ModifiedPremera BluecrossPolicy N/A

Cutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Defines medical necessity criteria, documentation, coding, and coverage rules for oral, topical, and intravenous systemic therapies used to treat cutaneous T-cell lymphomas for Premera Blue Cross members.

Policy Summary

PayerPremera Bluecross

PolicyCutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Policy CodePolicy N/A

Change TypeMaterial: added Lymphirremoved romidepsin PTCL indicationgeneric bexarotene requirement

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document trials of required prior therapies and objective response assessments to support medical necessity.

SourceLink

POLICY UPDATE CHANGES

Added Lymphir (denileukin diftitox-cxdl) for the treatment of relapsed or refractory Stage I-III CTCL.

Removed use of Istodax (romidepsin) and romidepsin injection for treatment of peripheral T‑cell lymphoma because the indication was withdrawn from prescribing information.

Updated coverage criteria for oral and topical Targretin (bexarotene) to require trial and failure with generic bexarotene formulations; added coverage criteria for generic topical bexarotene.

Non‑formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months.

Added brand romidepsin injection to policy with identical coverage criteria as Istodax (romidepsin).

≈20,000estimated US prevalence of CTCL

≈25%proportion with advanced disease

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50%bexarotene ORR (pivotal)

167individuals in romidepsin CTCL studies

J9161new HCPCS code for Lymphir

Coverage Criteria and Medical Necessity

Oral bexarotene and vorinostat (Zolinza) — medical necessity

Covered when ALL of the following are met

Population and diagnosis: Individual diagnosed with ONE of: Mycosis fungoides, Sezary syndrome, Cutaneous T-cell lymphoma, or Peripheral T-cell lymphoma

Prior therapy for simple skin involvement: For simple skin involvement, has tried ONE of: systemic retinoids (isotretinoin, acitretin, etc.), interferons (alpha, gamma), methotrexate, or Campath (alemtuzumab)1

Prior therapy for late-stage disease: For late-stage disease (usually with solid organ involvement), has tried ONE of: gemcitabine or liposomal doxorubicin1

Topical bexarotene (gel) and topical mechlorethamine (Valchlor) — medical necessity

Covered when ALL of the following are met

Population: Diagnosis of cutaneous T-cell lymphoma (Stage IA or IB)

Prior topical/skin-directed therapy failures: Has tried and had inadequate response or intolerance to THREE of: phototherapy (UVB, NB-UVB, PUVA), topical imiquimod, topical corticosteroids, topical mechlorethamine, or local radiation3

Prior trial of generic topical bexarotene where specified: Has tried and had inadequate response or intolerance to generic bexarotene topical gel when required prior to brand topical Targretin

Generic topical bexarotene trial required per updated criteria

Intravenous agents (belinostat, romidepsin, denileukin diftitox, mogamulizumab) — medical necessity

Covered when ALL of the following are met (agent-specific variations apply)

Age and prior systemic therapy: Individual is aged 18 years or older AND has received at least one prior systemic therapy for relapsed or refractory disease

Applies to agents such as Lymphir, Poteligeo, and romidepsin

Agent-specific diagnoses and indications: Belinostat: relapsed or refractory angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or other PTCL subtypes; Romidepsin (Istodax/romidepsin injection): mycosis fungoides, Sezary syndrome, or CTCL; Lymphir (denileukin diftitox-cxdl) and Poteligeo (mogamulizumab): relapsed or refractory CTCL/mycosis fungoides/Sezary syndrome as specified

See individual product criteria and trial populations

Investigational uses

Other uses: All other uses of the medications listed in this policy are considered investigational

Evidence-aligned drug coverage summaries

drug_evidence_summaries

romidepsin_CTCL: Two single‑arm CTCL studies (total N=167) used romidepsin 14 mg/m2 IV on days 1, 8, 15 of a 28‑day cycle; primary endpoint ORR; median time to first response ~2 months; treatment could continue until progression at investigator discretion.
See romidepsin CTCL trials.
romidepsin_PTCL: PTCL Study 3 (N≈131) used romidepsin 14 mg/m2 IV days 1,8,15 q28d; ORR ~25% and CR ~15%; median time to response ≈1.8 months.
See romidepsin PTCL trial.
vorinostat: Vorinostat (Zolinza) 400 mg once daily produced ~30% response (≥50% skin improvement) in refractory CTCL populations; median response duration ~3–4 months.
See vorinostat studies.

Notable coverage updates

Key coverage stance updates and requirements from this document segment

Romidepsin indication update: Romidepsin (Istodax and romidepsin injection) coverage criteria were updated to remove use for peripheral T‑cell lymphoma because the indication was withdrawn from prescribing information.

Providers should not request coverage for PTCL with romidepsin based on prior labeling.

Bexarotene generic trial requirement: Coverage for oral and topical bexarotene (Targretin) requires trial and failure with generic bexarotene formulations before brand products are approved.

Generic topical bexarotene coverage criteria were added.

Lymphir addition: Lymphir (denileukin diftitox‑cxdl) was added as a covered therapy for relapsed or refractory Stage I‑III CTCL with an associated HCPCS code J9161.

Refer to product prescribing information and specific coverage criteria elsewhere in the policy.

All uses of the medications listed in this policy that are not explicitly addressed in the agent‑specific coverage criteria are considered investigational. The policy applies the FDA product dosing and administration prescribing information to all listed agents and limits coverage to the indications and populations specified in the coverage criteria; any other indication, regimen, or patient population is investigational and not covered.

Belinostat’s approval for relapsed or refractory peripheral T‑cell lymphoma (PTCL) is based on a single‑arm phase 2 pivotal trial that used tumor response rate as the primary endpoint. The trial did not establish an improvement in survival or disease‑related symptoms, and the pivotal trial report has not been published; therefore, clinical benefit beyond response rates is uncertain. Coverage for belinostat is aligned to the trial population and FDA indication (relapsed/refractory PTCL) and requires prior systemic therapy consistent with that context.

Romidepsin’s labeled indication for peripheral T‑cell lymphoma was withdrawn from the prescribing information and the policy was updated accordingly in the 2024 review. As a result, requests to treat PTCL with romidepsin no longer align with current product labeling and are not supported by this coverage policy.

Use of belinostat outside of its approved relapsed/refractory PTCL indication is limited by the evidence: the accelerated approval was granted on the basis of response rates from a single‑arm study and an improvement in survival or disease‑related symptoms has not been established. Therefore, belinostat is covered only for the relapsed/refractory PTCL populations consistent with the trial and FDA approval; other indications are not supported by the pivotal evidence presented.

Therapy requests for romidepsin to treat peripheral T‑cell lymphoma are not supported by current prescribing information because that indication was removed from the label during the 2024 update. Such requests are inconsistent with the product’s current FDA prescribing information and may be denied under this policy.

Initial Authorization Criteria

Initial authorization

Initial authorization criteria vary by agent and route — conditional on diagnosis and prior therapy attempts

Oral/topical initial authorization: Diagnosis of specified CTCL subtype AND documented trials/failures of listed skin‑directed or systemic agents as applicable (see per‑drug criteria).

For topical agents, number of prior topical therapies required varies (usually three).

Initial therapy trial contexts

Trial-based initial therapy contexts

romidepsin_initial: Romidepsin was studied in individuals who had failed prior systemic therapy or prior skin‑directed therapies; dosing in studies was 14 mg/m2 IV on days 1, 8, and 15 of a 28‑day cycle.

Responders in trials could continue until progression at investigator discretion.

Re-authorization and Continuation Criteria

Re-authorization

Re-authorization rules

Continuation approval: Non‑formulary exception reviews and other reviews for oral, topical, and intravenous drugs may be approved for up to 12 months if drug‑specific criteria are met and chart notes demonstrate continued positive clinical response.

Continuation after initial cycles

Continuation beyond planned cycles in trials:

romidepsin_continuation: In clinical studies, responders could continue romidepsin beyond planned cycles at investigator discretion until progression or withdrawal; treatment durations varied.

Reflects trial practice for continued therapy in responders.

Continuation/authorization duration

Authorization duration clarification

Step Therapy and Required Prior Trials

Requirement	Details
Trials of specified alternatives required prior to authorization
Coverage requires documented trials of specified alternative therapies before approval. Examples in the policy include: for simple skin involvement, trial of one systemic agent (systemic retinoids, interferons, methotrexate, or alemtuzumab); for late‑stage disease, trial of gemcitabine or liposomal doxorubicin; for topical therapy, failure/intolerance to three skin‑directed options (phototherapy, topical imiquimod, topical corticosteroids, topical mechlorethamine, or local radiation). Authorization requires documentation of the specified number and type of prior therapies as applicable to agent and disease stage.

Requirement

Details

Trials of specified alternatives required prior to authorization

Coverage requires documented trials of specified alternative therapies before approval. Examples in the policy include: for simple skin involvement, trial of one systemic agent (systemic retinoids, interferons, methotrexate, or alemtuzumab); for late‑stage disease, trial of gemcitabine or liposomal doxorubicin; for topical therapy, failure/intolerance to three skin‑directed options (phototherapy, topical imiquimod, topical corticosteroids, topical mechlorethamine, or local radiation). Authorization requires documentation of the specified number and type of prior therapies as applicable to agent and disease stage.

Coverage label	Requirement
Covered
Both oral and topical brand Targretin (bexarotene) require a prior trial and documented failure or intolerance to generic bexarotene formulations (generic capsules for oral; generic topical gel for topical) before brand product authorization.

Coding and Billing

HCPCS codes referencedHCPCS

C9399	Unclassified drugs or biologicals (use to report: Lymphir)
J9032	Injection, belinostat (Beleodaq), 10 mg
J9161	Injection, denileukin diftitox-cxdl (Lymphir), 1 mcg (new code effective 04/01/25)
J9204	Injection, mogamulizumab-kpkc (Poteligeo) 1 mg
J9318	Injection, romidepsin, nonlyophilized (Romidepsin IV) 0.1 mg
J9319	Injection, romidepsin, lyophilized (Istodax) 0.1 mg

Added/Relevant HCPCS CodesHCPCS

J9161	HCPCS code added for Lymphir (denileukin diftitox-cxdl)
C9399	Unlisted HCPCS code (added to policy)
J9999	Unlisted HCPCS code (added to policy)

Historical HCPCS codes referenced in policy historyHCPCS

J9318	HCPCS code added previously (referenced in history)
J9319	HCPCS code added previously (referenced in history)
C9065	HCPCS code added previously (referenced in history)
J3490	HCPCS code previously added/removed in history
J9204	HCPCS code added (10/1/19)

inv-15: Lipid monitoring frequency with systemic bexarotene

Recommended lipid monitoring scheduleBaseline, weekly for 2-4 weeks after starting systemic bexarotene, then every 8 weeks thereafter

Purpose of monitoringDetect and manage major hypertriglyceridemia and other lipid abnormalities associated with systemic bexarotene

Management of abnormalitiesAbnormalities are reversible with therapy cessation and may be managed with dose reduction or concomitant antilipemic agents

Other laboratory monitoringMonitor liver function tests and thyroid function routinely due to risks of hepatotoxicity and hypothyroidism

Ophthalmologic monitoringRecommend periodic ophthalmologic evaluations due to reported cataracts in some patients

Provider Action Items, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for all drugs covered by this policy. The drugs may be managed under the pharmacy or medical benefit; providers must request prior authorization through the appropriate benefit channel.

Non-formulary exception reviews for any drug listed in this policy may be approved up to 12 months.
Initial authorizations for oral and topical drugs may be approved up to 3 months unless processed as a non-formulary exception.
Re-authorization (continuation) approvals may be issued up to 12 months when drug-specific criteria are met and chart notes document ongoing positive clinical response.

Denial Risk

Missing Prior Therapy or Diagnostic Criteria May Lead to Denial

Incomplete submissions that do not document required prior therapies or diagnostic criteria risk denial. Denials are likely when prior/concurrent therapy trials or objective response documentation required by the criteria are absent.

Site of Care and Administration

Billing Rule

Benefit processing determines pharmacy vs medical benefit and site of care

Drugs included in this policy may be managed under either the pharmacy or medical benefit; the site‑of‑care determination (infusion center vs pharmacy dispensing) is driven by benefit processing.

Verify benefit processing to determine whether the medication will be administered/billed under pharmacy or medical benefit.

Billing Rule

IV systemic agents administered in infusion settings consistent with trials

IV‑administered systemic agents (for example, romidepsin) should be administered in infusion settings consistent with trial administration (infusion center or hospital outpatient) as reflected in the coverage context.

Romidepsin dosing in trials: 14 mg/m2 IV infused over 4 hours on days 1, 8, and 15 of a 28‑day cycle.
Administer IV systemic agents in an infusion center or hospital outpatient consistent with trial practice.

Background and Clinical Context

Cutaneous T‑cell lymphomas (CTCL) are a group of rare T‑cell malignancies that primarily affect the skin; common clinical entities include mycosis fungoides (the most common, typically indolent form presenting as patches or plaques) and Sézary syndrome (a more aggressive form with erythroderma and circulating malignant T cells). Disease course ranges from skin‑limited, slowly progressive disease to advanced stages with lymph node, blood, or visceral involvement, and treatment selection depends on disease stage, prior therapies, and symptoms.

Definitions and Key Terms

inv-29: Mycosis fungoides / Sézary syndrome — Examples of CTCL

Mycosis fungoidesMost common indolent form of CTCL presenting as patches/plaques that can progress to raised pruritic plaques and tumors

Sézary syndromeAggressive CTCL form characterized by widespread erythroderma and circulating malignant CD4+ T-cells (Sézary cells)

Anatomic distributionCTCL primarily affects the skin but can involve lymph nodes, blood, and visceral organs in advanced disease

inv-30: Targretin (bexarotene) — agent definition and indication summary

Drug class and mechanismBexarotene (Targretin) is a retinoid X receptor (RXR)-selective agent that regulates gene transcription affecting cellular differentiation and proliferation

Indication summary

Policy Summary

PayerPremera Bluecross

PolicyCutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Policy CodePolicy N/A

Change TypeMaterial: added Lymphirremoved romidepsin PTCL indicationgeneric bexarotene requirement

Effective DateApr 1, 2025

Next Review DateN/A

Key ActionObtain prior authorization and document trials of required prior therapies and objective response assessments to support medical necessity.

SourceLink

On This Page

belinostat: Belinostat (Beleodaq) approved for relapsed/refractory PTCL based on a single‑arm phase 2 study with ORR ~25.8% and median duration of response ~8.4 months; survival benefit not established.

See belinostat pivotal trial.

mechlorethamine_topical: Valchlor topical gel indicated for Stage IA/IB MF‑CTCL after prior skin‑directed therapy; daily application up to 12 months in trial; CAILS response reported; systemic exposure undetectable.

See Valchlor trial data.

denileukin_diftitox_Lymphir: Lymphir indicated for relapsed/refractory Stage I‑III CTCL after ≥1 prior systemic therapy; Phase III ORR 36.2% (CR 8.7%), median time to response ~1.41 months; boxed warning for capillary leak syndrome.

See Lymphir pivotal Study 302.

Non‑formulary exception duration: Non‑formulary exception approvals for drugs listed in this policy may be granted for up to 12 months.

Clarified in the 2025 update.

vorinostat_initial: Vorinostat (Zolinza) 400 mg once daily showed ~30% response in refractory CTCL studies and was used in individuals with prior therapies.

Lymphir_initial: Lymphir pivotal Phase III Study 302 enrolled individuals with ≥1 prior systemic therapy; primary efficacy population received 9 μg/kg/day with ORR 36.2%.

See Lymphir trial for prior therapy requirement.

Initial therapy requirements

Bexarotene preferred sequencing

Bexarotene generic-first: Coverage for oral and topical bexarotene requires prior trial and failure with generic bexarotene formulations before brand Targretin is approved.

Generic topical bexarotene coverage criteria were added in the 2024 update.

Non-formulary exception duration: Non‑formulary exception review authorizations for medications listed in this policy may be approved for up to 12 months.

Other initial approvals for oral and topical agents may be shorter (e.g., up to 3 months) per policy sections.

If required prior therapies (e.g., trials of systemic retinoids, interferons, methotrexate, phototherapy, topical agents, or specified systemic chemotherapies) are not documented, the request may be denied.
Document stage of disease (eg, Stage IA/IB vs late-stage or systemic involvement) to support appropriate pathway (topical vs systemic).

Documentation Required

Topical Valchlor Monitoring and Documentation

Topical Valchlor (mechlorethamine) has negligible systemic exposure after topical administration; monitor and document local skin reactions and treatment tolerability in the medical record.

Systemic plasma concentrations were undetectable in clinical evaluations — systemic monitoring for mechlorethamine levels is not required.
Document any moderately-severe to severe skin-related adverse events, dose reductions, suspensions, or discontinuations (most discontinuations occurred within the first 90 days).
Include notes on timing of onset of local reactions and management steps (dose holds, frequency reductions, topical/supportive care).

Denial Risk

Romidepsin (Istodax/romidepsin injection) Indication Removed — PTCL Requests at Risk for Denial

Romidepsin (Istodax/romidepsin injection): the indication for peripheral T‑cell lymphoma (PTCL) was removed from the prescribing information; requests for PTCL are likely to be denied.

Coverage criteria have been updated to remove PTCL as an approved indication for romidepsin; only approved indications in the current prescribing information are considered.
When submitting for romidepsin, providers must document the specific diagnosis and ensure it aligns with the current FDA‑approved indications in the product labeling.

Documentation Required

Required Clinical Documentation

Submit complete clinical documentation with every prior authorization request to demonstrate that medical necessity criteria are met.

Office visit notes documenting diagnosis, relevant history, physical exam, medication history, and disease stage.
Documentation of prior therapies tried (agents, dates, doses), reason for discontinuation (intolerance or inadequate response), and objective response assessments (skin, lymph node, visceral, circulating Sézary cells as applicable).
For agents with required step or sequencing (eg, generic bexarotene trial before brand Targretin), include evidence of trial and failure.
For IV agents and specialty products, include prior systemic therapy history and number of prior lines of therapy.

Documentation Required

Prior Therapy and Response Documentation Required

Document prior therapies, disease stage, and objective response assessments to support both initial and re-authorization reviews.

Specify prior systemic and skin-directed therapies, number of prior lines, dates of therapy, and best response to each.
Provide objective disease response data where applicable (eg, ORR, CR/PR definitions, time to response, duration of response) or clinician assessments of clinical benefit.
For re-authorization, include chart notes showing ongoing clinical benefit and tolerability consistent with drug‑specific criteria.

Note

Verify Member Benefit and Plan Coverage

Providers must verify member benefits and any applicable coverage limitations before requesting authorization; this policy is a clinical coverage guide and member contracts govern actual benefits.

Consult the member benefit booklet or contact member services to determine whether the drug is covered under the pharmacy or medical benefit and to identify any plan-specific limitations or prior authorization processes.
Coverage determinations are subject to the member's contract; the medical policy guides medical necessity review but does not guarantee payment.

Step Therapy

Guideline-Aligned Sequencing and Step Therapy Expectations

Step-therapy and sequencing expectations reflect guideline-aligned sequencing (eg, NCCN) and policy-specific requirements such as generic-first trials for bexarotene prior to brand approval.

Follow guideline-recommended sequencing for skin‑directed versus systemic therapies based on disease stage.
Policy requires trial and failure of generic bexarotene (oral or topical as applicable) before approval of brand Targretin formulations.
Ensure prior authorization submissions clearly describe sequencing rationale and prior-agent trial outcomes.

Note

Topical Valchlor administered at home; monitor for local reactions

Topical Valchlor is applied by the member at home (daily for up to 12 months in the trial) with monitoring for local skin reactions; systemic exposure was undetectable in trial sampling.

Daily home application for up to 12 months was the trial regimen; monitor monthly for first 6 months then every 2 months.
Systemic blood concentrations were undetectable after topical administration.

Billing Rule

Follow FDA dosing/administration; site‑of‑care determined by benefit processing

Medications must be used according to FDA product dosing and administration prescribing information; site‑of‑care specifics and benefit processing determine the final administration setting and billing.

Follow labeled dosing/administration (e.g., romidepsin 14 mg/m2 IV days 1, 8, 15 q28d where applicable).
Confirm site‑of‑care and billing per member benefits and product labeling.

Indicated for treatment of cutaneous manifestations of CTCL in individuals refractory to at least one prior systemic therapy

Key safety considerationsTeratogenic (boxed warning); associated with major lipid abnormalities, hypothyroidism, pancreatitis, hepatotoxicity, leukopenia, and cataracts

inv-31: Objective Response (ORR) — definition

DefinitionObjective response rate (ORR) is the proportion of individuals with a confirmed complete response (CR) or partial response (PR)

Partial response (PR) criterionPR commonly defined as ≥50% improvement in composite disease assessments (skin, lymph node, visceral, circulating malignant cells)

Use in trialsORR was the primary efficacy endpoint in romidepsin CTCL studies and PTCL study assessments

inv-32: CAILS — Composite Assessment of Index Lesion Severity definition

DefinitionComposite Assessment of Index Lesion Severity (CAILS) is the summed score of severity categories for up to five index lesions (erythema, scaling, plaque elevation, surface area)

Response thresholdResponse defined as ≥50% reduction in baseline CAILS score confirmed at a subsequent visit at least 4 weeks later

Complete responseComplete response defined as a confirmed CAILS score of 0

inv-33: NCCN guidance — Reference to NCCN T‑Cell Lymphomas Version 1.2025

Guideline referenceNCCN Clinical Practice Guidelines in Oncology: T-Cell Lymphomas, Version 1.2025

Role in policyNCCN T-Cell Lymphomas guidance is cited as a reference for sequencing and management recommendations in this policy

Access noteVersion 1.2025 accessed March 12, 2025 (per policy references)