Mycosis Fungoides.pdf

a report by

Lawrence A Mark , MD , PhD , FAAD

Assistant Professor of Dermatology, Indiana University School of Medicine, and Service Chief, Dermatology, Wishard Hospital

Successful Treatment of Mycosis Fungoides

Primary cutaneous T-cell lymphoma is a heterogenous group of non-

Hogkin’s lymphomas—including mycosis fungoides (MF), anaplastic large cell

lymphoma, adult T-cell lymphoma/leukemia, subcutaneous panniculitis-like

T-cell lymphoma, and extranodal natural killer (NK)/T-cell lymphoma, nasal

type—each uniquely distinguishable based on clinical presentation,

immunohistochemistry, prognosis, and treatment strategies. The classification

schema is constantly being revised to accommodate new information as it is

gathered on this rare set of diseases; however, it is widely recognized that MF

is by far the most prevalent of this group, accounting for approximately 50%

of primary cutaneous T-cell lymphomas1 with an incidence of 0.64/100,000

person-years.2 This incidence has been on the rise over the last 30 years,

although it is not clear whether this is due to better diagnostic tools (such as

polymerase chain reaction [PCR]-based T-cell gene rearrangement

technology), heightened awareness among clinicians, or a true rise secondary

to an as yet unidentified environmental factor or infectious agent.

Nonetheless, it has become a more prominent disease, posing difficult

management choices for the clinician, but also drawing clinical research to

help tackle this difficulty. New treatment choices are now available that were

unheard of 10–20 years ago, such as retinoid therapy with bexarotene,

histone deacetylase therapy with vorinostat, and monoclonal antibody

therapy with alemtuzumab and denileukin diftitox. In this article, I would like

to first discuss tenets of therapy in general, but then focus on the treatment

options readily manageable by the dermatologist specifically.

Tenets of Therapy

Clinically Visible Disease Should Be Actively Treated

Once the diagnosis of MF has been established, one must determine what the

goal of therapy will be: palliation or remission. As MF usually occurs in an

aging population that may have numerous other comorbidities leading to

limited life expectancy, palliative interventions may be considered for these

individuals to avoid unnecessary side effects of more aggressive therapy. A

frank and honest discussion with the patient and family regarding the typical

indolence of MF and the place of various therapies in this disease will help

guide the decision.

However, for younger patients or those in general good health, an attempt

at achieving remission or near complete remission is recommended. This is

because without treatment it is expected that the disease will continue to

progress, however slowly or quickly, from the patch stage to involve more

skin area, become plaque stage, form tumors, and then involve lymph

nodes and/or blood. The exception to this may be Woringer-Kollop disease

or pagetoid reticulosis subsets of MF, which by definition are non-

progressive and isolated in skin involvement. As indirect evidence for the

assertion that MF will progress if untreated, one may scrutinize a seminal

article from Stanford University reporting the prognoses for the various

stages of MF. Their data show that only stage IA disease is associated with

no measurable decrease in life expectancy, possibly because all of their

patients obtained treatment, even those with early-stage disease in whom

treatment may be able to eliminate tumor burden.3 This agrees with the

findings of Swanbeck et al., who compared mortality of MF in the pre- and

post-psoralen with ultraviolet A therapy (PUVA) eras, a therapy generally

considered useful only in stage IA–IIA disease, revealing an overall 50%

reduction in death rate.4 The logical conclusion is to actively treat clinically

identifiable disease when able, thereby halting progression through

decreased tumor burden and avoiding increased mortality. Additionally,

early-stage disease is more amenable to obtaining sustainable complete

remission, whereas this is usually unrealistic in more advanced stages of MF.

However, one must remain cognizant that maintenance of remission may

require long-term ongoing treatment regimens, which may have cumulative

adverse effects in themselves. A frank discussion of risk versus benefit is

always required before embarking on long-term therapy for these patients.

Specific Therapy Is Based on Stage of Disease

Just as the astute oncologist would avoid multi-agent chemotherapy for MF

with only a few patches of involvement, so the astute dermatologist would

not treat progressive tumor-stage disease with topical nitrogen mustard

alone. However, most patients do present with early disease that is

amenable to skin-directed therapies that the dermatologist will be able to

manage. Table 1 addresses which first-line therapies may be best suited for

any particular disease stage and generally expected responses. Obviously,

clinician-specific preferences, medication side-effect profiles, patient

comorbidities, and disease aggressiveness exhibited by clinical behavior

often color the specific choice of therapy. This list is not intended to be

comprehensive, nor an edict for correct choices of therapy for any one

individual, but merely a guideline to aid clinical practice.

Skin Cancers

69© T O U C H B R I E F I N G S 2 0 0 8

Lawrence A Mark, MD, PhD, FAAD, is an Assistant Professorof Dermatology at the Indiana University School of Medicinein Indianapolis and Service Chief for Dermatology at the local county-funded hospital, Wishard Hospital, and thedermatological arm of the Mel and Bren Simon CancerCenter’s Multidisciplinary Melanoma Clinic. Dr Mark’sresearch interests are in cutaneous T-cell lymphomas andmelanoma. He is a Fellow of the American Academy ofDermatology (AAD) and a member of both the Society for

Investigative Dermatology (SID) and the Biophysical Society. Dr Mark received his MD, PhD,and residency training at Indiana University School of Medicine.

E: [email protected]

mark_subbed.qxp 31/3/09 15:09 Page 69

Patients in Remission Should Be Followed Up Indefinitely

Certainly, those patients with only partial response or palliation require

continued follow-up to periodically assess for disease progression. Such

progression would weigh heavily on further therapeutic choices and expected

prognosis. However, if complete remission has been achieved, what guidelines

are there for continued follow-up? This author is currently unaware of any

specific evidence-based recommendations such as there are for melanoma or

squamous cell carcinoma. While patients are on maintenance therapy for their

remission, they are usually seen at least three to four times per year, allowing

for relatively close monitoring. What if the patient remains in remission, even

after complete cessation of all therapeutic modalities? My practice is to at least

see these individuals every three to four months for two years, followed by

once every six months for three years and then yearly thereafter, with

instructions to return more urgently if they have concern for recurrence.

Typically, they have high-potency topical steroids on hand, and should raise

concern if there is a ‘rash’ that persists despite four to six weeks of medication

applications. For practical purposes, the definition of ‘cure’ as being free of

disease for eight years after all therapy has ended worked in a nitrogen

mustard trial5 and has been suggested by Peter Heald as a standardizable

definition to uphold.6 Again, without evidence-based medicine to guide, other

than standard of care for non-Hogkins lymphomas as described by the National

Comprehensive Cancer Network (NCCN) guidelines,7 I see these individuals

once yearly indefinitely.

Particular therapies that the dermatologist should be expected to manage are

any skin-applied, skin-directed, or oral therapies available for this disease.

When special equipment is needed (such as for light therapy, total skin electron

beam, and extracorporeal photopheresis) or infusional therapies are required,

referral to the oncologist or specialized medical center may be indicated.

Nonetheless, most dermatologists feel comfortable with directing light therapy,

especially if their practice maintains the light box. Therefore, the following

successful therapeutic modalities will be briefly discussed: topical steroid,

bexarotene gel, nitrogen mustard ointment, phototherapy, bexarotene oral

capsules, interferon alfa (INF-α) injections, methotrexate, and vorinostat. For a

more complete discussion, please refer to Heald et al.8

High-potency topical steroids are typically used as adjunctive therapies

in MF owing to their anti-inflammatory and lymphocytic pro-apoptotic

characteristics. It is considered palliative as monotherapy due to the short times

before recurrence of disease on discontinuation. However, complete responses

to clobetasol applied twice daily for two to three months were seen in 63% of

limited early-stage disease.9 Aggressive use of a class I steroid on any suspicious

eruption that could represent early relapse, including contact dermatitis and

insect bites, may help maintain remission and differentiate between benign

dermatitis and malignant disease. Should lesions persist for more than four to

six weeks in this scenario, histological evaluation is recommended.

Bexarotene 1% gel (Targretin®) is typically used for <15% body surface area

due to its ability to cause retinoid-induced irritant dermatitis.10 Patients are

instructed to begin applying the medication once nightly for one week,

followed by twice daily for one week, and then finally thrice daily thereafter for

a total of three months. If tolerated, four-times-a-day application is best as

there is dose responsiveness to the medication. Irritant response is managed by

either decreasing the frequency of application or, better still, by adding daily

applications of topical corticosteroid. Once the course has been completed, the

patient is allowed to rest for one month to allow for the retinoid dermatitis to

Skin Cancers

70 U S D E R M A T O L O G Y

Table 1: Suggested First-line Therapies Matched to Disease Stage

Stage Modality Response TypeI. Limited patches to generalized plaques Topical steroid Palliative, maintenance for non-descript lesions

Bexarotene gel Remittive or palliative

Nitrogen mustard ointment Remittive (includes mechlorethamine and bis-chlorethyl nitrosourea)

Spot radiation Remittive

Phototherapy Remittive

II. Generalized plaques or tumors with dermatopathic nodes Nitrogen mustard ointment Remittive

Phototherapy Remittive

Total skin electron beam Remittive, requires encore maintenance therapy

Bexarotene oral Palliative, remittive in conjunction with phototherapy

Interferon alfa Palliative, remittive in conjunction with phototherapy

Denileukin diftitox Palliative

Gemcitabine Palliative

III. Erythroderma Extracorporeal photopheresis Palliative

Total skin electron beam Remittive, requires encore maintenance therapy

Bexarotene oral Palliative


IV. Nodal or visceral involvement Bexarotene oral Palliative


Alemtuzumab Remittive

Traditional single-agent chemotherapy Methotrexate, gemcitabine, chlorambucil, cyclophosphamide, etoposide,

liposomal doxarubacin; all considered palliative with rare remission

Relapsed/unresponsive disease Alternate agent in stage-specific list As above

Vorinostat Palliative

Traditional single-agent chemotherapy Methotrexate, gemcitabine, chlorambucil, cyclophosphamide, etoposide,

liposomal doxarubacin; all considered palliative with rare remission

Allogeneic stem-cell transplantation Remittive


resolve and then reassessed for disease burden (cycle 1). If objective response

is obtained, another cycle of therapy may be considered. As a retinoid, there

should be no cumulative toxicity with regard to cutaneous carcinogenesis or

structural damage. In fact, the retinoids typically have activities that counter

mutagenic effects. The drug is not absorbed to any significant level, so no

blood monitoring is required.

Topical alkylating agents are available in two varieties for MF treatment:

mechlorethamine (nitrogen mustard) (Mustargen®) and bis-chloroethyl

nitrosourea (BCNU) (BiCNU, Carmustine®). Both are best when compounded

into ointment form for delivery because the solution forms are more prone to

allow development of contact sensitization, the alcohol in the vehicle has no

emollient property, and the product is labile in solution at room temperature.

Each compound has a similar risk of causing post-inflammatory hyper-

pigmentation, erythema, telangectasias, skin tenderness, and burning

sensations apart from the contact hypersensitivity reactions.

Ten or 20mg% mechlorethamine ointment is applied topically from chin to

toes, with sparing application for intertriginous folds once daily in the induction

phase. This is performed for up to three or four months to adequately assess

for response. One should expect a 60–90% complete remission rate with this

therapy on early-stage disease.5,11 Once remission is obtained, a maintenance

regimen is recommended, but no specific regimen has been studied. One

recommendation could be to taper application frequency over several weeks

down to at least once weekly, as long as no recurrence is found.

Mechlorethamine applications are often used as an encore to maintain

remission after radiotherapy. Unfortunately, non-melanoma skin cancer is a

known long-term side effect of chronic application, even in the absence of

pre-existing photodamage.12,13 Twenty or 40mg% BCNU ointment is applied

topically as spot treatment for less than 15% body surface area at a time. This

is performed for three to four months to adequately assess for response. One

should expect a 60–85% complete response rate with this therapy on early-

stage disease.14 Maintenance regimens have not been studied and most

practitioners repeat cycles of treatment as needed. Only a limited skin area can

be treated at any one time due to percutaneous absorption of BCNU leading

to bone marrow suppression (thrombocytopenia and lymphopenia). Therefore,

it is recommended that blood counts be obtained every other week while on

therapy and for one month post-therapy. The risk seems greatest if daily

application exceeds 25mg.15 Secondary cutaneous malignancies have not been

reported with BCNU.

Phototherapy may be delivered as broad-band ultraviolet B (BB-UVB),

narrowband ultraviolet B (NB-UVB), ultraviolet A (UVA), or

photochemotherapy using PUVA. There is dose responsiveness to the

therapy and most regimens use at least three-times-a-week dosing in the

induction phase. Initial dose is limited by Fitzpatrick skin type, but

incremental dose increases are given as therapy continues. For a detailed

discussion of how to deliver phototherapy safely and effectively, refer to the

work by Zanolli and Feldman.16 In general, at least 20–30 doses need to be

delivered before being able to adequately assess for efficacy. If a response is

obtained, dosing is continued until complete clearance is obtained (usually

50–60 treatments). Expect to reliably obtain remission of early-stage disease

with PUVA therapy.17,18 If complete response is not obtained, the addition of

adjuvant therapy with an oral retinoid (such as bexarotene) or subcutaneous

INF injections can be quite efficacious. Once remission is obtained, the

maintenance phase is obtained by slowly tapering dose frequency to the

most infrequent that maintains long-term remission. This ends up being

about once every other week for UVB and as little as once a month for

PUVA. If remission has been retained for five years, cessation of therapy may

be considered.

UVB phototherapy is best suited for patients with thin lesions (patches), owing

to the fact that UVB penetrates much less deeply than UVA wavelengths.

However, home phototherapy with UVB appeals to many patients due to not

having to take an oral pill and convenience, particularly if they live more than

half an hour from a phototherapy center. Light therapy has cumulative risks for

non-melanoma and melanoma skin cancers. It is recommended that the total

number of UVA treatments not exceed 250 over a lifetime to reduce this risk.

Other risks include photosensitivity, phototoxicity, cataract formation, and

hyperpigmentation. Furthermore, psoralen exacerbates the risk for

phototoxicity and adds a risk for nausea and vomiting, particularly if doses

greater than 30 or 40mg per session are used. Nonetheless, PUVA is considered

more efficacious, especially for plaque-stage disease.19,20 Sites of sanctuary from

light often occur in intertriginous zones, in skin folds, and on the eyelids.

Adjunctive therapy with localized bexarotene gel, BCNU, imiquimod 5%

cream, or radiation therapy can be effective for achieving complete remission.

Bexarotene (Targretin®) oral therapy is available in 75mg tablets and initially

dosed at 300mg/m2/day. It is generally well tolerated but does lead to central

hypothyroidism, hypercholesterolemia, and hyperlipidemia that must be

monitored and controlled with concomitant medications. Other side effects

may include headache, hepatitis, pancreatitis (with uncontrolled

hyperlipidemia), neutropenia, and thrombocytopenia. Often dose reduction is

necessary to avoid these effects, but is to be discouraged if possible as MF is

dose-responsive to this medication. Expectations are for response rates ranging

from 30 to 60% depending on disease stage. This therapy is considered

palliative as disease rapidly returns when the medication is discontinued and

median response times are about 18 months before relapse.21,22 In combination

with INF and/or phototherapy, it can be a component of a remittive

regimen.23,24 Combination therapy is advantageous in that bexarotene may be

used at lower doses, reducing the risk for systemic toxicity.

In order to safely and effectively deliver the medication, the following

recommendations have been proposed:

• Before starting a patient on oral bexarotene, obtain a baseline fasting lipid

panel, liver function test, thyroid-stimulating hormone (TSH), free thyroxine

(T4), pregnancy test, and complete blood count (CBC). Screen for comorbid

conditions that may interfere with therapy (obesity, diabetes, alcoholism,

and estrogen and thiazide use). Provide information on diet and exercise.

Pregnancy is an absolute contraindication to therapy with bexarotene.

• Start a fibric acid derivative, fenofibrate (Tricor®) 200mg daily, for one week

prior to instituting bexarotene capsules. Gemfibrozil (Lopid®) is not

recommended as it increases bexarotene levels.

• If the lipid panel is abnormal, start an HMG Co-A reductase inhibitor,

atorvastatin (Lipitor®) 20mg once daily for one week, prior to instituting

bexarotene capsules. Be aware that combination therapy with fenofibrate

and atorvastatin increases the risk for rhabdomyolysis, myopathy, and acute

renal failure; therefore, additional monitoring of creatine kinase (CPK) and

symptoms is required.

Successful Treatment of Mycosis Fungoides

71U S D E R M A T O L O G Y


• Optimize thyroid function with levothyroxine for at least one week prior

to instituting bexarotene capsules.

• Monitor fasting lipid panel, liver function test, CPK (if needed), T4, and a

CBC every two weeks until on a stable dose with no further concomitant

medication changes required. Note that TSH need not be further tested as

this will reliably go to zero on bexarotene oral therapy. Once stable,

monitoring labs may be reduced to once every three months.

INF-α (Roferon-A®, Intron-A®) is self-administered by the patient as a

subcutaneous injection of three to 18 million units three times per week.

Starting with three million units per dose for three months is

recommended, and if there is minimal or no response, the dose may be

increased as tolerated. When the patient clears or is at maximal response,

the dose should be maintained for three additional months and then

slowly tapered over 12 months either by frequency of administration or

by dose. Expected partial response varies from 30 to 75%, but there is

rarely a complete response.25–28 Acute side effects include flu-like

symptoms of malaise, myalgia, headache, and fever. Bedtime dosing and

pre-treatment with acetaminophen help reduce these side effects, but

most patients note diminishment of these symptoms after four to six

weeks of therapy. Unfortunately, chronic toxicity includes neuropathy,

depression, chronic fatigue, and hypothyroidism. Side effects are dose-

related and reversible. Laboratory studies should be directed at

monitoring for abnormalities of leukopenia, thrombocytopenia, anemia,

proteinuria, transaminitis, and hypothyroidism.

Methotrexate is delivered either orally or subcutaneously in doses ranging from

5 to 50mg once weekly. Patients with early-stage disease can be expected to

have overall response rates of 33% and should occur within six to 12 weeks of

instituting therapy.29 Toxicities include nausea, gastritis, leukopenia, hepatitis,

mucositis, and pneumonitis. Therefore, baseline CBC, urinalysis, basic

metabolic profile, liver panel, and viral hepatitis screening is recommended. A

frank discussion regarding avoidance of pregnancy, alcohol, sulfa-based

antibiotic and chronic non-steroidal anti-inflammatory drugs use is warranted.

Suggested monitoring includes CBC and liver function tests at one, two, and

four weeks after initiation of therapy. If no abnormalities occur, less frequent

monitoring of at least once every three months is recommended.

Vorinostat affects gene expression by inhibiting histone deacetylase, but how

this mechanism translates into clinical efficacy in MF is still largely unknown. It

is administered as monotherapy at 400mg per day with decreased efficacy at

lower doses. Partial response rates in the pivotal trial were around 30%, with

palliation of pruritus as a notable aspect of vorinostat therapy. The most

common side effects include thrombocytopenia, dehydration, and diarrhea;

therefore, blood monitoring, pushing oral fluids, and symptomatic use of

loperamide are required. The median time to response is 12 weeks.30

In summary, there is an exciting list of therapies, some old and some new, with

which the dermatologist can readily treat their MF patients. Expect more oral

formulations to be on the way in the near future, as this appears to be where

the greatest thrust of current pharmaceutical research lies. Although the array

of choices may seem daunting at first, once the goal of therapy has been

defined—remission or palliation—the choices become clearer. Additionally,

limiting therapeutic choices to those appropriate for the patient’s current stage

of disease eases the decision-making process. With common sense and

knowledge of the therapy being administered, the dermatologist can

effectively and safely treat their ward. As with other cutaneous malignancies,

the dermatologist is best suited not only to treat, but also to perform long-term

follow-up, once the patient is in remission. ■

Skin Cancers

72 U S D E R M A T O L O G Y

1. Willemze R, Jaffe ES, Burg G, et al., WHO-EORTC classification forcutaneous lymphomas, Blood, 2005;105:3768–85.

2. Criscione VD, Weinstock MA, Incidence of cutaneous T-celllymphoma in the United States, 1973–2002, Arch Dermatol, 2007;143:854–9.

3. Kim YH, Liu HL, Mraz-Gernhard S, et al., Long-term outcome of525 patients with mycosis fungoides and Sezary syndrome: clinicalprognostic factors and risk for disease progression, Arch Dermatol,2003;139:857–66.

4. Swanbeck G, Roupe G, Sandstrom MH, Indications of aconsiderable decrease in the death rate in mycosis fungoides byPUVA treatment, Acta Dermato-Venereologica, 1994;74:465–6.

5. Vonderheid EC, Tan ET, Cantor AF, et al., Long term efficacy,curative potential, and carcinogenicity of topical mechlorethaminechemotherapy in cutaneous T-cell lymphoma, J Am Acad Dermatol,1989;20:416–28.

6. Heald PW, Memorials and Mandates for Cutaneous Lymphomas,Arch Dermatol, 2003;139:926–8.

7. National Cancer Center Network. NCCN Clinical PracticeGuidelines in Oncology: Non-Hodgkin’s Lymphomas (V.3.2008).Available at: www.nccn.org/professionals/physician_gls/PDF/nhl.pdf

8. Heald PW, Latkowski JA, Wilson LD, Mark LA, Successful therapyof cutaneous T cell lymphoma, Exp Rev Dermatol, 2008;3:99–110.

9. Zackheim HS, Kashani-Sabet M, Amin S, Topical corticosteroids formycosis fungoides. Experience in 79 patients, Arch Dermatol,1998;134:949–54.

10. Heald P, Mehlmauer M, Martin AG, et al., Topical bexarotenetherapy for patients with refractory or persistent early-stagecutaneous T-cell lymphoma: results of the phase III clinical trial,J Am Acad Dermatol, 2003;49:801–15.

11. Vonderheid EC, Van Scott EJ, Wallner PE, et al., A 10 year

experience with topical mechlorethamine for mycosis fungoides:comparison with patients treated by total-skin electron-beamradiation therapy, Cancer Treat Rep, 1979;63:681–9.

12. Lee LA, Fritz KA, Golitz L, et al., Second cutaneous malignancies inpatients with mycosis fungoides treated with topical nitrogenmustard, J Am Acad Dermatol, 1982;7:590–98.

13. Price NM, Hoppe RT, Deneau G, Ointment based mechlorethaminetreatment for mycosis fungoides, Cancer, 1983;52:2214–19.

14. Zackheim HS, Epstein EH, Crain WR, Topical carmustine (BCNU) forcutaneous T cell lymphoma: A 15-year experience in 143 patients,J Am Acad Dermatol, 1990;22:802–10.

15. Zackheim HS, Epstein E, McNutt NA, et al., Topical carmustine formycosis fungoides and related disorders: A 10 year experience,J Am Acad Dermatol, 1983;9:363–72.

16. Zanolli MD, Feldman SR, Phototherapy Treatment Protocols forPsoriasis and other Phototherapy-responsive Dermatoses, SecondEdition, Pearl River, NY: The Parthenon Publishing Group, 2000.

17. Diederen PV, Van Weelden H, Sanders CJ, Van Vloten WA,Narrowband UVB and psoralen-UVA in the treatment of earlystage mycosis fungoides: a retrospective study, J Am AcadDermatol, 2003;48:215–19.

18. Herrmann JJ, Roenigk HH Jr, Hurria A, et al., Treatment of mycosisfungoides with photochemotherapy (PUVA): long-term follow-up,J Am Acad Dermatol, 1995;33:234–42.

19. Ramsay DL, Lish KM, Yalowitz CB, Soter NA, Ultraviolet-Bphototherapy for early-stage cutaneous T-cell lymphoma, ArchDermatol, 1992;128:931–3.

20. Hofer A, Cerroni L, Kerl H, Wolf P, Narrowband (311-nm) UV-Btherapy for small plaque parapsoriasis and early-stage mycosisfungoides, Arch Dermatol, 1999;135:1377–80.

21. Duvic M, Hymes K, Heald P, et al., Bexarotene is effective and safefor treatment of refractory advanced-stage cutaneous T-cell

lymphoma: multinational Phase II-III trial results, J Clin Oncol,2001;19:2456–71.

22. Duvic M, Martin AG, Kim Y, et al., Phase 2–3 clinical trial of oralTargretin (bexarotene) capsules for the treatment of refractory orpersistent early stage cutaneous T-cell lymphoma, Arch Dermatol,2001;137:581–93.

23. McGinnis KS, Junkins-Hopkins JM, Crawford G, et al., Low-dosebexarotene in combination with low-does interferon alfa in thetreatment of cutaneous T-cell lymphoma: clinical synergism andpossible immunologic mechanisms, J Am Acad Dermatol, 2004;50:375–9.

24. Talpur R, Duvic M, Treatment of mycosis fungoides with denileukindiftitox and oral bexarotene, Clin Lymph Myel, 2006;6:488–92.

25. Bunn PA, Foon KA, Ihde DC, et al., Recombinant leukocyte Ainterferon: An active agent in advanced cutaneous T-celllymphomas, Ann Intern Med, 1984;101:484–7.

26. Dreno B, Godefroy WY, Fleischmann M, et al., Low-doserecombinant interferon-alpha in the treatment of cutaneous T-celllymphoma, Br J Dermatol, 1989;121:543–4.

27. Kohn EC, Steis RG, Sausville EA, et al., Phase II trial of intermittenthigh-dose recombinant interferon alfa-2a in mycosis fungoidesand the Sezary syndrome, J Clin Oncol, 1990;8:155–60.

28. Olsen EA, Rosen ST, Vollmer RT, et al., Interferon alfa-2A in thetreatment of cutaneous T-cell lymphomas, J Am Acad Dermatol,1989;23:395–407.

29. Zackheim HS, Kashani-Sabet M, McMillan A, Low-dosemethotrexate to treat mycosis fungoides: a retrospective study in69 patients, J Am Acad Dermatol, 2003;49:873–8.

30. Duvic M, Talpur R, Ni X, et al., Phase 2 trial of oral vorinostat forrefractory cutaneous T-cell lymphoma, Blood, 2007;109:31–9.


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