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.

Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

Radiotherapy and prognostic factors in adnexal carcinomas: A retrospective study of 657 patients from the French CARADERM network.

BACKGROUND: Cutaneous adnexal carcinomas are a heterogeneous group of rare neoplasms. Surgical excision is the first-line treatment in localized stage. The use and effectiveness of radiotherapy have not been thoroughly evaluated in these neoplasms. OBJECTIVES: The present work analyses prognostic factors on outcomes in skin adnexal carcinomas, based on data from the CARADERM (CAncers RAres DERMatologiques) database. METHODS: Data were collected retrospectively including demographic data, tumour types and therapeutic characteristics of all patients included in the CARADERM database, with at least one informative follow-up visit. Analyses were performed on three populations: patients with complete resection of the primary tumour (ADJ/primary population), patients achieving complete remission after complete resection of a recurrent tumour (ADJ/recurrent population) and patients with unresectable locally advanced or metastatic tumours (ADV/MET population). Overall and recurrence/progression-free survivals at 3-year were analysed using Cox regression models. RESULTS: Radiotherapy did not affect overall survival (OS) in the ADJ/primary population. Adjusted recurrence-free survival (RFS) was significantly lower in the radiotherapy group in ADJ/primary group. Older patients had significantly poorer OS and RFS. Tumour size and immunosuppression were significantly associated with poorer RFS only. Radiotherapy had no effect on OS and RFS in the ADJ/recurrent population. Age was the only factor associated with a poorer OS. Radiotherapy was significantly associated with longer progression-free survival (PFS) in age-sex adjusted analysis in the ADV/MET population, without effect on OS. CONCLUSIONS: Our study shows that age, tumour size and immunosuppression are significantly associated with survival in localized adnexal carcinomas. Radiotherapy may improve PFS in the ADV/MET population but not in localized and recurrent carcinomas after complete excision.

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort.

BACKGROUND: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. OBJECTIVE: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). METHODS: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. RESULTS: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. LIMITATIONS: No record of standard diagnostic criteria of MUP used in the participating centers. CONCLUSIONS: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

Evolution of Bullous Pemphigoid Clinical Pattern over Time: A 17-Year Single-Centre Retrospective Survey of 312 Cases.

BACKGROUND AND OBJECTIVES: Bullous pemphigoid (BP) clinical profile may have evolved during the last 2 decades. A retrospective, single-centre analysis investigated a possible shift of clinical presentation of the disease over time regarding both lesions' clinical pattern and locations and more particularly an increased frequency of characteristics considered as less classical regarding the usual clinical description of BP. PATIENTS AND METHODS: Initial clinical data from all BP patients treated between January 2001 and April 2017 in a reference centre were collected and compared between four 4-year successive chronological subsets (G1 to G4). RESULTS: 213/312 patients retained for final analysis (68.3%) displayed at least one initial non-classical characteristic, mainly head and neck, palmo-plantar, and/or mucosal involvement. Chronological analysis confirmed a significant increase over time of the percentage of patients displaying such features (G1 57.9% vs. G4 73.7%, p = 0.041). CONCLUSION: Changes in BP clinical pattern may have occurred over the last two decades with the progressive emergence of forms with a number of less classical features. No significant clinical difference was observed between patients receiving or not DPP4 inhibitors at the time of diagnosis.

Clinical Features, Histological Characteristics, and Disease Outcomes of Mycosis Fungoides in Children and Adolescents: A Nationwide Multicentre Cohort of 46 Patients.

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.

Anti-BP180 IgG antibody ELISA values correlate with adverse pregnancy outcomes in pemphigoid gestationis.

BACKGROUND: Adverse pregnancy outcomes (APO) occur in 35% of patients with pemphigoid gestationis (PG). No biological predictor of APO has been established yet. OBJECTIVES: To assess a potential relationship between the occurrence of APO and the serum value of anti-BP180 antibodies at the time of PG diagnosis. METHODS: Multicentre retrospective study conducted from January 2009 to December 2019 in 35 secondary and tertiary care centres. INCLUSION CRITERIA: (i) diagnosis of PG according to clinical, histological and immunological criteria, (ii) ELISA measurement of anti-BP180 IgG antibodies determined at the time of PG diagnosis with the same commercial kit and (iii) obstetrical data available. RESULTS: Of the 95 patients with PG included, 42 had one or more APO, which mainly corresponded to preterm birth (n = 26), intrauterine growth restriction (IUGR) (n = 18) and small weight for gestational age at birth (n = 16). From a ROC curve, we identified a threshold of 150 IU ELISA value as the most discriminating to differentiate between patients with or without IUGR, with 78% sensitivity, 55% specificity, 30% positive and 91% negative predictive value. The threshold >150 IU was confirmed using a cross-validation based on bootstrap resampling, which showed that the median threshold was 159 IU. Upon adjusting for oral corticosteroid intake and main clinical predictors of APO, an ELISA value of >150 IU was associated with the occurrence of IUGR (OR = 5.11; 95% CI: 1.48-22.30; p = 0.016) but not with any other APO. The combination of blisters and ELISA values higher than 150 IU led to a 2.4-fold higher risk of all-cause APO (OR: 10.90; 95% CI: 2.33-82.3) relative to patients with blisters but lower values of anti-BP180 antibodies (OR of 4.54; 95% CI 0.92-34.2). CONCLUSION: These findings suggest that anti-BP180 antibody ELISA value in combination with clinical markers is helpful in managing the risk of APO, in particular IUGR, in patients with PG.

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study.

OBJECTIVE: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. METHODS: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. RESULTS: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. CONCLUSION: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

Late-onset adverse events of anti-PD1 therapy in melanoma patients: An observational study from MELBASE, a nationwide prospective cohort.

BACKGROUND: Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described. OBJECTIVES: The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting. METHODS: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab. RESULTS: AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively). CONCLUSIONS: Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs.

A localized salt-dependent aquagenic urticaria successfully treated with omalizumab.

We present the first case of a localized salt-dependent aquagenic urticaria confirmed by a challenge test. A good therapeutic response was achieved after only the first dose of omalizumab.

A new case of photoallergic contact dermatitis caused by benzophenones in magazine covers.

BACKGROUND: Allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) to benzophenone present in printing ink have been reported. However, precise chemical analyses and extended photo-patch tests have not been performed in these cases. OBJECTIVES: To determine which components present in a magazine cover are responsible for a patient's skin reaction, to determine the primary sensitizer, and precisely diagnose ACD and PACD. METHODS: After initial photo-patch tests were performed on a patient with a history of reaction to magazine covers after sun exposure, gas chromatography-mass spectrometry and high-performance liquid chromatography analyses of the magazine covers, and additional photo-patch tests were performed. RESULTS: The first photo-patch test results confirmed PACD to ketoprofen and fenofibrate and evoked PACD to the magazine covers. 4-methyl benzophenone (4-MBP) and 1-hydroxy-cyclohexyl-phenyl-ketone (1-HCPK) were found in the magazine cover. Additional photo-patch tests confirmed PACD to 1-HCPK and to benzophenone, and photo-aggravated ACD to 4-MBP. The primary sensitizer was ketoprofen. CONCLUSIONS: Benzophenones are present in a wide variety of products, without always being listed on the packaging. Patients previously sensitized to other ketones, such as ketoprofen, may react to benzophenones without being able to avoid contact with these molecules. New regulations may be needed for more efficient eviction advice.

Benefit/risk Ratio of Low-dose Methotrexate in Cutaneous Lesions of Mycosis Fungoides and Sézary Syndrome.

Low-dose methotrexate is widely used in mycosis fungoides and Sézary syndrome, but few studies have evaluated this treatment. The aim of this study was to evaluate the benefit/risk ratio of this regimen on skin lesions. A retrospective survey of a series of patients treated for mycosis fungoides or Sézary syndrome with low-dose methotrexate and followed for at least one year in a tertiary referral centre was performed. From a total of 48 patients, complete response and partial response were achieved in 10 (21%) and 25 (52%) patients, respectively, with no significant difference in response rates between mycosis fungoides and Sézary syndrome. Of the responders, 20 out of 35 (57%) relapsed after a median time of 11 months. Forty-four of the total of 48 patients discontinued methotrexate, mainly due to primary or secondary failure and/or limiting toxicity (9 patients). Overall, the benefit/risk ratio of low-dose methotrexate in mycosis fungoides and Sézary syndrome appears favorable and this treat-ment remains a valid option in mycosis fungoides/Sézary syndrome. However, its activity is limited in duration and significant toxicity may occur in some patients.

Methotrexate-induced Primary Cutaneous Diffuse Large B-cell Lymphoma in Patients with Erythrodermic Cutaneous T-cell Lymphoma.

is missing (Short communication).

Cutaneous localization of angioimmunoblastic T-cell lymphoma may masquerade as B-cell lymphoma or classical Hodgkin lymphoma: A histologic diagnostic pitfall.

BACKGROUND: We report the cases of three patients presenting skin lesions whose biopsies showed nodular polymorphic infiltrates consisting of lymphocytes, plasma cells, histiocytes, eosinophils, B blasts, and Hodgkin Reed-Sternberg (HRS)-like cells. Two of them were initially diagnosed as classical Hodgkin lymphoma (cHL), on the other hand, the last one as a B-cell lymphoma. All patients have been treated for angioimmunoblastic T-cell lymphoma (AITL). METHODS: We performed a second review of the skin biopsies with further immunophenotypic molecular analyses. Scrupulous observation revealed, in the background of the three cases, atypical small to medium-sized lymphocytes carrying a CD3+, CD4+ T-cell phenotype and expressing PD1 and CXCL13 follicular helper T-cell markers. The two lesions initially diagnosed as cHL showed scattered HRS-like cells with CD30+, CD15+, PAX5+, CD20-, Epstein Barr Virus (EBV) + classical phenotype. The case initially diagnosed as B-cell lymphoma showed a diffuse B-cell proliferation associated with small B-cell and medium to large-sized B blasts that were positive for EBV. CONCLUSION: Those cases highlighted that atypical T-cells may be obscured by B-cell proliferation mimicking cHL or B-cell lymphoma in cutaneous localization of AITL and confirmed the requirement of collecting clinical information before performing a diagnosis.

Low- vs. Middle-dose Total Skin Electron Beam Therapy for Mycosis Fungoides: An Efficiency-based Retrospective Survey of Skin Response.

Optimal doses of total skin electron beam therapy for mycosis fungoides remain to be established. Clinical efficiency and adverse effects of middle-dose (25 Gy) vs. low-dose (10-12 Gy) total skin electron beam therapy were retrospectively compared in a series of 14 and 12 mycosis fungoides, respectively. Overall skin response rate was 96.2% (92.9% middle-dose and 100% low-dose; not significant (NS)). Overall complete and partial skin response rates were 57.7% (42.9% middle-dose and 75% low-dose; NS) and 38.5% (50% middle-dose and 25% low-dose; NS), respectively. All responding patients relapsed after an overall median time of 5 months (7 months middle-dose vs. 4 months low-dose; p = 0.164, NS). Tolerance was equally fair in both groups, with only grade 1 and 2 adverse events observed in 100% vs. 66.7% of patients in middle-dose and low-dose groups (NS). Although no significant difference was observed, middle-dose protocol may be recommended owing to a longer relapse-free survival for a similar tolerance.