Brentuximab Vedotin for Relapsed or Refractory Sézary Syndrome.

Importance: Treatment options for Sézary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial. Objective: To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS. Design, Setting, and Participants: From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center. Interventions: Intravenous brentuximab vedotin administration approximately every 3 weeks. Main Outcomes and Measures: The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer-International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria. Results: The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1). Conclusions and Relevance: In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides.

Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.

Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities.

Pruritus is one of the cardinal symptoms found in patients with leukemic cutaneous T cell lymphoma (CTCL). The nature of the pruritus experienced by CTCL patients is complex, involving different pathways and cell mediators, thus making it poorly responsive to conventional anti-itch therapies. Recent reports highlight the role of interleukin 31 (IL-31) as a novel cytokine involved in the pathogenesis of pruritus in atopic dermatitis and CTCL. Here we provide both in vivo and in vitro evidence suggesting that histone deacetylase (HDAC) inhibitors may mitigate itch through lowering of levels of IL-31-expressing T cells. Furthermore, we demonstrate that chemokine receptor type-4 (CCR4)-bearing T cells are a main source of IL-31 in CTCL, and that neutralizing the IL-31 pathway through targeting of the CCR4-expressing T cells may represent a promising therapeutic strategy for symptomatic relief in CTCL.

Improvement in peripheral blood disease burden in patients with Sézary syndrome and leukemic mycosis fungoides after total skin electron beam therapy.

BACKGROUND: There is a paucity of effective therapies for patients with Sézary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. OBJECTIVE: We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sézary syndrome. METHODS: All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. RESULTS: Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. LIMITATIONS: This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. CONCLUSION: In patients with advanced mycosis fungoides and Sézary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Peripheral blood findings in erythrodermic patients: importance for the differential diagnosis of Sézary syndrome.

Although Sézary syndrome (SS) represents an advanced stage of cutaneous T-cell lymphoma, this diagnosis presents a challenge even for the most experienced dermatologic clinicians. SS is characterized clinically by erythroderma, but can also be identified in the presence of specific histologic and peripheral blood findings. Erythrodermic cutaneous T-cell lymphoma can mimic a number of nonmalignant disorders with erythroderma, including pityriasis rubra pilaris, psoriasis, atopic dermatitis, and graft-versus-host disease. The diagnosis is made even more challenging because the histology of SS is often nonspecific and rarely pathognomonic. As a result, peripheral blood studies in patients with erythroderma are frequently informative in the diagnosis of SS. Peripheral blood abnormalities including elevated CD4/CD8 ratio, aberrant CD26, CD27 and CD7 expression, and T-cell clonality can all be used to help arrive at a diagnosis. This review evaluates current data on the usefulness and limitations of specific peripheral blood markers detected by flow cytometry and T-cell receptor gene rearrangement polymerase chain reaction.

Inhibition of cell-mediated immunity by the histone deacetylase inhibitor vorinostat: implications for therapy of cutaneous T-cell lymphoma.

Several histone deacetylase inhibitors (HDACi), including vorinostat, have been approved for the therapy of cutaneous T-cell lymphoma (CTCL). Emerging data suggest that HDACi may exert immune suppressive effects which would be disadvantageous for therapy of CTCL. We describe a patient with Sezary syndrome who was monitored for drug-induced immunosuppression while undergoing treatment with vorinostat. Analysis of the patient's natural killer cell function before and after initiation of treatment confirmed inhibition of this important cell-mediated immune function. In addition, the in vitro effects of vorinostat on the immunity of healthy volunteers confirmed that this class of drug can profoundly suppress multiple arms of the cellular immune response. These findings raise concerns of increased susceptibility to infection in this high-risk population.

High clinical response rate of Sezary syndrome to immunomodulatory therapies: prognostic markers of response.

OBJECTIVES: To quantify response rates of Sézary syndrome (SS) to multimodality immunomodulatory therapy and to identify the important prognostic parameters that affect overall response to treatment. DESIGN: Retrospective cohort study. SETTING: Cutaneous T-cell lymphoma clinic at The Hospital at the University of Pennsylvania. PARTICIPANTS: Ninety-eight patients who met the revised International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment of Cancer (EORTC) criteria for the diagnosis of SS and were seen over a 25-year period at the University of Pennsylvania. Intervention Patients were treated with at least 3 months of extracorporeal photopheresis and 1 or more systemic immunostimulatory agents. MAIN OUTCOME MEASURES: Overall response to treatment was the main measurement of outcome. RESULTS: A total of 73 patients had significant improvement with multimodality therapy: 30% had complete response, with clearing of all disease (n = 29), and 45% had partial response (n = 44). At baseline, the complete response group had a lower CD4/CD8 ratio than the nonresponse group (13.2 vs 44.2) (P = .04) and a lower median percentage of CD4(+)/CD26(-) cells (27.4% vs 57.2%) (P = .01) and CD4(+)/CD7(-) cells (20.0% vs 41.3%) (P < .01). Median monocyte percentage at baseline was higher for patients who had a complete response than for nonresponders (9.5% vs 7.3%) (P = .02). The partial response group did not have any statistically significant variables compared with the nonresponse group. CONCLUSIONS: In this large cohort study of patients with SS, a high clinical response rate was achieved using multiple immunomodulatory therapies. A lower CD4/CD8 ratio, a higher percentage of monocytes, and lower numbers of circulating abnormal T cells at baseline were the strongest predictive factors for complete response compared with nonresponse and warrant further examination in a larger cohort.

A novel regimen of vorinostat with interferon gamma for refractory Sézary syndrome.

Long-term prognosis for advanced stages of cutaneous T-cell lymphoma may be beneficially altered with the use of multimodality therapy. However, refractory disease exists in which current therapeutic options fail to halt the progression of disease. We present 3 cases of refractory Sézary syndrome in which the combination of vorinostat and interferon gamma was well tolerated and produced significant clinical improvement. The potential immunologic basis for this is discussed.

CD8+ epidermotropic cytotoxic T-cell lymphoma with peripheral blood and central nervous system involvement.

BACKGROUND: Most cutaneous T-cell lymphomas demonstrate a malignant population with a CD4(+) phenotype. In rare cases, CD8(+) phenotypes have been described based on immunostaining of skin specimens. Although some CD8(+) lymphomas have an indolent course, others, such as CD8(+) epidermotropic cytotoxic T-cell lymphomas, are typically more aggressive. To our knowledge, involvement of peripheral blood or cerebrospinal fluid with a malignant population of CD8(+) cells demonstrated by flow cytometry and T-cell receptor gene rearrangement has not been previously described. OBSERVATIONS: We describe a patient with a CD8(+) cutaneous T-cell lymphoma with an initially indolent course and early stage diagnosed on the basis of a skin biopsy specimen. However, when flow cytometry was performed looking specifically at CD8(+)/CD4(-) cells in the peripheral blood and cerebrospinal fluid, a malignant population of CD8(+)/CD4(-)/CD26(-)/CD7(-) cells was discovered. CONCLUSIONS: It is important for prognosis and treatment to be able to identify CD8(+) epidermotropic cytotoxic T-cell lymphoma and separate it from other relatively indolent CD8(+) lymphomas. Furthermore, detection of an abnormal CD8(+)/CD26(-)/CD7(-) T-cell population within the peripheral blood has important prognostic and therapeutic implications. The use of flow cytometry looking for abnormal CD8(+) populations in the peripheral blood or cerebrospinal fluid can assist with this critical information.

Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Sézary syndrome.

Total skin electron beam radiation is an effective therapy for palliation of the cutaneous symptoms of the most common types of cutaneous T-cell lymphomas, mycosis fungoides and Sézary syndrome. We report 4 cases of patients with Sézary syndrome who had significant improvement in their blood burden of malignant cells in addition to complete cutaneous responses to total skin electron beam therapy. The data from these 4 patients illustrate the potential for total skin electron beam to be used as both a skin and blood tumor debulking agent, and not merely as a palliation for skin symptoms.

Mycosis fungoides and sezary syndrome: an update.

Mycosis fungoides (MF), and the associated leukemic variant Sezary Syndrome (SS), are the most common group of cutaneous T-cell lymphomas. MF/SS is a non-Hodgkin's lymphoma of mature, skin-homing, clonal, malignant T lymphocytes that initially presents in the skin as patches, plaques, tumors, or generalized erythema (erythroderma) and can involve the lymph nodes and peripheral blood. Much progress has been made in recent years in understanding the origin of the malignant T cell in MF/SS and the pathophysiology and immunology of the disease. This recent work has made a great impact on diagnosis, prognostication, and treatment. In this review, we survey the MF/SS published literature over the past year and highlight some of the important advances.

High clinical response rate with multimodality immunomodulatory therapy for Sézary syndrome.

PURPOSE: The goal of this study was to evaluate the clinical response rate of patients with Sézary syndrome (SS) to multimodality immunomodulatory therapy consisting of extracorporeal photopheresis in combination with >/= 2 systemic biologic response modifiers (interferon-, interferon-, retinoids, and/or sargramostim) and psoralen plus UV-A. PATIENTS AND METHODS: Twenty-eight patients who met established criteria for SS were treated with multimodality immunomodulatory therapy at the Hospital of the University of Pennsylvania between January 2000 and December 2002. All patients received > 6 cycles of extracorporeal photopheresis. Patients were categorized into groups based on their response to therapy. RESULTS: An overall clinical response of 89% was achieved with multimodality immunomodulatory therapy. Twenty-nine percent of patients exhibited a complete response, characterized by no evidence of cutaneous disease and a Sézary count 5%. Sixty-one percent exhibited a partial response. Eleven percent were nonresponders. CONCLUSION: Based on our experience, multimodality immunomodulatory therapy is an exceptionally effective treatment for SS. The durability of response and impact on overall survival remains to be determined; however, this approach offers an appealing alternative to treatments associated with higher morbidity rates.