ModifiedPremera BluecrossPolicy 5.01.532

Cutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Defines medical necessity criteria, benefit management (pharmacy vs medical), documentation, coding, and clinical rationale for systemic and topical therapies used to treat cutaneous T-cell lymphomas (including mycosis fungoides and Sézary syndrome). Applies to Premera benefit determinations for affected members and providers.

Policy Summary

PayerPremera Bluecross

PolicyCutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Policy CodePolicy 5.01.532

Change TypeUpdated authorization lengthsadded Lymphirremoved romidepsin PTCL indication

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionSubmit office visit notes documenting diagnosis, prior therapies, and objective lesion assessments (e.g., CAILS/SWAT) with prior authorization requests.

SourceLink

POLICY UPDATE CHANGES

Added Lymphir (denileukin diftitox‑cxdl) for relapsed or refractory Stage I‑III CTCL and HCPCS code J9161.

Valchlor (mechlorethamine) was added to the policy on 07/27/2015 per NCCN guideline recommendations.

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use of romidepsin (Istodax and romidepsin injection) for treatment of peripheral T‑cell lymphoma because indication was withdrawn from prescribing information.

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

Updated initial authorization duration for oral and topical drugs listed in the policy from 3 months to 6 months.

2026-05-01most recent approval

12 monthsmax exception period

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6 monthsinitial auth length

Removedromidepsin PTCL

60%Valchlor CAILS response

Coverage Criteria

Oral agents (bexarotene capsules, vorinostat) - initial coverage criteria

Covered when ALL of the following are met for specific oral/topical agents:

General diagnosis requirement: Individual has diagnosis of 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), interferons (alpha, gamma), methotrexate, or alemtuzumab (Campath).

Applies to generic bexarotene capsules and vorinostat.

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

Applies to generic bexarotene capsules and vorinostat.

Topical bexarotene gel - coverage criteria

Topical bexarotene gel (Targretin) medical necessity criteria:

Diagnosis and stage: Individual has diagnosed cutaneous T-cell lymphoma (Stage IA or IB).

Prior topical/skin-directed therapies: Has tried and had an inadequate response or intolerance to three of the following: phototherapy (UVB, NB-UVB, PUVA), topical imiquimod, topical corticosteroids, topical mechlorethamine, or local radiation.3 of listed therapies

Prior systemic trial when specified: Has tried and had an inadequate response or intolerance to generic bexarotene capsules when required by sections referencing systemic bexarotene prior to topical use.

Document inadequate response or intolerance in records.

Intravenous agents - coverage criteria

IV agents (medical benefit) medical necessity criteria examples:

Belinostat (Beleodaq): Diagnosis of relapsed or refractory angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or other peripheral T-cell lymphoma.

Romidepsin (Istodax / romidepsin injection): Age ≥18 AND diagnosis of one of: mycosis fungoides, Sezary syndrome, or cutaneous T‑cell lymphoma; for simple skin involvement, has tried one of systemic retinoids, interferons, or methotrexate.

Romidepsin historically had a PTCL indication for individuals who received at least one prior systemic therapy; PTCL indication removed from coverage after prescribing information withdrawal.

Denileukin diftitox-cxdl (Lymphir): Age ≥18 AND relapsed or refractory Stage I-III cutaneous T‑cell lymphoma AND has received at least one prior systemic therapy.

Mogamulizumab-kpkc (Poteligeo):

All uses of the drugs listed in this policy that are not explicitly enumerated in the coverage criteria are considered investigational and are not covered. Requests must meet the specific diagnosis and prior-therapy requirements detailed in each drug section (e.g., mycosis fungoides, Sézary syndrome, CTCL, or peripheral T‑cell lymphoma where applicable) to be considered medically necessary. The medications remain subject to the product's FDA dosage and administration prescribing information.

Valchlor (mechlorethamine) is a topical alkylating agent indicated for Stage IA and IB mycosis fungoides–type CTCL after prior skin-directed therapy; in the pivotal randomized trial it was applied daily for up to 12 months with response assessed by CAILS. In pharmacokinetic testing within that program, systemic exposure was undetectable after topical administration. Because systemic absorption was not detected in measured samples, systemic chemotherapy indications are not supported by the Valchlor data and systemic exposure–related uses are outside the basis of the topical indication.

Romidepsin (Istodax and brand romidepsin injection) previously had a labeled indication for peripheral T‑cell lymphoma; that indication was withdrawn from the prescribing information. As a result, requests for romidepsin for treatment of peripheral T‑cell lymphoma are no longer consistent with the product label and were removed from the policy's coverage criteria.

Uses other than those specifically enumerated in this policy (that do not meet the stated diagnosis and required prior-therapy conditions in each drug section) are considered investigational / not medically necessary. Providers must document the exact diagnosis and prior therapy history called for in the applicable drug criteria to support medical necessity.

Belinostat (Beleodaq) received accelerated approval for relapsed or refractory peripheral T‑cell lymphoma on the basis of tumor response rate from a single‑arm phase 2 study. An improvement in survival or disease‑related symptoms has not been established, and approval was based on response rate rather than demonstrated survival benefit.

Coding

HCPCS codes for medical benefit-managed IV drugsHCPCSCovered

J9032	Injection, belinostat (Beleodaq), 10 mg
J9161	Injection, denileukin diftitox-cxdl (Lymphir), 1 mcg
J9204	Injection, mogamulizumab-kpkc (Poteligeo), 1 mg
J9318	Injection, romidepsin, nonlyophilized (Romidepsin IV), 0.1 mg
J9319	Injection, romidepsin, lyophilized (Istodax), 0.1 mg

Policy-related HCPCS codes (history of additions/removals)HCPCS

J9161	HCPCS code added for Lymphir (denileukin diftitox‑cxdl)
C9399	Unlisted HCPCS code (added earlier, later removed in 05/01/26)
C9065	Previously added HCPCS code (removed later)
J9315	Previously added HCPCS code (removed earlier)
J9318	HCPCS code added 10/01/21
J9319	HCPCS code added 10/01/21
J3490	HCPCS code added and later removed
J3590	HCPCS code added and later removed

Lipid monitoring frequency on systemic bexarotene

Lipid monitoring scheduleBaseline, weekly for 2-4 weeks, then every 8 weeks for individuals receiving systemic (oral) bexarotene

Purpose of monitoringDetect and manage major lipid abnormalities (notably hypertriglyceridemia) which occur in most individuals on systemic bexarotene

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

Other recommended monitoringRegular monitoring of liver function tests, thyroid function, and ophthalmologic evaluations due to associated hepatotoxicity, hypothyroidism, and cataracts

Time to response

Median time to first response (CTCL romidepsin studies)

Provider Actions and Requirements

Prior Authorization

Prior Authorization Required; Length of Approval

Prior authorization required for all drugs listed in this policy. Initial authorization durations: oral and topical drugs — initial approvals updated to 6 months; non‑formulary exception reviews may be approved up to 12 months. Re‑authorization reviews may be approved up to 12 months when drug‑specific criteria are met and chart notes document continued clinical benefit.

Medical‑benefit managed IV drugs (Beleodaq, Istodax/romidepsin, Lymphir, Poteligeo, romidepsin injection) require medical benefit prior authorization.
Pharmacy‑benefit managed topical and oral agents (generic bexarotene capsules/gel, Targretin capsules/gel, Valchlor, Zolinza) require pharmacy prior authorization.

Prior Authorization

Valchlor Prior Authorization

Valchlor (mechlorethamine) topical gel requires prior authorization. Coverage is limited to Stage IA and IB mycosis fungoides‑type CTCL in individuals who have received prior skin‑directed therapy as described in the pivotal trial.

Indicated population: Stage IA and IB MF‑type CTCL after ≥1 prior skin‑directed therapy.

Covered Regimens and Dosing

Regimen
14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days; may continue until progression or unacceptable toxicity

Regimen
14 mg/m2 IV over 4 hours on days 1, 8, and 15 of a 28-day cycle; continue until progression or unacceptable toxicity

Regimen
400 mg orally once daily

Regimen
As per pivotal study dosing (not fully specified in excerpt)

Regimen
Topical gel applied daily for up to 12 months with monitoring and dose adjustments for dermatitis

Regimen
Study dosing included 9 μg/kg/day (specific schedule not fully enumerated in this excerpt)

Coverage status	Notes
Covered for CTCL per policy criteria	Romidepsin not covered for peripheral T‑cell lymphoma after indication withdrawal from prescribing information

Requirement	Notes
Trial of generic bexarotene required prior to coverage	Applies to both oral capsules and topical formulations (require trial and failure of generic bexarotene before brand coverage)

Agent	Policy action / note
Lymphir (denileukin diftitox‑cxdl)	Added for treatment of relapsed or refractory Stage I‑III CTCL (approved dosing evaluated in Phase III Study 302)

Line of Therapy Criteria

second-line

Romidepsin PTCL label: Used in individuals who have received at least one prior systemic therapy.

second-line

Vorinostat label: Indicated for individuals with CTCL who have progressive, persistent, or recurrent disease on or following two systemic therapies.

second-line

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

Background

Cutaneous T‑cell lymphomas (CTCL) are a group of T‑cell malignancies that primarily involve the skin. Examples include mycosis fungoides and the more aggressive leukemic form, Sézary syndrome. Management is stage‑directed: early‑stage disease is typically treated with skin‑directed therapies, while advanced or refractory disease may require systemic agents. This policy defines when specific topical and systemic therapies are considered medically necessary after prior therapies have been tried and documented.

Definitions

Sézary syndrome

DefinitionSézary syndrome is an aggressive form of cutaneous T‑cell lymphoma characterized by widespread erythroderma and malignant CD4+ T‑cells in both skin and peripheral blood

PrognosisPrognosis is poor with median survival usually less than 3 years

Clinical featuresMay include scaling pruritic plaques or tumors, alopecia, leonine facies, hyperkeratosis of palms/soles, nail dystrophy, and paresthesia

Targretin (bexarotene)

Drug class and mechanismTargretin (bexarotene) is a retinoid X receptor (RXR)-selective agent that activates RXRα, RXRβ, and RXRγ

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

Revision History

2014 Updateadded

Added Beleodaq (belinostat) following FDA approval with indications consistent with NCCN recommendations.

2015-07-27added

Valchlor (mechlorethamine) was added to the policy per NCCN guideline recommendations.

2016 Updaterevised

Reorganized safety and efficacy content to be under each relevant drug (format/layout change).

Policy Summary

PayerPremera Bluecross

PolicyCutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Policy CodePolicy 5.01.532

Change TypeUpdated authorization lengthsadded Lymphirremoved romidepsin PTCL indication

Effective DateMay 1, 2026

Next Review DateN/A

Key ActionSubmit office visit notes documenting diagnosis, prior therapies, and objective lesion assessments (e.g., CAILS/SWAT) with prior authorization requests.

SourceLink

On This Page

Age ≥18 AND relapsed or refractory mycosis fungoides or Sezary syndrome AND has received at least one prior systemic therapy.

2 months (range 1 to 6)

Median time to complete response (CTCL studies)Study 1: 4 months; Study 2: 6 months (range 2 to 9)

Median time to objective response (PTCL study)1.8 months (~2 cycles) for responders; median time to complete response 3.7 months (~4 cycles)

Valchlor was added to the policy per NCCN recommendations (added 07/27/2015).

Denial Risk

Insufficient Documentation May Result in Denial

Requests lacking required documentation of diagnosis or prior therapies are subject to denial.

Required documentation: office visit notes with diagnosis, relevant history, physical exam, and medication history.
If prior‑therapy trials or intolerance/refractoriness are not documented, the request may be denied.

Denial Risk

Indication Removed — Romidepsin

Use of romidepsin (Istodax) and romidepsin injection for peripheral T‑cell lymphoma is no longer covered per updated prescribing information; requests for this indication are inconsistent with current coverage.

Coverage criteria were updated to remove peripheral T‑cell lymphoma indication after withdrawal from prescribing information.

Documentation Required

Valchlor Documentation Requirements

Valchlor documentation must reflect the prior skin‑directed therapies required in the pivotal trial and include objective response assessments (CAILS and/or SWAT) where available. Document treatment duration, dosing, response timing, and any dermatitis management (dose suspension or reduced frequency).

Pivotal trial required ≥1 prior skin‑directed therapy (examples: topical corticosteroids, phototherapy, Targretin gel, topical nitrogen mustard).
Responses were assessed monthly for 6 months then q2 months to 12 months using CAILS and/or SWAT; a response = ≥50% reduction from baseline confirmed ≥4 weeks later.
Document mean/maximum usage if available (trial mean daily usage 2.8 g; max reported 10.5 g).

Note

Follow Prescribing Information; Exception and Approval Duration

Prescribing information must be followed for dosage and administration for all medications listed. Non‑formulary exception review authorizations for drugs in this policy may be approved up to 12 months; all other reviews may be approved up to 12 months if criteria and clinical response are documented.

Follow each product's FDA dosing and administration guidance.
Non‑formulary exception reviews: approvals up to 12 months.
Continuation approvals: up to 12 months when coverage criteria are met and chart notes show ongoing clinical benefit.

Step Therapy

Required Trials of Prior Therapies

Many agents require documented trials of prior therapies with inadequate response or intolerance before coverage. Examples include systemic retinoids, interferons, methotrexate, alemtuzumab, phototherapy, topical steroids, topical imiquimod, topical mechlorethamine, and local radiation as specified by route and stage.

Oral agents (e.g., Targretin, vorinostat): require prior trials such as systemic retinoids, interferons, methotrexate, or alemtuzumab for simple skin involvement.
Topical therapies (e.g., bexarotene gel, Valchlor): require trials of phototherapy, topical imiquimod, topical corticosteroids, topical mechlorethamine (where listed), or local radiation per stage‑specific criteria.
IV agents: many require at least one prior systemic therapy for relapsed/refractory disease.

Step Therapy

Sequencing for Topical Mechlorethamine (Valchlor)

Policy notes sequencing considerations for topical mechlorethamine (Valchlor): pivotal trial enrolled individuals who had received prior skin‑directed therapies; Valchlor use is considered after prior skin‑directed therapy as specified (i.e., not necessarily required to be refractory to all prior options but following prior therapy).

Sequencing: Valchlor indicated for use in patients who have received prior skin‑directed therapy; document prior therapies and timing.
Pivotal trial allowed prior therapies and did not require documented refractory status to those therapies.

Step Therapy

Bexarotene Generic Trial Requirement

Coverage for oral and topical Targretin (bexarotene) now requires trial and failure (or intolerance) of generic bexarotene first; topical and oral generic bexarotene options were added to the policy.

Updated 2024: oral Targretin required trial and failure with generic bexarotene capsules.
Updated 2024: topical Targretin required trial and failure with generic topical bexarotene; generic topical bexarotene added to policy.

Romidepsin CTCL study eligibility: CTCL patients in pivotal studies had failed at least 1 prior systemic therapy (Study 1) or received at least 2 prior skin-directed therapies or ≥1 systemic therapy (Study 2).

Romidepsin PTCL study eligibility: PTCL patients in Study 3 had failed at least 1 prior systemic therapy.

Denileukin diftitox (Lymphir) indication: Relapsed or refractory Stage I-III CTCL after at least one prior systemic therapy (Study 302 population).

Safety considerationsAssociated with teratogenicity (boxed warning) and major lipid abnormalities; contraindicated in pregnancy

Objective response rate (ORR)

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

Use in studiesORR was the primary efficacy endpoint in romidepsin CTCL studies, incorporating assessments of skin, lymph node/visceral involvement, and circulating malignant T‑cells

Context for PTCL studyIn the romidepsin PTCL study, ORR was 25% with a complete response rate of 15%

CAILS score (Composite Assessment of Index Lesion Severity)

DefinitionCAILS (Composite Assessment of Index Lesion Severity) sums severity categories for up to 5 index lesions (erythema, scaling, plaque elevation, surface area)

Scoring elementsErythema and scaling scored 0–8; plaque elevation 0–3; surface area 0–9

Response thresholdA response is defined as ≥50% reduction in baseline CAILS score confirmed at the next visit at least 4 weeks later; complete response = confirmed CAILS score of 0

2021 Updateadded

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

2024 Updaterevised

Removed romidepsin use for peripheral T-cell lymphoma after withdrawal of that indication and updated coverage to require trials of generic bexarotene for oral and topical Targretin; added coverage criteria for generic topical bexarotene.

2025-01-01added

Added Lymphir (denileukin diftitox-cxdl) for relapsed or refractory Stage I-III CTCL and added HCPCS codes including C9399 and J9999 (later modified).

2026-05-01clarifiedLatest

Updated initial authorization duration for oral and topical drugs from 3 months to 6 months (approved 2026-04-13); removed HCPCS code C9399 and noted non‑formulary exception approvals may be up to 12 months.