Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual

Policy #:

2024080

Category:

Pharmacy

Initiated:

December 2024

Last Review:

December 2025

Imetelstat (e.g., Rytelo)

Description:

The policy applies to the following medication: Imetelstat (e.g., Rytelo)

Policy/
Coverage:

Prior Approval is required for Imetelstat (e.g., Rytelo).

INITIAL AND CONTINUATION APPROVAL will be for duration of the treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL

Imetelstat (e.g., Rytelo) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:

Initial Approval and Continuation of Therapy:

Member receives a “recommended” determination from InterQual Criteria Imetelstat (e.g., Rytelo),

based on diagnosis and requested product. Click the following link to view the InterQual® criteria: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Imetelstat (e.g., Rytelo) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.

For contracts without Primary Coverage Criteria, Imetelstat (e.g., Rytelo), is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.

Effective March 19, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Imetelstat (e.g., Rytelo) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:

FDA Labeled Indications:

The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).

INITIAL APPROVAL:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of low to intermediate risk myelodysplastic syndromes (MDS) (Rytelo, 2024; NCCN 2A); AND

3. Individual is transfusion-dependent (i.e., requiring 4 or more red blood cell units transfused over an 8-week period within the last 16 weeks) (Steensma, 2021); AND

4. Individual is ineligible for or relapsed/refractory to erythropoiesis stimulating agent (ESA) and luspatercept treatment (see policy guidelines) (Steensma, 2021); AND

5. Individual will not be using Imetelstat (e.g., Rytelo) concurrently with another ESA; AND

6. Individual has an absolute neutrophil count of 1.5 x 1 billion/L or greater (Steensma, 2021); AND

7. Individual has platelets 75 x 1 billion/L or greater (Steensma, 2021); AND

8. Individual has an Eastern Cooperative Oncology Group (ECOG) (see policy guidelines) Performance Status score of 0 to 2 (Steensma, 2021); AND

9. Individual is not pregnant or breast feeding (Rytelo, 2024); AND

10. Imetelstat (e.g., Rytelo) will not be given with live or attenuated vaccines (Steensma, 2021).

CONTINUATION OF THERAPY:

1. Individual met initial criteria above; AND

2. Individual has experienced a positive clinical response to therapy as evidenced by a decrease in need for red blood cell transfusions.

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Imetelstat (e.g., Rytelo), for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.

For members with contracts without Primary Coverage Criteria, Imetelstat (e.g., Rytelo), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

Erythropoiesis Stimulating Agent relapsed/refractory

To be considered ESA relapsed/refractory, individual must have received 8 weeks or more of treatment with a minimum weekly dose of epoetin alfa 40,000 U, epoetin beta 30,000 U, or darbepoetin alfa 150 μg (or equivalent agent/dose), either: without having achieved hemoglobin rise of 1.5 g/dL or more or decreased RBC transfusion requirement by four or more units over 8 weeks; or increasing transfusion dependence (TD) or reduction in hemoglobin by 1.5 g/dL or more after hematologic improvement (HI) in the absence of another explanation. Individuals are also eligible if they were not considered candidates for ESA treatment as a result of endogenous sEPO level greater than 500 mU/mL. (Steensma, 2021)

Eastern Cooperative Oncology Group (ECOG) Performance Status

0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3 Capable of only limited selfcare; Confine to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any selfcare; totally confided to be or chair
5 Dead

DOSAGE AND ADMINISTRATION

For FDA labeled indications, Imetelstat (e.g., Rytelo) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.

The recommended dose of Imetelstat (e.g., Rytelo) is 7.1 mg/kg administered as an intravenous infusion over 2 hours every 4 weeks. Discontinue Imetelstat (e.g., Rytelo) if an individual does not experience a decrease in red blood cell (RBC) transfusion burden after 24 weeks of treatment (administration of 6 doses) or if unacceptable toxicity occurs at any time

Premedicate prior to dosing with Imetelstat (e.g., Rytelo) for potential infusion-related reactions.

Imetelstat (e.g., Rytelo) is available as 47 mg or 188 mg powder in single-dose vials for reconstitution.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective December 11, 2024 to March 18, 2026

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Imetelstat (e.g., Rytelo) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

FDA Labeled Indications:

For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

1. Individual is 18 years of age or older; AND

2. Individual has a diagnosis of low to intermediate risk myelodysplastic syndromes (MDS) (Rytelo, 2024; NCCN 2A); AND

3. Individual is transfusion-dependent (i.e., requiring 4 or more red blood cell units transfused over an 8-week period within the last 16 weeks) (Steensma, 2021); AND

4. Individual is ineligible for or relapsed/refractory to erythropoiesis stimulating agent (ESA) treatment (see policy guidelines) (Steensma, 2021); AND

5. Individual will not be using Imetelstat (e.g., Rytelo) concurrently with another ESA; AND

6. Individual has an absolute neutrophil count of 1.5 x 1 billion/L or greater (Steensma, 2021); AND

7. Individual has platelets 75 x 1 billion/L or greater (Steensma, 2021); AND

8. Individual has an Eastern Cooperative Oncology Group (ECOG) (see policy guidelines) Performance Status score of 0 to 2 (Steensma, 2021); AND

9. Individual is not pregnant or breast feeding (Rytelo, 2024); AND

10. Imetelstat (e.g., Rytelo) will not be given with live or attenuated vaccines (Steensma, 2021).

CONTINUED APPROVAL for up to 12 months:

1. Individual met initial criteria above; AND

2. Individual has experienced a positive clinical response to therapy as evidenced by a decrease in need for red blood cell transfusions.

Off-label Indications:

For off-label indications, authorizations will not exceed 7.1 mg/kg every 4 weeks unless medical literature supports a higher dose.

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Myelodysplastic Syndromes

1. Treatment of lower risk* disease associated with symptomatic anemia with del(5q), with or without one other cytogenetic abnormality (except those involving chromosome 7) (NCCN 2A):

a. Following no response to or relapse after lenalidomide if poor probability to respond to immunosuppressive therapy (IST); OR

b. Following no response to or relapse after an erythropoiesis-stimulating agent (ESA) if poor probability to respond to IST; OR

2. Treatment of lower risk* disease with no del(5q), with or without other cytogenetic abnormalities NCCN 1 for ring sideroblasts >15 % (or ring sideroblasts >5% with an SF3B1 mutation) following no response or relapse to luspatercept-aamt if serum erythropoietin <500 mU/mL; or for ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation) with serum erythropoietin <500 mU/m; NCCN 2A for all others):

a. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation) as initial treatment if serum erythropoietin >500 mU/mL (ineligible for ESAs); OR

b. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation) following no response to or relapse after luspatercept-aamt; OR

c. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin >500 mU/mL and a poor probability to respond to immunosuppressive therapy; OR

d. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after ESA's (despite adequate iron stores) or luspatercept-aamt; OR

e. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after either an ESA alone (despite adequate iron stores) or luspatercept-aamt, followed by no response to or relapse after either an ESA with or without either lenalidomide or a granulocyte-colony stimulating factor (G-CSF), or to luspatercept-aamt alone (if not previously used); OR

3. Treatment of lower risk* disease associated with symptomatic anemia with no del(5q), with or without other cytogenetic abnormalities (NCCN 2A):

a. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after luspatercept-aamt, followed by no response to or relapse after an erythropoiesis-stimulating agent (ESA) with or without a granulocyte-colony stimulating factor (G-CSF) if a poor probability to respond to immunosuppressive therapy (IST); OR

b. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), with serum erythropoietin >500 mU/mL following no response to or relapse after luspatercept-aamt, followed by no response to or relapse after lenalidomide if a poor probability to respond to IST; OR

c. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin >500 mU/mL following no response to or intolerance or relapse after IST; OR

d. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after an ESA alone, followed by no response to or relapse after an ESA with or without a G-CSF or lenalidomide; OR

e. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after an ESA alone, followed by no response to or relapse after luspatercept-aamt; OR

f. With ring sideroblasts <15% (or ring sideroblasts <5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after luspatercept-aamt, followed by no response to or relapse after an ESA with or without a G-CSF or lenalidomide; OR

4. Treatment of lower risk* disease associated with symptomatic anemia with del(5q), with or without one other cytogenetic abnormality (except those involving chromosome 7) (NCCN 2A):

a. Following no response to or relapse after lenalidomide, followed by no response to or intolerance or relapse after immunosuppressive therapy (IST); OR

b. Following no response to or relapse after an erythropoiesis-stimulating agent (ESA) with serum erythropoietin ≤500 mU/mL, followed by no response to or intolerance or relapse after IST; OR

5. Treatment of lower risk* disease associated with symptomatic anemia with no del(5q), with or without other cytogenetic abnormalities (NCCN 2A):

a. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), with serum erythropoietin ≤500 mU/mL following no response to or relapse after luspatercept-aamt, followed by no response to or relapse after an erythropoiesis-stimulating agent (ESA) with or without a granulocyte-colony stimulating factor (G-CSF), followed by no response to or intolerance or relapse after immunosuppressive therapy (IST); OR

b. With ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), with serum erythropoietin >500 mU/mL following no response to or relapse after luspatercept-aamt, followed by no response to or relapse after lenalidomide, followed by no response to or intolerance or relapse after IST.

* Lower risked defined as IPSS-R (very low, low, intermediate)

CONTINUED APPROVAL for up to 12 months:

1. Individual met initial criteria above; AND

2. Individual has experienced a positive clinical response to therapy as evidenced by a decrease in need for red blood cell transfusions.

The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Policy Guidelines

Erythropoiesis Stimulating Agent relapsed/refractory

Eastern Cooperative Oncology Group (ECOG) Performance Status

0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3 Capable of only limited selfcare; Confine to bed or chair more than 50% of waking hours
4 Completely disabled; cannot carry on any selfcare; totally confided to be or chair
5 Dead

Dosage and Administration

Dosing per FDA Guidelines

Premedicate prior to dosing with Imetelstat (e.g., Rytelo) for potential infusion-related reactions.

Imetelstat (e.g., Rytelo) is available as 47 mg or 188 mg powder in single-dose vials for reconstitution.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Imetelstat (e.g., Rytelo), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, Imetelstat (e.g., Rytelo), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. Efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs were reported.

In a two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid.

Data from the phase II part of the study were reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks.

Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone. (Steensma, 2021)

2025 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2025

CPT/HCPCS:

References:

ECOG(2024) ECOG Performance Status Scale. Available at ECOG Performance Status Scale - ECOG-ACRIN Cancer Research Group; Accessed December 2, 2024.

NCCN(2024) Drugs & Biologics Compendium for Imetelstat (e.g., Rytelo). Accessed December 2, 2024. online to NCCN.org.

Rytelo(2024) package insert Foster City, CA; Geron Corporation; 2024.

Steensma DP, Fenaux P, Van Eygen K, Raza A, Santini V, Germing U, Font P, et.al.(2021) Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. J Clin Oncol. 2021 Jan 1;39(1):48-56. doi: 10.1200/JCO.20.01895. Epub 2020 Oct 27. PMID: 33108243.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.