Supresión de un cuadro de micosis fungoide recurrente con distribución zosteriforme mediante tratamiento de mantenimiento con valaciclovir / Successful Suppression of Recurrent Zosteriform Mycosis Fungoides With Maintenance Valacyclovir

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Inflammatory cytokines and peripheral mediators in the pathophysiology of pruritus in cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) includes a diverse group of neoplasms, including mycosis fungoides and Sézary syndrome. One of the earliest and most common symptoms of CTCL is pruritus, which affects up to 88% of patients. The severity of pruritus can range from mild to very debilitating, producing tremendous discomfort and a significant decrease in quality of life. Patients with advanced disease, in particular, may experience a more chronic, intractable pruritus. However, the underlying mechanism of pruritus in CTCL remains unknown. Conventional antipruritic agents, such as antihistamines, gamma-aminobutyric acid analogs and antidepressants, are only partially effective in relieving symptoms, suggesting a more complex, unique pathophysiology. In this review, we summarize the current research on cytokines and peripheral mediators implicated in pruritus in CTCL.

Pruritic arthropod bite-like papules in T-cell large granular lymphocytic leukaemia and chronic myelomonocytic leukaemia.

T-cell large granular lymphocytic leukaemia (T-LGLL) is a clinically indolent mature T-cell neoplasm characterized by a monoclonal population of CD3+ CD8+ cytotoxic T cells, which usually presents as neutropenia, anaemia and thrombocytopenia. Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic disorder with features of both a myeloproliferative neoplasm and myelodysplastic syndrome (MDS). Patients with CMML exhibit a persistent peripheral blood monocytosis in addition to myelodysplastic features. Because of the rarity of T-LGLL, its cutaneous manifestations are poorly documented, but include vasculitis, vasculopathy, persistent ulcerations, generalized pruritus and disseminated granuloma annulare. Various types of skin lesions have been observed in patients with CMML and reportedly occur in approximately 10% of cases. We report the extraordinary case of a patient with MDS who developed T-LGLL, and subsequently the MDS progressed to CMML. The patient then developed diffuse arthropod bite-like papules and intractable pruritus.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

Allogeneic stem-cell transplantation in patients with cutaneous lymphoma: updated results from a single institution.

BACKGROUND: Cutaneous T-cell lymphomas (CTCLs) and its common variants mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are rare extranodal non-Hodgkin's lymphomas. Patients who present with advanced disease and large-cell transformation (LCT) are incurable with standard treatments. In this article, we report the largest single-center experience with allogeneic stem-cell transplantation (SCT) for advanced CTCL. PATIENTS AND METHODS: This is a prospective case series of 47 CTCL patients who underwent allogeneic SCT after failure of standard therapy between July 2001 and September 2013. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) curves. The method of Fine and Gray was used to fit regression models to the same covariates for these cumulative incidence data. RESULTS: The Kaplan-Meier estimates of OS and PFS at 4 years were 51% and 26%, respectively. There was no statistical difference in the OS in patients who had MF alone, SS, MF with LCT, or SS with LCT. PFS at 4 years was superior in patients who had SS versus those who did not (52.4% versus 9.9%; P = 0.02). The cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 40% and 28%, respectively. The cumulative nonrelapse mortality rate was 16.7% at 2 years. CONCLUSION: Allogeneic SCT may result in long-term remissions in a subset of patients with advanced CTCL. Although post-SCT relapse rates are high, many patients respond to immunomodulation and achieve durable remissions. CLINICALTRIALSGOV: NCT00506129.

Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome).

BACKGROUND: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. RESULTS: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. CONCLUSION: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Final results of phase II trial of doxorubicin HCl liposome injection followed by bexarotene in advanced cutaneous T-cell lymphoma.

BACKGROUND: High response rates for doxorubicin HCl liposome injection (DLI) in cutaneous T-cell lymphoma (CTCL) have been reported with vague criteria until recently. Approximately 50% of CTCL patients respond to bexarotene (Bex). PATIENTS AND METHODS: A phase II trial was carried out to clarify the true overall response rate (ORR) for DLI and to assess the role of sequential Bex. Patients were treated with DLI 20 mg/m(2) i.v. every 2 weeks for 16 weeks (8 doses) followed by 16 weeks with Bex 300 mg/m(2) orally. Response assessments were carried out after 16 (DLI) and 32 weeks (Bex). Skin responses were measured by the modified Severity-Weighted Assessment Tool (mSWAT) and the Composite Assessment of Index Lesion Severity (CA). RESULTS: Thirty-seven patients were treated: stage IV (22, 8 with Sézary syndrome), IIB (10), earlier stage refractory to skin-directed therapies or radiation therapy (5). For 34 assessable patients: ORR 14/34 [41%: partial response (PR) 12, clinical complete response (CCR) 2]. Maximum responses were all seen after 16 weeks DLI. Median progression-free survival (PFS) was 5 months. There were 22 deaths: 21 of disease and 1 of heart failure. Twenty-seven grade 3 and 5 grade 4 toxic events were observed. CONCLUSION(S): With strict criteria, DLI ORR is among the highest reported for single agents in CTCL. Sequential Bex did not increase the response rate or duration.

A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome.

BACKGROUND: There is no prognostic index for primary cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sezary syndrome (SS). METHOD: Two prognostic indices were developed for early (IA-IIA) and late stage (IIB-IVB) disease based on multivariate data from 1502 patients. End-points included overall survival (OS) and progression free survival (PFS). External validation included 1221 patients. FINDINGS: Significant adverse prognostic factors at diagnosis consisted of male gender, age >60, plaques, folliculotropic disease and stage N1/Nx for early stage, and male gender, age >60, stages B1/B2, N2/3 and visceral involvement for late stage disease. Using these variables we constructed two separate models each defined using 3 distinct groups for early and late stage patients: 0-1 (low risk), 2 (intermediate risk), and 3-5 factors (high risk). 10 year OS in the early stage model was 90.3% (low), 76.2% (intermediate) and 48.9% (high) and for the late stage model 53.2% (low), 19.8% (intermediate) and 15.0% (high). For the validation set significant differences in OS and PFS in early stage patients (both p<0.001) were also noted. In late stage patients, only OS differed between the groups (p=0.002). INTERPRETATION: This proposed cutaneous lymphoma prognostic index provides a model for prediction of OS in early and late stage MF/SS enabling rational therapeutic choices and patient stratification in clinical trials.

Age-stratified phase I trial of a combination of bortezomib, gemcitabine, and liposomal doxorubicin in patients with advanced malignancies.

BACKGROUND: Preclinical data suggest synergistic activity of bortezomib, gemcitabine, and liposomal doxorubicin. Because tolerance to therapy may be attenuated in elderly patients, we performed an age-stratified phase I trial of this combination. PATIENTS AND METHODS: Two parallel age-stratified arms (< 65 and ≥ 65 years old) were accrued (3 + 3 design). Starting doses included bortezomib 0.7 mg/m(2) (days 1 and 8), gemcitabine 500 mg/m(2) (days 1 and 8), and liposomal doxorubicin 20 mg/m(2) (day 1). RESULTS: In the < 65-year-old group, 65 patients were treated; the maximum-tolerated dose was bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 35 mg/m(2). In the ≥ 65-year-old group, 28 patients were treated; the recommended phase II dose was bortezomib 1.0 mg/m(2), gemcitabine 800 mg/m(2), and liposomal doxorubicin 20 mg/m(2). Dose-limiting toxicities included thrombocytopenia and neutropenia. The most common toxicities were mild cytopenias, fatigue, and neuropathy. Ten patients achieved partial responses (6 of 7 patients with cutaneous T-cell lymphoma; 4 of 16 patients with small cell carcinomas, including lung, prostate, ovarian, and nasopharyngeal). CONCLUSION: Combination of bortezomib, gemcitabine, and liposomal doxorubicin is well tolerated, but with a lower recommended phase II dose in elderly patients, and demonstrated antitumor activity, especially in T-cell and small cell histology malignancies.

Dendritic cells and cutaneous T-cell lymphomas.

Dendritic cells (DCs) are potent antigen-presenting cells that help orchestrate the innate and adaptive immune systems to induce tolerance and immunity. They are diversified in their phenotypes, stages of maturation, degrees of activation, and functions. Several subtypes of DCs exist among human lymphoid tissues, non-lymphoid tissues, and in peripheral blood. In the skin, three types of DCs are described: Langerhans cells (LCs), dermal dendritic cells (DDCs), and plasmacytoid dendritic cells (pDCs). In the peripheral blood, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells are well described. Dysfunctional DCs are found in many autoimmune disorders, allergies, and cancers. In this paper, we focus on DCs as related to cutaneous T cell lymphomas (CTCLs). Abnormal DC number and defective DC function are found in the blood of patients with advanced stage Sézary syndrome (SS), a leukemic variant of CTCLs. Extracorporeal photopheresis (ECP), an effective therapy for erythrodermic CTCLs, is thought to work by inducing apoptosis of tumor cells and monocytes-derived DCs. DC vaccination has been carried out successfully in some patients with CTCLs when combined with immune modifiers like toll like receptor agonists, which may enhance the function of DCs. However, DCs may perform a dual role in the pathogenesis of CTCLs. Immature DCs (langerhans cells) could promote the survival of malignant T cells. Further understanding of DCs and their role in CTCLs can help us to uncover the pathogenesis of this disease and to further explore the therapeutic uses of DCs.

Serum T helper 1 cytokine levels are greater in patients with alopecia areata regardless of severity or atopy.

BACKGROUND: Alopecia areata (AA) is an organ-specific autoimmune disease characterized by folliculotropic T-cell infiltrates around anagen-stage hair follicles. The role of T helper (Th)1 and Th2 cytokines in the pathogenesis of AA have not been established. AIM: To determine whether serum cytokine profiles define the severity of the AA phenotype or are affected by co-existent atopy. METHODS: In total, 17 serum cytokines were measured and compared in 269 patients with AA of varying severity with and without atopy and 18 unrelated controls. RESULTS: Of the 269 patients with AA, 96% had active disease and 54% were atopic. The disease phenotype was transient patchy AA in 27 patients, persistent patchy AA in 89 and alopecia totalis or alopecia universalis in 153. Levels of Th1, interleukin (IL)-1 receptor antagonist (ra) and IL-8 levels were higher in all patients with AA than in controls. IL-1alpha, IL-12 and tumour necrosis factor-alpha levels were higher in patients with AA and atopy than in patients with AA without atopy. CONCLUSIONS: Increased Th1 serum cytokines (IL-2, IL-12 and interferon-gamma) and IL-1ra levels are associated with AA regardless of disease severity or the presence of atopy.

Lymphomatoid papulosis and associated lymphomas: a retrospective case series of 84 patients.

AIMS: To determine incidence and risk factors for developing lymphoma in patients with lymphomatoid papulosis (LyP), and to identify putative triggers amenable to treatment. METHODS: The prognostic effect of severity of LyP, viral infection by history or serology, beta-2-microglobulin level, lactic dehydrogenase (LDH) level, and CD4 : CD8 ratio were evaluated using logistic regression models. Responses to prophylactic or palliative treatment were assessed. RESULTS: In total, 84 patients (38 men, 46 women, median age at diagnosis 48.5 years) were identified. Of these, 34 (40%) were also diagnosed with one or more lymphomas: 16 (19%) had mycosis fungoides, 15 (17%) had primary cutaneous anaplastic large-cell lymphoma (pcALCL), 2 had both MF and pcALCL, and 1 had MF with large cell transformation and 1 had peripheral T-cell lymphoma. Of the 61 people presenting with LyP alone, only 11 (18%) subsequently developed lymphoma, with a median onset of 17.6 years (95% CI: 4, not obtained). Men were 2.5 times more likely than women to develop lymphoma (P = 0.04). Exposure to Epstein-Barr virus (EBV) was associated with an increase in incidence of 4.8 times (P = 0.16). Treatment for a putative infectious trigger resulted in improvement for 15 of 24 patients (63%). CONCLUSION: Referral bias may explain the higher (40%) incidence of lymphoma in this population of LyP patients, compared with the 10-20% incidence commonly cited in the literature. In the subset of patients presenting with LyP alone, only 18% later developed lymphoma. Male patients or patients with prior EBV infection may have a higher risk for developing lymphoma, and some patients improved with treatment of putative infectious triggers.

Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS), variants of cutaneous T-cell lymphoma, may arise from antigen-driven clonal expansion and accumulation of helper-memory T cells. Superantigens from Staphylococcus aureus can stimulate T cells. OBJECTIVES: (i) To determine the prevalence of S. aureus carriage in nares and skin in patients with MF/SS compared with historical rates in other conditions. (ii) To determine whether eradication of S. aureus carriage is associated with clinical improvement. Methods Skin and nares cultures were performed prospectively. Patients with positive nares and skin cultures were treated with oral antibiotics and intranasal mupirocin 2% and samples were taken for reculturing at 3 days, 4 weeks and 8 weeks. An exact binomial test was used to compare the carriage rates among different groups. RESULTS: Among 106 patients with MF/SS, 67 (63%) had skin colonization and 57 (54%) had nasal colonization. Staphylococcus aureus was isolated from 44 patients, 33 (31%) each from skin and nares. Colonization was highest in erythrodermic SS (48%), similar to atopic dermatitis (64%), and lowest in MF without erythroderma (26%), psoriasis (21%), and the general population (10%). Oral and topical antibiotics eradicated S. aureus colonization in nares in 28 of 33 (85%) patients and in MF skin lesions in 30 of 33 (91%) patients at 4-8 weeks, with rapid clinical improvement seen in 58% of S. aureus-colonized patients. CONCLUSIONS: Staphylococcal carriage in nares and skin lesions of patients with MF is similar to that in atopic dermatitis. Eradication of staphylococci from the skin is possible with treatment and was associated with clinical improvement.