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.

CD158k and PD-1 expressions define heterogeneous subtypes of Sezary syndrome.

Sezary syndrome (SS) is a rare leukemic form of cutaneous T-cell lymphoma. Diagnosis mainly depends on flow cytometry, but results are not specific enough to be unequivocal. The difficulty in defining a single marker that could characterize Sezary cells may be the consequence of different pathological subtypes. In this study, we used multivariate flow cytometry analyses. We chose to investigate the expression of classical CD3, CD4, CD7, and CD26 and the new association of 2 markers CD158k and PD-1. We performed lymphocyte computational phenotypic analyses during diagnosis and follow-up of patients with SS to define new SS classes and improve the sensitivity of the diagnosis and the follow-up flow cytometry method. Three classes of SS, defined by different immunophenotypic profiles, CD158k+ SS, CD158k-PD-1+ SS, CD158k and PD-1 double-negative SS, showed different CD8+ and B-cell environments. Such a study could help to diagnose and define biological markers of susceptibility/resistance to treatment, including immunotherapy.

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017 (Toulouse, N = 202; Limoges, N = 91). Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group [95% confidence interval (CI) 9.14-19.36] and 27.26% in the other group (95% CI 19.38-35.71), P = 0.004. The cumulative incidence was 9.49% in the anti-PD-1 group (95% CI 5.43-14.90) vs 30.11% in the other group (95% CI 22.59-37.97), P < 0.0001. In multivariable analysis (model with 277 patients), anti-PD-1 reduced the risk of brain metastases by almost 70% (hazard ratio = 0.29, 95% CI 0.15-0.56, P < 0.0001). The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

Integrated multidisciplinary approach to hidradenitis suppurativa in clinical practice,.

BACKGROUND: The European hidradenitis suppurativa (HS) guidelines recommend a multidisciplinary approach for patients with HS and management of comorbidities. OBJECTIVE: We aimed to describe the organization of a multidisciplinary HS program and characterize the patient population. METHODS: We conducted a retrospective study of patients with HS undergoing prospectively defined multidisciplinary work-up including examinations by a dermatologist, plastic surgeon, smoking specialist, and nutritionist in our outpatient unit between October 2015 and January 2017. RESULTS: The study included 49 patients with a sex ratio of 1:1. A total of 73.4% of patients were smokers, 20.4% were overweight, 48.9% were obese, and 30.6% had symptoms of depression. The mean Sartorius score was 30.4 (±17.6). The outcome of plastic surgery consultation was as follows: 16 patients had operations, 5 were excluded based on medical history, 9 refused surgery, and 16 remained undecided. The refusal rates for consulting with the smoking cessation and nutrition specialists were 55.8% and 69.5%, respectively. Twelve patients received antibiotics, 9 received biologics, 9 underwent medico-surgical treatment, 9 underwent surgery, and 10 were lost to follow-up. The mean visual analogue scale score for satisfaction was 8.3 (±1.6; n = 28). CONCLUSION: An integrated multidisciplinary care model for HS is associated with high patient satisfaction. Adherence to the proposed comorbidity management was higher in female patients and related to empathetic interactions with physicians.

Survival estimation of melanoma patients with brain metastasis using the Melanoma-molGPA score: external validation from a French cohort.

While immunotherapies and targeted therapies such as BRAF inhibitors have improved the prognosis, BM is still associated with poor outcome and a short survival. Metastatic melanoma patients are a heterogeneous subgroup with variable prognosis. As several prospective clinical trials have addressed the question of optimal therapy for these patients, an accurate validated selection tool is needed. Melanoma molecular graded prognostic assessment (Melanoma-molGPA) is a new prognostic score for BM melanoma patients. We decided to perform an external validation of this score. All consecutive patients treated between May 2014 and December 2017 for a newly diagnosed locally advanced or metastatic melanoma with available status for BRAF mutation were identified. Melanoma mol-GPA was applied in each patient with BM and correlated to overall survival. One hundred patients were included. Median follow-up was 27.8 months. Distribution for the Melanoma-molGPA groups GPA 0-1, GPA 1.5-2, GPA 2.5-3 and GPA 3.5-4 were as follows: 23, 51, 24 and 2.0%, respectively. Subgroups GPA 2.5-3 and 3.5-4 were combined. Median overall survival for groups GPA 0-1, 1.5-2 and 2.5-4.0 was 4.2, 6.9 and 18.4 months, respectively, P = 0.0032. Our study is the most recent, and with the largest cohort, to validate the Melanoma-molGPA score as an accurate and reproducible score for estimating overall survival. As several prospective clinical trials are addressing the issue of optimal therapy including the impact of local treatment for these patients, the Melanoma-molGPA is a useful tool in BM melanoma patients.

Advanced Cutaneous Squamous Cell Carcinoma Is Associated with Suboptimal Initial Management in a Cohort of 109 Patients.

BACKGROUND: Little is known about the epidemiological characteristics of patients with advanced cutaneous squamous cell carcinoma (A-cSCC). OBJECTIVE AND METHOD: A retrospective study was conducted on a routine care cohort of 109 patients to identify the epidemiological factors associated with A-cSCC. RESULTS: The median age was 83 years (IQR: 73.9-89.8), and the median ECOG was 1 (IQR: 1-2). Sixty percent of the patients had a history of cardiac disease and 22% had cognitive disorders. Seventy-four percent of patients were from rural/semi-rural areas (towns of <15,000 residents) and 17% were living in nursing homes. The cSCC lesions were on the head and neck in 72% of cases. Thirty-seven percent of patients were not diagnosed until the disease was in an advanced stage, indicating a lack of cSCC identification. In the remaining 69 patients, 7% did not received treatment within 3 months of the cSCC being identified, 62% had an incomplete histological report, and 37% had incomplete treatment. CONCLUSION: A-cSCC is associated with incomplete initial treatment in an elderly and rural population with good general condition. We hypothesize that a lack of access to good dermatological expertise may have led to underestimation of the aggressiveness of cSCC and/or therapeutic mismanagement.

Staging of primary cutaneous follicle centre B-cell lymphoma: bone marrow biopsy, CD10, BCL2 and t(14;18) are not relevant prognostic factors.

BACKGROUND: There is a certain degree of controversy as to whether bone marrow biopsy is required during the staging procedures for primary cutaneous follicle centre B-cell lymphoma (PCFCCL). OBJECTIVES: Firstly, to determine extra-cutaneous involvement at initial diagnosis, in particular, based on bone marrow biopsy, and secondly, evaluate the phenotypic features associated with extra-cutaneous involvement during follow-up (in particular, the predictive value of BCL2 and CD10 coexpression and identification of t[14;18] in skin lesions, as well as bone marrow biopsy involvement at initial staging) in a cohort of patients with PCFCCL. MATERIALS & METHODS: A bicentric retrospective study was established to investigate 75 cases of PCFCCL, for which 44 bone marrow biopsies were performed. RESULTS: Two of 44 (5%) patients had bone marrow involvement. These two patients had no relapse during follow-up, either cutaneous or extra-cutaneous. BCL2 staining in B cells was positive in 39/75 (52%) cases and CD10 was positive in 39/73 (53%). Only 4/26 (15%) cases showed t(14;18) based on fluorescence in situ hybridisation. CONCLUSIONS: Our study combined with data from the literature suggests that systematic bone marrow biopsy at initial staging for putative PCFCCL is not to be recommended. Moreover, BCL2 or CD10 expression does not currently represent a reliable basis to introduce significant changes in initial therapy or the follow-up strategy.

Characterization and Outcomes of Disease Progression in 52 Patients Treated with BRAF-V600 + MEK Inhibitors for Advanced Melanoma.

BACKGROUND: Combined treatment with BRAF-V600 and MEK inhibitors has significantly improved progression-free and overall survival of patients with BRAF-mutated melanoma. Pattern of disease progression and outcomes in patients have not been fully characterized. METHODS: We conducted a single-center, retrospective, descriptive analysis of a cohort of 52 patients treated with BRAF-V600 + MEK inhibitors for advanced melanoma over a 12-month period. The aim of this study was to characterize disease progression, defined as metastatic pattern, disease kinetics, and response to subsequent therapies, in melanoma patients treated with BRAF-V600 + MEK inhibitors. RESULTS: Disease progression was observed in 31/52 (59.6%) patients treated with BRAF-V600 + MEK inhibitors. Relapse of melanoma involved the CNS for 22/31 (70.9%) patients with disease progression, including 18/31 (58%) patients who had exclusive intracranial metastases. Sixteen patients died from disease progression. Among the 31 patients who had disease progression, the median time until a relapse was 8 months, and the median survival time after disease progression was 2 months. CONCLUSION: Our study shows that, for patients treated with BRAF-V600 + MEK inhibitors who lose response, disease progression was aggressive and had poor outcomes. Most patients had CNS metastases and low rates of therapeutic response to any subsequent therapy.

Extracorporeal Photopheresis: An Efficacious and Well-Tolerated Treatment for Cutaneous and Oral Mucosal Chronic Graft-versus-Host Disease.

BACKGROUND: Extracorporeal photopheresis (ECP) is a second-line therapy for steroid-refractory chronic graft-versus-host disease (cGVHD). OBJECTIVE: We describe the long-term efficacy and tolerability of ECP according to the cutaneous phenotype of cGVHD and report on the reduced need for immunosuppressant drugs in this setting. PATIENTS AND METHODS: Fourteen patients (8 females) with cutaneous and/or mucosal cGVHD, treated with ECP between October 2010 and May 2016 within a single center, were included. Final analyses included patients who had received ECP for at least 12 months. We prospectively evaluated the efficacy of ECP using lesion-specific clinical scores and by recording changed doses of systemic immunosuppressants. RESULTS: Of the 14 patients, sclerotic skin lesions were present in 10 (71%). The mRODNAN score decreased in all patients from month 9 onwards, with 40 and 77% reductions at 12 and 36 months, respectively. Six patients (43%) presented with cutaneous lichenoid lesions: this score was reduced in all patients by month 3, reaching a 93% reduction by month 12. Five patients (36%) experienced oral mucosal lichenoid lesions: these scores were decreased by 55% at month 12 and by 100% by month 33. The use of systemic immunosuppressants was reduced in all patients; 4 patients could stop all immunosuppressant drugs after 2 years. ECP was stopped in 3 patients after a complete response. No major ECP-associated adverse effects were observed. DISCUSSION AND CONCLUSION: ECP was an effective long-term therapy for oral and cutaneous cGVHD: consequently, dose levels of therapeutic immunosuppression could be reduced.

Double-hit or dual expression of MYC and BCL2 in primary cutaneous large B-cell lymphomas.

In nodal diffuse large B-cell lymphoma, the search for double-hit with MYC and BCL2 and/or BCL6 rearrangements or for dual expression of BCL2 and MYC defines subgroups of patients with altered prognosis that has not been evaluated in primary cutaneous large B-cell lymphoma. Our objectives were to assess the double-hit and dual expressor status in a cohort of 44 patients with primary cutaneous large B-cell lymphoma according to the histological subtype and to evaluate their prognosis relevance. The 44 cases defined by the presence of more than 80% of large B-cells in the dermis corresponded to 21 primary cutaneous follicle centre lymphoma with large cell morphology and 23 primary cutaneous diffuse large B-cell lymphoma, leg type. Thirty-one cases (70%) expressed BCL2 and 29 (66%) expressed MYC. Dual expressor profile was observed in 25 cases (57%) of either subtypes (n = 6 or n = 19, respectively). Only one primary cutaneous follicle centre lymphoma, large-cell case had a double-hit status (2%). Specific survival was significantly worse in primary cutaneous diffuse large B-cell lymphoma, leg type than in primary cutaneous follicle centre lymphoma, large cell (p = 0.021) and for the dual expressor primary cutaneous large B-cell lymphoma group (p = 0.030). Both overall survival and specific survival were worse for patients belonging to the dual expressor primary cutaneous diffuse large B-cell lymphoma, leg type subgroup (p = 0.001 and p = 0.046, respectively). Expression of either MYC and/or BCL2 negatively impacted overall survival (p = 0.017 and p = 0.018 respectively). As the differential diagnosis between primary cutaneous follicle centre lymphoma, large cell and primary cutaneous diffuse large B-cell lymphoma, leg type has a major impact on prognosis, dual-expression of BCL2 and MYC may represent a new diagnostic criterion for primary cutaneous diffuse large B-cell lymphoma, leg type subtype and further identifies patients with impaired survival. Finally, the double-hit assessment does not appear clinically relevant in primary cutaneous large B-cell lymphoma.

Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination.

A combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities (graded according to Common Terminology Criteria for Adverse Events, v 4.3) were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%, P=0.02) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4% (P=0.42), respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.

Panniculitis Associated with MEK Inhibitor Therapy: An Uncommon Adverse Effect.

The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors. We present here the first observation of panniculitis strictly induced by MEK inhibitors. Indeed, 10 days after the initiation of combined treatment with cobimetinib and vemurafenib for metastatic melanoma, our patient developed panniculitis predominantly on the upper and lower extremities. These cutaneous nodules disappeared during cobimetinib intermissions and recurred while the molecule was resumed. Recurrence of cutaneous nodules was observed after initiation of trametinib combined with dabrafenib, and resolved once again with trametinib discontinuation. We believe that clinicians should be aware of this cutaneous adverse event in patients treated with combined therapy, which can lead to unfounded BRAF inhibitor treatment discontinuation and compromise the antitumor response. Our case suggests a class effect linked with the MEK inhibition pharmacodynamic activity. Finally, laboratory investigation and histopathological examination are mandatory to exclude other panniculitis etiologies and subcutaneous metastasis of melanoma.

Development of Photoonycholysis with Vandetanib Therapy.

Vandetanib therapy is a novel once-daily oral multitargeted tyrosine kinase inhibitor, which is currently used in advanced or metastatic medullary thyroid cancer. Skin toxicities are among the most prevalent adverse events reported with this targeted therapy (e.g. acne-like rash, hand-foot skin reaction, hair changes, and paronychia). In addition, photosensitivity reactions may affect more than one third of treated patients. We report here 2 patients developing photosensitivity reactions with vandetanib therapy, including photoonycholysis. Our patients presented a wide range of phototoxic reactions with exaggerated sunburn reactions solely located to photoexposed areas or hyperpigmentation with visible blue dots. More importantly, both patients concomitantly developed nail changes consistent with type 1 photoonycholysis, which had never been reported so far neither with vandetanib therapy nor with other anticancer-targeted therapies. In addition, histopathologic findings and reflectance confocal microscopy imaging performed in one patient suffering from photodistributed skin hyperpigmentation both strengthen the likelihood of a postinflammatory mechanism. Clinicians should be aware of these underestimated but very characteristic photoinduced adverse events, which can lead to treatment interruption and require very strict photoprotective measures in treated patients.

Acute interstitial nephritis related to immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (anti-PD1 or anti-CTLA-4) are increasingly used in various cancers. Immune checkpoint inhibitors (ICI)-related renal disorders are poorly described (9 cases) and were only related to Ipilimumab. METHODS: Retrospective collection of clinical charts of all the patients admitted for renal disorders following ICI in the University Hospital of Toulouse (France). RESULTS: We report on adverse renal events that occurred in three patients treated with anti-PD1 (nivolumab or pembrolizumab) or anti-CTLA-4 (ipilimumab). Acute kidney injury occurred at 4-12 weeks after initiation of treatment, and harbored features of tubulo-interstitial nephritis (interstitial polymorphic inflammatory infiltrate with predominant CD3+ CD4+ T cells, associated with granuloma in one). Following withdrawal of ICI and steroid intake, estimated glomerular-filtration rate had improved in all patients. CONCLUSIONS: These data suggest that all ICI can lead to acute interstitial nephritis, possibly related to the presence of autoreactive clonal T cells. We recommend that patients receiving ICI should undergo renal monitoring every 2 weeks for 3-6 months.

Chemotherapy-Related Reticulate Hyperpigmentation: A Case Series and Review of the Literature.

BACKGROUND: Inherited or acquired reticulate hyperpigmentation represents a heterogeneous group of infrequent dermatological conditions. The development of reticulate hyperpigmentation has so far been rarely reported to be associated with chemotherapeutic agents, including fluorouracil, bleomycin or a combination of cytarabine and idarubicin. CASE REPORTS: We describe 5 cases of chemotherapy-related reticulate hyperpigmentation in patients treated with different chemotherapeutic regimens, in particular paclitaxel or cytarabine. The lesions were similar in all cases, with reticulate and/or linear hyperpigmented streaks, which were mainly located to the back and buttocks. Histology showed increased melanogenesis, which suggests a direct toxic effect of chemotherapy on melanocytes. Reflectance confocal microscopy was performed in 2 patients showing a similar pattern, with an increased amount of melanin in basal keratinocytes. These features have been compared with the available data through a literature review. CONCLUSION: Reticulate hyperpigmentation is an underestimated but characteristic complication of chemotherapy. Neither specific management nor discontinuation of the chemotherapeutic regimen is required.