Cutaneous T-Cell Lymphomas (CTCL): Systemic Therapies

Number 5.01.532*

Effective Date December 8, 2014

Revision Date(s) 12/08/14; 05/13/13; 04/10/12; 05/10/11

Replaces N/A


Bexarotene (Targretin®), vorinostat (Zolinza®) or romidepsin (Istodax®) may be considered medically necessary for the treatment of cutaneous or peripheral T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Bexarotene (Targretin®), vorinostat (Zolinza®) or romidepsin (Istodax®) may be considered medically necessary for the treatment of mycosis fungoides/Sezary syndrome in patients who are refractory to at least one prior systemic therapy.

Belinostat (Beleodaq®) may be considered medically necessary for the treatment of patients with relapsed or refractory angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma or other peripheral T-cell lymphoma who have failed or are refractory to at least one prior systemic therapy.

All other uses of belinostat, bexarotene, vorinostat or romidepsin are considered investigational.

Related Policies


Extracorporeal Photopheresis

Policy Guidelines

Bexarotene (Targretin®), vorinostat (Zolinza®) or romidepsin (Istodax®) may be approved when one or more systemic therapies have failed (including but not limited to the following list of agents recommended by NCCN guidelines):

For simple skin involvement:

  • Systemic retinoids (isotretinoin, acitretin, etc.);
  • Interferons (alpha, gamma);
  • Methotrexate; and
  • Alemtuzumab (Campath®).

For late stage disease usually with solid organ involvement, more aggressive therapy is usually required, for example:

  • Gemcitabine, or
  • Liposomal doxorubicin.


Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare type of cancer of unknown etiology. In the United States, the estimated annual incidence of CTCL is 0.4 to 1 case per 100,000 (or 1,000 to 3,000 new cases per year). Since most cases are not fatal and patients can live with CTCL for 10 or more years, estimated U.S. prevalence is approximately 20,000. Approximately 25% of these cases (5,000) have advanced disease.

CTCL is characterized by abnormal malignant T-cells residing in the skin which cause skin lesions and pruritis. The disease often remains confined to the skin and has an indolent course. However, in more aggressive CTCL, the disease may progress to involve other areas of the body such as lymph nodes, blood, and organs. The most common indolent form is mycosis fungoides. This form usually manifests as flat red or pink scaly patches that appear in sun-protected areas of the body (e.g., buttocks or trunk) first. As the disease progresses, the patches evolve into a raised pruritic plaque phase. Plaques can also evolve into nodular skin tumors. Nodules may also ulcerate and there can be blood involvement.

The most common aggressive form of CTCL is Sézary syndrome. This syndrome accounts for about 5% of all CTCL cases and prognosis is poor. Median survival is usually less than 3 years. It is characterized by widespread erythroderma and the presence of abnormal CD4+ T-cells (called Sézary cells) in both the skin and peripheral blood at presentation. This condition may also be accompanied by scaling pruritic plaques or tumors. In advanced stages, patients with Sézary syndrome may develop alopecia, leonine facies, hyperkeratosis of the palms and soles, nail dystrophy, and parasthesia.

Therapeutic management of CTCL is based largely on the stage of the disease. In early, mild, and slowly progressive stages of the disease, treatment is mainly targeted at reducing symptoms and lesions with topical therapies (topical corticosteroids, topical retinoids (bexarotene, tazarotene), topical chemotherapy (nitrogen mustard, carmustine), local radiation (for limited skin involvement) or electron beam therapy (for severe skin involvement), phototherapy (UVB, nbUVB or patch/thin plaques; PUVA for thicker plaques), topical imiquimod (for limited localized skin involvement). In patients with advanced stages of the disease, mycosis fungoides and Sezary syndrome, systemic therapies, such as retinoids (e.g., bexarotene, acitretin), may be employed.

Bexarotene (Targretin®) is a member of a subclass of retinoids that selectively activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid receptors (RARs). Retinoids are associated with birth defects in humans. Bexarotene also caused birth defects when administered orally to pregnant rats. Therefore, it must not be administered during pregnancy.

Bexarotene selectively binds and activates retinoid X-receptor subtypes (RXRα, RXRβ, RXRγ). RXRs can form heterodimers with various receptor partners such as retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome proliferator activator receptors (PPARs). Once activated, these receptors function as transcription factors that regulate the expression of genes that control cellular differentiation and proliferation. Bexarotene inhibits the growth in vitro of some tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor regression in vivo in some animal models. The exact mechanism of action of bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown.

Bexarotene (Targretin) is indicated for the treatment of cutaneous manifestations of cutaneous T cell lymphoma in patients who are refractory to at least one prior systemic therapy.

Vorinostat (Zolinza®) and romidepsin (Istodax®) are a histone deacetylase (HDAC) inhibitors with enzymatic inhibitory activity at nanomolar concentrations for HDAC1, HDAC2, HDAC3 [class I], and HDAC6 [class II]. These enzymes catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, HDACs are overexpressed or are aberrantly recruited for oncogenic transcription causing hypoacetylation of core nucleosomal histones. While the exact mechanism of action of these agents has not been fully characterized, in vitro, they cause accumulation of acetylated histones, induces cell cycle arrest, and/or apoptosis of some transformed cells.

Vorinostat (Zolinza) is indicated for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies.

Romidepsin (Istodax) is indicated for treatment of cutaneous T-cell lymphoma (CTCL) or peripheral T-call lymphoma in patients who have received at least one prior systemic therapy.


Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical and pharmacy services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This policy does not apply to Medicare Advantage.

Benefit Application

The drugs included in this policy may be covered under either the pharmacy or medical benefit.




No randomized controlled trial for bexarotene in CTCL was found on literature search. The efficacy of oral bexarotene was demonstrated in 2 pivotal multinational, open-label, phase II-III studies in 94 adults with advanced refractory CTCL and 58 with early stage refractory or persistent CTCL. At recommended dosing (300 mg/m2/day), overall response to monotherapy as measured by PGA and CAILDS was about 50%. Two supportive open-label studies show systemic combination therapy to be efficacious as measured by response rates.

The efficacy of topical bexarotene was demonstrated in 1 pivotal multinational, open-label, phase II-III study in 50 adults with treatment refractory early stage CTCL. Like systemic bexarotene, overall response was about 50%. Bexarotene gel is the only topical product treatment of CTCL which has received approval by the U.S. Food and Drug Administration (FDA).

Off-label studies for systemic bexarotene have been reported for prevention of breast cancer, head and neck cancer, psoriasis, non-small cell lung cancer, and acute myeloid leukemia. Off-label studies for topical bexarotene have been reported for alopecia areata, parapsoriasis, severe hand dermatitis, and psoriasis.

No comparative studies between bexarotene and therapeutic alternatives for CTCL have been published and no comparative trials are currently underway.

Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells (“Sézary cells”). The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response. Median time tofirst response was 2 months (range 1 to 6) in both studies. Median time to CR was 4 months in Study 1 and 6 months in Study 2 (range 2 to 9).

The efficacy and safety of vorinostat was established in two nonrandomized, uncontrolled, open-label studies in adult patients with treatment refractory CTCL. A response rate (defined as at least 50% improvement in cutaneous manifestations) of approximately 30% was observed in patients receiving the approved dosing regimen of 400 mg once daily. Median time to response was <3 months, median response duration was approximately 3-4 months, and median time to progression was approximately 6-7 months.

Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe and Australia were treated with romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met. Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR). The complete response rate was 15% and overall response rate was 25%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 33 patients who achieved CR, CRu or PR and was 3.7 months (~4 cycles) for the 19 patients with complete response. The responses in 11 of the 19 patients achieving CR and CRu were known to exceed 9.2 months; the follow-up on the remaining 8 patients was discontinued prior to 9.2 months.


Bexarotene carries a boxed warning the drug should not be used in pregnant females because of its association with birth defects. Systemic bexarotene induces major lipid abnormalities in most patients, particularly hypertriglyceridemia. Lipids should be monitored at baseline, weekly for 2-4 weeks, then at 8 week intervals. Abnormalities are reversible with cessation of therapy and can be managed with dose reduction or concomitant antilipemic agents. Other serious adverse events reported following use of systemic bexarotene are pancreatitis, liver function test abnormalities and hepatotoxicities, hypothyroidism, leukopenia, and cataracts. Regular monitoring of related laboratory measures and ophthalmologic evaluations are recommended.

In oral CTCL trials, adverse events leading to dose reduction or study drug discontinuation in at least two patients were hyperlipemia, neutropenia/leukopenia, diarrhea, fatigue/lethargy, hypothyroidism, headache, liver function test abnormalities, rash, pancreatitis, nausea, anemia, allergic reaction, muscle spasm, pneumonia, and confusion. In topical CTCL trials, adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus.

In 504 patients participating in oral CTCL and non-CTCL clinical trials, 3 patients experienced a severe adverse event that was fatal; one each from acute pancreatitis, a subdural hematoma, and liver failure. In topical CTCL trials, only one patient (2%) experienced a severe adverse event (rash).

The most common adverse events observed in patients with CTCL (n=86) receiving vorinostat 400 mg once-daily in uncontrolled clinical were diarrhea, fatigue, nausea, thrombocytopenia, anorexia, and dysgeusia. The most commonly reported serious adverse events, regardless of causality, were pulmonary embolism and anemia. In addition, laboratory abnormalities (e.g., increased serum glucose, increased serum creatinine, proteinuria) were observed in all patients. Approximately 9% of the 86 patients discontinued the drug due to adverse events.

The safety of romidepsin was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months). Infections were the most common type of serious adverse event reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.



Belinostat is a histone deacetylase (DHAC) inhibitor indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). It received accelerated approval based on the results of 1 single-arm, phase 2 study using tumor response rate as the primary outcome measure. An improvement in survival or disease-related symptoms has not been established. The pivotal trial has not been published.

In all evaluable patients (n=120) treated with belinostat, the overall response rate per independent central review using the International Workshop Group (IWG) criteria was 25.8% (n=31), with rates of 23% for PTCL not otherwise specified (NOS) and 46% for angioimmunoblastic T-cell lymphoma (AITL), the 2 largest subtypes enrolled. Further, the response rate was higher (28%) in patients with baseline platelet counts at or above 100,000/µL and lower (15%) in those with baseline platelet counts below 100,000/µL. The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% confidence interval [CI], 4.5 to 29.4). Of the responders, the median time to response was 5.6 weeks (range, 4.3-50.4 weeks).


Sixty-one patients (47.3%) in the pivotal study experienced serious adverse reactions (grade 3 or higher) while taking belinostat or within 30 days after their last dose. The most common serious adverse reactions (>2%) were pneumonia, pyrexia, infection, anemia, increased creatinine, thrombocytopenia, and multiorgan failure. One treatment-related death associated with hepatic failure was reported in the study. Twenty-five patients (19.4%) in the pivotal study discontinued treatment with belinostat due to adverse reactions. Dose adjustments were made in 12%.

2013 Update

A literature search for new publications from 01/01/2012 to 04/30/2013 did not reveal new evidence that would require changes to this policy. The policy was compared with current NCCN guideline recommendations and found to be consistent. An updated systematic review of treatment for mycosis fungoides/Sezary syndrome was published by the Cochrane Skin Group in September 2012.

2014 Update

A literature search for new publications from 01/01/2013 to 10/31/2014 did not reveal new evidence that would require changes to the drugs previously in this policy. Added belinostat, recently approved by FDA with medically necessary indications consistent with current NCCN guideline recommendations.


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Type of Service

Prescription Drug


Place of Service








Add to Prescription Drug Section - New Policy.


Replace policy. Policy updated with romidepsin (Istodax®) and a new medically necessary policy statement for the treatment of mycosis fungoides/Sezary syndrome for patients refractory to at least one prior systemic therapy. Description, Policy Guidelines and Rationale also updated.


Replace policy. Policy reviewed with literature search/ reference added. No change in policy statement.


Annual review. Medically necessary policy statement added for belinostat, recently approved by the FDA, per NCCN guideline recommendations; approved by P&T December 2014. Literature review performed.


Update Related Policies. Change title to 8.01.36.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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