Novel Treatment Is Approved for Myelodysplastic Syndromes With Transfusion-Dependent Anemia

In June 2024, the FDA approved imetelstat (Rytelo) for “treatment of adult patients with low- to intermediate–1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia” who have not responded, lost response to, or are ineligible for erythropoiesis-stimulating agents (ESA).^1,2 Transfusion-dependent anemia is defined as the transfusion of 4 or more red blood cell units over 8 weeks.¹ It is common for patients with MDS to experience anemia and require transfusions.

Imetelstat is an oligonucleotide telomerase inhibitor, and an increase in telomerase enzymatic activity is associated with malignant cells in MDS.¹ Imetelstat helps reduce the proliferation and apoptosis of malignant cells and has the clinical benefit of reducing the transfusion burden for patients.¹

Efficacy

Approval was based on efficacy demonstrated in IMerge (NCT02598661), a randomized, double-blind, placebo-controlled, multicenter phase 3 trial. In the trial, 178 participants with low- to intermediate–1 risk myelodysplastic syndromes, as rated by International Prognostic Scoring System criteria, were randomly assigned to receive either imetelstat 7.5 mg/kg or placebo as a 2-hour infusion. The study drug was administered every 4 weeks until the occurrence of unacceptable adverse effects (AEs), disease progression, or withdrawal of consent by the participant.³

The primary efficacy end point was the proportion of participants without red blood cell transfusions for a minimum of 8 consecutive weeks between randomization and next chemotherapy. Median follow-up was 19.5 months (IQR, 12.0-23.4) and 17.5 months (IQR, 12.1-22.7) in the imetelstat and placebo groups, respectively. Overall, 40% of participants in the imetelstat group (95% CI, 30.9-49.3) and 15% (95% CI, 7.1-26.6) in the placebo group experienced a transfusion-free window of at least 8 weeks.³ Additionally, 28% (95% CI, 20.1%-37%) and 3.3% (95% CI, 0.4%-11.5%) of participants in the imetelstat and placebo groups, respectively, experienced a transfusion-free window of 24 weeks or more.¹

Safety

AEs occurred in 10% or more of participants in the imetelstat group and with greater than 5% difference vs placebo. AEs included decreased platelets, neutrophils, and/or white blood cells; increased aspartate aminotransferase, alanine aminotransferase, alkaline phosphate levels, and/ or partial thromboplastin time; fatigue; myalgia; arthralgia; infections; and headache.¹

Grade 3 or 4 treatment-emergent AEs were experienced by 91% and 47% of participants who received either imetelstat or placebo. The most common treatment-emergent AEs in the treatment group were thrombocytopenia (68%) and neutropenia (62%).¹

In practice, a baseline complete blood cell count must be obtained prior to initiating imetelstat therapy. Additional complete blood cell counts must be obtained weekly throughout the first 2 cycles of therapy and before each cycle thereafter. Infusion reactions are a concern. The manufacturer recommends premedication and monitoring during the infusion in case of a severe infusion reaction.¹

Animal models indicate imetelstat is teratogenic. Women of childbearing age must use contraception throughout treatment with imetelstat and for 1 week after the last dose. Therapy should be discontinued if the transfusion burden experienced by the patient does not decrease after 24 weeks of imetelstat therapy.¹

Dosing and Administration

The recommended starting dose of imetelstat is 7.1 mg/kg administered as a 2-hour intravenous infusion. Patients receiving an imetelstat infusion should premedicate with antihistamine and corticosteroid therapy as directed by the manufacturer at least 30 minutes prior to starting the infusion.¹

If the patient experiences a grade 3 or 4 AE, a delay, reduction, or discontinuation of dosing may be warranted. The manufacturer recommends using 5.6 mg/kg for the first dose reduction, 4.4 mg/kg for the second dose reduction, and discontinuation of therapy if the lowest recommended dose (4.4 mg/kg) is not tolerated. Imetelstat comes in a single dose in a 47-mg or 188-mg vial requiring reconstitution and dilution prior to infusion.¹

Kathryn Wheeler, PharmD, BCPS, is the associate dean of academic affairs and an associate clinical professor of pharmacy practice in the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy in Storrs.

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References

1. Rytelo. Prescribing information. Geron Corporation; 2024. Accessed July 3, 2024. https://pi.geron.com/products/US/pi/rytelo_pi.pdf

2. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. June 6, 2024. Accessed July 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent

3. 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, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5