Allogeneic transplantation and cellular therapies in cutaneous T-cell lymphoma.

INTRODUCTION: Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of cutaneous T-cell lymphoma. Although many available treatments offer temporary disease control, allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative treatment option for advanced stage MF and SS. CAR T-cell therapy is a promising new avenue for treatment. AREAS COVERED: In this review, we discuss the evidence supporting the use of allo-HSCT for the treatment of MF/SS, including disease status at the time of transplant, conditioning regimen, total body irradiation (TBI), and donor lymphocyte infusion (DLI). We also address the potential role for CAR T-cell therapy in CTCL. EXPERT OPINION: Allo-HSCT is an effective treatment for patients with advanced MF and SS. However, significant research is required to determine optimal treatment protocols. Data support the use of reduced-intensity conditioning regimens and suggests that the use of TBI for debulking of skin disease may result in more durable remissions. Donor lymphocyte infusions (DLI) appear to be particularly effective in inducing complete remission in MF/SS patients with relapsed or residual disease. Challenges with CAR-T therapies in T-cell lymphoma include T-cell fratricide due to shared antigens on malignant and nonmalignant T-cells, penetrance into the skin compartment, and CAR-T cell persistence.

Clusters, crop dusters, and myth busters: a scoping review of environmental exposures and cutaneous T-cell lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin lymphomas. Similar presentation to benign conditions, significant genetic variation, and lack of definitive biomarkers contributes to diagnostic delay. The etiology of CTCL is unknown, and environmental exposures, such as geographic, occupational, chemicals, sunlight, and insects have been investigated. EVIDENCE ACQUISITION: Review of the literature for CTCL and exposures was performed in PubMed and Google Scholar in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews. This search yielded 193 total results, which were initially screened with defined inclusion and exclusion criteria. The 45 remaining articles were reviewed and classified by exposure type. EVIDENCE SYNTHESIS: The most frequently investigated CTCL exposure type was geographic (13/45 articles, 29%). Chemical exposures were commonly discussed (10/45 articles, 22%), along with occupational (10/45 articles, 22%). Insect exposures (6/45, 13%) and sun exposure (3/45, 7%) were also reviewed, along with articles describing multiple exposure types (3/45, 7%). Article types ranged from cases to systematic reviews and case-control studies. Evidence linking CTCL and these exposures was mixed. Limitations of this investigation include reliance on patient reporting and frequent speculation on disease association versus causality. CONCLUSIONS: This investigation synthesizes the current literature on exposures potentially implicated in the pathogenesis of CTCL, while offering guidance on patient history-taking to ensure potential exposures are captured. Awareness of these possible associations may improve understanding of disease pathogenesis and diagnosis. Moreover, these insights may help with public health decision-making and disease mitigation.

Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study.

BACKGROUND: Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS: In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS: From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION: Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING: French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

Characterization of primary cutaneous T-cell lymphoma following solid organ transplantation.

BACKGROUND: Immunosuppression following solid organ transplantation is a known risk factor for the development of posttransplant lymphoproliferative disorders (PTLD). Primary cutaneous T-cell lymphoma (CTCL) occurring in the posttransplant setting is rare, which has made comprehensive understanding of this disease challenging. This study aims to further characterize the spectrum of clinicopathologic features of CTCL in solid organ transplant recipients (SOTR). METHODS: A retrospective chart review was performed for SOTR who were diagnosed with CTCL at a multi-site academic medical center from January 1, 1998, to December 31, 2013. Eight patients fulfilled the inclusion criteria and were included in this study. Data collected included patient demographics, transplanted organ, the time between transplant and CTCL diagnosis, clinical presentation and rash morphology, a histological subtype of CTCL, immunosuppression regimens, and patient status. Twelve diagnostic skin biopsies for five patients were examined and reviewed by a board-certified dermatopathologist. RESULTS: Six (75%) out of the eight patients were men, two (25%) were women, and the median age was 53 years. The median time from the date of transplant to the diagnosis of CTCL was 8.2 years. Transplanted organs included the liver (4), kidney (3), and heart (1). Clinical presentation varied from papulonodules, comedone-like lesions, intense pruritis, and scaly erythematous eruptions. The most common histologic presentation was folliculotropic mycosis fungoides (FMF) (7/12). Epstein-Barr virus-in situ hybridization (EBV-ISH) was negative in all specimens. CONCLUSIONS: We emphasize the rarity of CTCL among SOTR. Although rare in the general population, the FMF subtype appears to be disproportionately seen in SOTR compared with other CTCL.

Cost-Effectiveness of Extracorporeal Photopheresis for the Treatment of Patients With Erythrodermic (Stage T4, M0) Cutaneous T-Cell Lymphoma in the Australian Setting.

OBJECTIVES: Cutaneous T-cell lymphoma (CTCL) is a rare and incurable disease, and patients currently experience a lack of treatment options in Australia. This analysis evaluated the cost-effectiveness of extracorporeal photopheresis (ECP) compared with standard of care therapy for the treatment of patients with erythrodermic (stage T4, M0) CTCL, who are refractory to previous systemic treatment. METHODS: A Markov model was developed from the perspective of the Australian government. Health states were treatment specific and transition probabilities were modeled from time-to-next-treatment data from a published Australian observational study of ECP and comparator treatments. Quality of life utility values were based on psoriasis as a proxy for CTCL, which was validated by consultation with local clinicians. The time horizon for the model was 5 years. The ECP treatment regimen was compared with a weighted treatment comparator based on results of a treatment survey and Australian prescribing data. RESULTS: ECP as a second-line treatment option for CTCL was less costly and more effective than other treatment strategies. ECP had an average cost saving of $37 592 and incremental quality-adjusted life-year gained of 0.20 to 0.21, attributed to patients being able to better tolerate ECP thus avoiding subsequent treatment with high-cost alternatives. CONCLUSIONS: This is the first published cost-utility analysis of ECP for CTCL. This analysis demonstrates that ECP is a cost-effective option for the treatment of patients with erythrodermic CTCL in Australia.

Allogeneic hematopoietic stem cell transplantation for heavily pretreated patients with mycosis fungoides and Sezary syndrome.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of heavily pretreated mycosis fungoides/Sezary syndrome (MF/SS). Herein, we aimed to evaluate the outcomes of AHSCT for heavily pretreated patients with MF/SS retrospectively. This analysis included consecutive 19 patients with MF/SS who received 20 AHSCT between 2012-2021 in our transplant center. Eight patients have been previously reported. Fifteen patients had diagnosis of MF and referred to SS in five patients. In our cohort, all cases had advanced disease (stages IIB: n = 1, IIIA: n = 7; IIIB: n = 4, IVA: n = 4, and IVB: n = 3). Nine patients (47.4%) had developed large cell transformation. Only two patients received AHSCT in complete response, one very good partial response and two partial response while the others had progressive disease (n = 15) before transplant. Seven (35%) patients were alive at the time of analysis, with a median follow up of 10.5 months (range, 0.3-113 months) after AHSCT. Nine patients (47.4%) died without disease relapse or progression. Non-relapse mortality was 35.9% at 1 year and 26.9% at 3 years and thereafter. For all patients the probability of overall survival was 48.5% and 32.3% at 1- and 5-year post-transplant, respectively. AHSCT for MF/SS resulted in an estimated progression free survival of 45.4% at 1 year. Given the poor prognosis of patients not receiving transplants and in the absence of curative non-transplantation therapies, our results support that AHSCT is able to effectively rescue 32.3% of the population of transplant eligible, heavily pretreated patients in 5 years.

Determining the immune environment of cutaneous T-cell lymphoma lesions through the assessment of lesional blood drops.

Detailed analysis of the cells that infiltrate lesional skin cannot be performed in skin biopsy specimens using immunohistochemistry or cell separation techniques because enzyme treatments applied during the isolation step can destroy small amounts of protein and minor cell populations in the biopsy specimen. Here, we describe a method for isolating T cells from drops of whole blood obtained from lesions during skin biopsy in patients with cutaneous T-cell lymphoma. Lesional blood is assumed to contain lesional resident cells, cells from capillary vessels, and blood overflowing from capillary vessels into the lesion area. The lesional blood showed substantial increases in distinct cell populations, chemokines, and the expression of various genes. The proportion of CD8+CD45RO+ T cells in the lesional blood negatively correlated with the modified severity-weighted assessment tool scores. CD4+CD45RO+ T cells in the lesional blood expressed genes associated with the development of cancer and progression of cutaneous T-cell lymphoma. In addition, CD8+CD45RO+ T cells in lesional blood had unique T-cell receptor repertoires in lesions of each stage. Assessment of lesional blood drops might provide new insight into the pathogenesis of mycosis fungoides and facilitate evaluation of the treatment efficacy for mycosis fungoides as well as other skin inflammatory diseases.

Cutaneous T-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management.

DISEASE OVERVIEW: Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS: The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY: TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.

Cutaneous T-cell lymphoma in Asian patients: a multinational, multicenter, prospective registry study in Asia.

Cutaneous T-cell lymphomas (CTCLs) are a group of T-cell lymphomas with low incidence. Due to their indolent characteristics, treatment strategies have not yet been established for advanced CTCLs. In this study, relative incidence of CTCLs in Asia was estimated and the therapeutic outcomes presented based on various treatments currently used in clinics for advanced CTCLs. As part of a prospective registry study of peripheral T-cell lymphoma (PTCL) conducted across Asia, including Korea, China, Taiwan, Singapore, Malaysia, and Indonesia, subgroup analysis was performed for patients with CTCLs. Among 486 patients with PTCL, 37 with CTCL (7.6%) were identified between April 2016 and February 2019. Primary cutaneous ALK-negative anaplastic large cell lymphoma (ALCL, 35.1%) was the most common subtype. With a median follow-up period of 32.1 months, median progression-free survival (PFS) was 53.5 months (95% CI 0.0-122.5), and overall survival was not reached. 14 patients (48.2%) underwent subsequent treatment after the first relapse, but the response rate was 20% with a PFS of 2.2 months (95% CI 0.3-4.0). Six patients received autologous stem cell transplantation (auto-SCT). However, auto-SCT did not result in better outcomes. Additional studies are needed on standard care treatment of advanced or refractory and relapsed CTCLs.

Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma.

Staphylococcal enterotoxins are believed to fuel disease activity in cutaneous T-cell lymphoma. Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sézary syndrome, the most common forms of cutaneous T-cell lymphoma. Yet, it remains incompletely characterized how staphylococcal enterotoxins fuel disease activity. In this study, we show that staphylococcal enterotoxins induce the expression of the oncogenic microRNA miR-155 in primary malignant T cells. Thus, staphylococcal enterotoxins and Staphyloccocus aureus isolates from lesional skin of patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus, express Y-phosphorylated signal transducer and activator of transcription 5, and display enhanced miR-155 expression, when compared with nonlesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with Sézary syndrome. In conclusion, we show that S. aureus and its enterotoxins induce enhanced expression of oncogenic miR-155, providing mechanistic insight into the role of S. aureus in cutaneous T-cell lymphoma. Our findings support that environmental stimuli such as bacteria can fuel disease progression in cutaneous T-cell lymphoma.

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma.

T-cell non-Hodgkin's lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin's lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin's T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.

Primary Cutaneous Natural Killer/T-Cell Lymphoma: A Posttransplant Lymphoproliferative Disorder Demonstrated by 18F-FDG PET/CT.

ABSTRACT: A 24-year-old man with a history of hemophagocytic lymphohistiocytosis (HLH) presented with swelling of the left foot and skin ulcer. The patient received bone marrow transplantation for HLH 3 years ago for his HLH. Biopsy of left foot skin demonstrated primary cutaneous natural killer/T-cell lymphoma: a posttransplant lymphoproliferative disorder. FDG PET/CT images demonstrated multiple foci of abnormal accumulation in the body, especially in the skin. Follow-up PET/CT after chemotherapy demonstrated that most abnormal activities disappeared except for the lesion in the left foot.

Long-standing dermatitis treated with dupilumab with subsequent progression to cutaneous T-cell lymphoma.

This case series discusses 3 patients with long-standing eczematous or psoriasiform dermatitis, demonstrated by multiple biopsies. Following off-label treatment with dupilumab, all 3 patients had clinical expansion of disease, with histopathologic features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsy. We postulate that this expansion likely was secondary to an exacerbation of extant CTCL following exposure to dupilumab. A proposed mechanism of promotion of CTCL is based on the functional increase in IL-13 available for binding at the upregulated IL-13 receptor (IL-13R) α2 site on cells, following blockade of the α1 receptor with dupilumab. This progression merits further investigation.

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified, associated with lymphomatoid papulosis after a 9-year follow up: A case report.

Lymphomatoid papulosis (LyP) is a self-limiting cutaneous T-cell lymphoproliferative disorder that may progress into malignant lymphoma. Most of the previously reported associated lymphomas are primary cutaneous anaplastic large-cell lymphoma and mycosis fungoides with a low mortality rate. We report a case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), associated with LyP after long-term follow up. The patient was a 79-year old Japanese man followed up for 9 years. He suddenly developed a 3-cm ulcerated lesion on his forehead, which was diagnosed as an exacerbation of LyP. The lesion regressed after conservative treatment, but the patient soon developed multifocal pcPTCL-NOS. Thereafter, the patient developed pneumonia and cerebral infarction and died within a few months of the onset of malignant lymphoma. Aggressive cutaneous lymphoma may develop in LyP patients. The present case re-emphasizes the need for careful follow up of patients with persistent LyP.

Expression Profiles of Genes Encoding Cornified Envelope Proteins in Atopic Dermatitis and Cutaneous T-Cell Lymphomas.

The skin barrier defect in cutaneous T-cell lymphomas (CTCL) was recently confirmed to be similar to the one observed in atopic dermatitis (AD). We have examined the expression level of cornified envelope (CE) proteins in CTCL, AD and healthy skin, to search for the differences and their relation to the courses of both diseases. The levels of FLG, FLG2, RPTN, HRNR, SPRR1A, SPRR1B, SPRR3 and LELP-1 mRNA were determined by qRT-PCR, while protein levels were examined using the ELISA method in skin samples. We have found that mRNA levels of FLG, FLG2, LOR, CRNN and SPRR3v1 were decreased (p ≤ 0.04), whereas mRNA levels of RPTN, HRNR and SPRR1Av1 were increased in lesional and nonlesional AD skin compared to the healthy control group (p ≤ 0.04). The levels of FLG, FLG2, CRNN, SPRR3v1 mRNA increased (p ≤ 0.02) and RPTN, HRNR and SPRR1Av1 mRNA decreased (p ≤ 0.005) in CTCL skin compared to the lesional AD skin. There was a strong correlation between the stage of CTCL and increased SPRR1Av1 gene expression at both mRNA (R = 0.89; p ≤ 0.05) and protein levels (R = 0.94; p ≤ 0.05). FLG, FLG2, RPTN, HRNR and SPRR1A seem to play a key role in skin barrier dysfunction in CTCL and could be considered a biomarker for differential diagnosis of AD and CTCL. SPRR1Av1 transcript levels seem to be a possible marker of CTCL stage, however, further studies on a larger study group are needed to confirm our findings.

Cutavirus: A newly discovered parvovirus on the rise.

Cutavirus is a new member of the Parvoviridae family. It was first discovered in 2016 through unbiased metagenomics performed on fecal samples collected from patients with diarrhea, and also in skin biopsies collected from patients with cutaneous T-cell lymphoma (CTCL, also known as mycosis fungoides). We have systematically reviewed the literature to describe the discovery, genomic organization, prevalence, and geographic distribution of cutavirus.

Granulomatous slack skin mycosis fungoides developing simultaneously with sarcoid-like lesions in a patient with repeated anabolic injections in the past?

We present a 32-year-old man with successful treatment and remission of mycosis fungoides of both axillae in 2016 after PUVA therapy and systemic and local administration of corticosteroids. Subsequently, in 2017, the patient also achieved remission of a T-cell CD 30 positive, ALK-1 negative large-cell lymphoma of a retroperitoneal and inguinal lymph node after chemotherapy and radiotherapy. One year later, in 2018, the patient presented to our clinic with progression of skin lesions in both axillary areas and the appearance of а tumor in the right gluteal region.Dermatological examination showed livid-to-erythematous, partly sclerotic plaques in the right inguinal area, cutis laxa-like plaque formations in the right axillary region with similar but less-developed changes in the left axillary fold, a solitary subcutaneous tumor formation affecting the entire right gluteal region, and enlarged, palpable lymph nodes in the right para-axillary area. Biopsies were obtained from an axillary lesion and the surgically removed axillary lymph nodes, and histological examination revealed changes of granulomatous slack skin in the axilla and reactive inflammatory changes in the lymph nodes. Histology of gluteal tissue showed a "foreign body" type of reaction with sarcoid-like features, where the patient in the past have been injected with anabolic and steroidal drugs. Herein we describe a patient with simultaneous occurrence of granulomatous slack skin type mycosis fungoides and a sarcoid-like reaction. The question remains open whether this represents the so-called sarcoidosis-lymphoma syndrome or, more likely, granulomatous slack skin MF associated with a sarcoid-like reaction of "foreign body" type. The possibility that disturbance of tissue homeostasis by incorporation of certain adjuvants within injections (for example) in the past might have been an inducer of cutaneous T cell lymphoma and sarcoidosis/sarcoid like lesions seems reasonable but also speculative.