NCCN Recommends Imetelstat for Symptomatic Anemia in Lower-Risk MDS

On July 26, 2024, the National Comprehensive Cancer Network (NCCN) updated their Clinical Practice Guidelines in Oncology for the treatment of patients with myelodysplastic syndromes (MDS) to include imetelstat (Rytelo) in category 1 and 2A recommendations for patients with symptomatic anemia and lower-risk MDS.^1,2

The updated guideline includes a category 1 recommendation for imetelstat as a second-line therapy for patients with ring sideroblasts-negative lower-risk MDS with symptomatic anemia and serum erythropoietin levels up to 500 mU/mL following treatment with erythropoiesis-stimulating agents (ESAs) or luspatercept-aamt (Reblozyl). The telomerase inhibitor also has a category 2A recommendation as frontline therapy for patients with ring sideroblasts-negative lower-risk MDS with symptomatic anemia and serum erythropoietin levels above 500 mU/mL who are unlikely to respond to immunosuppressive therapy.

Imetelstat is recommended as a category 1 second-line therapy following luspatercept in patients with serum erythropoietin levels up to 500 mU/mL and as a category 2A frontline treatment among those with serum erythropoietin levels over 500 mU/mL in patients with ring sideroblasts-positive lower-risk MDS with symptomatic anemia.^1,2

“We believe that the placement of imetelstat in the updated MDS NCCN Guidelines reflects the strength of the IMerge phase 3 clinical data and the US Prescribing Information, as well as the high unmet need in transfusion-dependent lower-risk MDS,” Faye Feller, MD, executive vice president and chief medical officer of Geron, said in a statement to OncLive®. “NCCN Guidelines are influential in clinical decision-making and we expect these recommendations as a category 1 and 2A treatment will drive awareness of this new treatment option.”

The guideline update follows the June 2024 FDA approval of imetelstat for the treatment of adult patients with low- to intermediate-1–risk MDS and transfusion-dependent anemia requiring at least 4 red blood cell (RBC) units over 8 weeks who have not responded to, have lost response to, or are ineligible for ESAs. The regulatory decision was supported by findings from the pivotal phase 3 IMerge trial (NCT02598661), which compared imetelstat with placebo in patients with RBC transfusion-dependent lower-risk MDS who did not respond to or were ineligible for ESAs.^3,4

At a median follow-up of 19.5 months (IQR, 12.0-23.4) in the imetelstat arm (n = 118) and 17.5 months (IQR, 12.1-22.7) in the placebo arm (n = 60), patients achieved RBC transfusion independence for at least 8 weeks at rates of 40% (95% CI, 30.9%-49.3%) vs 15% (95% CI, 7.1%-26.6%), respectively, for a rate difference of 25% (95% CI, 9.9%-36.9%; P = .0008). These findings achieved statistical significance for the study’s primary end point of 8-week RBC transfusion independence; the end point was reached in 45% of patients with ring sideroblasts (n = 73) and 32% of patients without ring sideroblasts (n = 44) in the imetelstat arm compared with 19% (n = 7/37) and 9% (n = 2/23) of patients in the placebo arm, respectively. Moreover, a single continuous RBC transfusion independence period was achieved in 83% of 8-week RBC transfusion independence responders in the imetelstat arm vs 56% in the placebo arm.⁴

"Patients treated with imetelstat experienced durable and sustained red blood cell transfusion independence, increases in hemoglobin levels, and reductions in transfusion burden, with consistent effect across MDS subgroups that have historically been difficult to treat," Feller said. "The safety profile was well-characterized with generally manageable and short-lived thrombocytopenia and neutropenia, which are familiar adverse effects [AEs] for hematologists who are experienced with managing cytopenias."

IMerge was a double-blind, placebo-controlled study that enrolled adult patients with low- or intermediate-1–risk MDS per IPSS criteria who were RBC transfusion dependent requiring at least 4 units over an 8-week period. Patients also had disease that was relapsed/refractory to ESAs or they were ineligible for ESAs. Eligible patients were randomly assigned 2:1 to receive intravenous imetelstat at a starting dose of 7.5 mg/kg every 4 weeks or placebo. Key secondary end points of the study consisted of 24-week RBC transfusion independence rate, duration of RBC transfusion independence, and hematological response rate.

In terms of safety, grade 3 or 4 treatment-emergent AEs (TEAEs) occurred in 91% of patients in the imetelstat arm (n = 107/118) vs 47% of patients in the placebo arm (n = 28/59). Serious TEAEs were reported at rates of 32% vs 22%, respectively. Patients in both arms experienced dose reductions (49% vs 7%) and 16% vs 13% of patients, respectively, died during the study.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 3.2024. Accessed July 29, 2024. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf
2. 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://ir.geron.com/investors/press-releases/press-release-details/2024/Geron-Announces-Updated-NCCN-Guidelines-Recommending-RYTELO-imetelstat-for-the-Treatment-of-Symptomatic-Anemia-in-Patients-with-Lower-Risk-MDS/default.aspx
3. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2024. Accessed July 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent
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