Mycosis Fungoides and Sézary Syndrome: Updates and Review of Current Therapy.

OPINION STATEMENT: While most patients with early-stage mycosis fungoides (MF) follow an indolent course, patients with advanced-stage MF/Sézary syndrome (SS) have a poor prognosis with a median survival of less than 5 years. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, especially in advanced-stage MF/SS. The choice of frontline therapy is dependent on the stage of disease. For early-stage MF, the treatment concept is to control skin lesions mainly by skin-directed therapies, such as topical therapies, phototherapies, and radiotherapies. For advanced-stage MF/SS, systemic treatments by biological or targeted therapies including bexarotene and interferon either alone or in combination are tried first, with more immunosuppressive chemotherapies being reserved for refractory or rapidly progressive disease. Recent improvements in biological or targeted therapies include brentuximab vedotin and mogamulizumab. When biopsy samples have 10% or more CD30-positive malignant cells, brentuximab vedotin, an anti-CD30 antibody conjugated to monomethyl auristin E, can be a desirable treatment option. For cases with blood involvement, mogamulizumab, an antibody binding to C-C chemokine receptor 4, is effective with high response rates. In the refractory setting, alemtuzumab, histone deacetylase inhibitors, pralatrexate, gemcitabine, and doxorubicin are considered as the treatment option. Because only allogeneic hematopoietic stem cell transplantation can offer a chance of cure with durable complete remission, advanced-stage patients with a markedly short life expectancy should be evaluated for eligibility. Given that there are few randomized controlled studies in the literature, it is necessary to investigate which therapy is preferable for each patient with MF/SS by comparative prospective trials.

Mycosis fungoides and Sézary syndrome: Australian clinical practice statement.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).

Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome.

Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease.

The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication.

Cutaneous T cell lymphomas (CTCLs) are malignancies of skin-trafficking T cells. Patients with advanced CTCL manifest immune dysfunction that predisposes to infection and suppresses the antitumor immune response. Therapies that stimulate immunity have produced superior progression-free survival compared with conventional chemotherapy, reinforcing the importance of addressing the immune deficient state in the care of patients with CTCL. Recent research has better defined the pathogenesis of these immune deficits, explaining the mechanisms of disease progression and revealing potential therapeutic targets. The features of the malignant cell in mycosis fungoides and Sézary syndrome are now significantly better understood, including the T helper 2 cell phenotype, regulatory T cell cytokine production, immune checkpoint molecule expression, chemokine receptors, and interactions with the microenvironment. The updated model of CTCL immunopathogenesis provides understanding into clinical progression and therapeutic response.

Survival prediction model for patients with mycosis fungoides/Sezary syndrome.

Aim: A nomogram was constructed to forecast the overall survival (OS) of patients with mycosis fungoides/Sezary syndrome. Patients & methods: The clinicopathological information of patients was obtained from the Surveillance, Epidemiology and End Results (SEER) database. A model was established based on the independent prognostic factors. Predictive ability of the model was evaluated with the concordance index and calibration curves. Risk stratification was conducted for patients with similar tumor node metastasis (TNM) stages. Results: The model included 1997 eligible patients and seven prognostic factors for OS. The concordance index of the nomogram was 0.84 in the training and external validation cohorts, which indicated good predictive ability of the model and reliability of the results. The high agreement between the model predictions and actual observations was identified by calibration curves, which demonstrated the prediction accuracy of the model. Risk stratification displayed significant differences for patients with similar TNM stages, which suggested that the OS of patients with similar TNM stages could be further distinguished. Conclusion: We established a reliable nomogram to predict the OS of patients with mycosis fungoides/Sezary syndrome, which highlighted the advantages of nomograms over the conventional TNM staging system and promoted the application of individualized therapeutic strategies.

Outcome of allogeneic hematopoietic stem cell transplantation for mycosis fungoides and Sézary syndrome.

Although allogeneic hematopoietic stem cell transplantation (HSCT) has been reported to provide prolonged remission of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS), its role has not been fully evaluated. Here, the outcomes of allogeneic HSCT for patients with MF/SS were retrospectively evaluated by using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-eight patients were evaluable and enrolled in the analysis. Median age was 45.5 years. Eighteen patients (38%) received myeloablative conditioning, and 33 (69%) received HSCT from an alternative donor. Disease status was complete or partial response in 25% of the patients and relapsed or refractory in the others. At the time of analysis, 18 patients were alive, with a median follow-up of 31.0 months (range, 3.8-31.1). Three-year overall survival (OS) and progression-free survival (PFS) were 30% (95%CI, 16-45%) and 19% (95%CI, 9-31%), respectively. Disease progression was not observed later than 17 months after transplantation. Both disease status and performance status at transplant significantly affected OS and PFS. Although our findings suggest that allogeneic HSCT provides long-term PFS in patients with MF/SS, the timing of transplantation should be decided carefully based on the disease status and the patient's condition in order to improve the outcome.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Cutaneous T Cell Lymphoma: Results of a Systematic Review and Meta-Analysis.

Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.

Outcomes and prognostic factors in African American and black patients with mycosis fungoides/Sézary syndrome: Retrospective analysis of 157 patients from a referral cancer center.

BACKGROUND: The prevalence of mycosis fungoides/Sézary syndrome (MF/SS) is higher in the black population than in the white population in the United States and worse outcomes have been observed in black patients. OBJECTIVE: To describe the outcomes and to identify prognostic factors in African American and black patients with MF/SS. METHODS: Clinical features and follow-up data were analyzed in 157 self-identified African American or black patients seen during 1994-2018. RESULTS: We included 122 patients with early stage MF and 35 patients with advanced-stage disease (median follow-up of 25 months). Overall, >80% of the patients who died from disease or progressed had erythema or hyperpigmentation without hypopigmentation. Patients with hypopigmentation, either as the sole manifestation or in combination with other lesions, had better overall survival (P = .002) and progression-free survival (P = .014). Clinical stage, TNMB classification, plaque disease, and elevated serum lactate dehydrogenase were also significantly associated with outcomes. Demographic and socioeconomic parameters were not associated with prognosis. LIMITATIONS: A retrospective study at a single cancer center. CONCLUSION: MF/SS manifestations and outcomes in African American and black patients are heterogeneous. Demographic and socioeconomic factors do not seem to have a prognostic role, while clinical characteristics might help in the stratification of risk of progression and shorter survival, allowing for individually tailored therapeutic interventions.

Clinical and Histological Characteristics of Mycosis Fungoides and Sézary Syndrome: A Retrospective, Single-centre Study of 43 Patients from Eastern Denmark.

Diagnosis of mycosis fungoides and Sézary syndrome can be very challenging. Clinical and histopathological data for patients with mycosis fungoides and Sézary syndrome in Denmark are limited. A retrospective study was performed in Region Zealand, Denmark from 1990 to 2016. A total of 43 patients with mycosis fungoides or Sézary syndrome were identified during the period. At the time of diagnosis the patients' mean age was 64.3 years and 74.5% had early-stage (≤IIA) disease. The mean time from onset of skin disease to diagnosis was 4.4 years. Surprisingly, 43% progressed to a higher disease stage, and risk of disease progression was higher for stage IB than IA (p = 0.01). All cases displayed some degree of epidermotropism and the infiltrates consisted of pleomorphic lymphocytes with a T-helper (CD4+/CD8-) phenotype. This study describes, for the first time, all aspects of clinical and histopathological findings in patients with mycosis fungoides and Sézary syndrome in a well-characterized Danish cohort.

Prevalence of atopy and staphylococcal superantigen-specific immunoglobulin E (IgE) antibodies and total serum IgE in primary cutaneous T- and B-cell lymphoma.

The prevalence of atopy was investigated in 20 patients with Sézary syndrome (SS), 20 patients with plaque phase mycosis fungoides (MF), 9 patients with primary cutaneous marginal zone lymphoma (pcMZL) and 8 patients with primary cutaneous follicle center lymphoma (pcFCL) with the Phadiatop multi-allergen test. The relationship among serologic atopy, IgE reactivity against Staphyloccocal enterotoxin superantigens, and serum total IgE (IgE-t) levels and their prognostic implications in SS was investigated. Phadiatop test was positive in 45%, 15%, 33% and 0% of samples of SS, MF, pcMZL and pcFCL, respectively. IgE-t levels were also increased in SS, pcMZL and marginally MF. No correlation was found with patients' history of atopic disorders. Staphylococcal superantigen-specific IgE ≥ 0.35 kUa/L, most often against toxic shock syndrome toxin-1, was detected in 40% of Sézary samples followed by MF (20%). In the absence of serologic atopy (negative Phadiatop test), IgE-t levels for patients with SS and MF were not significantly higher than controls whereas the levels for pcMZL remained high. Furthermore, even with a negative Phadiatop test, IgE-t values were higher in sera of patients with SSAg-IgE ≥ 0.35 kUa/L vis-à-vis < 0.35 kUa/L across all diagnostic categories including controls albeit the difference was statistically significant only for SS. The presence of specific IgE antibodies ≥ 0.35 kUa/L, IgE-t > 122 kU/L or eosinophils > 500/µL had no impact on survival of patients with SS. These results indicate that a pathogenic link may exist between an atopic diathesis and development of SS and possibly pcMZL.

[Cutaneous lymphomas : Clinical presentation - diagnosis - treatment]. / Kutane Lymphome : Klinik ­ Diagnostik ­ Therapie.

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T­cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B­cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B­cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.

Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome.

Extracorporeal photopheresis (ECP) has demonstrated therapeutic benefit in patients with Sézary syndrome (SS) and erythrodermic mycosis fungoides (e-MF). To examine the efficacy of ECP in the modern era of novel therapies, we conducted a retrospective analysis of 65 patients with a diagnosis of SS or e-MF with blood involvement who were treated with ECP at our institute. Overall survival (OS), time to next treatment (TTNT), and skin response rate (RR) were used as the study end points to determine patient outcome. The median follow-up from diagnosis was 48 months (range 1-225 months), with a median predicted OS of 120 months. The majority (88%) of patients commenced ECP at treatment lines 1 to 3, either as a monotherapy or in conjunction with other systemic agents. The use of ECP monotherapy resulted in a significantly longer median TTNT when compared with interferon-α (P = .0067), histone deacetylase inhibitors (P = .0003), novel immunotherapy agents (P = .028), low-dose methotrexate (P < .0001), and chemotherapy (P < .0001). In particular, early commencement of ECP at treatment lines 1 to 3 yielded a TTNT of 47 months. The results of our study support the utilization of ECP for SS/e-MF, and we recommend that ECP should be considered as early as possible in the treatment paradigm for these patients.

Overview of Cutaneous T-Cell Lymphomas.

Non-Hodgkin's lymphoma (NHL) encompasses a diverse collection of systemic and primary cutaneous lymphomas. Cutaneous T-cell lymphomas (CTCLs) represent about 13% of all NHLs, which are further subdivided into a heterogeneous group with vastly different presentations and histologic features. Diagnosis requires integration of clinical, pathologic, and molecular features. Among CTCLs, mycosis fungoides and Sézary syndrome are the most prevalent. Treatment is aimed at limiting morbidity and halting disease progression. Hematopoietic stem cell transplantation is the only therapy with curative intent.

Expression of CCR3 and CCR4 Suggests a Poor Prognosis in Mycosis Fungoides and Sézary Syndrome.

Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, lym-phomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30+ lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30+ lym-phoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.

Targeting CD47 in Sézary syndrome with SIRPαFc.

Sézary syndrome (SS), the leukemic variant of cutaneous T-cell lymphoma, has limited treatment options and rare occurrences of long-term remission, thus warranting research into new treatment approaches. CD47 has emerged as a promising target for multiple tumor types, but its role in SS remains unknown. Here, we show that CD47 is highly expressed on Sézary cells in the peripheral blood and skin, and the high level of CD47 expression correlates with worse overall survival (OS) in patients with SS. We also demonstrate that CD47 expression on Sézary cells is under the influence of interleukin 4 (IL-4), IL-7, and IL-13. Signal regulatory protein αFc (SIRPαFc; TTI-621), a novel CD47 decoy receptor, triggers macrophage-mediated phagocytosis of Sézary cells and, when administered in clinical trial settings, results in significant tumor load reduction. We conclude that inhibition of the CD47-SIRPα signaling pathway has therapeutic benefit for patients with SS. This trial was registered at www.clinicaltrials.gov as #NCT02663518.

Prognostic Significance of Serum Copper in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Serum copper has been reported to be increased in various cancers, including lymphoma. The purpose of the present study was to investigate the clinical and prognostic importance of serum copper levels in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Serum copper was measured in 60 men and 38 women with mycosis fungoides (MF) and 14 men and 3 women with erythrodermic CTCL (6 with Sézary syndrome) consecutively evaluated from July 1980 to June 1985. RESULTS: A greater than normal copper level was present in nearly 20% of patients and was associated with an increased risk of disease progression and shortened disease-specific survival for patients with patch or plaque phase MF, but not for those with tumor phase MF or erythrodermic CTCL. In contrast, the serum lactate dehydrogenase level and neutrophil/lymphocyte ratio were not significantly associated with prognosis in our patient cohort. CONCLUSION: The reason for the association between the high serum copper levels and adverse prognosis is unknown. We hypothesized that interleukin-6 is secreted primarily by non-neoplastic cells at MF skin sites, leading to release of copper by the liver. Local production of interleukin-6 at the lesion sites might conceivably also promote neoplastic cell progression by stimulation of the STAT3 pathway. Further studies on the relationship between activated tumor-associated macrophages, serum copper levels, interleukin-6, or C-reactive protein and prognosis might be informative.

Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance.

Sézary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS.

Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome.

Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sézary syndrome are the most common histological subtypes. Although next-generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sézary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such as TP53, PTEN, and RB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found that ZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevant ZEB1 germline variants. The survival analysis shows a worse clinical course for patients with ZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated with ZEB1 depletion in Sézary patients we verified that ZEB1 exerts a role in oxidative response of Sézary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization of ZEB1 abnormalities in Sézary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, that ZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence that ZEB1 activity in Sézary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis.

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. FUNDING: Kyowa Kirin.