Pharmacist's Application to Practice: imetelstat

FDA approves imetelstat for low- to intermediate-1 risk myelodysplastic syndromes with transfusion-dependent anemia

What is the potential role for imetelstat in the treatment of lower-risk myelodysplastic syndromes (MDS)?

• Imetelstat is a novel, first-in-class, oligonucleotide human telomerase inhibitor that binds to the template region of the RNA component of human telomerase (hTR), inhibits telomerase enzymatic activity and prevents telomere binding.1
• Imetelstat induces apoptosis in selectively targeted cells with increased telomerase activity and human telomerase reverse transcriptase RNA expression, which has been reported in MDS and malignant stem and progenitor cells.1-3
• Imetelstat was approved based on the MDS3001 (IMerge) trial, a randomized, double-blind, placebo-controlled phase 3 trial, evaluating patients with low- or intermediate-risk MDS (LR-MDS) with transfusion-dependent (TD) anemia requiring four or more red blood cell (RBC) units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs).2
• Patients were randomized 2:1 to receive imetelstat 7.1 mg/kg IV administered over 2 hours every 4 weeks or placebo.
• Primary endpoint of 8-week transfusion independence (TI) was achieved in 40% patients with imetelstat vs. 15% with placebo (p<0.001).
• Key secondary endpoint of 24-week TI was achieved in 28% patients with imetelstat vs. 3% with placebo (p<0.001).
• Median duration of TI for patients achieving ≥8-week TI, ≥24-week TI, and ≥1-year TI was 52 weeks, 80 weeks, and 132 weeks, respectively.
• Grade 3-4 neutropenia (68%) and thrombocytopenia (62%) were the most common treatment-emergent adverse events in patients receiving imetelstat.
• The National Comprehensive Cancer Network (NCCN) recently added imetelstat as a first-line treatment option in patients with LR-MDS with ring sideroblasts who are ineligible for ESAs.3
• Luspatercept is the category 1 recommendation for first-line treatment in patients with LR-MDS with ring sideroblasts and ESA naive based on results from the phase 3 COMMANDS trial.
• NCCN also included imetelstat as category 1 recommendation in patients with LR-MDS without del(5q) with no response to ESAs or luspatercept.3
• Luspatercept and lenalidomide are also approved for patients with LR-MDS that are RBC-TD as second-line therapies after loss of response to ESAs. However, their use is limited to LR-MDS with ring sideroblasts and LR-MDS with del5(q), respectively.
• Although there is a lack of head to head data to compare imetelstat and luspatercept in the second-line setting, in patients with LR-MDS with ring sideroblasts, 8-week TI occurred in 38% of patients treated with luspatercept and 45% with imetelstat. Notably, in patients with a high RBC transfusion burden at baseline, requiring at least 6 units per 8 weeks, 8-week RBC-TI occurred in 9% of patients with luspatercept compared to 34% with imetelstat.2,4
• Overall, the significant and clinically meaningful improvement in RBC-TI demonstrated the potential of imetelstat as a second-line therapy across multiple subsets of patients with LR-MDS.

What role can the pharmacist play in the management of patients on imetelstat?

• Pharmacists can help select the appropriate patients to receive imetelstat given the evolving treatment paradigm for MDS and based on patient comorbidities.
• Pharmacists can assist in managing toxicities and adverse events, including providing appropriate supportive care, and dose modifications.

Adverse events

• Hematologic adverse events
• All grade neutropenia (74%); Grade 3-4 neutropenia (68%); All grade thrombocytopenia (75%); Grade 3-4 thrombocytopenia (62%)
• Supportive care include: granulocyte colony-stimulating factors (GCSF), anti-infective prophylaxis, platelet transfusions, and dose modifications.
• Monitor blood counts weekly for first two cycles, prior to each cycle thereafter, and as clinically indicated.
• Common non-hematologic adverse events
• Fatigue (29%)
• Arthralgia/myalgia (25%)
• Elevated liver function tests: alkaline phosphatase (52%), alanine transaminase (43%), and aspartate aminotransferase (53%)

Recommended dose reduction for Grade 3-4 adverse events:

• Standard dose: 7.1 mg/kg
• First dose reduction: 5.6 mg/kg
• Second dose reduction: 4.4 mg/kg

Dose modifications for Grade 3-4 hematologic adverse events:

Thrombocytopenia and Neutropenia

• Grade 3
• First occurrence: delay treatment until recovery of platelets to 50 x 109 /L or ANC to 1 x 109 /L; restart at same dose level
• Second and third occurrence: delay treatment until recovery of platelets to 50 x 109 /L or ANC to 1 x 109 /L; restart at one dose level lower
• Fourth occurrence: discontinue treatment
• Grade 4
• irst and second occurrence: delay treatment until recovery of platelets to 50 x 109 /L or ANC to 1 x 109 /L; restart at one dose level lower
• Third occurrence: discontinue treatment

Infusion-Related Reactions

• Grade 2 or 3
• First and second occurrences: interrupt infusion until resolution of adverse reaction or until the intensity of reaction decreases to Grade 1; restart infusion at 50% of the prior infusion rate
• Third occurrence: For Grade 2, stop infusion. May restart at next cycle. For Grade 3, permanently discontinue treatment
• Grade 4
• First occurrence: stop infusion, administer supportive care as appropriate and permanently discontinue treatment

Other adverse events including elevated LFTs

• Grade 3 or 4
• First and second occurrence: delay treatment until recovery of adverse events to Grade 1 or baseline; restart at one dose level lower
• Third occurrence: permanently discontinue treatment

REACH4RYTELO Copay Program:

• For eligible, commercially insured patients. No income requirements to participate in the program. Available at: www.reach4rytelo.com.5

Clinical Pearls

• Imetelstat is infused over 2 hours. Pre-medications with diphenhydramine (or equivalent) 25 mg to 50 mg IV or PO and hydrocortisone (or equivalent) 100 mg to 200 mg IV or PO at least 30 minutes prior to administration is recommended. Additionally, a 1-hour post-infusion observation period is recommended.
• Although there is an increased risk of grade 3-4 neutropenia and thrombocytopenia, these events were short lived and did not worsen survival. The incidence of Grade 3-4 bleeding events, infections, and febrile neutropenia were similar between imetelstat and placebo group in the IMerge trial.2
• Treatment parameters for initiation of imetelstat include ANC ≥1.5 and platelet ≥75, based on exclusion criteria in the IMerge trial.2
• Patients with diagnosis of MDS with del(5q) were excluded in the IMerge trial. Lenalidomide is the preferred treatment in this patient population.

References

1. Rytelo (imetelstat) [package insert] Foster City, CA: Geron Corporation; 2024
2. 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. The Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5
3. National Comprehensive Cancer Network. Myelodysplastic Syndromes (Version 3.2024). https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed Sep 4, 2024
4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
5. Reach4rytelo. https://www.rytelohcp.com/patient-support-program. Accessed Aug, 2024.