Brentuximab-vedotin in combination with cyclophosphamide, doxorubicin, prednisolone for the treatment of aggressive CD30-positive cutaneous T-cell lymphomas.

Aggressive CD30-positive cutaneous T-cell lymphomas (CD30+CTCL) are associated with unfavorable prognosis. Anthracycline-based polychemotherapy (CHOP) and brentuximab-vedotin (BV) monotherapy are related to poor outcomes in case of extracutaneous involvement or rapidly-progressing disease. Our objective was to assess the effectiveness of BV + CHP in aggressive CD30+CTCL. We included 7 patients treated with BV + CHP from April 2015 to January 2022: 4 had mycosis fungoides with large-cell transformation, 2 had primary cutaneous anaplastic large-cell lymphoma, and 1 harbored a primary cutaneous aggressive epidermotropic CD8-positive T-cell lymphoma. After a median [IQR] follow-up of 17.2 [13.2-21.0] months, 6/7 patients achieved an ORR lasting ≥4 months. The median [IQR] duration of response was 9.5 [5.9-11.1] months and the median [IQR] progression free survival was 14.9 [11.6-16.4] months. Four patients displayed progression with a median (range) time to next treatment of 15.8 (6.5-16.3) months. Two grade-3 adverse events were reported: febrile neutropenia and thromboembolic event. BV + CHP displayed substantial antitumor activity and favorable safety profile in 7 patients with aggressive CD30+CTCL.

Deciphering the spectrum of cutaneous lymphomas expressing TFH markers.

T-follicular helper (TFH) markers are expressed in the microenvironnement of marginal zone B-cell lymphoma (MZL), and in lymphomas arising from TFH-cells, sometimes making the differential diagnosis difficult. In the skin, the "TFH-spectrum" is poorly defined, going from primary cutaneous lymphoproliferative disorder with small/medium CD4+ T-cells (SMLPD) to cutaneous localizations of systemic angioimmunoblastic T-cell lymphoma (cAITL), and may pass through intermediate forms (primary cutaneous T-follicular helper derived lymphoma, not otherwise specified (PCTFHL,NOS)). We retrospectively analyzed 20 MZL, 13 SMLPD, 5 PCTFHL, and 11 cAITL clinically, histologically, and molecularly, to define tools to differentiate them. Characteristics that might favor the diagnosis of MZL over SMLPD are: multiple skin nodules (p < 0.001), nodular architecture (p < 0.01), residual germinal centers with follicular dendritic cell network (p < 0.001), monotypic plasma cells (p < 0.001), and few staining with PD1 (p = 0.016) or CXCL13 (p = 0.03). PCTFHL and cAITL presented as multiple (p < 0.01) lesions, in older patients (p < 0.01), with systemic symptoms and/or biological alterations (p < 0.01). Immunophenotypic loss of T-cell markers (p < 0.001), BCL6 (p = 0.023) and/or CD10 staining (p = 0.08), and a higher proliferative index (≥ 30%, p = 0.039) favoured these diagnoses over SMLPD. Pathogenic variants were observed by genomic sequencing in 47% of MZL (TNFAIP3 (32%), EP300 (21%), NOTCH2 (16%), KMT2D (16%), CARD11 (10.5%)), 8% of SMLPD (TET2), 40% of PCTFHL (SOCS1 (20%), ARID1A (20%)) and 64% of cAITL (TET2 (63.6%), RHOA (36.4%), NOTCH1 (9%)). This study characterizes the various clinical and histological features between cutaneous lymphomas expressing TFH markers and highlights the value of the interest of screening for genomic mutations in difficult cases.

Diagnostic Concordance in Tertiary (Dermatologists-to-Experts) Teledermoscopy: A Final Diagnosis-Based Study on 290 Cases.

BACKGROUND: Teledermoscopy (TDS) improves diagnostic accuracy and decreases the number of unnecessary consultations. OBJECTIVES: To determine the diagnostic concordance in tertiary (dermatologist-to-experts) TDS with histopathology/follow-up-based diagnosis. METHODS: A descriptive retrospective cohort study including 290 requests. RESULTS: Perfect diagnostic concordance was found in 202 (69.7%) cases and partial agreement in 29 (10%). Disagreement was found in 59 (20.3%) cases. Perfect concordance on the benign/malignant nature of the lesion was found in 227 (78.3%) cases and disagreement in 63 (21.7%). In onychology, diagnostic concordance was perfect in 43 (76.8%) cases, partial in 7 (12.5%), and there was disagreement in 6 (10.7%). Final concordance on the benign/malignant nature of the lesion was perfect in 48 (85.7%) and there was disagreement in 8 (14.3%) nail cases. For pediatric requests, diagnostic concordance was perfect in 29 (65.9%) cases, partial in 5 (11.4%), and there was disagreement in 10 (22.7%). Final concordance on the benign/malignant nature of the lesion was observed in 34 (77.3%) cases, disagreement in 10 (22.7%). CONCLUSIONS: This study confirms that tertiary TDS improves diagnostic accuracy of pigmented skin lesions. Moreover, it shows encouraging results in unusual conditions such as ungual and pediatric skin tumors. The main limitation was the retrospective nature and the "real-life" setting of our study that could have created a selection bias toward inclusion of the most difficult cases.

Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors.

BACKGROUND: The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies. METHODS: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate. RESULTS: In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50-0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43-0.74, P < 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer. CONCLUSION: In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.

Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.

BACKGROUND: Age-related immune dysfunction might impair the efficacy of immune checkpoint inhibitors (ICIs) in older patients. We aimed to evaluate the impact of age on clinical outcomes and tolerance of ICIs in a real-life setting. METHODS: All patients receiving a single-agent ICI (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] or programmed death(ligand)1 [PD(L)-1] inhibitors) for the standard treatment of a locally advanced or metastatic cancer were included in this retrospective multicentric series. The primary end-point was overall survival (OS). Progression-free survival (PFS) and immune-related adverse events (irAEs) were secondary end-points. The impact of age was assessed using the threshold of 70 years. RESULTS: A total of 410 patients were included, for 435 lines of treatment, including 150 lines (34%) given to patients aged 70 years or older. The primary tumour types were lung cancer (n = 304, 74%), melanoma (n = 79, 19%) and urologic cancer (n = 27, 7%). Most of the administered treatments were PD(L)-1 inhibitors (n = 356, 82%). Median follow-up reached 46 months in the CTLA-4 cohort, and 20 months in the PD(L)-1 cohort. In both treatment cohorts, age did not impact OS (respectively, HR = 0.82, 95% CI 0.5-1.4; log-rank P = 0.49 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.27) or PFS (HR = 0.7, 95% CI 0.4-1.1; log-rank P = 0.13 and HR = 0.9, 95% CI 0.7-1.1; log-rank P = 0.19). Grade 3-4 irAEs rates were not statistically different between older and younger patients (11% vs 12%, P = 0.87). CONCLUSION: In a large real-world series of patients treated by ICI monotherapy, the long-term clinical outcomes were not statistically different between older or younger patients, with no increased immune-related toxicity.

Association of Immunotherapy With Overall Survival in Elderly Patients With Melanoma.

Importance: Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction. Objective: To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma. Design, Setting, and Participants: This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed. Main Outcomes and Measures: Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age. Results: A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P = .04) and overall survival (not reached vs 10.1 months; P = .009) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts. Conclusions and Relevance: Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.

Adjunction of a MEK inhibitor to Vemurafenib in the treatment of metastatic melanoma results in a 60% reduction of acute kidney injury.

INTRODUCTION: A combined therapy MEK inhibitor, Cobimetinib (CB) and BRAF inhibitor, Vemurafenib (VMF), results in an improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma. VMF skin adverse effects attributed to ERK paradoxical activation are decreased by the adjunction of CB. The aim of this study was to determine if this combination also improved the renal side effects of VMF. PATIENTS AND METHODS: To investigate the incidence of acute kidney injury (AKI), we conducted a retrospective observational monocentric study in Lyon Sud University Hospital in France. We included 38 patients with metastatic BRAF-mutated melanomas treated by VMF and CB between March 2015 and June 2016. According to the NCI-CTCAE classification, AKI was defined as an increase in serum creatinine exceeding the baseline concentration by 1.5-fold. Serum creatinine was measured before treatment, then on a monthly basis during treatment, and 1 month after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-), and further subdivided into three groups according to AKI severity (stage 1-5). RESULTS: Of 38 patients, 29 (76%) were AKI-, and all 9 AKI+ patients (24%) were diagnosed within the first trimester of treatment. Three-quarters of AKI (n = 7, 77%) had stage 1 AKI and the remaining 23% stage 2 AKI. Pre-treatment renal function was significantly better in AKI+ group: 105 vs. 80 ml/min/1.73m² AKI-, p = 0.009. Compared to previous results, the AKI incidence under the combined VMF-CB vs. VMF monotherapy was reduced by 60%. CONCLUSION: We reported a reduced incidence and severity of nephrotoxicity of the association inhibitors of BRAF and MEK compared to a BRAF inhibitor monotherapy.

Tumor-free osteosclerotic lesions in patients treated for metastatic melanoma using BRAF inhibitors.

BRAF inhibitors (vemurafenib and dabrafenib) are commonly prescribed in BRAF-mutant metastatic melanoma and allow improvement of the overall survival and progression-free survival. They are, however, accompanied by many adverse effects which mainly affect the skin. We observed on computed tomographic scans in three different patients after 3 months of treatment, the onset of osteosclerotic lesions. In parallel, the computed tomographic scans showed a significant reduction in all of the previously identified metastases in all patients. The occurrence of such bone modifications under treatment was reported previously in others cancers, such as inoperable non-small-cell lung cancers under epidermal growth factor receptor inhibitors, as the 'osteoblastic bone flare phenomenon'. However, it had never been reported in melanoma patients treated with targeted therapies, and the results of two performed bone biopsies are reported here. This phenomenon is generally believed to indicate a better response under treatment, whereas in our study, the patients experienced, after a short partial response, a severe cerebral relapse leading to death. Finally, although its physiopathological mechanisms are poorly understood, the occurrence of tumor-free osteosclerotic lesions in patients under BRAF inhibitors should not be misinterpreted as a progression of the disease.

ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors.

Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.

New insights into renal toxicity of the B-RAF inhibitor, vemurafenib, in patients with metastatic melanoma.

PURPOSE: Vemurafenib (VMF) is a B-RAF inhibitor used in the treatment of B-RAF-V600-mutant metastatic melanomas. Reports of acute kidney injury (AKI) in patients treated with VMF are scarce. METHODS: To investigate the incidence and severity of AKI, we conducted a retrospective, observational, monocentric study in the Lyon Sud Hospital University, France, which included 74 patients with metastatic B-RAF-mutated melanomas treated with VMF, between June 2011 and August 2014. According to the Kidney Disease Improving Global Outcomes Guidelines, AKI is defined as an increase in serum creatinine concentration exceeding the baseline concentration by 1.5 fold. Serum creatinine was thus determined before treatment, on a monthly basis during treatment, and 3 months after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-) and further subdivided into three groups according to AKI severity (stage 1, 2 or 3). To visualize the tissue damage caused by VMF, kidney biopsies were performed for two stage 1 AKI+ patients. RESULTS: Of the 74 patients, 30 (40.5 %) were AKI-, and of the 44 AKI+ patients (59.5 %), 29 (66 %) were diagnosed within the first three months of treatment. There were significantly more men in the AKI+ group: n = 33 (75 %) versus n = 12 (40 %) women, p = 0.004 with an odds ratio for developing AKI of 4.6 (95 % CI 1.48-14.23). Most AKI + cases were considered as stage 1 (n = 40; 91 %) and the remaining four (9 %) as stage 2 AKI. Kidney biopsies revealed interstitial fibrosis and acute focal tubular damage. However, renal failure was reversible in 80 % of patients within 3 months of VMF discontinuation. CONCLUSIONS: We observed frequent, reversible, moderately severe AKI with some histological evidence of tubular and interstitial damage in VMF-treated patients, suggesting that renal function should be carefully monitored in male patients, especially during the first 3 months.

Endocrine side-effects of anti-cancer drugs: the impact of retinoids on the thyroid axis.

Bexarotene (Targretin), approved since 1999 as a second-line treatment for late stage cutaneous T-cell lymphomas, has been shown to induce significant hypothyroidism through TSH suppression. This review revisits, through a case report, mechanisms by which rexinoids repress the expression of TSHB gene as well as αTSH and TRH genes. It appears that rexinoids suppress TSH independently from tri-iodothyronine. Bexarotene also differently affects the gene expression of deiodinases 1 and 2 as well as the peripheral clearance of thyroxine. These data might open new ways of research on the potential interaction between thyroid axis and endogenous rexinoids.

Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.

Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.