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Mycosis Fungoides and Sezary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy.

ABSTRACT: Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.

SUBMITTER: Garcia-Diaz N

PROVIDER: S-EPMC8074086 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Mycosis Fungoides and Sezary Syndrome: An Update.

Project description:Cutaneous T-cell lymphomas are a heterogeneous collection of non-Hodgkin lymphomas that arise from skin-tropic memory T lymphocytes. Among them, mycosis fungoides (MF) and Sézary syndrome (SS) are the most common malignancies. Diagnosis requires the combination of clinical, pathologic, and molecular features. Significant advances have been made in understanding the genetic and epigenetic aberrations in SS and to some extent in MF. Several prognostic factors have been identified. The goal of treatment is to minimize morbidity and limit disease progression. However, hematopoietic stem cell transplantation, considered for patients with advanced stages, is the only therapy with curative intent.

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Project description:Cutaneous T-cell lymphoma (CTCL) is an umbrella term that encompasses a group of neoplasms that have atypical T-lymphocytes in the skin. Mycosis fungoides (MF) is the most common type of CTCL and Sézary syndrome (SS) is the leukemic form. Treatment for CTCL is dependent on the stage of disease and response to previous therapy. Therapy is divided into skin-directed treatment, which tends to be first line for early-stage disease, and systemic therapy, which is reserved for refractory CTCL. Bexarotene is a rexinoid and was licensed in Europe in 2002 for use in patients with advanced disease that have been refractory to a previous systemic treatment. We review the use of bexarotene as monotherapy and in combination with other treatments.

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Novel and Future Therapeutic Drugs for Advanced Mycosis Fungoides and Sezary Syndrome.

Project description:Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and plaques and the lesions are usually limited to the skin. On the other hand, in some cases, patients show skin tumors or erythroderma followed by lymph node involvement and rarely visceral organ involvement. SS is a rare, aggressive cutaneous T-cell lymphoma marked by exfoliative erythroderma, lymphadenopathy, and leukemic blood involvement. Because patients with relapsed or refractory MF/SS display a poor prognosis and the current treatment options are characterized by high rates of relapse, there is unmet need for the efficient treatment. This review provides a discussion of the recent and future promising therapeutic approaches in the management of advanced MF/SS. These include mogamulizumab, brentuximab vedotin, alemtuzumab, immune checkpoint inhibitors, IPH4102 (anti-KIR3DL2 antibody), histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, belinostat, and resminostat), pralatrexate, forodesine, denileukin diftitox, duvelisib, lenalidomide, and everolimus.

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Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and Sezary syndrome.

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Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts.

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Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2.

Project description:Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-?B signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

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Denileukin diftitox for the treatment of CD25 low-expression mycosis fungoides and Sezary syndrome.

Project description:In a placebo-controlled study, denileukin diftitox (DD) was effective against cutaneous T-cell lymphoma (CTCL) expressing CD25. An open-label companion study examined the efficacy and safety of DD in 36 patients with skin biopsies containing < 20% CD25 cells by immunohistochemistry staining (CD25 low expression). Patients received DD 18 ?g/kg/day for 5 consecutive days every 3 weeks for up to eight courses. The primary endpoint, overall response rate, was 30.6% (95% confidence interval: 16.3, 48.1), 33.3% for stage IIA or lower disease, and 26.7% for stage IIB or greater disease. Median progression-free survival (PFS) was > 487 days, and median time to treatment failure was 68.5 days. No difference in PFS by disease stage was observed. The safety profile of DD in CD25 low-expression disease was similar to that in CD25+ disease. These findings suggest that CD25 low expression does not preclude a meaningful clinical response to DD in patients with CTCL.

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Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study.

Project description:PurposeTo assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).Patients and methodsCITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.ResultsPatients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-? gene expression signature.ConclusionPembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

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Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sezary Syndrome.

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Advancements in the treatment of mycosis fungoides and Sezary syndrome: monoclonal antibodies, immunotherapies, and Janus kinase inhibitors.

Project description:Mycosis fungoides (MF) and Sézary syndrome (SS) are forms of cutaneous T cell lymphoma (CTCL) that pose significant challenges in their clinical management, particularly in refractory and advanced-stage disease. With the emergence of novel therapeutic modalities however, there are increasing opportunities to exploit the current understanding of pathophysiologic mechanisms of MF/SS for treatment. This review summarizes recent advances in the treatment of MF/SS, with a focus on monoclonal antibodies, immunotherapies, and Janus kinase (JAK) inhibitors, including ongoing clinical trials.

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