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Background Coronavirus disease 2019 (COVID-19) has affected more than 210 million people worldwide. An optimal therapeutic approach for COVID-19 remains uncertain, to date. Since the history of cancer was linked to higher mortality rates due to COVID-19, the establishment of a safe and effective vaccine coverage is crucial in these patients. However, patients with cancer were mostly excluded from vaccine candidates’ clinical trials. This systematic review aims to investigate the current available evidence about the immunogenicity of COVID-19 vaccines in patients with cancer (PsC). Patients and methods All prospective studies that evaluated safety and efficacy of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were included, with immunogenicity after the first and the second dose as the primary endpoint, when available. Results Vaccination against COVID-19 for PsC seems overall safe and immunogenic after well-conducted vaccinations schedules. Yet, the seroconversion rate remains lower, lagged or both compared to the general population. Patients with hematologic malignancies, especially those receiving B cell depleting agents in the last 12 months are the most at risk of poor seroconversion. Conclusion A tailored approach to vaccination may be proposed to PsC, especially on the basis of the type of malignancy and of the specific oncologic treatments received.

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Objectives To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R-mini-CYVE) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Methods We included pretreated adult patients with B-cell NHL who were ineligible for high-dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. Results Between 2013 and 2019, 56 patients with diffuse large B-cell lymphoma (n = 45, 80%) and indolent B-cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36-88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R-mini-CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression-free survival and overall survival times were 5.7 (95% CI: 0.5-10.9) and 14.7 (95% CI: 3.5-25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non-haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine-related neurotoxicity (5%). Conclusion R-mini-CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B-cell NHL who were ineligible for HDT.

Introduction Le traitement du cancer a ete profondement modifie ces dernieres annees avec l’introduction des inhibiteurs du checkpoint immunologiques (ICI). Le pronostic de certains cancers, tels le melanome ou le cancer pulmonaire non a petites cellules s’en est trouve largement ameliore [1] , [2] . Ces traitements sont cependant a l’origine d’effets secondaires appeles effets indesirables lies a l’immunotherapie (EILI), dont les atteintes les plus frequentes (digestives, cutanees, endocriniennes) sont maintenant bien decrites, et relativement simples a diagnostiquer et traiter [3] . A contrario, certaines atteintes plus rares comme la myocardite sont peu decrites, alors que le taux de mortalite est eleve (jusqu’a 40 %) et de prise en charge plus delicate. Patients et methodes Nous avons conduit une etude transversale retrospective multicentrique sur une periode allant de juillet 2019 a novembre 2020. Les criteres d’inclusion etaient : traitement par un inhibiteur du checkpoint immunologique, survenue d’une suspicion de myocardite en s’appuyant sur les criteres de la societe europeenne de cardiologie, donnees de suivi disponibles pour chaque patient. Les myocardites etaient classees en possible/probable/definies selon des criteres internationaux, la severite a ete cotee en utilisant la classification CTCAE v5.0. Resultats Vingt-neuf patients ont ete inclus, de 6 centres differents, avec un âge median de 69 (32-83) ans. Les cancers traites etaient majoritairement pulmonaires (10 patients), des melanomes (8 patients), ou urotheliaux (4 patients). La myocardite survenait dans un delai median de 39 (2-181) jours, principalement avec des anti-PD1 (16 patients, 55 %). La plupart des patients (83 %) etaient symptomatiques, la dyspnee etant le symptome le plus frequent (17 patients, 59 %). Tous avaient une troponine HS elevee, avec une mediane de 5,35 fois la normale superieure, l’ECG montrait des anomalies chez 19 patients (68 %), alors que l’ETT etait disponible chez 27 patients et montrait une FEVG alteree chez 10 d’entre eux (37 %). Une IRM cardiaque a ete realisee chez 24 patients, montrant une prise de contraste tardive chez 9 d’entre eux (37 %). Quatorze patients (48 %) ont subi une coronarographie, et 6 ont beneficie d’une biopsie endomyocardique. Ces dernieres montraient chez 5 patients une infiltration lymphocytaire, majoritairement CD8+. Parmi les toxicites associees, la myosite etait la plus frequente (13 patients, 45 %), suivie du syndrome sec (11 patients, 38 %). Les patients les plus severes (CTCAE grade 4 et 5, n = 11) avaient un taux plus important de maladies auto-immunes systemiques preexistantes (5 patients contre 1, p = 0,018), une frequence cardiaque plus elevee a l’admission (113 contre 79,5, p = 0,001), une troponinemie d’entree plus elevee (42 fois la norme superieure contre 3,55, p = 0,001), et presentaient plus souvent des anticorps anti-recepteur de l’acetylcholine (5 contre 0, p = 0,001). L’analyse en courbe ROC nous a permis de selectionner une valeur seuil de troponinemie a 4,89 fois la norme superieur (sensibilite = 90,9 %, specificite 66,7 %) pour predire l’evolution vers une forme grave. Concernant le traitement, la plupart des patients (28) ont recu des corticoides, le plus souvent apres des bolus initiaux (19 patients, 68 %). Les autres modalites de traitement concernaient les plasmaphereses (10 patients), les immunoglobulines polyvalentes (8 patients), et d’autres immunosuppresseurs (5 patients). 7 patients (24 %) sont morts lors de la prise en charge initiale. Nous disposions d’une evaluation de la reponse carcinologique chez 21 patients, dont seulement 1 presentait une progression de la maladie. Au cours du suivi (d’une mediane de 4 mois), 7 patients supplementaires sont decedes. 6 patients ont recu a nouveau un traitement par ICI, seulement 1 ayant presente une rechute de myocardite. Conclusion Certains facteurs de mauvais pronostic ont ete mis en evidence, comme un taux eleve de troponine a l’admission, ce qui pourrait aider a la decision therapeutique. La mortalite est moindre dans notre serie, possiblement par le depistage de formes subintrantes en dosant la troponine de facon systematique. Cependant, la contre-indication definitive de l’immunotherapie sera peut etre a rediscuter selon la balance benefice/risque.

Background Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the current standard of therapy in several cancer types. Patients (pts) with lung cancer display higher response rates to CT when given after ICIs. Although ICIs have failed to demonstrate antitumour activity in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), little is known about CT effect after ICIs. We aimed to assess whether sequential ICIs followed by CT may be an alternative therapeutic approach in a population of pts with mCRC. Material and methods We retrospectively assessed CT after ICI (CAICI) failure in pts with mCRC. The ICI regimen consisted of anti-PD(L)1 alone or in combination. The primary end-point was objective response rate. Progression-free survival (PFS) and overall survival (OS) were secondary end-points. Results Between 2014 and 2018, 29 pts with mCRC received CAICI (MSS tumours, 27 pts [86%]). The median number of previous lines was 4 (range, 2–7). Regimens included TAS-102 (n = 14), FOLFIRI (irinotecan, leucovorin, and fluorouracil; n = 6) or FOLFOX (oxaliplatin, leucovorin, and fluorouracil; n = 4), regorafenib (n = 3) and carboplatin (1 pt with BRCA mutation). Partial response and stable disease were observed in 4 (19%) and 9 (43%) pts, respectively (disease control rate, 62%). The median PFS and OS were 3.8 months (95% confidence interval [CI] = 1.5–5.4) and 8.0 months (95% CI = 4.2–14.0), respectively. Conclusion ICIs administered before CT might enhance cytotoxic effects even in pts with immunorefractory MSS mCRC. The results of this small cohort need to be validated in independent prospective cohorts. The role of ICIs as modifiers of both tumour cells and microenvironment in mCRC deserves further research.

International audience; Use of checkpoint inhibitors to treat cancer was one of the most important revolution these last years and an increasing number of new types of tumors is currently under investigation with these new treatments. However, immune-related adverse events associated with these agents frequently affect various organs, mimicking auto-immune or inflammatory diseases. Some of these effects can be severe, often requiring hospitalization and specialized treatment (immunosuppression). Most known agents are ipilimumab (anti-CTLA-4 antibody) nivolumab and pembrolizumab (anti-PD-1 antibodies). New molecules are now approved or in development as anti-PD-L1 antibodies, anti-LAG-3 or anti-TIM-3 antibodies, increasing the probability and new description of immune-related adverse events. With his experience in auto-immune diseases, the immunologist/internal medicine specialist has an important role in the management of these toxicities. The goal of this review is to focus on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.; Les inhibiteurs de points de contrôle immunitaire ont révolutionné la prise en charge thérapeutique de nombreux cancers permettant des gains de survie globale jamais atteints auparavant. Leur champ de prescription ne cesse de croître. Malgré leur efficacité, ces traitements sont responsables d’effets indésirables immunologiques touchant l’ensemble des organes et mimant des pathologies auto-immunes et inflammatoires connues. Non seulement ces manifestations peuvent être sévères, menacer le pronostic vital et nécessiter une prise en charge spécialisée rapide mais en plus la chronologie de leur apparition est très variable d’un cas à l’autre et leur symptomatologie initiale est souvent fruste et trompeuse. Elles peuvent également remettre en question la reprise du traitement anti-cancéreux en raison du risque de récidives. Les molécules les plus connues ciblent CTLA-4, PD-1 ou PD-L1 et les indications de ces traitements se multiplient (nouvelles tumeurs, administration adjuvante aux stades précoces, combinaisons). De plus, de nouvelles molécules sont en développement ciblant d’autres antigènes d’intérêt (LAG-3, TIM-3…). Il faut donc s’attendre à une incidence accrue d’effets indésirables immunologiques et à l’apparition de nouvelles manifestations. Le pleiotropisme des manifestations indésirables associées aux inhibiteurs de checkpoint immunitaire place l’interniste et son approche médicale transversale au poste de régulation du nécessaire réseau multidisciplinaire organisé autour de ces molécules. Cet article a pour but de faire une mise au point sur les connaissances utiles à la prise en charge des patients exposés à des toxicités immunologiques liées aux inhibiteurs de point de contrôle immunitaire.

Background: The COVID-19 pandemic deeply threatens the rigorous conduct of clinical trials, notably by delaying site initiation visits, patient enrolment, treatment administration, trial-associated procedures, and data monitoring. Unlike most other medical specialties, clinical trials are an integral part of patient care in oncology. Limiting access to clinical trials therefore results in a loss of chance for patients. Methods: In this retrospective single-center study, we collected clinical trial-specific items (including patient-related or trial management-related items) during the first pandemic wave (March– June 2020) and lockdown (March 17th-May 11th) at Gustave Roussy, and compared them to those of the same period in 2019. Results: In March 2020, 84 phase I (P1) and 210 phase II/III (P2/3) trials were open. During the first pandemic wave, 21 (25%) P1 and 20 (9%) P2/3 trials were temporarily halted, following a unilateral sponsor decision in virtually all cases;all but one were industry-sponsored. Despite this, all important metrics of the P1/2 trial activity remained similar to those of 2019, including the number of patients referred for inclusion (599 vs 620), inclusion consultations (215 vs 247), patients starting treatment (130 vs 130), Internal Review Board (IRB) submissions (14 vs 16), and site initiation visits (11 vs 15), all in 2020 vs 2019, respectively. The impact of the first lock-down was more marked on P2/3, with 152 patient inclusions (vs 346 in 2019), 125 randomizations (vs 278), 43 IRB submissions (vs 50) and 34 site initiation visits (vs 40). However, in parallel, 475 patients were included in three “COVID and cancer” trials. Among the 443 P1 and 2851 P2/3 patients, 198 and 628 COVID-19 PCR were performed internally, and five and 15 (2.5%) were positive, respectively. One patient with a community-based COVID-19 died after transfer in intensive care. Conclusions: Cancer clinical trials can, and must be maintained despite challenges brought by COVID-19. Sharing experiences and retrospectively evaluating the impact on patients’ safety and cancer-related outcomes will be critical to durably improve the clinical trials conduct and to anticipate at best challenges brought by future similar crises. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: Outcomes and risk factors associated with COVID-19 worsening among cancer patients have previously been reported. However, the actual impact of SARs-Co-V2 infection on the cancer treatment strategy remains unknown. Here, we report the Gustave Roussy (GR) experience, one year after the onset of the pandemic focusing on the impact of COVID-19 in patients with ongoing management of oncohematological disease. Methods: All patients positively tested for SARS-CoV-2 and managed at GR between Mar 14th 2020 and Feb 15th 2021 (data cut-off) have been included. Patients underlying oncohematological disease and COVID19 characteristics have been collected. Cancer and COVID-19 management and outcomes have been assessed. Primary endpoint was the overall impact of COVID-19 on oncological and hematological treatment strategy assessed at 1, 3, 6 and 12 months. Results: At the time of the analysis, 423 patients (median age: 62 years) were found positive for SARS-CoV-2 and managed at GR with a median follow up of 5.6 months (0-13 months). Among them, 284 (67%) were admitted due to COVID-19. Clinical deterioration occurred in 87 patients (21%), 43 patients (10%) were transferred in intensive care unit and 123 (29%) patients died, among which 47 (11%) died from COVID-19. Overall, 329 (78%) patients were on active treatment for underlying oncohematological disease at time of COVID diagnosis. Impact of COVID-19 on cancer treatment strategy in those patients is presented in the Table. The majority (N=268, 81%) had no change in oncological strategy. For those who experienced a delay, median delay in treatment was 21 days (N=99, [1-77]), 30 days (N=15, [15-56]), 7 days (N=8,[3-35]) for systemic treatment, surgery and radiotherapy respectively. [Formula presented] Conclusions: COVID-19 outbreak is associated with a significant mortality in patients with cancer. However, for patients who did not die from COVID-19, we provide the first report supporting that ongoing treatment was maintained or could be resumed in the majority of cases in a timely manner. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Introduction L’immunotherapie par Inhibiteurs de Checkpoint (ICP) est indiquee dans un nombre croissant de pathologies onco-hematologiques et represente un espoir considerable pour les patients atteints de cancer, en permettant des reponses durables avec un profil de tolerance generalement meilleur que les autres traitements anticancereux concentionnels. Ces immunotherapies sont longtemps restees contre-indiquees chez les patients atteints de maladies auto-immunes ou inflammatoires chroniques, devant un risque potentiel accru d’effets secondaires immunologiques et d’exacerbation de leur pathologie sous-jacente. La sclerodermie systemique (ScS) est une pathologie auto-immune et fibrosante dont certaines formes peuvent etre associees au cancer, en particulier celles associees aux anticorps anti-ARN polymerase III [ARNpolIII]. La tolerance des ICP chez les patients ayant une ScS est inconnue. Cette etude vise a evaluer la tolerance des ICP chez les patients porteurs de ScS. Patients et methodes Etude retrospective, nationale (en France), des patients ayant un antecedent de ScS prealable et traites par un anti-PD1 ou un anti-PD-L1 en France, pour une indication onco-hematologique, sur la periode 2013-2020. Le recrutement des patients a ete realise via un appel a observation de la societe nationale francaise de medecine interne (SNFMI), du Club Rhumatisme et Inflammation (CRI) et du groupe francophone de recherche sur la sclerodermie (GFRS). Resultats Dix-sept patients ont ete inclus dans l’etude (10 femmes et 7 hommes) dont l’âge median (extremes) etait de 61 (34 - 82) ans. Les patients etaient traites pour un cancer pulmonaire (n = 13), ORL (n = 2), cutane (n = 1), colorectal (n = 1). Les patients etaient traites par anti-PD1 (n = 15) ou par anti-PD-L1 (n = 2). L’immunotherapie anti-PD1 ou PDL1 etait donnee en monotherapie (n = 15) ou en combinaison avec une chimiotherapie cytotoxique (n = 2). La ScS etait diagnostiquee en mediane (extremes) depuis 7,0 (0 - 30) annees avant le diagnostic de cancer. Deux (12 %) patients avaient une ScS paraneoplasique avec anticorps anti-ARNpolIII. Les donnees de tolerances retrouvaient des effets secondaires immunologiques de grade I-II chez 11 (65 %), et seulement 1 patient (6 %) a presente une toxicite endocrinologique de grade IV. Quatre des 17 patients (23,5 %) ont presente une aggravation de leur ScS, avec une nouvelle atteinte d’organe chez 1 (5,9 %) des patients. Aucun patient n’est decede d’un effet secondaire immuno-relie ou d’une evolution de la ScS au cours du suivi. La duree mediane (extremes) de suivi des patients depuis initiation du traitement etait de 1,13 (0,08 - 3,2) ans. L’efficacite de l’immunotherapie restait comparable a celle observee en population generale pour les memes indications oncologiques : 9 patients ont presente une reponse partielle a l’immunotherapie, soit un taux de reponse objective de 52,9 %. Au dernier follow-up, 8 patients (47 %) etaient decedes du fait d’une progression de leur maladie cancereuse. Conclusion Le profil de tolerance des inhibiteurs de checkpoint chez les patients ayant une sclerodermie systemique et traites pour un cancer semble acceptable, en concedant un taux de poussees de la sclerodermie qui survient chez un quart des patients.

Resume Centre sur l’exploration de la place du soignant dans les soins et la gestion de ses fragilites et dysfonctionnements, ce travail est issu d’une reflexion a partir des pratiques de terrain. Il se veut une maieutique d’aide a la decision partagee, dans une visee d’apaisement et d’enrichissement des pratiques et des personnes. Penser la medecine, c’est aussi la raconter a l’aune de l’evacuation imperieuse et impossible, puis de la reintroduction progressive et ineluctable du sujet-medecin. Cette evolution vient ainsi eclairer le devenir medecin et sa gestion. Une reflexion est de ce fait necessaire sur comment penser la medecine. Mais penser la medecine c’est aussi accepter qu’a l’instar des patients et de la collectivite qui l’utilisent, les soignants habitent la medecine, et que leur identite professionnelle et la facon dont ils l’habitent, est a prendre en compte si l’on veut ameliorer le systeme de sante. Ainsi, la recherche des criteres du bien-faire necessite aussi de questionner les pratiques soignantes et la notion de savoir etre, surtout lorsque ces pratiques ne sont pas optimales, posant ainsi la question des failles, defaillances et de la vulnerabilite des soignants. Mais aussi et surtout il est urgent de ressentir et de penser la medecine surtout lorsque tout defaille. Ce « pourquoi, penser la medecine », est un des outils, fondamental et necessaire, pour pouvoir continuer a discuter sans se disputer, surtout lorsque survient le drame du dommage associe au soin, qu’il soit coupable ou non. Ces echanges derangeant et difficiles restent feconds parce qu’ils compensent l’humilite d’une medecine pas toujours triomphante par une alterite en dialogue inscrite dans un humanisme plus large.

Background: The severe pneumonitis in coronavirus disease 2019 (COVID-19) requires prolonged treatment in intensive care units, leading to overwhelmed hospital facilities Treatment with tocilizumab (Actemra, Roche), a monoclonal antibody targeting interleukin 6 receptor (IL6R), has shown promising efficacy in alleviating the severe pneumonitis However, only around 50% of the treated patients benefit from this intervention It is therefore an unmet medical need to identify biomarkers associated with the severity of disease and theranostic biomarkers to predict and differentiate potential responders from non-responders to the treatment Methods: An unbiased hyper reaction monitoring mass spectrometry (HRM™-MS) approach was used to analyze serum samples from severe COVID-19 cases before and 7 days after treatment with tocilizumab (n = 28), enabling simultaneous identification and quantification of all detectable serum proteins All samples were measured using 1h gradient on a nano-flow LC-MS/MS setup operated in data-independent acquisition (DIA) mode Data was extracted using Spectronaut™ (Biognosys) Univariate and multivariate statistical analyses were conducted to identify biomarker candidates Pathway analysis was used to identify dysregulated biological functions and signaling pathways Results: Over 450 proteins were quantified across all samples by HRM-MS Univariate statistical analysis identified significantly changing proteins across conditions (mortality day 30, pre-post treatment, responder/non-responder, q-value > 0 05 and fold change >1 5) Multivariate analysis (PLS-DA) was also used to classify proteins based on their abundance across condition Proteomic data was further integrated with clinical outcome data to identify a panel of protein biomarker candidates potentially useful in predicting tocilizumab treatment efficiency and the COVID-19 disease severity Conclusions: Unbiased proteomic profiling of COVID-19 patient serum identified a panel of candidate protein biomarkers that associate with tocilizumab treatment response as well as the ensuing course of the disease Further validation of these biomarker candidates opens the way for a personalized medicine approach in treating COVID-19 Legal entity responsible for the study: Biognosys AG Funding: Biognosys AG Disclosure: J-M Michot;F-X Danlos;F Pommeret;A Marabelle: Full/Part-time employment: Institut Gustave Roussy V Dozio;E Kishazi;C Escher;K Kakalacheva - Beeler: Full/Part-time employment: Biognosys AG M Vasse;J Rohmere;M Roumier: Full/Part-time employment: Hopital Foch

Introduction La vascularite a IgA (V-IgA) est une vascularite systemique associee a des depots d’IgA1. Classiquement decrite comme secondaire a une infection muqueuse ou comme une forme idiopathique, quelques cas de V-IgA ont ete rapportes au cours ou dans la proximite du diagnostic de neoplasie, et leur relation causale a ete suspectee. Nous rapportons ici une serie de patients atteints de V-IgA et de cancers dans le but de decrire leur phenotype et leur profil evolutif comparativement a des patients atteints de V-IgA indemnes de neoplasie. Patients et methodes Nous avons conduit une etude retrospective multicentrique au sein des services de Medecine Interne et d’Oncologie. Les patients colliges (> 18 ans) devaient presenter une neoplasie solide et une V-IgA histologiquement prouvee. L’intervalle entre les diagnostics respectifs des deux entites ne devait pas exceder 24 mois. Les donnees clinicobiologiques de ces patients ont ete comparees a celles issues de la cohorte nationale de V-IgA (IGAVAS). Resultats Trente patients ont ete inclus. L’âge moyen au diagnostic etait de 69 ans (± 12 ans) et 80 % des patients etaient de sexe masculin. Les manifestations au diagnostic de la V-IgA incluaient une atteinte articulaire, digestive et renale dans respectivement 33, 23 et 57 % des cas. En comparaison aux patients de la cohorte IGAVAS, les patients atteints de cancer et de V-IgA etaient plus âges (69 vs 50 ans p Conclusion La proximite temporelle du diagnostic d’une neoplasie, surtout muco-glandulaire, et d’une V-IgA conferent a cette derniere, comparativement aux autres formes decrites (idiopathiques ou post-infectieuses), des caracteristiques cliniques et demographiques particulieres que sont : un âge au diagnostic plus avance, un caractere plus souvent necrotique du purpura et une plus grande frequence d’hemorragie intra-alveolaire. Le suivi therapeutique a plus long terme des patients montrant cette association devrait permettre d’etudier la correlation, les profils evolutifs et le lien de causalite entre ces des deux affections.

Introduction Depuis l’autorisation, en 2011, de l’ipilimumab comme traitement dans le melanome metastatique, des nombreux « immune checkpoint inhibitors » (ICIs) ont ete developpes et leur utilisation est de plus en plus large dans le domaine de l’oncologie. Les reactions adverses immunologiques (RAI) sont connues et des protocoles therapeutiques pour chaque systeme/organe ont ete developpes. Du fait de taux de reponses eleves aux ICI, un nombre croissant de patients survit de maniere prolongee grâce a ces traitements. Une nouvelle categorie des patients est donc en train d’apparaitre : « survivants a long terme » (SLT), et leur prise en charge est, pour le moment, inconnue. La question de survenue tardive de RAI a distance de l’arret de l’ICI se pose. En effet, commencent a etre rapportes des cas de RAI apres arret des ICIs. L’objectif de ce travail est de rechercher des RAI meconnus dans un groupe de patients SLT. Patients et methodes Des patients adultes, traites dans un centre anticancereux entre 2013 et 2017, ayant recu la premiere perfusion minimum 2 ans avant la consultation, ont ete inclus. Une evaluation clinique et paraclinique a ete realisee dans un service de medecine interne. L’evaluation paraclinique a inclus des examens biologiques (hemogramme, etude de la fonction renale, ionogramme, bilan hepatique, bilan lipidique, BNP, CPK, phenotypage lymphocytaire, anticorps antinucleaires, electrophorese des protides, bilan endocrinien, bandelette urinaire), des explorations cardiaques (electrocardiogramme, echocardiographie), pulmonaires (explorations fonctionnelles respiratoires), un fibroscan a la recherche d’une fibrose hepatique. Les patients ont eu par ailleurs une evaluation neuropsychologique. Resultats Seize patients (4 femmes et 12 hommes), avec un âge moyen de 58 ans, ont ete inclus. Dix patients avaient un melanome, 5 patients avaient une neoplasie pulmonaire et un patient avait un carcinome renal. Les ICIs recus etaient : ipilimumab (n = 6), un anti-PD-1 (n = 12) et un anti-PD-L1 (n = 3). Certains patients ont recu deux ICIs, voire trois. Six patients ont recu une chimiotherapie et cinq une therapie ciblee anterieurement. Neuf patients ont eu des RAI de grade 2 ou plus pendant le traitement avec ICIs et cinq d’entre eux ont eu plus d’un systeme/organe atteint. Cinq patients ont recu des corticoides dans le cadre du traitement des RAI. Neuf patients etaient en reponse complete lors de l’arret de l’ICI. Quatre patients recevaient toujours l’ICI. Le performance statuts des patients evalues etait compris entre 0-1. Des symptomes etaient signales lors de la visite par 13 patients, dix d’entre eux declarant avoir plus de deux symptomes. Les symptomes etaient : atteinte cutanee (n = 8), dyspnee (n = 5), myalgies/arthralgies (n = 5). Deux patients etaient sous traitement morphinique. Un patient a ete diagnostique avec une insuffisance surrenalienne, non diagnostiquee prealablement. Cinq patients avaient un ECG anormal, anomalie inconnue auparavant chez trois d’entre eux. Chez ces 5 patients, il n’y avait pas d’anomalie biologique ou echocardiographique. Un patient avait un dosage de BNP eleve, sans expression clinique ou paraclinique. L’evaluation par fibroscan retrouvait un score F2 pour un patient et un score F1 pour cinq patients. Conclusion Les patients SLT restent symptomatiques pour la majorite. Des evaluations regulieres par un interniste ou un specialiste d’organe doivent etre prevues en particulier pour surveiller les axes endocriniens. Une toxicite cardiaque tardive semble possible et justifie des investigations plus poussees, actuellement en cours chez ces patients.

Introduction La toxicite pulmonaire touche 3 a 7% des patients traites par immunotherapie et le traitement repose classiquement sur l’utilisation d’une corticotherapie orale. Toutefois, il existe peu de donnees detaillees portant sur les benefices de ce traitement. Methodes Etude monocentrique retrospective de patients traites par Ac anti-PD1 ou anti-PD-L1 avec toxicite pulmonaire ≥ grade2. Description des donnees cliniques, fonctionnelles et scanographiques avant/apres corticotherapie. Resultats Entre novembre 2016 et octobre 2019, 26 patients traites par immunotherapies ont presente une toxicite pulmonaire de grade ≥ 2 justifiant une corticotherapie orale. Parmi eux, 16 (62%) etaient des hommes et l’âge median etait de 65 [58–73] ans. Soixante-seize pour cent etaient exposes a un tabagisme. Les cancers faisant porter l’indication d’immunotherapie etaient principalement pulmonaires et melanomes metastatiques dans 11 (42%) et 6 (22%) des cas respectivement. La nature de l’immunotherapie etait un anti-PD1 en monotherapie dans 17 (65%). Les grades de toxicite etaient 2, 3 et 4 dans 22 (86%), 2 (7%) et 2 (7%), respectivement avec un delai moyen de survenue de 3,8 [2,4–8,4] apres l’institution de l’immunotherapie. Les motifs scanographiques dominants etaient consolidation, n = 12 (46%), verre depoli, n = 6 (23%) et infiltrats non specifiques, n = 8 (31%). La dose mediane de corticotherapie etait de 0,75 [0,5–1] mg/kg/j pour une duree mediane de 74 [51–150] jours. L’evaluation de la reponse au traitement montrait une resolution dans 12 (46%) cas, une amelioration dans 11 (42%) cas, une stabilite dans 1 (4%) cas et une aggravation chez 2 (8%) patients. Les donnees principales des epreuves fonctionnelles respiratoires montraient les evolutions suivantes : CVF passant de 3090 ± 660 mL a 3208 ± 1079 mL (p = 0,28) et DLCO passant de 54 ± 14% a 63 ± 17% (p = 0,03). Les plus grands benefices d’amelioration des parametres respiratoires etaient observes dans la population des patients avec consolidation (p = 0,007). Une reprise du traitement etait realisee chez 8 (32%) des patients, emaillee d’une recidive de toxicite dans 1 (12%) cas. Conclusion Le traitement des toxicites pulmonaires d’immunotherapie s’accompagne dans la grande majorite des cas d’une resolution ou d’une amelioration de l’atteinte. La DLCO apparait etre un outil pertinent de suivi. Les patients avec consolidation au scanner semblent les plus repondeurs au traitement, soulevant la question d’un raccourcissement de la duree du traitement dans ce sous-groupe.

Background Patients (pts) living with cancer are exposed to higher risk for thrombotic event (TE). The thrombotic risk (TR) is related to cancer disease and could also be associated with anti-cancer drugs such as antiangiogenic (AA). AA are currently being used more and more widely, alone or in combination (combo) with anti-PD(L)1 immunotherapies. It isn’t known whether combining anti-PD1 or PD-L1 with AA drug could increase the risk of TE. This study aimed at evaluating the TR in patients receiving a combo of AA and anti-PD1 or PD-L1. Methods Observational study conducted from January 2017 to September 2019 and retrospectively investigated all consecutive adults pts with cancer treated with a combo of AA plus anti-PD(L)1. All TE (venous and arterial) occurring following investigated treatment(s) and Khorana scores (KS) were analyzed. The TR was assessed in pts receiving the combo and compared with pts treated with single anti-PD(L)1. For the single anti-PD(L)1 cohort, data were collected from the pharmacovigilance Register of Severe Adverse Effects of Immunomodulatory Monoclonal Antibody in Cancer (REISAMIC). Data were compared between the combo and REISAMIC cohort using the Fisher’s exact and CHI2 tests (α = 5%). Results Overall, 83 pts receiving a combo of anti-PD(L)1 plus AA and 484 pts treated with anti-PD(L)1 were included. Both cohorts were similar for baseline characteristics: sex ratio, age, weight. Main tumor types in single anti-PD(L)1 vs combo were (in %): renal cell carcinoma, 5 vs 37; urothelial carcinoma, 3 vs 4; thoracic (lung or mesothelioma), 45 vs 32; gynecologic, 1 vs 8. The KS score was heterogeneous. It found 334/484 (69%) pts at intermediary or high risk of TE in the REISAMIC cohort and 70/83 (84%) in combo cohort (p = 0.006). In REISAMIC cohort, TE incidence was 7% compared to 18% in the combo cohort (p value=0.0006). Conclusion These results suggest that pts treated with combo AA plus anti-PD(L)1 seem to be more at risk of developing TE compare to single therapy anti-PD(L)1, according to a KS higher in this cohort. Further prospective study're warranted to investigate the risk of TE in pts receiving AA plus anti-PD(L)1 and to investigate the benefit of preventive anticoagulants therapy. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitor therapy is showing marked efficacy in advanced non-small cell lung cancer (NSCLC). Meanwhile, it is concomitant with distinctive immune-related adverse effects. We aim to describe the incidence of pneumonitis and other rare but severe immune-related adverse effects (IRAEs), as well as treatment related deaths. In addition, we analyze the differences in incidence of pneumonitis between PD-1 and PD-L1 inhibitors and standard-of-care chemotherapy. Methods PubMed was searched up to 24 March 2017 for clinical trials of PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) in treatment of NSCLC. Besides, references of relevant articles were screened. Results Finally, 22 trials were included in our study, 14 with data of pneumonitis, 19 with other severe IRAEs or treatment related deaths and 5 with control groups. Incidence of all-grade pneumonitis was 2.9% (95% CI, 2.0-4.8%) and grade 3 or higher pneumonitis 2.0% (95% CI, 1.0-2.0%). Incidence of all-grade pneumonitis in PD-1 and PD-L1 inhibitor therapy (n=1,313) was significantly higher than that in chemotherapy (n=918) (OR=2.35, 95% CI, 1.32-4.20, P=0.004), but had no significance in grade 3-5 pneumonitis. Incidence of cardiorespiratory arrest (n=537) was 1.0% (95% CI, 0-2.0%), cardiac failure (n=214) 2.0% (95% CI, 1.0-5.7%), myocardial infarction (n=402) 1.0% (95% CI, 0-3.8%), stroke (n=135) 2.0% (95% CI, 0-13.0%), disease progression (n=391) 1.0% (95% CI, 0-2.9%), pancreatitis (n=700) 1.0% (95% CI, 0-2.0%) and severe skin reactions (n=836) 2.0% (95% CI, 1.0-3.8%). Incidence of treatment related deaths was 0.7%. Conclusions Immune related adverse effects can on occasion be life-threatening even though usually rare. Incidence of pneumonitis in PD-1 and PD-L1 inhibitors was significantly higher than that in chemotherapy. More studies should be conducted to investigate the incidence of these rare but life-threatening IRAEs.

Background: Patients (pts) with NHL experiencing early relapse (ER) within two years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al JCO 2015; Gopal et al. NEJM 2014). Preliminary results from CC-122-NHL-001, the first study of CC-122, a novel cereblon-modulating agent, in combination with obinutuzumab (G), showed promising response rates in pts with R/R B-cell NHL (Michot et al Blood 2016). Herein, we report updated results for safety and efficacy from CC-122-NHL-001 (NCT02417285) with further 12 months follow up. Methods: CC-122 was given orally (5/7 d) for 28-d cycles in escalating doses plus a fixed dose of intravenous G 1000 mg on d2, 8, 15 of cycle 1 (c1) and d1 of c2–8. CC–122 active ingredient in capsule formulation (AIC) 1, 2, 3, and 4 mg and CC-122 formulated capsules (F6) 3 and 4 mg were evaluated in separate cohorts. Primary end points included safety and tolerability, NTD, and MTD. Response was assessed using the Cheson 2007 criteria every 2 cycles to c6, every 3 cycles to c12, and every 6 cycles thereafter. Results: As of September 1, 2017, 44 pts with R/R B-cell NHL were enrolled in the dose-escalation phase. Tumor types included 19 pts with DLBCL, 24 with FL, and 1 with MZL. Median age was 60 y (range, 26–81 y), 29 (66%) were men, and 33 (75%) had stage III/IV disease. Median number of prior anticancer therapies was 3 (range, 1– 11), and 18 pts (41%) had 1 prior ASCT; 2 pts had a dose-limiting toxicity (grade 4 neutropenia, n ¼ 1 [CC-122 AIC 3 mg]; grade 5 tumor flare, n ¼ 1 [CC-122 F6 4 mg]). The most common (15%) grade 3/4 TEAEs were neutropenia (52%) and thrombocytopenia (25%). ORR/CR rate in the total population was 68%/27% (DLBCL, 47%/11%; FL, 84%/42%). The mDOR was 19.4 mo (95% CI:7.9, NR). Subgroup analysis showed comparable mPFS and DOR for high-risk (ERþDR) and standard-risk FL pts (mPFS, 21.1 mo [2.9, NR] vs 16.2 mo [1.7, 16.2]; DOR, 19.3 mo [1.9, NR] vs NR). Conclusions: CC-122þG is well-tolerated, with promising response rates and durable remissions in R/R B-cell NHL. Subgroup analysis showed CC-122þG has similar efficacy in the high-risk and standard-risk FL population

Background The use of immune checkpoint inhibitors (ICI) has revealed a new panel of tumor response and adverse events. Immune-related sarcoidosis-like reactions is frequently misdiagnosed as progressive or recurrent disease. This study aims to decipher the diagnosis hallmark of immune-related sarcoidosis-like reactions as well as its association with patients’ outcome. Methods From August 2014 and December 2018, in a centralized single center review, we retrospectively included all patients with histologically proven immune-related sarcoidosis-like reaction during a treatment with ICI in monotherapy or combination. 54 variables were retrospectively recorded: clinical (n = 17), biological (n = 11) and radiological (n = 26), as well as the objective response to treatment using the best overall response according to iRECIST. Results Out of 3,200 patients treated with ICI, a total of 18 histologically proven sarcoidosis were diagnosed. The majority were female patients (n = 11/18) treated for melanoma (n = 14/18) or clear renal cell carcinoma (n = 3/18). The median [range] time to diagnosis of a sarcoidosis-like reaction was 30 [5-126] weeks after ICI treatment initiation. On CT-scans, the most common radiological findings were: absence of radiographical progression of the primary tumor per RECIST1.1 (100%), bilateral symmetrical mediastinal lymphadenopathy (100%), symmetrical hilar lymphadenopathy (84%), and micronodules with lymphatic distribution (15%). On PET-CT, an extrathoracic glucose uptake was observed in 65% of patients. The sites involved were pleural involvement, abdominal lymph nodes, liver, and spleen. Patients with immune-related sarcoidosis-like reactions were objective responders according to iRECIST in 84% (n = 15/18) of patients, while only 15% had stable disease. Conclusions Immune-related sarcoidosis is characterized by the appearance of new mediastinal and/or pulmonary lesions, usually at 30 weeks after initiation of treatment, with stability of baseline target lesions. PET/CT demonstrated extrathoracic uptake in 65% of patients. This should not be misinterpreted as disease progressive since 84% of patients will show an objective response to ICI. Legal entity responsible for the study Ammari Sami. Funding Has not received any funding. Disclosure S. Champiat: Advisory / Consultancy: Astrazenaca; Advisory / Consultancy: BMS; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche. J. Michot: Advisory / Consultancy: BMS. All other authors have declared no conflicts of interest.

Background Epigenetic therapies (epidrugs) modify cancer cells transcriptional programmes and influence all hallmarks of cancer. Thus, epidrugs have been reported to modulate sensitivity to conventional chemotherapy (CCT) preclinically. We explored whether sensitivity to CCT differed before and after epidrug therapy. Methods Patients (pts) enrolled in phase 1 trials evaluating epidrugs at the Drug Development Department (DITEP) in Gustave Roussy between March 2010 and May 2017 who received at least one CCT just before and after epidrug therapy were eligible. Progression free survival (PFS) of the CCT line before (PFSpre) and after (PFSpost) epidrug were compared using Wilcoxon signed rank in a paired data subset (uncorrected α-risk). Results 69% of the 93 eligible pts had haematological malignancies. Epidrug treatments consisted of: IDH inhibitors (IDHi) (30%), HDACi (19%), protein degradation modulators (20%), EZH2i (17%), BETi (12%) and LSD1i (2%); 52 (56%) pts derived clinical benefit (CB) from epidrugs (objective response or SD>2 months). Median PFSpre and PFSpost were 4.2 and 3.8 months (NS), respectively; PFSpost was significantly worse for pts who did not derive CB from epidrugs (1.8 vs 5.6 months, p=0.01), whereas significance was lost for pts who derived CB (5.1 vs 3.6 months, NS). Analysis stratified on the CCT type evidenced that PFSpost was significantly worse for pts receiving anthracyclines, topoisomerase inhibitors and alkylating agents (excluding platinum salts) (p=0.004, p=0.02 and p=0.01, respectively), whereas no significant difference was observed for platinum, antimetabolites, anti-microtubule agents or antiangiogenic agents. Conclusions Epidrug therapy might modify sensitivity to certain CCT; patients who derive clinical benefit from epidrugs tend to have better PFS on CCT after epidrug treatment than patients who do not benefit from epidrugs. Further studies on larger and homogeneous series are warranted. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure P. Romano-Martin: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Jannsen; Research grant / Funding (self): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Roche. C. Baldini: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. S. Champiat: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. A. Varga: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Roche. A. Gazzah: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. R. Bahleda: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. P. Vuagnat: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. A. Hollebecque: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. J. Michot: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. V. Ribrag: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi. C. Massard: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Lilly; Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Jannsen. S. Postel Vinay: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (self): Roche; Research grant / Funding (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.