Search

BACKGROUND Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment. OBJECTIVES To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients. PATIENTS/METHODS The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. RESULTS Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. CONCLUSIONS Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.

Summary Background Patients with mycosis fungoides (MF) experience frequent disease recurrences following total skin electron irradiation (TSEI) and may benefit from adjuvant therapy. Objectives To review the McGill experience with adjuvant alpha-interferon (IFN) in the treatment of MF. Methods From 1990 to 2000, 50 patients with MF were treated with TSEI: 31 with TSEI alone and 19 with TSEI + IFN. Median TSEI dose was 35 Gy. In the TSEI + IFN group, IFN was given subcutaneously at 3 × 106 units three times per week starting 2 weeks prior to start of TSEI, continued concurrently with the radiation and for an additional 12 months following TSEI. The TSEI alone group included 16 men and 15 women with a median age of 61 years (range 31–84). The TSEI + IFN group included 14 men and five women with a median age of 51 years (range 24–83). Clinical stage was IA, IB, IIA, IIB, III and IVA in 2, 9, 4, 8, 1 and 7 patients of the TSEI group and 0, 3, 3, 7, 4 and 2 patients of the TSEI + IFN group. Results Median follow up for living patients was 70 months. All patients responded to treatment. Complete response (CR) rate was 65% following TSEI and 58% following TSEI + IFN (P = 0·6). Median overall survival (OS) was 61 months following TSEI and 38 months following TSEI + IFN (P = 0·4). Acute grade II–III dermatitis was seen in all patients. Fever, chills or myalgia were seen in 32% of patients treated with TSEI + IFN. Conclusions Concurrent IFN and TSEI is feasible, with acceptable toxicity. Even when controlling for disease stage, the addition of IFN did not appear to increase CR rate, disease-free survival or OS.

Many types of skin disorders concomitantly occur with hepatitis C virus infection. These skin lesions may be induced or worsened during antiviral therapy with interferon-alpha (IFN). To our knowledge, hyperpigmentation of the skin--and especially of the tongue--has not been reported so far. We describe two dark-skinned patients who developed hyperpigmented skin and tongue lesions during combination therapy with IFN and ribavirin. Immunohistochemical analysis of tongue biopsies confirmed the suspicion of melanin deposits in these areas of hyperpigmentation. We hypothesize that during interferon therapy, melanocytes may produce more melanin pigment in the presence of alpha-melanocyte stimulating hormone and sufficient amounts of tyrosine, leading to melanin deposits and clinical hyperpigmentation.

Summary Background Cutaneous side-effects of treatment with interferon alfa or interferon alfa plus ribavirin in patients with hepatitis C have already been reported but they are mostly local with inflammation and, much less frequently, necrosis at the injection points. By contrast, very few data are available with regard to distant skin reactions, particularly inflammatory lesions on other parts of the body. Objectives To assess the clinical and histological pattern of inflammatory skin lesions outside the injection points in patients treated with interferon alfa and ribavirin for chronic hepatitis C. Methods Twenty patients attending a University Hospital in Southern France (secondary referral centre) were evaluated regard to clinical history, type and localization of lesions, progression and histology. Skin testing was performed in some patients and the relevance of the results was evaluated. Results Eczema-like skin lesions were mainly distributed on the extremities, sometimes associated with photosensitivity. They usually occurred between 2 and 4 months of treatment. Histology was nonspecific, with a dermal, mainly perivascular, mononuclear infiltrate. Skin testing was poorly informative and was not predictive of relapse. Treatment had to be interrupted in half the patients, of whom two of three relapsed on resuming therapy. Conclusions The incidence of inflammatory skin lesions at a distance from injection sites in patients treated with interferon alfa and ribavirin for chronic hepatitis C is currently unknown, but this adverse event must be taken into consideration as it may lead to the transient or definitive interruption of treatment.

Extracorporeal photopheresis is generally accepted as standard therapy for the leukaemic and erythrodermic variant of cutaneous T-cell lymphoma, the Sezary syndrome (SS). Because of the limited efficacy in some patients with SS, combination therapy is often necessary. We report a new combination therapy for an intensively treated 62-year-old woman with advanced SS (T4N1BM1, stage IVb). Previous treatment with PUVA, retinoids alone and in combination with photopheresis, chlorambucil, and chemotherapy using cyclophosphamide, doxorubicin, vincristine and prednisone failed and were associated with significant side-effects. Six cycles of combination therapy with extracorporeal photopheresis, low-dose interferon alfa and interleukin-2 resulted in fading of the erythroderma and in a decrease of Sezary cells in the white blood cell count. The CD4/CD8 ratio decreased from 66 to 6 and the proportion of CD4 + CD7 - cells from 47% to 11%. Only mild side-effects such as influenza-like symptoms, fever and nausea were observed. Two months after this therapy, the patient developed enlarged lymph nodes without erythroderma, and died 1 year later from the lymphoma. Combination therapy with extracorporeal photopheresis, interferon alfa and interleukin-2 might be useful in selected patients with SS.

Although interferon-alfa (IFN-alpha) has proved effective in treating epidermotropic cutaneous T-cell lymphoma (ECTL), few studies have considered the follow-up of treated patients and whether complete remission was maintained. We studied 51 patients (one stage Ia, seven stage Ib, one stage IIa, 30 stage IIb, 11 stage III (Sézary syndrome) and one stage IV) who received low-dose IFN-alpha as monotherapy for ECTL (mean daily dose of IFN-alpha 2.7 x 106 units for 14.9 months), giving special consideration to the significance of My7 (CD13) antigen expression by epidermal basal cells in predicting the maintenance of complete remission. For a mean follow-up period of 43.4 months, the results showed 21 complete remissions, 13 partial remissions and 17 patients with stable or progressive disease. Twelve patients died during the follow-up (3-52 months). IFN-alpha led to an improved response in the early stages, with a greater number of complete remissions (P = 0.03) and partial remissions (P = 0.01). The mean time to complete remission was 4 months, regardless of clinical stage (P = 0.1). Of 21 patients in complete remission, 57% had a relapse within a mean period of 7.5 months. For patients maintained in complete remission, the mean period of response was 31 months. The length of complete remission was independent of clinical stage, and My7 antigen expression was not predictive of complete remission.

The pathogenesis of Kaposi's sarcoma (KS) is often attributed to an infectious agent. In particular, the human herpesvirus 8 (HHV-8) was currently shown to be closely related to all known KS types, including HIV-associated KS, European classic KS, African endemic KS and iatrogenic KS. We report here on an HIV-negative, German patient of neither Jewish nor Mediterranean descent with disseminated classic KS showing unusual rapid progression into the tumour stage. After systemic administration of interferon α-2a over 4 weeks all tumour lesions cleared completely. Interestingly, HHV-8 DNA sequences detected by nested polymerase chain reaction in KS lesions before the onset of treatment were still present in lesional skin after complete remission of the tumour. No recurrence was seen after a follow-up period of 6 months.

Six patients with documented systemic mast cell disease were enrolled in a 1-year, phase I study to determine the possible benefits of interferon alpha-2b (IFN-alpha). IFN-alpha therapy was begun at a dosage of 0.5 million units/day (MU/day) by subcutaneous injection and increased, as tolerated, to 3.0 MU/day. Subsequent dose modifications were made based on clinical tolerance and response. No immediate, adverse reactions to IFN-alpha occurred. Several patients showed symptomatic improvement. In two patients ascites resolved and did not recur. Two other patients reported improved energy levels and had decreased size of retroperitoneal, measenteric and retrocrural nodes. One patient failed to benefit and died shortly after completing 12 months of therapy. Bone marrow mastocytosis decreased by 5% to 10% after 12 months of therapy with IFN-alpha. Although five of the six patients had a decrease in the urinary excretion of 1-methyl-4-imidazole acetic acid, serum tryptase values did not appreciably change in any patient. Side-effects from IFN-alpha included hypothyroidism, thrombocytopenia and depression. It is concluded that although treatment with IFN-alpha was associated with a decline in bone marrow mastocytosis and reduced excretion of histamine metabolites, prolonged therapy may be needed and dose-limiting side-effects are frequent.

Graft-versus-host disease (GvHD) is a common sequel to allogeneic bone marrow transplants, which may be accompanied by desirable graft-versus-tumour effects. Sclerodermatous GvHD is a rare subtype that is very difficult to treat. We report the first case of sclerodermatous GvHD as part of the Koebner phenomenon. We propose that donor lymphocyte infusion and interferon-alpha were involved in the pathogenesis of this case.

Five young male patients with HIV-associated Kaposi's sarcoma (KS) were treated with recombinant interferon alpha 2a (rIFN-alpha-2a) over a period of 2-2.5 years. An IFN dose of 18 x 10(6) IU was given subcutaneously every day during the first 3 months of treatment and then on alternate days. Additional treatment with radiotherapy and laser therapy was given and, in some cases, isolated skin nodules were excised. Within 7 months of initiation of therapy one patient had a complete remission of his tumours, however, tumour progression recurred after the patient discontinued treatment. In another patient the tumour cleared within 9 months of rIFN therapy, and after 52 months he is still free of KS. The condition of a third patient tended to become stabilized during the first 6 months of therapy, but after 60 months there has been a slow progression. The fourth and fifth patients died 25 and 28 months, respectively, after the histological diagnosis of KS and the initiation of treatment. While on therapy with rIFN-alpha-2a, no life-threatening opportunistic infections occurred. The side-effects were mostly well tolerated, and no severe changes in haematological parameters were caused by the therapy.

SUMMARY Ten patients suffering from either discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) were treated with interferon α2a. Eight received low or intermediate doses (18–45 × 106 U/week) for a short period of time (4–8 weeks), with marked improvement of skin lesions in six, an exacerbation in one patient and no change in the other. Two patients with SCLE received high doses (100–120 × 106 U/week) over 12 weeks, with complete clearing of the lesions in one and a marked improvement in the other. The responses were of short duration and within a few weeks of stopping treatment all who had improved or cleared relapsed. The side-effects in all the patients were fever and a flu-like syndrome which necessitated a reduction of the dose in one case. In two patients there were increases in the liver enzyme levels, but no haematological toxicity was noted.

Three patients, negative for human immunodeficiency virus (HIV), with histologically and polymerase chain reaction-proven non-HIV Kaposi's sarcoma who received low-dose interferon (IFN) as first-line treatment because of disseminated symptomatic disease are reported. Applying 3-18 million IU of IFN-alpha 2a per day, 3 days a week, subcutaneously for 8-20 months, major responses were achieved in all three cases. Tumour regression was observed within 4 months and has continued for 57 and 18 months to date (cases 1 and 2, respectively). Influenza-like symptoms, including fever, headaches and fatigue, were mild side-effects. However, in the third patient interferon injections had to be stopped because of hepatic enzyme elevation. Including this case report, 27 non-HIV Kaposi's sarcoma patients subcutaneously treated with IFN-alpha have been reported in literature. Most therapy regimens included 3-18 million IU IFN-alpha per day for 3 days a week. Twenty of 27 patients, or 74%, responded to therapy, whereas seven patients or 26% had stable or progressive disease. Relapse after IFN withdrawal can occur but is frequently delayed and limited, as in case 1. Following the response to IFN treatment, human herpesvirus-8 DNA was detected in the blood mononuclear cells of all three patients, possibly contributing to future relapses.

We report two patients treated with interferon-alpha who developed Raynaud's phenomenon followed by multiple digital necrosis. Arteriography of the legs revealed diffuse distal narrowing. Histological examination of the resected tissue showed ischaemic necrosis within the dermis and subcutaneous tissue without vasculitis. Resolution of the symptoms was observed when interferon-alpha was withdrawn. Since other causes of Raynaud's phenomenon and digital necrosis were ruled out, a drug cause is likely. Raynaud's phenomenon should be looked for in patients treated with interferon-alpha. If present, immediate withdrawal of the drug is required.

Summary Recombinant human interferon-α has been used in the treatment of several cancers, but there have been several reports that it may exacerbate psoriasis or trigger off its onset. We report four patients, three of whom first developed psoriasis and one who had an aggravation of the condition during treatment with interferon-α. Three of the patients had the carcinoid syndrome and one a renal carcinoma, and all were treated with interferon-α 2b or 2a (IFN-α2b, 2a) with doses ranging from 1·5 ± 106 U daily to 18 ± 106 U three times weekly. In two of the patients there appeared to be a correlation between the severity of the psoriasis and the dosage of interferon.