Treatment of Transformed Mycosis Fungoides with ...

Case Report

Oncology

Received: September 3, 2007 Accepted: September 3, 2007 Published online: March 13, 2008

Oncology 2007;73:130–135 DOI: 10.1159/000121002

Treatment of Transformed Mycosis Fungoides with Intermittent Low-Dose Gemcitabine Omar Awar a Madeleine Duvic b a Department of Internal Medicine, UCLA Medical Center, Los Angeles, Calif., and b Department of Dermatology, MD Anderson Cancer Center, Houston, Tex., USA

Abstract The malignant helper T cells of mycosis fungoides, a type of cutaneous T cell lymphoma, are capable of transforming into large cerebriform cells. Large cell transformation usually renders the disease more resistant to treatment and prone to relapse. Currently investigated treatment modalities for transformed mycosis fungoides are few and include phototherapy, chemotherapy, biologic response modification, targeted molecular therapy and combinations thereof. A tolerable and reliable modality has yet to be identified. Gemcitabine, a novel purine analogue, is gaining recognition as a potent agent for advanced nontransformed cutaneous T cell lymphoma. Here we present a brief review of the literature with 3 illustrative cases that additionally reveal gemcitabine monotherapy to be a practical, safe and efficacious option for mycosis fungoides that has undergone large cell transformation. Copyright © 2008 S. Karger AG, Basel

© 2008 S. Karger AG, Basel 0030–2414/07/0732–0130$23.50/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

Introduction

Cutaneous T cell lymphomas (CTCLs) include heterogeneous extranodal lymphoproliferative disorders characterized by malignant T cells localized in the skin [1]. In the most common type of CTCL, mycosis fungoides (MF), malignant cells are clonal CD4+ CD45RO+ helper T cells exhibiting epidermotropism and inducing skin lesions. Lesions may include patches, plaques, tumors, erythroderma and pruritus [2]. MF may evolve into a leukemic variant called Sézary syndrome (SS) or transform into large cell lymphoma. The latter is defined histologically by the presence of 125% large cerebriform cells [3]. Large cell transformation of MF (T-MF) has been reported to occur in 8–55% of MF patients and can be accompanied by expression of a TNF receptor CD30 or the T cell receptor ␣-chain, CD25 [4–8]. Diamandidou et al. [8] defined large cell transformation as 125% large cells within the lymphocytic infiltrates and reported a transformation rate of 23%. This is probably a closer reflection of the actual rate given the histopathological and clinical biases of earlier reports [8]. Transformation generally portends a grave prognosis, with median survival times reported from 2 to 36 months [4–9]. Transformation within 2 years of diagnosis and an advanced clinical stage Omar Awar Department of Internal Medicine, UCLA Medical Center 1441 Veteran Avenue, Unit #127 Los Angeles, CA 90024 (USA) Tel. +1 409 790 1459, Fax +1 713 745 3597, E-Mail [email protected]

Downloaded by: MD Anderson Research Medical Library 143.111.22.51 - 3/19/2014 6:34:22 PM

Key Words Lymphoma, non-Hodgkin ⴢ Lymphoma, cutaneous T cell ⴢ Gemcitabine ⴢ Gemzar쏐 ⴢ Mycosis fungoides ⴢ Lymphoma, large cell

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Fig. 1. Lesions before chemotherapy consisted of indurated violaceous plaques and tumors with eschars.

Case Reports Case 1 A 77-year-old white male with a history of hypertension, hypercholesterolemia, peripheral vascular disease, coronary artery disease, hepatitis C and prostate cancer presented with a 2-month history of asymptomatic pigmented purpura on the ankles [10]. A biopsy specimen demonstrated capillaritis but the lesions rapidly progressed over 2 months, forming multiple indurated plaques and violaceous tumors with necrosis and eschar formation (fig. 1). The involvement was 7.3% of his total body surface area (BSA), with 5.8% patch, 1.2% plaque and 0.3% tumors. Triamcinolone 0.1% cream, terbinafine cream and mupirocin 2% ointment provided no relief. Biopsy showed T-MF with high expression of CD25 and negative CD30 staining. Stage was T3N0B0M0 (IIB) based on lack of involvement of lymph nodes, bone marrow or peripheral blood.

Gemcitabine for Transformed Mycosis Fungoides

He received 1 course of chemotherapy with CMED (cyclophosphamide 500 mg/m2 for 1 day, methotrexate 500 mg/m2 for 1 day, etoposide 100 mg/m2 for 3 days, dexamethasone 40 mg for 5 days), but developed new tumors, progressing to 6% tumor BSA and 14% total BSA. He was treated with 2 cycles of denileukin diftitox (given with prednisone 10 mg daily), initially at 9 ␮g/kg and then at 18 ␮g/kg, with resolution of most existing tumors, but appearance of multiple new tumors. Next, he was treated with the oral histone deacetylase inhibitor vorinostat at an induction dose of 300 mg twice per day for 2 weeks, 1 week off, then 400 mg daily [11]. Initially, all tumors regressed rapidly to flat hyperpigmented patches but he developed grade 4 thrombocytopenia and new tumors appeared on the upper extremities. Almost 4.5 months after diagnosis of T-MF, the patient was started on a phase I protocol combination of intravenous gemcitabine (800 mg/m2), vinorelbine (15 mg/m2) and liposomal doxorubicin (10 mg/m2) [12]. He received 1 dose of each 8 days apart. He exhibited a near complete response with BSA of 0.25% tumor and 0.55% total. Doxorubicin was discontinued secondary to atrial fibrillation. One month later he resumed gemcitabine and vinorelbine for 8 treatments over 3 months, achieving complete tumor resolution after his second dose and complete remission shortly thereafter (fig. 2). He received a total of 19 doses of gemcitabine monotherapy (750 mg/m2) over the next 15 months with treatment periods ranging from 3 to 3.5 months (mean 3.3 months). His lesions showed exquisite sensitivity to gemcitabine and he achieved complete remissions of all new lesions. While on treatment, patch/plaque disease did not exceed 0.5% BSA and tumors developed only once, 2 small tumors on his left forearm for which he would receive local radiation therapy. However, after completing local radiation therapy to the forearm, the patient received another cycle of gemcitabine for tumors developing outside the radiation field and again achieved regression of all tumors. While the patient’s disease was extremely well controlled during treatment cycles, his tumor-free periods while off treatment ranged from !1 to 1.5 months, although the tumor recur-

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at the time of transformation add additional negative prognostic indicators [8]. Untransformed MF patients regardless of stage have a median overall survival of 163 months in comparison to MF patients with transformation who have a median overall survival of 37 months from the time of initial diagnosis of MF [8]. Transformation of tumor stage MF (T3) carries an especially unfavorable prognosis, with a survival rate of 23% and a median survival of 11.5 months (from time of transformation) [8]. We report 3 elderly males with large cell transformation of tumor stage MF who showed very favorable responses to intermittent low-dose gemcitabine.

Fig. 2. Eight courses into gemcitabine and vinorelbine the patient’s tumors showed complete regression.

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rence that would prompt re-initiation of therapy each time never exceeded 0.7% BSA. After 4 doses into his last cycle of gemcitabine, the patient was found to have brain masses in the frontal and temporal lobe by MRI. He expired shortly thereafter of progressive neurologic deterioration. While on gemcitabine monotherapy, he experienced 1 episode of grade 3 (WHO) thrombocytopenia (resolved with holding of treatment), and 2 episodes of neutropenia, 1 of which was grade 4 (ANC 480/cc) and corrected with a 6-gram dose of pegylated filgastim.

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Fig. 3. Gemcitabine therapy was complicated by red granuloma-

tous dermatitis that grew Mycobacterium abcessus.

sustainable tumor-free intervals ranging from 2 to 122 months with patch/plaque disease not exceeding 2.2% BSA. Toxicity on gemcitabine was limited to 2 episodes of neutropenia 6 months apart, 1 of which was grade 4 (ANC 28/cc). It was corrected with a 6-gram dose of pegylated filgastim and necessitated a dose reduction from 1,000 to 750 mg/m2. Gemcitabine was discontinued in October 2005. At this time he had developed a plaque of red granulomatous dermatitis on his right forearm not responding to therapy (fig. 3). A skin biopsy culture taken in December 2005 grew Mycobacterium abcessus and the lesion slowly cleared with clarithromycin 500 mg by mouth for 2 months and did not recur. At the time this report was authored, this patient had been off gemcitabine for 22 months, with only minimal patch and plaque disease remaining (0.7% total BSA). While off gemcitabine, he was on oral tapering doses of bexarotene (from 6 to 2 capsules per

Awar /Duvic


Case 2 An 83-year-old white male with hypertension had a 4.5-year history of MF diagnosed at stage IIA and was stable on nitrogen mustard ointment and triamcinolone 0.1% cream until he developed a tumor of the preauricular area. T-MF with 35% CD25 staining and negative CD4 and CD30 staining was present on biopsy. Staging work-up revealed no involvement of lymph nodes, bone marrow or peripheral blood and was T3LN0M0B0. Oral bexarotene capsules were started at 3 per day and local radiation therapy was given to a tumor on his ear. Over the next 14.5 months, the patient experienced new purple tumors of the trunk and extremities, requiring increasingly larger doses of oral bexarotene up to 6 capsules daily. Once his tumors involved 4.8% BSA (of 5.8% total area), he was started on gemcitabine (1,000 mg/m2 on days 1, 8 and 15 of a 28-day cycle). There was significant flattening of his tumors after his first dose and a near complete response after completing the course of gemcitabine (0.02% patch, 0.01% plaque and 0.01% tumor). Two weeks later the patient received his second course (1,000 mg/m2 on days 1 and 15) and achieved complete remission. Over the next 34 months the patient received a total of 22 doses of gemcitabine (first 5 at 1,000 mg/m2, subsequent 17 at 750 mg/m2). Treatment periods on gemcitabine ranged from 1.5 to 3 months (mean 1.95) and he was dosed every other week. The TMF lesions were extremely responsive to gemcitabine such that he frequently achieved complete remission of all disease and always experienced complete resolution of tumors with patch disease up to 1% BSA. Additionally, while off treatment he demonstrated

750 mg/m2. He received 3 more doses of gemcitabine (750 mg/m2) over the next 4 weeks. All his lesions flattened and 3 weeks after his last dose of gemcitabine only patch/plaque disease remained (5.25% total BSA), for which he received nitrogen mustard ointment and triamcinolone cream with longstanding disease control at 8 months.

Discussion

day), topical nitrogen mustard ointment and triamcinolone 0.1% cream alternating with clobetasol cream. Tumor recurrence never surpassed 0.5% BSA at any point. Case 3 A 65-year-old white male with asthma and a long-standing scaly macular pink rash on his trunk and extremities for 25 years presented with newly formed nodules on his left arm. Biopsy specimen revealed tumor stage T-MF with large cells. Staging work-up revealed no involvement of lymph nodes, bone marrow or peripheral blood. Before beginning systemic therapy, he had diffuse well-demarcated patches with clusters of scaly bright red plaques and an isolated 1-cm tumor (!1% tumor, 3% plaque, 45% total BSA). He was treated with Accutane (40–80 mg/day) and interferon (3 million units, 3 times per week) in addition to daily 0.1% triamcinolone cream for 5 months. The skin showed about 50% overall improvement, but new lesions continued to form (0.2% plaque, 26.7% total BSA). He received 2 courses of CMED with initial response to each. After 2 courses of CMED, he had initial response and then relapsed in skin within days. The extent of his MF was estimated to be 14.6% patch, 9% plaque and 0.4% tumor, for a total BSA of 24%. He received electron beam therapy over an 8-week period (total of 3,200 Gy), reaching near complete resolution of disease (0.6% total BSA, all patch). Radiation was complicated by a vesicular enterococcus infection on his feet, treated with dicloxacillin 500 mg twice daily. Eight months later, scattered pink patches and an isolated annular 6 ! 5 cm plaque on his left arm appeared for 0.7% plaque and 3.91% total BSA. Five months later he was still progressing due to noncompliance with topical steroids. Prior to beginning therapy with gemcitabine, his total BSA was as high as 28.25%, including 0.3% tumor BSA (fig. 4). After the first dose of gemcitabine (1,000 mg/m2), his lesions showed a significant response (0.5% plaque, 0.25% tumor, 12.5% total). He did experience grade 4 neutropenia (360 N) that required 250 mg GM-CSF and a dose reduction of gemcitabine to


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Fig. 4. Tumor formation prior to gemcitabine monotherapy.

Early-stage MF (IA–IIA) patients are successfully managed using serial or combination skin-directed therapies. First-line therapy consists of topical corticosteroids, bexarotene gel, topical mechlorethamine and UVB phototherapy. More advanced MF is treated with PUVA plus biological response modifiers such as interferon or oral retinoids such as the RXR agonist bexarotene or the RAR agonist soriatane, total body skin electron beam therapy and targeted denileukin diftitox [1]. Advanced MF (IIB–IVB) is substantially more difficult to put into remission and durable complete responses (CR) are obtained only in a minority of patients with curative therapy being less common [13]. Late-stage disease has been treated with systemic monotherapy or combined chemotherapy [1], with the greatest wealth of literature pertaining to the cytotoxic agents [14]. Cytotoxic chemotherapies, alone or in combination, have been associated with response rates of 20– 60%, typically lasting for a short duration (4–6 months) [15, 16]. A meta-analysis of CTCL patients reported in chemotherapeutic trials revealed CR rates of up to 32% in single-agent trials and 38% in polychemotherapy trials [14], but also demonstrated failure to cure disease in the vast majority of patients. They also raised the issue of cumulative myelotoxicity and immunosuppression encountered while on these regimens [14]. Recently, a retrospective study of pegylated liposomal doxorubicin (20–40 mg/m2 every 2–4 weeks) in patients with refractory or relapsed MF/SS showed the agent to be well tolerated, while achieving a response rate of 88.2% with an overall survival of 17.8 months in 33 patients [17]. The purine analogs – 2-deoxycoformycin (pentostatin), fludarabine and 2-chlorodeoxyadenosine – have been cited as having response rates ranging from 20 to 70% [16]. A meta-analysis of MF/SS patients receiving pentostatin monotherapy reported a response rate of 40% (7% CR), with a median time to disease progression of 1.3–8.3 months [18], although the duration of response increased to 13.1 months when given in combination with interferon-␣ in one study [19]; another study with SS patients as the majority reported a better overall re-

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pies had failed, reporting a partial response of 9–14 months in 3 of 4 patients with advanced CTCL/peripheral T cell lymphoma that did not respond to previous combinations of PUVA, fludarabine, interferon-␣ and CHOP, with all 3 still alive at follow-up of 23–29 months [29]. Gemcitabine as frontline treatment for advanced CTCL was the focus of 1 trial of 32 patients, achieving a response rate of 75% (21.9% CR) [30]. Associated toxicities with gemcitabine monotherapy were similar across studies, with WHO grade 1–3 myelosuppression being the most commonly reported adverse event [27–30]. Reversible hepatoxicity [27, 28, 30] and neutropenic fever [28, 29] were independently reported in at least 2 separate studies. Rarer reported toxicities included mild to moderate alopecia [30], mild nausea and vomiting [29], neutropenic sepsis, mucositis, pneumonitis and cutaneous hyperpigmentation [28]. Specifically regarding T-MF, there is a paucity of available data comparing different therapeutic approaches. One study of 26 T-MF patients treated with various modalities demonstrated a response rate of 73% (19.2% CR), with all CR achieved on a combination of interferon-␣, cis-retinoid acid, total body skin electron beam therapy, topical nitrogen mustard and CMED (cyclophosphamide, methotrexate, etoposide and dexamethasone) [8]. Overall, CMED was the most common treatment used and achieved a response rate of 66% with a median duration of response of 6 months [8]. When looking at patients who transformed from an advanced stage of MF (IIB–IVB), a 65.6% overall response rate was observed (7.7% CR) [8]. Of the 113 patients studied by Anadolu et al. [24], 2 carried a diagnosis of T-MF, both of whom transformed from T3 stage disease. One received PUVA, interferon and fludarabine, while the other received PUVA, interferon and CHOP. Neither patient responded and both died of their disease [24]. Gemcitabine monotherapy achieved a response rate of 53.8% with a median response duration of 4.1 months in 13 patients with MF that had transformed from an advanced stage [28]. This is comparable to the response rate achieved on various combinations of PUVA, photopheresis, radiotherapy, TBEB, interferon, Accutane, H65MoAb, pentostatin and polychemotherapy reported by Diamandidou et al. [8]. Collectively, these 3 cases highlight the activity, low toxicity and tolerability of intravenous gemcitabine for elderly patients with transformed MF for either aggressive refractory disease (cases 1 and 3) or frontline chemotherapy (case 2). Our experience with these 3 patients adds to the recent investigative literature, demonstrating Awar /Duvic


sponse rate [20]. Reported toxicities included myelosuppression (33%) [18], decreased CD4 counts (19% of patients had herpes zoster outbreak within 1 year of therapy) [20] and renal insufficiency (7%) [20]. Response rates of MF/SS patients on fludarabine have been reported at 19–29% when used alone [21], 51% (11% CR) when used with interferon-␣ [22] and 63.2% when used in combination with photophoresis [21], although this latter combination proved to have no significant effect on survival or time to progression [21]. Reported toxicities include neurotoxicity (17%), and, similarly to pentostatin, myelotoxicity and potentially severe immunosuppression, with reported rates of sepsis and opportunistic infections of 17 and 14%, respectively, when used in combination with interferon [22]. The novel toxin fusion protein denileukin diftitox is FDA approved for the treatment of relapsed CTCL. In a study of heavily pretreated advanced CTCL, it demonstrated a response rate of 30% (CR 10%) [23], or 60% when used with corticosteroids [16]. A recently published study on therapeutics in 113 patients with MF/SS included 14 patients with late-stage disease and reported a 35.6% overall response rate (14.2% CR) achieved on various combinations of PUVA, interferon-␣, CHOP, fludarabine, pentostatin and gemcitabine (compared to 80.5% CR for early-stage disease on PUVA and interferon alone) [24]. Gemcitabine was used in 2 patients, achieving a partial response in combination with fludarabine and pentostatin in one and no response in combination with CHOP in the other [24]. Of those patients treated with systemic chemotherapy regimens that did not include gemcitabine, there was a 14.3% response rate (0% CR) and 57.1% of all late-stage CTCL patients had died of their disease by follow-up [24]. Gemcitabine is a novel cytosine nucleoside analogue with demonstrated activity in a variety of solid and hematologic malignancies [25], exerting its action through ribonucleoside reductase inhibition and DNA chain termination [26]. The pyrimidine antimetabolite has recently gained attention as a promising agent for the treatment of advanced MF/SS, not only for its reported efficacy but also for its attractive low-toxicity profile and appealing dose scheduling, often given once a week for 3 consecutive weeks every month [1]. Studies investigating the efficacy of gemcitabine monotherapy (1,000–1,200 mg/m2 on days 1, 8 and 15 of a 28-day cycle) for refractory or relapsed CTCL have reported response rates of 68–70.5% (11–11.4% CR) [27, 28]. Another study focusing on gemcitabine for refractory T cell malignancies further illustrated the use of gemcitabine, where previous thera-

gemcitabine activity in advanced CTCL and T-MF [8, 26, 27]. Furthermore, although our patients transformed from tumor stage MF, which is especially difficult to treat, they responded to gemcitabine after failing other chemotherapies and had durable responses allowing breaks in treatment. Case 2 had a remarkably durable CR which is ongoing 22 months after tapering off gemcitabi-

ne. While gemcitabine does not usually give a permanent cure, in an era where such an agent has yet to be identified, its proven relative efficacy combined with its low toxicity profile and favorable dose scheduling should bring intermittent low-dose gemcitabine under consideration as a viable and effective approach towards MF in large cell transformation.

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