Updated NCCN Guidelines Recommend Imetelstat for Anemia in Lower-Risk MDS

The guideline update follows the FDA’s approval of imetelstat in patients with lower-risk MDS based on data from the phase 3 IMerge trial.

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology to recommend imetelstat (Rytelo) as a Category 1 and 2A treatment for patients with lower-risk myelodysplastic syndrome (MDS)–related symptomatic anemia, according to a news release published by the treatment developer, Geron Corporation.¹

Specifically, among those with ring sideroblast–negative disease, the guideline recommends imetelstat as a Category 1 second-line therapy following prior erythropoiesis-stimulating agents (ESAs) or luspatercept-aamt (Reblozyl) for patients with serum erythropoietin (EPO) of no more than 500 mU/mL.² Additionally, the agent is recommended as a Category 2A frontline therapy option for patients with serum EPO of more than 500 mU/mL who are unlikely to achieve a response with immunosuppressive therapy.

Among patients with ring sideroblast–positive disease and symptomatic anemia, imetelstat is recommended as a Category 1 second-line treatment following luspatercept in those with a maximum serum EPO of 500 mU/mL. The guideline also recommends the agent as a Category 2A frontline therapy option for those with serum EPO of more than 500 mU/mL.

NCCN’s guideline update follows the FDA approval of imetelstat in patients with low- to intermediate-risk MDS with transfusion-dependent (TD) anemia who lack response to or are ineligible for ESAs in June 2024.³ Additionally, the update follows clinical data from the phase 3 IMerge trial (NCT02598661) published in The Lancet.⁴

Data from the trial (n = 178) found that 40% (n = 47/118; 95% CI, 30.9-49.3) of patients receiving imetelstat had a red blood cell-transfusion independence (RBC-TI) duration of 8 or more weeks vs 15% (n = 9/60; 95% CI, 7.1-26.6) in the placebo group. Furthermore, no treatment-related deaths were reported in either cohort.

"We believe that the placement of [imetelstat] in the updated MDS NCCN Guidelines reflects the strength of our phase 3 data and the [United States] Prescribing Information, and that these updates will help to increase awareness and uptake of [imetelstat] as a compelling new treatment option for these patients," Faye Feller, MD, executive vice president and chief medical officer of Geron Corporation, said in the news release.¹ "We are encouraged by the increasing dialogue across hematologists rethinking treatment approaches and sequencing given the availability of [imetelstat] for eligible [patients with] lower-risk MDS with transfusion-dependent anemia."

Between September 11, 2019, and October 13, 2021, adult patients (n = 178) with MDS who were relapsed, refractory, or ineligible for ESAs were enrolled and randomly assigned 2:1 to receive either imetelstat (n = 118) or placebo (n = 60). Therapy in both arms was administered intravenously every 4 weeks until treatment discontinuation. Starting dosage for imetelstat was 7.5 mg/kg, and each dose for this arm was administered via intravenous infusion for 2 hours at a constant rate.

RBC transfusion status and quality of life were assessed at every visit, with disease assessment occurring every 12 weeks after first dose up to 72 weeks and every 24 weeks thereafter until discontinuation of treatment. Following treatment discontinuation, patients were assessed every 12 to 16 weeks and followed for RBC transfusion and disease status every 4 to 6 weeks until a post-trial follow-up transfusion.

Dosing was paused upon development of grade 3 or 4 toxicity, with the drug being reintroduced following toxicity recovery to grade 2 or lower, if necessary. Additionally, treatment was discontinued following disease progression, withdrawn consent, or meeting discontinuation criteria.

The primary end point of the study was the proportion of patients with RBC-TI for 8 or more weeks. Secondary end points included RBC-TI rate at 24 weeks, median duration of RBC-TI, the rate of hematological response, and safety.

Patients received a median of 8 treatment cycles for both imetelstat (IQR, 5-17) and placebo (IQR, 6-15) after a median follow-up of 18.5 months (IQR, 12.0-23.0) overall, 19.5 months (IQR, 12.0-23.4) for the imetelstat arm, and 17.5 months (12.1-22.7) for the placebo arm. The median duration of treatment was 33.9 weeks (IQR, 20.1-75.1) and 28.3 weeks (IQR, 20.3-60.3), respectively. Additionally, 23% of the imetelstat arm and 24% of the placebo arm were continuing treatment as of the data cutoff date.

RBC-TI for 24 or more weeks was observed in 28% (n = 33; 95% CI, 20.1-37.0) of patients who received imetelstat vs 3% (n = 2; 95% CI, 0.4-11.5) of those receiving placebo (P = .0001). Grade 3 or 4 and serious adverse events (AEs), respectively, occurred in 91% and 32% of the imetelstat arm and 47% and 22% of the placebo arm.

References

1. Geron announces updated NCCN Guidelines® recommending RYTELO™ (imetelstat) for the treatment of symptomatic anemia in patients with lower-risk MDS. News release. Geron Corporation. July 26, 2024. Accessed July 29, 2024. https://tinyurl.com/bdkhn8s4
2. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version3.2024. Accessed July 30, 2024. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf
3. Geron announces FDA approval of RYTELO™ (imetelstat), a first-in-class telomerase inhibitor, for the treatment of adult patients with lower-risk MDS with transfusion-dependent anemia. Geron Corporation. News release. June 6, 2024. Accessed July 30, 2024. https://tinyurl.com/2vnuntz5
4. Platzbecker U, Santini V, Fenaux P, et al. 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. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5