Imetelstat (Monograph)

Brand name: Rytelo
Drug class: Antineoplastic Agents

Introduction

Oligonucleotide human telomerase inhibitor.

Uses for Imetelstat

Myelodysplastic Syndromes

Management of low- to intermediate-1 risk myelodysplastic syndromes (MDS) in adults with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESA).

Designated an orphan drug by FDA for use in this indication.

There are limited treatment options for patients with MDS. RBC transfusions may be used for lower-risk MDS, but repeated RBC transfusions are associated with chronic anemia and iron overload.

Clinical practice guidelines recommend ESAs as first-line agents for patients with anemia in lower-risk MDS with serum erythropoietin levels ≤500 IU/L. Second-line treatment options include antithymocyte globulin (as an off-label use), cyclophosphamide (as an off-label use), azacitidine, lenalidomide, and luspatercept. Imetelstat is not mentioned in these guidelines as the drug was approved after the guidelines were published.

Imetelstat Dosage and Administration

General

Pretreatment Screening

Obtain CBC.
Obtain liver function tests.
Verify the pregnancy status of females of reproductive potential.

Patient Monitoring

Monitor CBCs weekly for the first 2 cycles, prior to each cycle thereafter, and as clinically indicated.
Monitor liver function tests weekly for the first cycle, prior to each cycle thereafter, and as clinically indicated.
Monitor for signs of infusion-related reactions for ≥1 hour following imetelstat infusion.
In patients with thrombocytopenia, monitor for signs of bleeding.
In patients with neutropenia, monitor for signs of infection, including sepsis.

Premedication and Prophylaxis

Administer diphenhydramine (or equivalent) 25-50 mg (orally or IV) and hydrocortisone (or equivalent) 100-200 mg (orally or IV) at least 30 minutes prior to the imetelstat infusion.

Administration

IV Infusion

Administer by IV infusion after reconstitution and dilution.

Available as 47 mg and 188 mg single-dose vials of preservative-free, white to off-white or slightly yellow, lyophilized powder for reconstitution. Must reconstitute with 0.9% sodium chloride injection and further dilute prior to administration.

Reconstitution and Dilution

Remove the required number of vials from the refrigerator and allow them to sit at room temperature for 10–15 minutes (not to exceed 30 minutes) prior to reconstitution.

Reconstitute 47 mg vials with 1.8 mL of 0.9% sodium chloride injection. Reconstitute 188 mg vials with 6.3 mL of 0.9% sodium chloride injection. Final concentration of each vial of reconstituted solution should be 31.4 mg/mL. Swirl each vial gently, avoiding foaming, until powder is fully reconstituted (not to exceed 15 minutes); do not shake. Reconstituted solution should appear as a clear to slightly hazy solution. Visually inspect for particulate matter and discoloration; do not use if present. Use reconstituted solution immediately to prepare the diluted solution.

Calculate required volume of reconstituted solution needed to obtain the appropriate dose according to the patient's body weight. Withdraw a volume equal to required volume of reconstituted solution from a 500 mL 0.9% sodium chloride infusion bag and discard.

Withdraw required volume of reconstituted solution from the vial(s) and add to the 0.9% sodium chloride infusion bag. Total final volume of the infusion bag should be 500 mL.

Gently invert the infusion bag at least 5 times to ensure that the solution is well-mixed. Do not shake.

Rate of Administration

Administer via IV infusion over 2 hours.

Administration rate may be modified for infusion-related reactions, as described in Table 2.

Dosage

Dosage of imetelstat sodium is expressed in terms of imetelstat.

Adults

Myelodysplastic Syndromes

IV

7.1 mg/kg via IV infusion over 2 hours every 4 weeks.

Adjust dosage based on hematologic and non-hematologic toxicities as described in Tables 1 and 2.

Discontinue if patients do not experience a response (decrease in RBC transfusion burden) after 24 weeks of treatment or if unacceptable toxicity occurs.

Dosage Modification for Hematologic Toxicity

Modify dosage for Grade 3–4 (as defined by National Cancer Institute Common Terminology for Adverse Events) hematologic adverse effects as described in Table 1. When an initial dosage reduction is required, reduce dose one level to 5.6 mg/kg. If a subsequent dosage level reduction is required, further reduce dose to 4.4 mg/kg. Treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of 4.4 mg/kg.

Table 1. Dosage Modification for Hematologic Adverse Effects in Patients with MDS Receiving Imetelstat15
Adverse Reaction	Severity Grade	Imetelstat Dosage Modification
Thrombocytopenia	Grade 3 (<50,000–25,000/mm³)	First occurrence: Delay imetelstat until recovery of platelets to 50,000/mm³; restart at same dose level. Second and third occurrence: Delay imetelstat until recovery of platelets to 50,000/mm³; restart at one dose level lower. Fourth occurrence: Discontinue imetelstat.
Thrombocytopenia	Grade 4 (<25,000/mm³)	First and second occurrence: Delay imetelstat until recovery of platelets to 50,000/mm³; restart at one dose level lower. Third occurrence: Discontinue imetelstat.
Neutropenia	Grade 3 (ANC <1000/mm³ with a single temperature of >38.3°C or or a sustained temperature of ≥38°C for >1 hour)	First occurrence: Delay imetelstat until recovery of ANC to 1000/mm³; restart at same dose level. Second and third occurrence: Delay imetelstat until recovery of ANC to 1000/mm³; restart at one dose level lower. Fourth occurrence: Discontinue imetelstat.
Neutropenia	Grade 4 (Life-threatening consequences; urgent intervention indicated)	First and second occurrence: Delay imetelstat until recovery of platelets to 1000/mm³; restart at one dose level lower. Third occurrence: Discontinue imetelstat.

Dosage Modification for Non-Hematologic Toxicity

Modify dosage for Grade 2–4 non-hematologic adverse effects as described in Table 2. When an initial dosage reduction is required, reduce dose one level to 5.6 mg/kg. If a subsequent dosage level reduction is required, further reduce dose to 4.4 mg/kg. Treatment should be permanently discontinued if the patient cannot tolerate the lowest dose level of 4.4 mg/kg.

Table 2. Dosage Modification for Non-Hematologic Adverse Effects in Patients with MDS Receiving Imetelstat15
Adverse Reaction	Severity Grade	Imetelstat Dosage Modification
Infusion-Related Reactions	Grade 2 (Therapy or infusion interruption indicated but responds promptly to symptomatic treatment [e.g., antihistamines, NSAIDS, narcotics, IV fluids]; prophylactic medications indicated for ≤24 hrs)	First and second occurrence: Interrupt infusion until resolution of adverse reaction or until intensity of reaction decreases to Grade 1; restart infusion at 50% of the infusion rate administered prior to the adverse reaction. Third occurrence: Stop infusion. May restart at next cycle.
Infusion-Related Reactions	Grade 3 (Prolonged [e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae)	First and second occurrence: Interrupt the infusion until resolution of adverse reaction or until intensity of the reaction decreases to Grade 1; restart infusion at 50% of the infusion rate administered prior to the adverse reaction. Third occurrence: Permanently discontinue imetelstat.
Infusion-Related Reactions	Grade 4 (Life-threatening consequences; urgent intervention indicated)	First occurrence: Stop infusion. Administer supportive care as appropriate and permanently discontinue imetelstat.
Other adverse reactions, including elevated LFTs	Grade 3 or 4	First and second occurrence: Delay imetelstat until recovery of adverse reactions to Grade 1 or baseline; restart at one dose level lower. Third occurrence: Permanently discontinue imetelstat.

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Dosage adjustment not necessary.

Cautions for Imetelstat

Contraindications

None.

Warnings/Precautions

Thrombocytopenia

Can cause thrombocytopenia. In the principal efficacy study, thrombocytopenia was the most commonly reported treatment-emergent adverse event.

Monitor CBCs prior to initiation, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated.

If thrombocytopenia occurs, monitor for bleeding, administer platelet transfusions as needed, and modify the dose or discontinue treatment as recommended in Table 1.

Neutropenia

Can cause neutropenia. In the principal efficacy study, neutropenia was the second most commonly reported treatment-emergent adverse event.

Monitor CBCs prior to initiation of imetelstat, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated.

If neutropenia occurs, monitor for infections, including sepsis, administer growth factors and anti-infective therapies as appropriate, and modify the dose or discontinue treatment as recommended in Table 1.

Infusion-Related Reactions

Can cause infusion-related reactions. The most commonly reported infusion-related reaction in the principal efficacy study was headache.

Premedicate at least 30 minutes prior to infusion with diphenhydramine and hydrocortisone as recommended and monitor patients for at least 1 hour following the infusion as recommended.

If an infusion-related reaction occurs, manage symptoms with supportive care and infusion interruptions, decreased infusion rate, or permanent discontinuation, as described in Table 2.

Fetal/Neonatal Morbidity and Mortality

Can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, administration to pregnant mice during organogenesis resulted in embryo-fetal mortality at maternal exposures 2.5-times the human exposure at the recommended clinical dose.

Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Specific Populations

Pregnancy

No available human data on use in pregnant women.

Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Lactation

Not known whether imetelstat is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. Because of the potential for adverse effects in breastfed children, advise women not to breastfeed during treatment and for 1 week after the last dose.

Females and Males of Reproductive Potential

Based on animal studies, can cause embryo-fetal harm when administered to a pregnant woman. Verify pregnancy status prior to initiating treatment.

Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Based on animal studies, imetelstat may impair fertility in females of reproductive potential; effect is reversible.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No differences in safety or efficacy were observed between older and younger patients.

Hepatic Impairment

Mild (total bilirubin ≤ ULN and AST >ULN, or total bilirubin >1-times to 1.5-times ULN and any AST) and moderate hepatic impairment (total bilirubin >1.5-times to 3-times ULN and any AST) do not appear to have a clinically important effect on pharmacokinetics; however, effects of severe hepatic impairment (total bilirubin >3x ULN and any AST) have not been established.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30 to <90 mL/minute) does not appear to have a clinically important effect on pharmacokinetics; however, effects of severe renal impairment (Cl_cr 15 to <30 mL/minute) and end-stage renal disease not established.

Common Adverse Effects

Most common adverse reactions (≥10%): decreased platelets, decreased white blood cells, decreased neutrophils, increased AST, increased alkaline phosphatase, increased ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, headache.

Drug Interactions

Does not inhibit or induce CYP isoenzymes.

Inhibits organic anion transporting polypeptide (OATP) 1B1 and OATP1B3.

Imetelstat Pharmacokinetics

Distribution

Plasma Protein Binding

>94%

Elimination

Metabolism

Expected to be primarily metabolized by nucleases to nucleotides of various lengths.

Half-life

4.9 hours.

Stability

Storage

Parenteral

Lyophilized Powder

Store vials in refrigerator at 2–8ºC in the original carton. Do not freeze.

Store reconstituted and diluted solution in refrigerator at 2–8ºC for 48 hours (including time from reconstitution to completion of IV infusion). May also store diluted solution at room temperature (20–25ºC) for ≤18 hours (including time from reconstitution to completion of IV infusion).

Actions

Oligonucleotide telomerase inhibitor.
Binds to human telomerase (hTR), inhibits telomerase enzymatic activity, and prevents telomere binding. Targets malignant clone progenitor cells, sparing normal counterparts. In MDS, high telomerase activity in malignant clone progenitor cells results in full clonal dominance in bone marrow, leading to ineffective erythropoiesis.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Advise patients of the risk of thrombocytopenia with imetelstat, and that their blood counts will be monitored routinely while on treatment and dose of imetelstat delayed or reduced as needed. Instruct patients to notify a healthcare provider immediately if they show signs or symptoms of thrombocytopenia such as unusual bleeding or bruising.
Advise patients of the risk of neutropenia with imetelstat and that their blood counts will be monitored routinely while on treatment and dose of imetelstat delayed or reduced as needed. Instruct patients to notify a healthcare provider immediately if they show signs or symptoms of neutropenia, such as fever or infection.
Inform patients that infusion-related reactions can occur during treatment with imetelstat and premedications will be given prior to each infusion. Patients will be monitored by their healthcare provider for at least an hour after the infusion. Advise patients that their healthcare provider may decide to give imetelstat more slowly or stop the infusion if an infusion-related reaction occurs.
Advise patients of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.
Advise patients not to breastfeed during treatment with imetelstat and for 1 week after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Obtained through designated specialty pharmacies. Contact manufacturer or consult the imetelstat website ([Web]) for specific availability information.