Extracorporeal Photopheresis for the Treatment of Cutaneous T-Cell Lymphoma

Journal of Cutaneous Medicine and Surgery -     

Verrucous presentation in patients with mycosis fungoides

Mycosis fungoides is a potentially fatal skin condition whose variable clinical appearance may mimic a variety of benign, inflammatory dermatoses, making it a diagnostic challenge. Three patients with mycosis fungoides, treated with multiple approved topical and systemic therapies, presented with acquired verrucous lesions on the extremities. The verrucous presentation of mycosis fungoides is one of the many atypical forms of the disease, with a paucity of documented cases in the medical literature. Although rare, verrucous and hyperkeratotic lesions in mycosis fungoides may increase the risk of considerable diagnostic delay if clinicians do not maintain a high degree of suspicion in cases of acquired verrucous lesions in the appropriate clinical setting.     

Multicenter photopheresis intervention trial in early-stage mycosis fungoides

PurposeTo demonstrate the efficacy of the UVAR XTS Photopheresis System and evaluate health-related quality of life in patients with early-stage mycosis fungoides (MF).Patients and MethodsExtracorporeal photopheresis was administered 2 days every 4 weeks for 6 months. Patients with partial responses by skin weighted assessment continued for 6 months; nonresponders added oral bexarotene and/or interferon α. Health-related quality of life was assessed at baseline and every 3 months with 3 validated tools.ResultsNineteen patients with early-stage MF (7 men, 12 women; 16 white, 3 African Americans) with median age of 63.5 years (range, 46-85 years) participated. Their stages were IA (n = 3), IB (n = 14), and IIA (n = 2). The overall response rate for extracorporeal photopheresis (ECP) alone, was 42% (8/19; including 7 partial response, 1 complete response), with a median of 12 ECP sessions (range, 3-32) given over a median of 12 months (3-32 months) and with an overall duration of response of 6.5 months (range, 1-48 months). Seven patients with stable disease at 3 months received additional bexarotene (3/5; 1 complete response) or bexarotene plus interferon α (1/2), and 4 (57%) of 7 responded. Treatment-related adverse effects were limited to those expected with interferon (fatigue, nausea, vomiting, and diarrhea), or with hypertriglyceridemia and bexarotene. Trends in health-related quality of life indicated an improvement in emotional scores over time.ConclusionsECP is effective for patients with early-stage MF alone or in combination with biologic response modifiers with low toxicity and improved quality of life.     

Optimizing bexarotene therapy for cutaneous T-cell lymphoma

BACKGROUND: Bexarotene (Targretin oral capsules), the first RXR-selective retinoid "rexinoid" approved for all stages of cutaneous T-cell lymphoma (CTCL), had a response rate (RR) of 45% at the optimal dose of 300 mg/m(2) per day in 2 multicenter trials. With hypertriglyceridemia reported at 79%, bexarotene is often administered with lipid-lowering agents (LLAs). Statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) may modulate class II major histocompatibility class expression and T-cell responses. OBJECTIVE: We attempted to optimize the clinical response to bexarotene by controlling dose-limiting hypertriglyceridemia and combining bexarotene with other active agents. METHODS: We prospectively evaluated 70 patients with CTCL at M. D. Anderson Cancer Center who were treated with oral bexarotene as monotherapy or in combination with other active agents. RESULTS: Fifty-four patients receiving bexarotene monotherapy achieved an overall RR of 48%. Thirteen had stage IA-IIA disease (RR = 53%, 1 complete response [CR]); 41 had stage IIB-IVB disease (RR = 46%, 2 CRs). Forty-two (77%) of these also required one or more LLAs: atorvastatin (n = 29, RR 43%), atorvastatin plus fenofibrate (n = 10, RR 90%), or gemfibrozil (n = 3, RR 33%). Gemfibrozil was discontinued because it increased bexarotene and triglyceride levels. Patients taking 2 LLAs had a significantly higher RR of 90% during monotherapy than those taking one or no LLAs (P <.0001). Forty of 54 patients (74%) received thyroid hormone replacement to normalize thyroxine levels. Four patients receiving monotherapy have complete CRs of >3 years' duration and received maintenance dosing. Sixteen patients with advanced disease treated with bexarotene (225-750 mg/d) in combination with other CTCL therapies achieved an overall RR of 69% (11/16) with concomitant statin therapy. Bexarotene was safely combined with psoralen ultraviolet A (PUVA) plus interferon alfa (IFN-alpha) (n = 2, RR = 50%), with extracorporeal photopheresis (ECP) (n = 8, RR = 75%, 1 CR), with ECP/IFN-alpha (n = 4, RR =50%), with ECP/IFN-alpha/PUVA (n = 1, RR = 100%), and with IFN-alpha/PUVA/topical nitrogen mustard (n = 1, RR = 100%). Two patients receiving IFN-alpha had slight leukopenia, but rhabdomyolysis associated with multiple LLAs did not occur. CONCLUSION: This single-center study supports the safety and efficacy of bexarotene as both a monotherapy and a combination therapy for CTCL. Long durable CRs may be achieved with oral monotherapy. Use of statins with bexarotene may also increase RRs by permitting higher doses to be administered without interruption, by modulating the immune response, or both. When bexarotene is combined with other active CTCL therapies, higher RRs were achieved in patients with advanced disease, without unacceptable side effects.     

Treatment of refractory peripheral T-cell lymphoma with denileukin diftitox (ONTAK)

Peripheral T-cell lymphomas (PTCLs) are an uncommon and heterogeneous group of well-differentiated, post-thymic T-cell malignancies that can present in the skin as cutaneous T-cell lymphomas. In general, their prognosis is poor, and specific therapy is not well defined. We report the successful treatment of a patient with relapsed, refractory PTCL who after failing 13 standard single and multiple chemotherapy regimens and experimental agents had a dramatic prolonged response to diftitoxin denileukin (ONTAK). This fusion protein, composed of diphtheria toxin coupled to interleukin-2, is approved for cutaneous T-cell lymphomas, including mycosis fungoides, and should be considered for treatment of the rare subset of peripheral T-cell lymphomas.     

Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sézary syndrome

Although mycosis fungoides (MF) may arise through persistent antigen stimulation, cytomegalovirus (CMV) is not a known risk factor. To study the incidence of seropositivity to viral infections, we compared MF and Sézary Syndrome (SS) patients to healthy bone marrow donors and other historical control groups. Baseline screening serologies at baseline were performed on 116 biopsy-proven MF/SS patients at MD Anderson Cancer Center from 1992 to 2001 and on healthy bone marrow donors evaluated by the transplant service from 1988 to 2001. Antibodies to HTLV-I/II, HIV-1, EBV, and CMV were measured using standard enzyme-linked immunosorbent (ELISA) and membrane enzyme immunoassay (MEIA) assays. One hundred thirteen (97.4%) of all MF/SS patients had positive CMV IgG serologies at initial presentation. Early- and late-stage patients' seropositivity rates were significantly higher than healthy bone marrow donor controls (chi(2).05(df=1) = 71.79). By stage, 98.1% of early-stage MF patients (IA, IB, IIA; 52/53) and 96.8% of late-stage MF and SS patients (IIB-IVB; 61/63) were seropositive compared with healthy bone marrow donors whose seropositivity rate was 57.3% (757/1322). Because the rate of CMV seropositivity increases with age, a subset of cutaneous T-cell lymphoma (CTCL) patients 55 years or younger were compared to age-matched healthy donor controls; their seropositivity rate for CMV was also significantly higher (chi(2).05 05(df=1) = 20.4). EBV titers were positive by serology in 13 patients who were examined prospectively. CMV seropositivity is highly associated with MF and SS, even in the earliest stages of the disease, and is significantly higher than that of healthy and immunocompromised controls.     

Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study

BACKGROUND: Topical skin-directed therapies are used to induce remissions in early-stage mycosis fungoides (MF). They are rarely curative, and responding patients are subject to frequent relapses, emphasizing the need for alternative therapies. OBJECTIVE: We sought to evaluate the efficacy and tolerability of topical tazarotene 0.1% gel as adjuvant therapy in the treatment of refractory MF lesions. METHODS: A total of 20 adult patients with early patch or plaque MF limited to less than 20% body surface area (BSA) involvement whose lesions were either stable or refractory to therapy for at least 8 weeks enrolled in an open-label pilot study. Tazarotene 0.1% gel was applied to MF lesions once daily for 24 weeks. Continued concomitant use of other medications such as low- to mid-potency topical corticosteroids was permitted for the alleviation of skin irritation. Global improvement, overall disease severity, percent BSA involvement, and pruritus were evaluated every 4 weeks. Up to 6 index lesions were followed up for area, plaque elevation, scaling, and erythema scores. Skin biopsy specimens were to be taken at baseline, week 8, and week 24. Evaluable specimens were stained with hematoxylin and eosin, CD8 antibody, and CD45RO antibody. RESULTS: In all, 20 patients enrolled, 19 received treatment, and 16 completed at least 4 weeks of topical treatment. By intent-to-treat analysis, 11 of 19 patients (58%) achieved at least a moderate (>50%) global improvement in BSA, and 35% of 99 index lesions cleared completely. Significant reductions (mean differences) were also found in the median lesional area score (-37, P =.0013), mean plaque elevation score (-.67, P =.016), mean scaling (-0.70, P =.033), and mean erythema score (-1.03, P =.002). Analysis of overall disease also disclosed statistical differences in percent of change for BSA involvement of 22% (P =.013) and of mean overall disease severity score of 34% (P =.011). Of 19 patients, 16 (84%) experienced mild or moderate local skin irritation manifested by peeling, erythema, burning, and tenderness that was managed successfully with topical steroids or reducing the frequency of treatment. Histopathology and immunohistochemistry results showed reductions in lymphocytic infiltrates and percentage of CD45RO(+) lymphocytes, and increases in the percentage of CD8(+) lymphocytes during the course of therapy. CONCLUSION: In this small pilot study, tazarotene 0.1% gel was a well-tolerated and effective adjuvant topical for the treatment of refractory MF lesions by clinical and histologic assessments.