (January 5, 2024) were included in the TWiTR analysis (Table 1)

Baseline characteristics were similar across arms

Characteristic

Imetelstat (n=118)

Placebo (n=60)

Age, median (range), y

72 (44-87)

73 (39-85)

Male, n (%)

71 (60)

40 (67)

Time since diagnosis, median (range), y

3.5 (0.1-26.7)

2.8 (0.2-25.7)

WHO classification, n (%)

RS+

73 (62)

37 (62)

RS−

44 (37)

23 (38)

IPSS risk category, n (%)

Low

80 (68)

39 (65)

Intermediate-1

38 (32)

21 (35)

Pretreatment Hb, median (range),a g/dL

7.9 (5.3-10.1)

7.8 (6.1-9.2)

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

6 (4-33)

6 (4-13)

Prior RBC transfusion burden, n (%)

≥4 to ≤6 RBC U/8 weeks

62 (53)

33 (55)

>6 RBC U/8 weeks

56 (48)

27 (45)

sEPO, median (range), mU/mL

174.9 (6.0-4460.0)

277.0 (16.9-5514.0)

sEPO level, n (%)b

≤500 mU/mL

87 (74)

36 (60)

>500 mU/mL

26 (22)

22 (37)

Prior ESA, n (%)

108 (92)

52 (87)

Prior luspatercept, n (%)c

7 (6)

4 (7)

ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; IPSS, International Prognostic Scoring System; RBC, red blood cell; RS, ring sideroblast; sEPO, serum erythropoietin; WHO, World Health Organization. aAverage of all Hb values in the 8 weeks before the first dose date, excluding values within 14 days after a transfusion, which was considered to be influenced by transfusion. bData missing for 5 patients in the imetelstat group and 2 in the placebo group. cInsufficient number of patients previously treated with luspatercept to draw conclusions about the effect of imetelstat treatment in such patients.

Post hoc TWiTR analyses in which TD was censored according to PFS censoring rules (assuming that the duration of TD periods was unknown for participants who were censored for PFS) showed that (Table 2, Figure 3):

after 2.6 years of follow-up, overall mean TWiTR was longer in the imetelstat arm than in the placebo arm by ~3 months

mean TD was almost 1.5 months shorter in the imetelstat arm than in the placebo arm

mean time in the REL state was almost 1 month shorter in the imetelstat arm than in the placebo arm

Results for the TWiTR analysis considering TD an event were similar (Table 3)

TWiTR in RBC-TI responders is shown in Table 4 and Figure 4

In ≥8-week RBC-TI responders, mean TWiTR was longer with imetelstat than placebo, regardless of censoring rules; this analysis was limited by the small number of responders in the placebo group

The small number of ≥24-week responders did not allow to perform the TWiTR analysis in these patients

As nonresponders do not have TWiTR periods by definition, TWiTR results in RBC-TI nonresponders were not interpretable

INCREASED DURATION OF TIME WITHOUT TRANSFUSION RELIANCE (TWITR) FOR PATIENTS WITH

LOWER-RISK MYELODYSPLASTIC SYNDROMES TREATED WITH IMETELSTAT VERSUS PLACEBO IN THE IMERGE TRIAL

Mikkael A. Sekeres,1 Valeria Santini,2 Amer M. Zeidan,3 Uwe Platzbecker,4 Rami S. Komrokji,5 María Díez-Campelo,6 Pierre Fenaux,7 Michael R. Savona,8 Yazan F. Madanat,9 David Valcárcel,10 Antoine Regnault,11 Flora Mazerolle,11 Libo Sun,12 Ying Wan,12 Tymara Berry,12 Faye Feller,12 Shyamala Navada,12 Esther Natalie Oliva13

1Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; 2MDS Unit, Hematology, DMSC University of Florence, AOUC, Florence, Italy; 3Yale School of Medicine and Yale Cancer Center, Yale University, New Haven, CT, USA; 4National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; 5Moffitt Cancer Center, Tampa, FL, USA; 6University Hospital of Salamanca, Salamanca, Spain; 7Hôpital Saint-Louis, Université de Paris 7, Paris, France; 8Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; 9Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; 10Hospital Universitario Vall d'Hebron, Barcelona, Spain; 11Modus Outcomes, a company of THREAD, Lyon, France; 12Geron Corporation, Foster City, CA, USA; 13Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy

PF646

Imetelstat

1.0

0.8

0.6

0.4

0.2

0.0

Placebo

1.0

0.8

0.6

0.4

0.2

Year 1

Year 2

0.0

100

200

300

400

500

600

700

800

900

Time, days

Health state

TWiTR

REL

Survival distribution function estimate

ITT, intention-to-treat; PFS, progression-free survival; REL, relapse; TD, transfusion dependent; TWiTR, time without transfusion reliance.

Health state

Imetelstat (n=118)

Placebo (n=60)

Difference (95% CI)

TD (95% CI), d

289.63 (241.69, 339.68)

339.07 (271.80, 412.32)

−49.44 (−141.3, 44.83)

TWiTR (95% CI), d

472.58 (409.68, 534.01)

380.99 (294.83, 489.74)

91.59 (−37.19, 209.40)

Relapse (95% CI), d

79.43 (24.40, 122.09)

106.40 (9.91, 194.02)

−26.97 (−147.4, 82.36)

ITT, intention-to-treat; TD, transfusion dependent; TWiTR, time without transfusion reliance.

aEstimations were restricted to 966 days to ensure comparability across health states and treatment arms, and were defined as the minimum of the end of the last observed TD event between arms.

Health state

Imetelstat

(n=47)

Placebo (n=9)

Difference (95% CI)

Censoring: TD censored according to PFS censoring rules

TD (95% CI), d

595.01 (500.93, 664.08)

836.29 (739.00, 865.11)

−241.3 (−347.8, −144.5)

TWiTR (95% CI), d

234.49 (162.20, 338.54)

36.71 (7.89, 134.00)

197.77 (97.99, 299.53)

Relapse (95% CI), d

61.09 (40.65, 85.18)

Censoring: TD as an event

TD (95% CI), d

249.55 (185.70, 321.64)

385.11 (160.22, 601.11)

−135.6 (−380.5, 95.31)

TWiTR (95% CI), d

579.94 (507.94, 648.18)

487.89 (271.89, 712.78)

92.05 (−143.4, 329.10)

Relapse (95% CI), d

61.09 (40.65, 85.18)

1.0

0.8

Imetelstat

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

Placebo

Year 1

Year 2

0.0

100

200

300

400

500

600

700

800

900

Time, days

1.0

0.8

0.6

0.4

0.2

0.0

Imetelstat

1.0

0.8

Placebo

0.6

0.4

0.2

0.0

Year 1

Year 2

0 100 200 300 400 500 600 700 800 900

Time, days

Health state TD TWiTR REL

In this post hoc analysis, patients with LR-MDS in the imetelstat arm had a longer mean duration of time without transfusion reliance or relapse compared with placebo

The difference between arms in the time spent without transfusion reliance and TD was fairly stable across the specification of the TWiTR analyses as follows: 49 days fewer in TD and 92 days more in TWiTR when TD was always considered an event, and 41 days fewer in TD and 83 days more in TWiTR when the PFS censoring rule was applied to TD

Among ≥8-week RBC-TI responders, TWiTR was longer and TD was shorter in the imetelstat arm compared with the placebo arm; however, this analysis was limited by the small number of responders in the placebo group

Because of the negative association between health-related QOL and TD,7,8 these findings suggesting the ability of imetelstat to lessen TD may be clinically meaningful to patients

These results should be interpreted with caution, given the analyses were exploratory, with no formal statistical testing applied, and the statistical uncertainties associated with the different censoring rules employed

Conclusions

Survival distribution function estimate

PFS, progression-free survival; RBC, red blood cell; REL, relapse; TD, transfusion dependent; TI, transfusion independence; TWiTR, time without transfusion reliance.

D, day; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RBC, red blood cell; REL, relapse; TD, transfusion dependent; TI, transfusion independence; TWiTR, time without transfusion reliance.

Two complementary censoring rules were applied to TD periods as follows:

TD state censored according to PFS censoring rules (TD was an event when PFS was an event and censored when PFS was censored) as the primary analysis

TD state always considered an event (participants who had TD were never censored) as a sensitivity analysis

Health states were calculated using Kaplan-Meier estimates; the mean duration in each state was estimated by the area under each survival curve obtained with Kaplan-Meier estimates

A bootstrap approach was applied to estimate the 95% CI for the mean TWiTR for each arm and mean TWiTR difference between arms

These analyses were exploratory, with no prespecified formal statistical hypothesis testing

Health state

Imetelstat (n=118)

Placebo (n=60)

Difference (95% CI)

TD (95% CI), d

659.76 (575.93, 750.55)

701.05 (594.52, 814.83)

−41.29 (−196.5, 120.19)

TWiTR (95% CI), d

102.44 (55.84, 149.60)

19.00 (1.92, 47.93)

83.44 (25.46, 135.18)

Relapse (95% CI), d

79.43 (24.40, 122.09)

106.40 (9.91, 194.02)

−26.97 (−147.4, 82.36)

ITT, intention-to-treat; PFS, progression-free survival; TD, transfusion dependent; TWiTR, time without transfusion reliance.

aEstimations were restricted to 966 days to ensure comparability across health states and treatment arms, and were defined as the minimum of the end of the last observed TD event between arms.

ITT, intention-to-treat; RBC, red blood cell; TD, transfusion dependent; TI, transfusion independence; TWiTR, time without transfusion reliance.

aEstimations were restricted to 966 days to ensure comparability across health states and treatment arms, and were defined as the minimum of the end of the last observed TD event between arms.

Oliva EN, et al. Blood Rev. 2021;50:100851.

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.

Sekeres MA, et al. Blood. 2024;144(suppl 1):3210.

Zeidner JF, et al. Haematologica. 2023;108(4):1196-1199.

Balducci L. Cancer. 2006;106(10):2087-2094.

Braga Lemos M, et al. Eur J Haematol. 2021;107(1):3-23.

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

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 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.