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.

Macrophage-derived CXCL9 and CXCL11, T-cell skin homing, and disease control in mogamulizumab-treated CTCL patients.

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 ß 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.

Porocarcinomas with PAK1/2/3 fusions: a series of 12 cases.

AIMS: Porocarcinoma is a malignant sweat gland tumour differentiated toward the upper part of the sweat duct and may arise from the transformation of a preexisting benign poroma. In 2019, Sekine et al. demonstrated the presence of YAP1::MAML2 and YAP1::NUTM1 fusions in most poromas and porocarcinomas. Recently, our group identified PAK2-fusions in a subset of benign poromas. Herein we report a series of 12 porocarcinoma cases harbouring PAK1/2/3 fusions. METHODS AND RESULTS: Five patients were male and the median age was 79 years (ranges: 59-95). Tumours were located on the trunk (n = 7), on the thigh (n = 3), neck (n = 1), or groin area (n = 1). Four patients developed distant metastases. Microscopically, seven cases harboured a benign poroma component and a malignant invasive part. Ductal formations were observed in all, while infundibular/horn cysts and cells with vacuolated cytoplasm were detected in seven and six tumours, respectively. In three cases, the invasive component consisted of a proliferation of elongated cells, some of which formed pseudovascular spaces, whereas the others harboured a predominant solid or trabecular growth pattern. Immunohistochemical staining for CEA and EMA confirmed the presence of ducts. Focal androgen receptor expression was detected in three specimens. Whole RNA sequencing evidenced LAMTOR1::PAK1 (n = 2), ZDHHC5::PAK1 (n = 2), DLG1::PAK2, CTDSP1::PAK1, CTNND1::PAK1, SSR1::PAK3, CTNNA1::PAK2, RNF13::PAK2, ROBO1::PAK2, and CD47::PAK2. Activating mutation of HRAS (G13V, n = 3, G13R, n = 1, Q61L, n = 2) was present in six cases. CONCLUSION: Our study suggests that PAK1/2/3 fusions is the oncogenic driver of a subset of porocarcinomas lacking YAP1 rearrangement.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Recurrent PAK2 rearrangements in poroma with folliculo-sebaceous differentiation.

AIMS: Poroma is a benign adnexal neoplasm with differentiation towards the upper portion of the sweat gland apparatus. In 2019, Sekine et al. demonstrated recurrent YAP1::MAML2 and YAP1::NUTM1 fusion in poroma and porocarcinoma. Follicular, sebaceous and/or apocrine differentiation has been reported in rare cases of poroma and whether these tumours constitute a variant of poroma or represent a distinctive tumour is a matter to debate. Herein we describe the clinical, immunophenotypic, and molecular features of 13 cases of poroma with folliculo-sebaceous differentiation. METHODS AND RESULTS: Most of the tumours were located on the head and neck region (n = 7), and on the thigh (n = 3). All presented were adults with a slight male predilection. The median tumour size was 10 mm (range: 4-25). Microscopically, lesions displayed features of poroma with nodules of monotonous basophilic cells associated with a second population of larger eosinophilic cells. In all cases, ducts and scattered sebocytes were identified. Infundibular cysts were present in 10 cases. In two cases high mitotic activity was noted, and in three cases cytologic atypia and areas of necrosis were identified. Whole transcriptome RNA sequencing demonstrated in-frame fusion transcripts involving RNF13::PAK2 (n = 4), EPHB3::PAK2 (n = 2), DLG1::PAK2 (n = 2), LRIG1::PAK2 (n = 1), ATP1B3::PAK2 (n = 1), TM9SF4::PAK2 (n = 1), and CTNNA1::PAK2 (n = 1). Moreover, fluorescence in situ hybridisation (FISH) analysis revealed PAK2 rearrangement in an additional case. No YAP1::MAML2 or YAP1::NUTM1 fusion was detected. CONCLUSION: Recurrent fusions involving the PAK2 gene in all analysed poroma with folliculo-sebaceous differentiation in this study confirms that this neoplasm represents a separate tumour entity distinct from YAP1::MAML2 or YAP1::NUTM1 rearranged poromas.

Microsecretory adenocarcinoma of the skin, a novel type of sweat gland carcinoma: Report of three additional cases.

Microsecretory adenocarcinoma (MSA) is a newly described salivary gland tumor harboring a characteristic balanced chromosomal translocation resulting in MEF2C::SS18 gene fusion. Six primary cutaneous MSA cases have been recently described. We report three additional cases confirming the relevance of this recently identified entity of primary cutaneous adnexal tumor. Three patients aged 53-, 64- and 78-year-old were retrospectively diagnosed with MSA of the skin (MSAS) as consultation cases of the CARADERM (CAncers RAres DERMatologiques) national network. The clinical presentation was an indolent nodule on the upper extremities. There was no history of salivary gland tumor. Histopathologically, the tumors presented as dermal nodular proliferation with slightly infiltrative borders, composed of cribriform and microcystic structures with abundant myxoid intraluminal secretion embedded in a fibromyxoid stroma. They diffusely expressed cytokeratin 8 and SOX10, focally p63 and heterogeneously smooth muscle actin. All tumors harbored the MEF2C::SS18 gene fusion. A complete surgical excision was performed. No local recurrence or distant metastases were observed so far (follow-up: 17, 38, and 45 months). MSAS is the cutaneous homologue of MSA of the salivary gland, a low-grade adnexal neoplasm whose prognosis seems to be excellent once the complete removal of the tumor is assured.

PD-1 blockade with pembrolizumab in classic or endemic Kaposi's sarcoma: a multicentre, single-arm, phase 2 study.

BACKGROUND: Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment. METHODS: We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0-1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants. FINDINGS: 30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1-24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44-90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths. INTERPRETATION: In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma. FUNDING: MSD France.

Mogamulizumab induces long-term immune restoration and reshapes tumour heterogeneity in 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 TCRVß 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 TCRVß 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.

Mitogen-activated protein kinase blockade in melanoma: intermittent versus continuous therapy, from preclinical to clinical data.

PURPOSE OF REVIEW: Although targeted therapy provides a high response rate and rapid disease control in advanced melanoma, most patients experience disease progression due to acquired resistance mechanisms leading to reactivation of mitogen-activated protein kinase pathway. The purpose of this article is to review the recently published data on the impact of an intermittent versus continuous dosing schedule of BRAF and MEK inhibition in advanced melanoma to determine the best approach in clinical practice. RECENT FINDINGS: Some preclinical studies have highlighted the concept that drug-resistant cells may also display drug dependency, such that intermittent dosing of targeted therapy may prevent the emergence of lethal drug resistance. Moreover, clinical observations have suggested that repeated treatment after a break or an intervening therapy may provide clinical benefit. However, recent preclinical and clinical studies have also failed to demonstrate an advantage of intermittent dosing and showed a similar efficacy of the intermittent versus continuous regimens of BRAF and MEK inhibitors in mice models and phase 2 clinical trial. SUMMARY: Owing to these discordant results, continuous dosing of BRAF and MEK inhibitors remains the optimal therapeutic approach until additional clinical data demonstrate the superiority of another combination or dosing regimen.

Estimated pill intake with on-demand PrEP with oral TDF/FTC using TFV-DP concentration in dried blood spots in the ANRS IPERGAY trial.

BACKGROUND: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations. METHODS: DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models. RESULTS: The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128-868) fmol/punch, corresponding to an estimated intake of 8-12 tablets per month (2-3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P < 0.001). In multivariate analysis, only systematic use of PrEP during SI and more frequent episodes of SI in the past 4 weeks were significantly associated with higher TFV-DP levels [OR (95% CI): 11.30 (3.62-35.33) and 1.46 (1.19-1.79), respectively; P < 0.001]. CONCLUSIONS: Among participants using on-demand PrEP, estimated pill intake reached 8-12 tablets per month and was correlated with frequency and systematic use of PrEP for SI.

Genetic landscape of adult Langerhans cell histiocytosis with lung involvement.

The clinical significance of the BRAF V600E mutation in adult Langerhans cell histiocytosis (LCH), including pulmonary Langerhans cell histiocytosis (PLCH), is not well understood. Similarly, the spectrum of molecular alterations involved in adult LCH has not been fully delineated. To address these issues, we genotyped a large number of adult LCH biopsies and searched for an association of identified molecular alterations with clinical presentation and disease outcome.Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAF V600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAF V600E mutation: 36%, BRAF N486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRAS Q61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAF V600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAF V600E status did not influence the risk of LCH progression over time.Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAF V600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.

Mechanisms of resistance and predictive biomarkers of response to targeted therapies and immunotherapies in metastatic melanoma.

PURPOSE OF REVIEW: Thanks to mitogen-activated protein kinase inhibitors (MAPKi) and immune checkpoint inhibitors (ICI), major progress has been made in the field of melanoma treatment. However, long-term success is still scarce because of the development of resistance. Understanding these mechanisms of resistance and identifying predictive genomic biomarkers are now key points in the therapeutic management of melanoma patients. RECENT FINDINGS: Multiple and complex mechanisms of resistance to MAPKi or ICI have been uncovered in the past few years. The lack of response can be driven by mutations and nonmutational events in tumor cells, as well as by changes in the tumor microenvironment. Melanoma cells are also capable of rapidly switching their molecular and cellular phenotype, leading to an initial drug-tolerant favorizing melanoma resistance. Tumor molecular profiling and circulating tumor cell analyses are of high interest as predictive biomarkers as well as studying immunogenic changes and microbiome in ICI-treated patients. SUMMARY: Resistance to MAPKi and ICI is a key point in therapeutic management of metastatic melanoma patients. Validated biomarkers predicting response to therapy are urgently needed to move toward personalized medicine. Combinatory treatments guided by the understanding of resistance mechanisms will be of major importance in the future of melanoma therapy.

Development and validation of a liquid chromatography tandem mass spectrometry quantification method for 14 cytotoxic drugs in environmental samples.

RATIONALE: Cytotoxic drug preparation in hospital pharmacies is associated with chronic occupational exposure leading to a risk of adverse effects. The objective was to develop and validate a quantification method for the following cytotoxic drugs in environmental wipe samples: cyclophosphamide, ifosfamide, cytarabine, dacarbazine, docetaxel, paclitaxel, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, methotrexate and pemetrexed. METHODS: The quantification method was developed using liquid chromatography coupled to tandem mass spectrometry and a wiping technique using viscose swabs. Linearity, accuracy, precision, limit of quantification, specificity and stability were assessed, from swab desorbed solution, to validate the analytical method, with respect to ICH guidelines. Environmental samples were collected by wiping five work surfaces of 225 cm2 with viscose swabs, during three days. RESULTS: The quantification method was linear over the calibration range with a lower limit of quantification ranging from 0.5 to 5.0 ng mL-1 depending on the cytotoxic drug. The intra-day and inter-day relative biases were below 1.5% and 13.5%, respectively. This method was successfully applied to surface-wipe sampling and environmental contaminations ranged from 0.7 to 1840.0 ng cm-2 for the most contaminated areas. CONCLUSIONS: This quantification method for 14 cytotoxic drugs was successfully applied to environmental contamination monitoring and could therefore be a useful tool for monitoring and toxicological studies.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Quantification of Idelalisib in Human Plasma by Ultra-Performance Liquid Chromatography Coupled to Mass Spectrometry in Negative Ionization Mode.

BACKGROUND: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice. METHODS: After a single-step protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-high performance liquid chromatography system coupled with mass tandem spectrometry in a negative ionization mode using isotope-labeled internal standard. This method was validated by studies of its linearity, accuracy, imprecision, limit of quantification, recovery, matrix effect, selectivity, and stability. RESULTS: The quantification method was linear from 10 to 2500 ng/mL with a 5 ng/mL lower limit of quantification that encompasses the clinical range of drug concentration. The intraday and interday imprecisions were below 8.1% and 11.4%, respectively. The recoveries and matrix effect of idelalisib were 85.6% ± 1.2% and 95.7% ± 3.0%, respectively, which are consistent, precise, and reproducible (coefficient of variation % < 15%). Peak plasma concentration and trough plasma concentration ranges of idelalisib reached 1591-1937 ng/mL and 256.3-303.3 ng/mL, respectively, in 3 follicular lymphoma patients treated with idelalisib 150 mg twice a day. CONCLUSIONS: A robust and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated to quantify idelalisib concentration in human plasma. This method was effectively applied to 3 follicular lymphoma patients.