Alain H. Rook

Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: A 10-year experience at a single institution

BACKGROUND Extracorporeal photopheresis is a pheresis-based therapy that permits the direct targeting of psoralen-mediated photochemotherapy to circulating pathogenic T cells. Although photopheresis is currently used to treat cutaneous T-cell lymphoma (CTCL), limited data are available regarding overall response rates and durability of responses among patients with advanced disease. Furthermore, little is known about the effectiveness and tolerability of combined regimens employing other biologic response modifiers including interferon alfa. OBJECTIVE Our purpose was to determine the efficacy of photopheresis among 41 patients with the clinical and laboratory diagnosis of CTCL; the majority of patients had stage III or IV disease with the presence of circulating malignant T cells. METHODS A retrospective chart review during a 10-year period at a single university hospital was performed for all patients receiving either photopheresis monotherapy on two consecutive days every 4 weeks (one cycle) and for an additional 12 patients who also received interferon alfa 1.5 to 5 million U subcutaneously three to five times weekly. RESULTS Thirty-one of 41 patients (76%) were treated for six or more cycles. The remaining 10 were treated with less than six cycles because of rapidly progressing disease (n = 6), death unrelated to CTCL (n = 2), or withdrawal from treatment (n = 1); one of the 10 patients had only received five cycles of treatment but is still receiving therapy. Twenty-eight of the 31 patients treated for six or more cycles received photopheresis alone. Among the 28, seven patients (25%) had a complete remission, 13 (46%) had a partial remission defined as more than 50% clearing of skin disease, and eight (29%) did not respond to treatment. The presence of Sézary cells in the peripheral blood was associated with a favorable response. Median time to treatment failure was 18 months, whereas median survival from initiation of therapy was 77 months and from the time of diagnosis exceeded 100 months. Nine of these 28 patients went on to receive combination therapy with interferon alfa and, in some cases, other agents. Among these nine patients, five had an enhanced clinical response to the combination therapy compared with treatment with photopheresis monotherapy. The combined regimen was well tolerated. CONCLUSION These results indicate that patients with advanced CTCL can achieve a high response rate for an extended period with photopheresis and that interferon alfa combined with photopheresis is a well-tolerated regimen that appears to produce higher response rates than photopheresis alone.

Radiotherapy for unilesional mycosis fungoides.

PURPOSE To evaluate the treatment outcome and natural history of patients with the diagnosis of unilesional mycosis fungoides, treated according to a prospective radiotherapy protocol in our institution since July 1975. METHODS AND MATERIALS A total of 325 patients with the diagnosis of mycosis fungoides have been referred to the Department of Radiation Oncology at Allegheny University of Health Sciences from July 1975 through September 1996. Of these, 18 patients (5%) were classified as having unilesional mycosis fungoides and were irradiated with a curative intent using local electron fields. One patient received 22 Gy; 1 patient received 40 Gy, and the rest of the patients 30.6 Gy. Daily fractions ranged from 1.8 to 2.0 Gy. Treatments prior to radiation consisted of topical steroids and/or antifungal creams in the majority of patients, with temporary partial responses. One patient had received 2 years of topical mechlorethamine (HN2) and another patient had received topical carmustine solution (BCNU) without response prior to irradiation. RESULTS The responses were measured clinically; posttreatment skin biopsy was not performed routinely unless there was clinical evidence of disease persistence. Complete response rate was 100%; all treated lesions cleared completely within 4 to 8 weeks after the completion of radiation. With a median follow-up of 43 months (range 12 to 240 months), 2 relapses have occurred, 2 and 71 months after the completion of radiation. Both relapses were confined to the skin and were remote from the original site. Both relapses responded to topical application of HN2. There have been no recurrences in the irradiated field nor systemic dissemination. No long-term side effects were found related to treatment, and all the patients are currently alive and without evidence of disease. Actuarial relapse-free and overall survival at 10 years are, respectively, 86.2% and 100%. CONCLUSION Unilesional mycosis fungoides has a long natural history, is possibly the earliest manifestation of a malignant process, and local treatments, including local radiotherapy, result in long-term disease-free intervals and, possibly, cure. Total skin electron beam radiotherapy is not indicated for this disease entity.

Extracorporeal photochemotherapy: a potentially useful treatment for scleromyxedema.

Scleromyxedema, a variant of papular mucinosis, is a rare condition that clinically resembles scleroderma. Itis characterized by a lichenoid papular eruption, induration of the skin, and a paraproteinemia of unknown significance. Histologic examination reveals dermal deposition of mucin; proliferation of large, stellate fibroblasts; and fibrosis. Multisystemic manifestations have also been reported. Scleromyxedema is often difficult to treat. One of the most effective therapies is melphalan or a similar alkylating agent but this carries the risk of acute toxicity and malignancy.l-4 We describe a patient who responded to extracorporeal photochemotherapy (photopheresis) after unsuccessful attempts with other treatment.

A phase I trial of recombinant human interferon-γ in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS)

A Phase I study of recombinant interferon-gamma (rIFN-γ) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposis sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-γ. rIFN-γ was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2–4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7–12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1–1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-γ is given at doses at or near this MTD.

Reversal of acute renal allograft rejection by extracorporeal photopheresis: A case presentation and review of the literature

There is a clear need for well‐tolerated immunomodulatory agents that can aid in the prevention of acute solid organ rejection. Extracorporeal photopheresis is an apheresis‐based therapy that is currently available at many medical centers worldwide. Preliminary studies utilizing photopheresis with standard immunosuppressives have shown this therapy to successfully reverse acute cellular rejection of cardiac allografts with minimal toxicity. No formal evaluation of the role of extracorporeal photopheresis had been performed in renal transplantation. In this report, photopheresis was successfully utilized to treat acute cellular rejection in a patient with a renal allograft. This lends further support to the existing literature suggesting that photopheresis may be useful for the reversal of acute solid organ rejection. Although our experience with this patient is anecdotal, photopheresis merits further study as treatment for severe renal allograft rejection.

De novo development of psoriatic plaques in patients receiving interferon alfa for treatment of erythrodermic cutaneous T-cell lymphoma

Presumably because of its potent immunomodulatory activity, the use of interferon has led to the development of autoimmune disease in susceptible individuals. Because psoriasis is considered to be, in part, an autoimmune phenomenon, it is plausible that interferon may influence disease activity. We describe the development of psoriatic plaques in two patients without a history of this disease while they were receiving interferon alfa and extracorporeal photochemotherapy for erythrodermic cutaneous T-cell lymphoma. Paradoxically, in both patients the erythroderma resolved with subsequent de novo onset of psoriasis. This clinical sequence provides support for disparate immune mechanisms in the pathogenesis of these disorders, both of which are typified by lymphoid infiltrates. A review of the literature reveals that all forms of interferons have been associated with the exacerbation of psoriatic plaques, but that only interferon alfa has induced de novo development of psoriasis.

Successful reversal of severe refractory cardiac allograft rejection by photopheresis

We treated 4 patients with refractory International Society of Heart and Lung Transplantation Grades IIIA to IV cardiac allograft rejection with extracorporeal photopheresis. Following treatment on 2 consecutive days, 3 patients demonstrated complete histologic reversal of rejection. The remaining patient improved more gradually, but manifested complete cessation of rejection following three 2-day treatments. We conclude that photopheresis is a safe and effective modality for the treatment of severe refractory cardiac allograft rejection and that these results support the use of photopheresis in this clinical setting.

Progressive epidermotropic CD8+/CD4− primary cutaneous CD30+ lymphoproliferative disorder in a patient with sarcoidosis☆

We describe a patient with a CD8+/CD4- primary cutaneous CD30(+) lymphoproliferative disorder with striking epidermotropic histology and coincident cutaneous and systemic sarcoidosis. This patient illustrates the spectrum of clinical and histologic features of CD30+ lymphoproliferative disorders and the need for adequate staging in such cases. This patients CD30/CD8 coexpression is rare and has clinical and prognostic implications, including mucosally and acrally accentuated lesions and a potentially more aggressive course. Primary cutaneous CD30+ lymphoproliferative disorders have an excellent prognosis; therefore multiagent chemotherapy modalities are generally not indicated. The combination of T-cell lymphoma and sarcoidosis is also rare and may limit treatment options.

The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma

Interferons are polypeptides that naturally occur in the human body as a part of the innate immune response. By harnessing these immunomodulatory functions, synthetic interferons have shown efficacy in combating various diseases including cutaneous T-cell lymphoma. This article closely examines the qualities of interferon alfa and interferon gamma and the evidence behind their use in the 2 most common types of cutaneous T-cell lymphomas, namely, mycosis fungoides and Sézary syndrome.

Global Quantitative Techniques for Positron Emission Tomographic Assessment of Disease Activity in Cutaneous T-Cell Lymphoma and Response to Treatment.

Global Quantitative Techniques for Positron Emission Tomographic Assessment of Disease Activity in Cutaneous T-Cell Lymphoma and Response to Treatment Fluorodeoxyglucose positron emission tomography (FDGPET) imaging has been suggested as a useful modality in staging, assessing response to treatment, and detecting disease recurrence in primary cutaneous T-cell lymphoma (CTCL).1 Indices of FDG uptake include conventional measurements such as maximum standardized uptake value (SUVmax) mean SUV (SUVmean) and global measurements such as global metabolic volume (GMV) and global lesion glycolysis (GLG). Some investigators support conventional metrics,2,3 while others have demonstrated greater value in global tumor measurements.4 Herein we present the cases of 2 patients with CTCL who had PET scans performed at baseline and follow-up in addition to the usual clinical and laboratory assessments. The FDGPET images were analyzed by ROVER software (ABX Advanced Biochemical Compounds GmbH), which is capable of measuring whole body disease burden by GMV and GLG. This software also measures SUVmax and SUVmean.