Cutaneous T-cell lymphomas are a rare and heterogeneous group of extranodal T-cell lymphomas characterised by skin involvement, with an overall US incidence of 7·5 cases per 1 million people.1 The most common type of cutaneous T-cell lymphoma is mycosis fungoides, an indolent neoplasm characterised by variable type and extent of skin disease (patches, plaques, tumour-type, and erythroderma), with a subset of patients either presenting with or developing extracutaneous disease. Sézary syndrome is a much rarer but more aggressive type of cutaneous T-cell lymphoma, characterised by erythroderma, lymphadenopathy, and blood involvement with neoplastic T cells. Together, mycosis fungoides and Sézary syndrome account for about two-thirds of all cutaneous T-cell lymphomas.2 With substantial clinical and biological overlap, both disease types can cause lifelong morbidity, decreased quality of life due to chronic skin impairment with intractable itching, recurrent infections, disfiguring skin lesions, sleep disturbance, and psychosocial problems.3 The burden of disease in skin and the presence of extracutaneous disease are primary determinants of survival.4, 5, 6, 7 Patients with advanced-stage mycosis fungoides and Sézary syndrome (stages IIB–IVB disease) have a median overall survival of approximately 5 years.6
Research in context
Evidence before this study
We searched PubMed, Embase, and Cochrane Library for phase 2 and phase 3 clinical trials in patients with cutaneous T-cell lymphoma done in the past 20 years (between Jan 1, 1998, and Jan 17, 2018) with the following search string: (“cutaneous T-cell lymphoma” OR “CTCL” OR “mycosis fungoides” OR “Sézary syndrome”), with no language restrictions. In the previous two decades, most prospective phase 2 or 3 clinical trials of systemic agents were either non-randomised (67 studies in total) or randomised to compare one or more doses of an agent, with or without a placebo or observational arm (five studies in total). Two non-randomised mogamulizumab trials were identified in our search—one phase 1/2 trial and one phase 2 trial. One phase 3 randomised trial published in 2017 (n=131; ALCANZA) compared systemic drugs (brentuximab vedotin vs physician's choice of methotrexate or bexarotene) in previously treated patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma—with exclusion of patients with Sézary syndrome—and used objective global response lasting at least 4 months as the primary endpoint. In published studies, the proportion of patients who achieved an objective response was determined by a range of methods, with trials before 2011 generally using less comprehensive assessments.
Added value of this study
Previous studies of systemic agents in cutaneous T-cell lymphoma that included Sézary syndrome as a major subtype were single-arm trials that mostly used the proportion of patients achieving an overall response as the primary endpoint. Although both overall response and progression-free survival are clinically relevant endpoints in cutaneous T-cell lymphoma, progression-free survival also captures the duration of disease control (absence of disease progression) with treatment, and therefore might more broadly reflect the overall clinical benefit in patients with cutaneous T-cell lymphoma, who often have a chronic disease course. To our knowledge, the phase 3 MAVORIC trial is the largest randomised study of systemic therapy in cutaneous T-cell lymphoma and the first to compare systemic therapies using progression-free survival as a primary endpoint. Our results show that mogamulizumab was superior to vorinostat for investigator-assessed median progression-free survival, the study's primary efficacy endpoint, and also for the proportion of patients who achieved an overall response and for quality-of-life outcomes, with a manageable safety profile consistent with previous studies.
Implications of all the available evidence
Our MAVORIC study found that, in patients with previously treated mycosis fungoides or Sézary syndrome, treatment with mogamulizumab, a first-in-class anti-CC chemokine receptor 4 monoclonal antibody, resulted in superior progression-free survival, a higher proportion of patients achieving an overall response, and better patient-reported outcomes than vorinostat, a US Food and Drug Administration-approved histone deacetylase inhibitor. Therefore, mogamulizumab could be a valuable new therapeutic option for patients with cutaneous T-cell lymphoma.
Patients with early-stage mycosis fungoides (IA–IIA) are treated primarily with skin-directed therapies, whereas those with treatment-resistant early-stage mycosis fungoides, advanced-stage mycosis fungoides, or Sézary syndrome require systemic drugs, including retinoids, methotrexate, interferons, histone deacetylase inhibitors (eg, vorinostat and romidepsin), brentuximab vedotin, or cytotoxic chemotherapeutic drugs.8, 9 Many of these drugs were approved on the basis of small, single-arm or non-randomised trials with varied response criteria. The largest phase 3 trial comparing systemic therapies reported so far included 131 patients.10 Except for allogeneic haemopoietic stem cell transplantation, there are no curative options for cutaneous T-cell lymphoma. Patients with cutaneous T-cell lymphoma often experience disease progression on therapy or become resistant to existing treatments, resulting in a need for newer therapies that target all disease compartments (skin, blood, lymph nodes, and viscera) and provide a durable response.
Mogamulizumab (KW-0761; Kyowa Kirin, Tokyo, Japan), a first-in-class defucosylated humanised IgG1 κ monoclonal antibody, selectively binds to C-C chemokine receptor 4 (CCR4) with enhanced antibody-dependent cellular cytotoxicity activity.11 CCR4, which is involved in cell trafficking of lymphocytes to skin, is consistently expressed on the surface of tumour cells in T-cell malignancies, such as cutaneous T-cell lymphoma (including mycosis fungoides and Sézary syndrome), adult T-cell leukaemia-lymphoma, and peripheral T-cell lymphoma.12, 13, 14, 15
Mogamulizumab has been approved in Japan for relapsed or refractory CCR4-positive adult T-cell leukaemia-lymphoma (2012), peripheral T-cell lymphoma (2014), and cutaneous T-cell lymphoma (2014).16 In a US-based phase 1/2 study in patients with cutaneous T-cell lymphoma, mogamulizumab showed an acceptable safety profile and promising efficacy, with 37% of patients achieving an overall response, and 95% achieving a response in the blood compartment.17 These encouraging results led to the development of our phase 3 MAVORIC study, which compared mogamulizumab to vorinostat, a US Food and Drug Administration (FDA)-approved drug with established clinical activity,18, 19 in previously treated patients with mycosis fungoides or Sézary syndrome. Both the proportion of patients achieving an overall response and progression-free survival are clinically relevant efficacy endpoints in cutaneous T-cell lymphoma. However, in contrast to the proportion of patients achieving an overall response, progression-free survival also provides information about the duration of disease control (ie, absence of disease progression) with treatment, and therefore might more broadly reflect overall meaningful clinical benefit in patients with cutaneous T-cell lymphoma, who often have a chronic disease course. Therefore, we undertook a phase 3 randomised trial comparing systemic therapies in previously treated patients with cutaneous T-cell lymphoma in which we used progression-free survival as the primary endpoint.