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Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS., Objectives: To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting., Methods: We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS., Results: In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression., Conclusions: PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR., Competing Interests: Conflicts of interest E.H. has received honoraria for consulting and/or lectures from Helsinn, Takeda, Vidac, Recordati and Rafa; and support for travel/meeting participation from Rafa. C.J. has received honoraria for consulting and/or lectures and support for travel/meeting participation from Takeda, Kyowa Kirin and Recordati. J.N. has received honoraria for consulting and/or lectures from Kyowa Kirin, Takeda, Recordati/Helsinn and Mallinckrodt/Therakos; and research funding from Kyowa Kirin. P.Q. has received honoraria for consulting and/or lectures from Takeda, Kyowa Kirin, Recordati/Helsinn, Mallinckrodt and 4SC. J.C.-M. has received honoraria for lectures from Takeda and Janssen. P.O. has received honoraria for lectures from Kyowa, Helsinn, Recordati, Mallinkrodt and 4SC; and support for travel/meeting participation from Kyowa, Almirall and LEO Pharma., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cutaneous T-cell lymphomas (CTCL) are a diverse group of malignant blood disorders characterized by initial skin infiltration, and sometimes, tumor spreading to lymph nodes, blood, and viscera. Mycosis fungoides is the most common form. Sézary syndrome is a distinctive form of CTCL marked by a significant presence of circulating tumor cells in peripheral blood. These diseases are characterized by the plasticity and heterogeneity of the tumor cells in the different tissue compartments, and a difficulty in identifying these tumor cells for diagnostic purposes and therapeutic monitoring. Progress has been made in the understanding of the pathophysiology of these diseases in recent years, and we provide here a review of these advancements., Competing Interests: Declaration of competing interest Caroline Ram-Wolff : Innate Pharma Adele de Masson, Martine Bagot, Maxime Battistella: Innate Pharma, Takeda, Recordati, Kyowa Kirin Helene Moins-Teisserenc, Armand Bensussan, Jerome Giustiniani, Ingrid Lazaridou: none, (Copyright © 2024 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Traditionally, Sezary syndrome (SS) has been associated with few therapeutic options and poor prognosis, with 5-year disease-specific survival (DSS) less than one-third in historical cohorts. However, newer therapies and combinations are associated with impressive time-to-next-treatment (TTNT), particularly allogeneic stem-cell transplantation (AlloSCT) and combination therapies notably those including extracorporeal photopheresis. In this multicentre, international study, we explored the prognostic outcomes of 178 patients exclusively managed for SS, diagnosed between 2012 and 2020, and treated in the modern therapeutic era. In this cohort, 58 different therapies were delivered, with 13.5% of patients receiving AlloSCT. Long-term survival exceeded historical reports with 5-year DSS and OS of 56.4% and 53.4% respectively. In those receiving AlloSCT, prognosis was excellent: 5-year DSS and OS were 90.5% and 78.0% respectively. Confirming the results from the Cutaneous Lymphoma International Consortium (CLIC), LDH and LCT had significant prognostic impact. Unlike earlier studies, stage did not have prognostic impact; we speculate that greater relative benefit favours patients with extensive lymphomatous nodal disease (Stage IVA2) compared to historical reports. For patients ineligible for AlloSCT, the prognosis remains relatively poor (5-year DSS 51.4% and OS 49.6%), representing ongoing unmet needs for more effective novel agents and investigation of improved therapeutic combinations., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting., Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045)., Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013)., Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome., Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3&#95;200253/1) and SKINTEGRITY.CH collaborative research program., Competing Interests: AdM declares nonfinancial support from Kyowa Kirin and Recordati Rare Diseases; fees from Takeda, Almirall and Recordati Rare Diseases, and research funding, outside the scope of this study, from Kyowa Kirin, Innate Pharma, Almirall and Takeda. MB declares consultant fees from Innate Pharma, Kyowa Kirin, Takeda, BMS, Sanofi, Quantum Genomics, and research funding from Kyowa Kirin and Takeda, outside the scope of this study. SM declares consultant fees outside the scope of this study, from Pierre Fabre, Sanofi, Novartis and Biocartis, and has received research funding from BMS, Novartis and Roche. NF declares having received nonfinancial support from Kyowa Kirin. PS received a research grant from Pierre Fabre, fees unrelated to this manuscript from Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; received nonfinancial support from Bristol-Myers Squibb, MSD, Roche-Genentech, Pierre Fabre, and Novartis outside of the scope of this study. MBB declares consultant fees from Kyowa Kirin, Takeda and Recordati and research funding from Kyowa Kirin and Almirall outside the scope of this study. HMT declares consultant fees outside from the scope of this study from Innate Pharma, and has received research funding, outside the scope of this study, from Kyowa Kirin. SIHO consultant fees outside the scope of this study from Takeda and Recordati. GD declares consultant fees outside of the scope of this study from Kyowa Kirin and Recordati. EG declares consultant fees and/or grant support from Mallinckrodt, Helsinn, Takeda, Novartis and Kyowa Kirin unrelated to this work. FG declares consultant fees from Recordati and Kyowa Kirin, outside from the scope of this study. GQ declares consultant fees from Takeda, Recordati and Kyowa Kirin, outside the scope of this study. CM declares nonfinancial support from MSD, Pfizer, Novartis, Bristol-Myers Squibb, Pierre Fabre, Leo Pharma, Sanofi Aventis, Jannsen Cilag outside of the scope of this study. SB declares having received nonfinancial support from Kyowa Kirin and Recordati. MBag declares consulting fees from Kyowa Kirin, Takeda, Recordati. HB declares consultant fees from Kyowa Kirin. EH declares consultant fees outside the scope of this study from Bristol-Myers Squibb, Takeda, Sanofi, Jannsen Cilag, Blueprint Medicines, AbbVie and nonfinancial support from Kyowa Kirin, MSD, UCB Pharma, Novartis, Almirall, Pierre Fabre. The other authors declare that they have no conflict of interest., (© 2024 The Authors.)

Competing Interests: Conflicts of interest Appendix S2 (see Supporting Information).

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

CD39, an ectoenzyme in the immunosuppressive CD39/CD73/adenosine pathway, known to promote solid tumour outgrowth and spreading, was investigated in both skin and blood compartments of cutaneous T cell lymphomas. CD39 was overexpressed by peripheral blood T-cells in Sezary syndrome and mycosis fungoides, and in skin-infiltrating lymphocytes of Sezary syndrome, mycosis fungoides, subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous CD30-positive lymphoproliferation. Our study emphasizes the interest in using CD39/CD73/adenosine pathway blocking agents for cutaneous T cell lymphomas treatment., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Despite increasing availability of therapies, patients with Sezary syndrome (SS) commonly endure multi-line treatment journeys, mostly with partial responses of short duration. Measuring clinical benefit is challenging; time-to-next-treatment (TTNT) provides a robust, objective measurement of efficacy. This international observational study examines patterns of clinical care and therapeutic benefit as measured by TTNT. TTNT was calculated for monotherapies and combination therapies, with consideration to treatment line. 178 patients with SS (73% de novo, 27% secondary) were included, receiving 721 lines of systemic therapy, with median follow-up of 56.9 months. Across all lines, 58 different therapeutic regimens were prescribed (54 were systemic therapies) and classified into 17 treatment groups. The most common first-line treatments were extracorporeal photopheresis (ECP)-containing combination therapy (20%) and retinoid monotherapy (19%). Median TTNT for all first-line therapies was short (5.4 months). First-line, combination therapies had longer median TTNT than monotherapies, 10.0 vs 5.0 months (P = .004), respectively. Later delivery of combination therapies was associated with shorter clinical benefit, with median TTNT reduced to 6.2 and 2.2 months for mid-line (2nd-4th line) and late-line (≥5th line), respectively (P < .001). First-line ECP-containing treatments were associated with longer median TTNT than non-ECP-containing treatments, 9.0 vs 4.9 months (P = .007). For both ECP-monotherapy and ECP-containing combination therapy, significant reductions in TTNT were seen in later lines. These data suggest therapeutic benefit from first-line delivery of combination therapy for SS and favor early inclusion of ECP in the treatment algorithm for those who can access it., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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., Competing Interests: Declaration of interests AdM reports research funding from Innate, Almirall, and Kyowa Kirin; travel expenses from Kyowa Kirin, Recordati Rare Diseases and Orphan Europe, and Janssen-Cilag; and fees from Takeda. MB-B reports consultancy at Kyowa Kirin and Recordati; and research funding from Celgene and Roche. SD reports institutional grants from Bristol Myers Squibb and Merck Sharp & Dohme. SI-H-O reports consultancy for Takeda and Recordati. CO reports honoraria from Novartis. JA reports honoraria from Roche and Janssen. OD reports consultancy from Bristol Myers Squibb, Kyowa Kirin, Merck, Sharpe & Dohme, Novartis, Pierre Fabre, Recordati Rare Diseases, Sanofi, and Sun Pharma; honoraria from Bristol Myers Squibb, Kyowa Kirin, LeoPharma, Merck, Sharpe & Dohme, Novartis, Pierre Fabre, Recordati Rare Diseases, Sanofi, and Sun Pharma; registration to meetings from Bristol Myers Squibb, Kyowa Kirin, LeoPharma, Merck, Sharpe & Dohme, Novartis, and Pierre Fabre; grants from Pierre Fabre; research funding from Kyowa Kirin, Novartis, and Pierre Fabre; and travel expenses from Bristol Myers Squibb, Janssen, Kyowa Kirin, LeoPharma, Merck, Sharpe & Dohme, Novartis, Pierre Fabre, and Sanofi. SBa reports consultancy at Amgen and Blueprint Medicines; and honoraria from Novartis, Leo Laboratories, and AbbVie. EW-H reports consultancy at Novartis, Bristol Myers Squibb, Pierre Fabre, BluePrint, Sun Pharma, AbbVie, and Sanofi; research funding from AbbVie; and honoraria from Bristol Myers Squibb, Novartis, AbbVie, Sanofi, and Pierre Fabre. FA reports consultancy at AbbVie, Almirall, Amgen, Bristol Myers Squibb, Janssen-Cilag, Leo, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Union Chimique Belge; honoraria from AbbVie, Almirall, Amgen, Bristol Myers Squibb, Janssen-Cilag, Leo, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, and Union Chimique Belge; and research funding from Galderma, Janssen, and Pfizer. RH reports honoraria from Kite and Gilead, Novartis, Incyte, Janssen, Merck Sharp & Dohme, Takeda, and Roche; and consultancy at Kite and Gilead, Novartis, Bristol Myers Squibb and Celgene, ADC Therapeutics, Incyte, and Miltenyi. AP-L reports honoraria from Bristol Myers Squibb and Novartis; and travel accommodation and meeting participation from Kyowa Kirin, Recordati, Novartis, and Bristol Myers Squibb. DM reports honoraria from Novartis, Incyte, CSL Behring, and Jazz Pharmaceuticals. J-DB reports being on a speaker or advisory board member for Boehringer-Ingelheim, Janssen, Novartis, Union Chimique Belge, Leo, AbbVie, Eli Lilly, Pfizer, Sanofi, and Almirall. FG reports consultancy at Recordati Rare Disease, Kyowa Kirin, Novartis, Pierre Fabre, Bristol Myers Squibb, and Merck Sharp & Dohme. HM-T reports consultancy at Innate; and research funding from Kyowa Kirin. SMo reports honoraria from Novartis, Pierre Fabre, Roche and Biocartis; and research funding from Novartis and Bristol Myers Squibb. MBat reports consultancy at Bristol Myers Squibb and Quantum Genomics; honoraria from Innate, Kyowa Kirin, Takeda, Meccellis Biotech, Cerba Research, and Sanofi; research funding from Kyowa Kirin; and grants from Takeda. ED reports grants from Pfizer and Mallinckrodt; and consultancy at Swedish Orphan Biovitrum. ML reports honoraria from Novartis, Pfizer, Alexion Pharmaceuticals, Sandoz, Novartis, Sanofi, Swedish Orphan Biovitrum, Gilead, and Bristol Myers Squibb. AP reports consultancy and honoraria from Novartis, Pierre-Fabre, Bristol Myers Squibb, Merck Sharp & Dohme, and Sun Pharma. AH reports consultancy at Novartis, Astellas, Jazz Pharmaceuticals, and Pfizer; and honoraria from Novartis, Astellas, Jazz Pharmaceuticals, and Pfizer. YLC reports consultancy at Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, and Pierre Fabre Oncologie; and honoraria from Novartis, Leo, AbbVie, Pfizer, and Pierre Fabre Oncologie. EF reports participation in advisory board at Gilead, GSK, and Sanofi; speakers bureau from Novartis and Alexion; honoraria from Novartis; and travel grants from Gilead, Merck Sharp & Dohme, Jazz Pharmaceuticals, and Novartis. GS reports consultancy at Novartis and Alexion Pharmaceuticals; honoraria from Novartis, Incyte, and Alexion Pharmaceuticals; and research funding from Alexion Pharmaceuticals. RPdL reports consultancy at Novartis, Pfizer, Amgen, Alexion Pharmaceuticals, Apellis Pharmaceuticals, and Swedish Orphan Biovitrum; honoraria from Novartis, Pfizer, Amgen, Alexion Pharmaceuticals, Apellis Pharmaceuticals, and Swedish Orphan Biovitrum; research funding from Novartis, Pfizer, Amgen, and Alexion Pharmaceuticals; and grants from Alexion Pharmaceuticals, Amgen, Novartis, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT) is an aggressive cutaneous lymphoma. Bone involvement is rare and poorly described. We present five cases of PCDLBCL-LT with bone localization. In four cases, the bone involvement was diagnosed during the initial staging with positron emission tomography (PET) or computed tomography (CT) scan, and in the fifth case after tibial fracture during treatment with rituximab (RTX) and polychemotherapy (PCT). PCDLBCL-LT can be asymptomatic and involve bone sites distant from cutaneous lesions. None had other extracutaneous involvement. In our series, all patients received RTX-PCT as first-line chemotherapy and all had early relapses or progression. Second-line treatments had poor efficacy. Our series shows that bone involvement seems to be associated with poor prognosis in PCDLBCL-LT. Bone localization is not diagnosed with initial thoracic-abdominal-pelvic CT when asymptomatic and affecting the limbs only. If there is a suspicion of PCDLBCL-LT, patients should undergo systematic investigation with alternative imaging techniques, including PET, both at baseline and if there is any concern during follow-up., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood., Methods: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients' clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed., Results: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF., Discussion: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood., (© 2022 S. Karger AG, Basel.)

Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with poor prognosis mainly characterized by the expansion of a tumor CD4 + T cell clone in both skin and blood. So far, the development of new therapeutic strategies has been hindered by a lack of reproducible in vivo models closely reflecting patients' clinical features. We developed an SS murine model consisting of the intravenous injection of Sézary patients' PBMC, together with a mixture of interleukins, in NOD-SCID-gamma mice. Thirty-four to fifty days after injection, mice showed skin disorders similar to that observed in patients, with the detection of epidermis thickening and dermal tumor T cell infiltrates. Although experimental variability was observed, Sézary cells could be tracked in the blood stream, confirming that our model could efficiently exhibit both skin and blood involvement. Using this model, we evaluated the therapeutic potential of RT39, a cell-penetrating peptide derived from the survival protein anti-apoptosis clone 11 (AAC-11), that we previously characterized as specifically inducing apoptosis of Sézary patients' malignant clone ex vivo. Systemic administration of RT39 led to cutaneous tumor T cells depletion, demonstrating efficient malignant cells' targeting and a favorable safety profile. These preclinical data confirmed that RT39 might be an innovative therapeutic tool for Sézary syndrome.

Background: Mogamulizumab, an anti-CCR4 monoclonal antibody, has been shown to increase progression-free survival in cutaneous T-cell lymphoma., Objectives: We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment., Methods: Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality., Results: Prior to mogamulizumab, the benign subset of CD4 + T cells displayed exhausted phenotypes, with an increased gradient in programmed death-1, TIGIT, DNAM-1, CD27, CD28 and CD70 expression from age-matched controls to patients' benign CD4 + T cells and to SCs. All patients presented SCs with heterogeneous phenotypes, and differential expression of individual markers was found within distinct malignant subsets. Early complete blood response was observed in 17 of 26 patients and was associated with higher baseline CCR4 expression. A drastic decrease in benign T cells and activated regulatory T-cell counts was observed during the first 4 weeks. Long-term follow-up revealed the emergence of an immune restoration involving CD8 + and naive and stem memory CD4 + T cells, with almost complete disappearance of exhausted lymphocytes. Development of resistance or tumour escape to mogamulizumab was associated with the emergence of CCR4 - SCs in blood and skin, displaying significant changes in their heterogeneity patterns, and not explained only by mutations within CCR4 coding regions., Conclusions: Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic? Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency. We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression. Mogamulizumab therapy, by targeting the skin-homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression-free survival in patients with SS. What does this study add? Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4 + T cells from patients with SS, separated using KIR3DL2 and TCRVβ expression. Mogamulizumab is not only aimed at eradicating malignant SCs but potentially contributes to the restoration of efficient immunity. Tumour escape is associated with the emergence of CCR4 - SCs, not explained only by mutations within CCR4 coding regions., (© 2022 British Association of Dermatologists.)

Cutaneous T-cell lymphomas (CTCLs) are rare malignancies involving primarily the skin. Responses to treatment are usually short-lived in advanced CTCL. The determinants of long-term CTCL control are unclear. Mogamulizumab, an anti-human CCR4 antibody that acts by antibody-dependent cell cytotoxicity against CCR4+ CTCL tumor cells and peripheral memory blood regulatory T cells, has been associated with long-lasting remissions and immune adverse events. Here, we reported skin rashes in 32% of 44 patients with CTCL treated with mogamulizumab, associated with significantly higher overall survival (hazard ratio, 0.16; 0.04-0.73; P = .01). Rash occurred in patients with Sézary syndrome and was associated with longer time to progression. These rashes were characterized by a CD163+ granulomatous and/or CD8+ lichenoid skin infiltrate. High-throughput sequencing analysis of T-cell receptor β genes in skin and blood flow cytometry confirmed the depletion of CTCL tumor cells, as well as the recruitment of new reactive T-cell clones in skin at the time of skin rash. CXCL9 and CXCL11, two macrophage-derived chemokines that recruit CXCR3+ T cells to skin, were overexpressed in skin rashes. A higher frequency of TIGIT+ and PD1+ exhausted reactive blood T cells was observed at baseline in patients with rash, and this frequency decreased with mogamulizumab treatment. These data are consistent with mogamulizumab-induced long-term immune CTCL control by activation of the macrophage and T-cell responses in patients with rash., (© 2022 by The American Society of Hematology.)

Background: Mogamulizumab is a novel defucosylated monoclonal antibody targeting the C-C chemokine receptor 4 (CCR4) that eradicates Sézary cells via antibody-dependent cellular cytotoxicity. Treatment of Sézary syndrome with mogamulizumab has recently shown an increase in progression-free survival compared to vorinostat in patients previously treated for cutaneous T-cell lymphoma., Objectives: To investigate immune side effects of mogamulizumab in patients with Sézary syndrome., Materials & Methods: Three patients with Sézary syndrome, treated with mogamulizumab, who developed clinically confirmed vitiligo, were investigated., Results: Case 1 was a 66-year-old woman from Tunisia. Seven months after the administration of mogamulizumab, she developed vitiligo on her face and hands while still in complete remission for Sézary syndrome. Case 2 was a 72-year-old woman from Martinique, with no history of autoimmune disease, who was diagnosed with Stage IVA1 Sézary syndrome. The patient received multiple lines of treatment with no improvement. After six months of mogamulizumab treatment, while still on treatment, the patient progressively developed well-demarcated depigmented patches on the scalp, upper limbs, and trunk, consistent with vitiligo. Case 3 was a 38-year-old woman from France, who was diagnosed with Sézary syndrome in October 2019. Mogamulizumab therapy was started in December 2019. Eight months later, she developed histologically-confirmed vitiligo on her legs., Conclusion: Vitiligo can be another autoimmune manifestation associated with mogamulizumab, and the occurrence of vitiligo could be a favourable predictive factor for response to treatment.

Introduction: Non-HIV-related visceral leishmaniasis (VL) is becoming increasingly prevalent in nontropical countries because of the increasing number of patients with chronic diseases and the development of immune-modulating drugs., Patient Concerns: Case 1 is a 60-year-old male patient of Senegalese origin presented with weight loss, lymphadenopathy, anemia, and elevated lactate dehydrogenases. Case 2 is a 46-year-old male patient of Algerian origin, with a negative HIV serology presented with cutaneous lesions., Diagnosis: Patient 1: The diagnosis of stage IV lymphocytic lymphoma (LL) was confirmed by an inguinal nodal biopsy in 2013. Patient 2: The diagnosis of T-cell lymphoma was made in 2003., Interventions: Patient 1 received 5 cycles of bendamustine and rituximab followed by a complete remission. Patient 2 was initially treated with >10 different treatments followed by 8 different chemotherapy regimens due to the disease progression., Outcomes: Patient 1: In 2017, after a follow-up of 4 years, the patient presented with fever, lymphadenopathy, splenomegaly, and pancytopenia in the setting of hemophagocytic syndrome. The initial diagnosis was a relapse of lymphoma and the patient was treated with ibrutinib. His status worsened, and Leishmania DNA was detected by polymerase chain reaction (PCR) on the blood and bone marrow aspirates. Ibrutinib was stopped. Amphotericin B treatment induced a complete clinical remission and clearance of Leishmania DNA from the blood.Patient 2: In 2017, after a follow-up of 14 years, the patient presented with fever, lymphadenopathy, hepatosplenomegaly, pancytopenia with hemophagocytic syndrome, and an increase in the tumor skin lesions. A skin biopsy was taken from the face and the patient. A careful reexamination of the skin biopsy revealed the presence of Leishmania bodies. He was treated with 40 mg/kg liposomal amphotericin B leading to a regression of the clinical symptoms and negativation of the blood PCR., Conclusions: This case study shows that VL may be a diagnostic challenge in patients with lymphoma. Reactivation or primary infection should be considered in the differential diagnosis. The purpose of this study is to remind clinicians to think of VL in patients with systemic symptoms that could be misdiagnosed as a progression of the underlying lymphoma.

Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare diseases. Many studies have reported on local epidemiology or geographic clustering, however we lack information from a global perspective. A systematic review and meta-analysis was conducted in Medline and the Cochrane Library based on a previously registered protocol and according to the preferred reporting of items for systematic reviews and meta-analyses (PRISMA). We selected publications that enrolled at least 100 patients with primary cutaneous lymphomas according to the current classifications. The relative frequencies (proportions) of subtypes were compared between studies and geographic regions in a meta-analysis. In total, 26 studies met our inclusion criteria, reporting on altogether 16,953 patients. Within primary cutaneous lymphomas, CTCL appeared to be 15% more frequent in Asian populations. Mycosis fungoides (MF) accounted for 62% of CTCL, with an important heterogeneity in frequencies between studies and continents. The proportion of Sézary syndrome (SS) was 3%, stable worldwide. Rare CTCL, such as NK/T-cell lymphoma or subcutaneous panniculitis-like lymphoma, were more frequent in Asian studies. This global meta-analysis of CTCL confirmed the predominance of CTCL among primary cutaneous lymphomas (83% on average) in the three analyzed continents, most of which were MF cases. It revealed the same proportions of SS across continents, and the heterogeneity of MF frequencies, suggesting the possible role of environmental factors in the pathophysiology of the latter. Registration number: CRD42020148295 (PROSPERO).

Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin lymphomas that develop primarily in the skin. They account for almost 80% of primary cutaneous lymphomas. Epidermotropic CTCLs (mycosis fungoides (MF) and Sézary syndrome (SS)) are the most common form of CTCL. The course of the disease ranges from an indolent clinical behavior in early-stage disease to an aggressive evolution in the advanced stages. Advanced-stage disease is defined by the presence of tumors, erythroderma, or significant blood, nodal or visceral involvement. Advanced-stage disease is characterized by frequent disease relapses, refractory disease, a severely impaired quality of life and reduced overall survival. In the last twenty-five years, allogeneic hematopoietic stem cell transplantation (HSCT) has led to prolonged remissions in advanced CTCL, presumably linked to a graft-versus-lymphoma effect and is thus emerging as a potential cure of the disease. However, the high post-transplant relapse rate and severe morbidity and mortality associated with graft-versus-host disease and infections are important issues. Allogeneic HSCT is thus mostly considered in young patients with no comorbidities and an aggressive, advanced-stage CTCL. Allogeneic HSCT gives the best results in patients with a pre-transplant complete remission of the lymphoma. For this reason, one of the challenges is to define the best time to consider allogeneic HSCT in the disease course. Early identification of patients at high risk for progression is important to identify candidates who may benefit from allogeneic HSCT before their disease becomes treatment-refractory. This review describes the role of allogeneic HSCT in CTCL, summarizes the published data and future perspectives in this area., Competing Interests: A.d.M. declares having received research funding from Innate Pharma and Kyowa Kirin, participated in boards for Therakos and received nonfinancial support from Kyowa Kirin and Recordati Rare Diseases. MB declares participating in Advisory boards for Kyowa Kirin, Takeda, Innate Pharma, and Helsinn/Recordati.

is missing (Short communication).

Cutaneous involvement in Waldenström's macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face). MYD88 L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the follow-up of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical, MYD88 L265P mutation).

Primary cutaneous B-cell lymphomas are rare entities that develop primarily in the skin. They constitute a heterogeneous group that represents around a quarter of primary cutaneous lymphomas. The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification differentiates primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma with an indolent course from primary cutaneous diffuse large B-cell lymphoma, leg type with an aggressive behavior. The broad spectrum of clinical presentations and the disease course marked by frequent relapses are diagnostic and therapeutic challenges. The classification of these diseases has been refined in recent years, which allows to better define their immunopathogenesis and specific management. In the present article, we review the main clinico-biological characteristics and the current therapeutic options of these three main subsets. Based on the recent therapeutic advances in nodal B-cell lymphomas, we focus on the development of novel treatment options applicable to primary cutaneous B-cell lymphomas, including targeted therapies, combination treatments and immunotherapeutic approaches, and cover basic, translational and clinical aspects aiming to improve the treatment of cutaneous B-cell lymphomas.

is missing (Short communication).

Background: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma., Methods: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045., Findings: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1])., Interpretation: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2., Funding: Innate Pharma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)