Rytelo: a novel option for transfusion-dependent anemia in myelodysplastic syndromes

INTRODUCTION

Myelodysplastic syndromes (MDS) are a diverse category of hematologic malignancies distinguished by inefficient blood cell synthesis in the bone marrow. Patients with lower-risk MDS frequently develop comorbidities such as transfusion-dependent anemia, which have a substantial influence on their quality of life. The FDA approved Rytelo (imetelstat) in June 2024, ushering in a new age of treatment and providing hope to this specific patient population.¹

RYTELO: MECHANSIM OF ACTION

Rytelo (imetelstat) operates as a first-in-class telomerase inhibitor, targeting the enzyme telomerase that maintains telomere length in cells.² Telomeres are DNA sequences at chromosome ends that shorten during cell division, and telomerase activity is typically upregulated in cancer cells, aiding their continued proliferation. By inhibiting telomerase, Rytelo disrupts the replicative potential of malignant hematopoietic cells in the bone marrow, leading to cellular apoptosis and decreased cancer cell viability.² This mechanism is particularly relevant in MDS, where ineffective hematopoiesis results in conditions such as transfusion-dependent anemia. The drug's ability to curb the overactive telomerase in MDS provides a targeted therapeutic strategy to reduce transfusion needs and improve patients' quality of life.^2,7

PHARMACOKINETICS OF RYTELO

Rytelo is administered as an intravenous infusion, typically delivered over two hours every four weeks. The pharmacokinetic profile of imetelstat is characterized by its plasma half-life, distribution, metabolism, and excretion. Following infusion, imetelstat demonstrates a biexponential decline in plasma concentrations with a terminal half-life allowing for sustained inhibition of telomerase.⁷ The drug is extensively distributed in body tissues, and its clearance is mediated primarily through hepatic metabolism and renal excretion. Dose adjustments may be necessary for patients experiencing severe neutropenia or thrombocytopenia, common adverse effects associated with the drug. Monitoring blood counts and adjusting the dosing schedule are essential to managing these side effects and optimizing therapeutic outcomes.⁷

CLINICAL TRIAL PHASE

The approval of Rytelo stemmed from clinical trials demonstrating its efficacy in reducing transfusion burden. In a phase II clinical trial evaluating two imetelstat dose regimens, the 9.4 mg/kg dose administered every 21 days demonstrated a favorable response rate with regards to patient-reported symptoms.³ The drug targets adult patients with lower-risk MDS experiencing transfusion-dependent anemia.⁴ These patients require frequent red blood cell transfusions (four or more units over eight weeks) and have either not responded to, lost response to, or are ineligible for erythropoiesis-stimulating agents (ESAs), previously the mainstay of treatment for this specific situation.⁴

Rytelo is given as an IV infusion lasting 2 hours every 4 weeks. Studies such as merge experiment have yielded promising outcomes, with patients going without blood transfusions for extended periods of time (possibly longer than 24 weeks).² This results in significant increase in their quality of life, lowering reliance on healthcare interventions and related consequences.⁴

SIDE EFFECT

It is critical to recognize that Rytelo is not without adverse effects. Neutropenia (low neutrophil count) and thrombocytopenia (low platelet count) are typical problems that necessitate regular patient monitoring and possible dose changes.⁶ Neutropenia weakens the immune system, making patients more susceptible to infections. Signs to watch for include fever, chills, and unusual fatigue. Thrombocytopenia increases the risk of bleeding, with easy bruising, nosebleeds, and bleeding gums being potential indicators.⁷

Table 1 summarizes some of the key facts about Rytelo.

CONCLUSION

Rytelo (imetelstat) marks a significant advancement in treating transfusion-dependent anemia in patients with lower-risk MDS. This first-in-class telomerase inhibitor offers a promising therapeutic option by targeting the underlying cause of disease and potentially reducing reliance on blood transfusions. Clinical trials have shown encouraging results, with patients experiencing extended transfusion-free periods and improved quality of life.

However, it's important to acknowledge the potential side effects, particularly neutropenia and thrombocytopenia, which necessitate close monitoring and dose adjustments. With ongoing research exploring its application in other blood cancers, the Rytelo holds immense potential for improving the lives of patients with various hematologic malignancies.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

REFERENCES

1. 1. FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia. FDA. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imetelstat-low-intermediate-1-risk-myelodysplastic-syndromes-transfusion-dependent. Accessed on 9 June 2024.
2. 2. Platzbecker U, Santini V, Fenaux P, Sekeres MA, Savona MR, Madanat YF, 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):249-60.
3. 3. Mascarenhas J, Komrokji RS, Palandri F, Martino B, Niederwieser D, Reiter A, et al. Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. J Clin Oncol. 2021;39(26):2881-92.
4. 4. Lewis R, Bewersdorf JP, Zeidan AM. Clinical Management of Anemia in Patients with Myelodysplastic Syndromes: An Update on Emerging Therapeutic Options. Cancer Manag Res. 2021;13:645-57.
5. 5. FDA Approves Imetelstat for Lower-Risk Myelodysplastic Syndromes With Transfusion-Dependent Anemia. Available at: https://www.pharmacytimes.com/view/fda-approves-imetelstat-for-lower-risk-myelodysplastic-syndromes-with-transfusion-dependent-anemia. Accessed on 9 June 2024.
6. 6. Imetelstat for the Treatment of Transfusion-Dependent Anemia in Adults with Low to Intermediate-1 Risk Myelodysplastic Syndromes (LR MDS). Available at: https://www.fda.gov/media/177021/download. Accessed on 9 June 2024.
7. 7. González-Sales M, Lennox AL, Huang F, Pamulapati C, Wan Y, Sun L, et al. Population pharmacokinetics of imetelstat, a first-in-class oligonucleotide telomerase inhibitor. CPT Pharmacometrics Syst Pharmacol. 2024;13(7):1264-77.