Pathogenesis of cutaneous T-cell lymphoma: implications for the use of recombinant cytokines and photopheresis.

Cutaneous T-cell lymphoma (CTCL) is a clonally derived, skin invasive malignancy of CD4+ cells with the phenotype of mature helper T cells. We previously demonstrated that the leukaemic form of CTCL (Sézary), is characterized by prominent immunological defects including depressed cell-mediated immunity. We also demonstrated increased production of T-helper type 2 (Th2) cytokines (IL-4, IL-5) and deficient Th1 cytokines (IL-2 and IFN-gamma) by their peripheral blood mononuclear cells (PBMC) and detected IL-4 and IL-5 mRNA within lesional skin of patients with all stages of CTCL. A marked defect in IL-12 production has also been noted, which may also play a role in depressed cell-mediated immunity. These results suggested that the malignant CD4+ cells were Th2 cells. Thus, the immune aberrations have been attributed to the cytokine abnormalities triggered by the malignant T-cell population. Because CTCL responds to biological response modification, we focused on strategies for reversing the cytokine and immune defects by in vitro testing of novel biological response modifiers. Our results indicate that IFN-alpha potently suppresses the abnormal IL-4 and IL-5 production, that IL-12 can correct the deficient IFN-gamma production and cell-mediated cytotoxicity, and that retinoids can enhance IFN-gamma and IL-12 production. We also studied the in vitro growth characteristics of the malignant CD4+ cells and determined that IL-12 and IFN-alpha significantly suppress growth of these cells. These studies led to a phase I trial of IL-12 to treat CTCL. Also, we have determined that photopheresis produces a high clinical response rate among Sézary syndrome patients. This therapy not only augments functions of monocytes but also induces the malignant T cells to undergo a high rate of apoptosis. We discuss how these therapies might be employed in concert to produce the optimum desired anti-tumour effect.

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.

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 photopherosis 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.

Short-contact anthralin treatment augments therapeutic efficacy of cyclosporine in psoriasis: a clinical and pathologic study.

BACKGROUND: Psoriasis is characterized by immune activation and increased epidermal proliferation. Cyclosporine acts by reducing T lymphocyte numbers and lymphokine production. Anthralin inhibits keratinocyte proliferation. OBJECTIVE: We investigated whether topical anthralin would augment clearing of psoriasis produced by systemic cyclosporine. METHODS: Twelve patients with psoriasis were treated with cyclosporine (5 mg/kg per day). Patients applied anthralin only to plaques on half of their body. They were treated until a remission or maximum benefit was achieved. Disease activity was assessed by a severity index and quantitative histopathologic markers. RESULTS: Of the 12 patients, the skin of five cleared within 10 weeks irrespective of anthralin use. The other seven (slow responders) continued treatment for a mean of 18 weeks. Slow responders had a significantly lower severity index, a thinner epidermis, fewer CD8+ cells, and fewer proliferating keratinocytes on the anthralin-treated side than on the non-anthralin-treated side. CONCLUSION: The combination of cyclosporine and topical anthralin is effective in patients who are slow to respond to cyclosporine alone.

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.

Psoriasis is a hyperproliferative and inflammatory skin disorder of unknown aetiology. A fusion protein composed of human interleukin-2 and fragments of diphtheria toxin (DAB389IL-2), which selectively blocks the growth of activated lymphocytes but not keratinocytes, was administered systemically to ten patients to gauge the contribution of activated T cells to the disease. Four patients showed striking clinical improvement and four moderate improvement, after two cycle of low dose IL-2-toxin. The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.

Detection of myocardial sarcoidosis by thallium 201 imaging.

Thallium 201 myocardial perfusion scanning revealed focal left ventricular defects at rest in four of 30 patients (13 percent) with systemic sarcoidosis. All the defects decreased in size during thallium stress imaging, a finding opposite of that usually seen in myocardial ischemia. Nine patients had abnormal right ventricular visualization at rest. Thus, 11 of 30 (37 percent) had abnormal resting myocardial scand. Two of the four patients with left ventricular defects were studied serially for up to 1.5 years to evaluate response to corticosteroid therapy. The myocardial defect diminished in one patient, whereas the second patient, maintained for 2 years on low doses of steroids, had no resolution. In patients suspected of focal myocardial involvement by sarcoidosis on thallium scanning dynamic changes in scan defects can occur during exercise which are the reverse of those usually seen in coronary artery disease. These defects probably represent myocardial sarcoid. Right ventricular uptake generally appears to correlate with the severity of pulmonary involvement by sarcoidosis, yet does not appear to be a specific finding.

Late, late doxorubicin cardiotoxicity.

Cardiac toxicity is a major complication which limits the use of adriamycin as a chemotherapeutic agent. Cardiomyopathy is frequent when the total dose exceeds 600 mg/m2 and occurs within one to six months after cessation of therapy. A patient is reported who developed progressive cardiomyopathy two and one-half years after receiving 580 mg/m2 which apparently represents late, late cardiotoxicity.