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Sickle cell disease (SCD) is the most frequent inherited disorder in the world. It is caused by a single amino acid mutation on the beta-globin chain, which lead to red blood cell deformation, haemolysis, and chronic inflammation. Clinical consequences are vaso-occlusives crisis, acute chest syndrome, thrombosis, infection, and chronic endothelial injury.Corticosteroids are an old therapeutic class, that are inexpensive and widely available, which can be administered in different forms. Their adverse effects are numerous and well-known. This class could appear to be useful in SCD treatment due to its anti-inflammatory effect. Moreover, corticosteroids remain an essential therapeutic class for many indications, besides SCD. Although specific adverse effects of corticosteroids have been suspected in SCD patients for decades, recent papers has reported strong evidence of specific and severe adverse effects in this population. Based on a literature review, we will discuss pathophysiological considerations, consequences, and practical use of corticosteroids in SCD.High corticosteroid doses, for any indication , induce vaso-occlusive crises, acute chest syndrome, and re-hospitalization in patients with SCD. There is no evidence of any benefits of corticosteroid use in the SCD acute events. Prevention by hydroxyurea and/or red blood cell transfusion or exchange should be discussed when corticosteroid use is indispensable.

Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα signaling via NF-κB" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974

Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to describe ITP in this subgroup. The data source was the prospective CARMEN-France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65-79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first-line treatment, need of second-line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex [odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31-17·32] and platelet count of

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicentre retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-Ras that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs. This article is protected by copyright. All rights reserved.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (

Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of

New insights into immune thrombocytopenia (ITP) epidemiology in adult patients highlight three main outcomes of morbidity and mortality: bleeding, infection and thrombosis. This review depicts current evidence about incidence and risk factors of bleeding, infection and thrombosis as well as predictors of chronicity, and shows how this assessment impacts the choice of ITP second-line treatment at the individual-level basis.

Prior studies have demonstrated an increased prevalence of autoimmune markers in patients with immune thrombocytopenia (ITP). Clinical experience has suggested that there may be an association between autoimmune markers and poor outcomes in ITP, but current guidelines do not encourage routine testing in these patients. We retrospectively assessed the prevalence of autoimmune markers in adult patients with ITP from our institutional database and used multiple logistic regression analyses to test for an association between autoimmune marker positivity and thrombotic events or clinical remission. We also assessed whether positivity for common autoimmune markers was associated with positivity for platelet autoantibodies. There was a high rate of autoimmune marker positivity in this population, with antinuclear antibody (65%), antithyroid peroxidase antibody (31%), and direct antiglobulin (29%) the most commonly found. Antithyroid peroxidase antibody positivity was associated with a lower probability of remission (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.09-0.79; P = .017). Lupus anticoagulant positivity was associated with a higher rate of thrombosis (OR, 8.92; 95% CI, 1.94-40.95; P = .005), and antinuclear antibody was strongly associated with thrombosis (P = .001). There was no relation between platelet autoantibody positivity and the presence of autoimmune markers. These results suggest that many patients with ITP have a state of immune dysregulation that extends beyond platelet autoantibodies and that certain autoimmune markers may be prognostically useful in this disorder.

Azacitidine can be effective in myelodysplastic syndromes (MDS) associated with inflammatory/autoimmune diseases. Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) is a new monogenic autoinflammatory syndrome caused by somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutation, often associated with MDS, whose treatment is difficult and not yet codified. Based on a French nationwide registry of 116 patients with VEXAS, we report the efficacy and safety of azacitidine treatment in 11 patients with VEXAS with MDS. Clinical response of VEXAS to azacitidine was achieved in five patients (46%), during 6, 8+, 12, 21, 27+ months respectively, suggesting that azacitidine can be effective in selected patients with VEXAS and associated MDS.

Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

A recent phase 3 trial showed that outcome of older patients with secondary acute myeloid leukemia (AML) may be improved by a liposomal encapsulation of cytarabine and daunorubicin (CPX‐351). This phase 3 study represents a unique example of prospective data in this rare subgroup providing basis for comparison with real life data. Here, we retrospectively assessed characteristics and outcome of patients aged 60‐75 years with secondary or therapy‐related AML in real life. Out of 218 patients that fulfilled CPX‐351 study criteria, 181 patients (83.0%) received antileukemic treatment either intensive chemotherapy (n = 121) or hypomethylating agents (HMA, n = 60). As compared with patients treated by chemotherapy, HMA‐treated patients were older, had lower WBC, more often AML with antecedent myelodysplastic syndrome and adverse cytogenetic risk. In chemotherapy‐treated patients, the complete response rate was 69%, median overall survival (OS) was 11 months whereas 3‐year and 5‐year OS was 21% and 17%, respectively. In HMA‐treated patients, the complete response rate was 15%, median OS was 11 months whereas 3‐year and 5‐year OS was 15% and 2%, respectively. In conclusion, although outcome of older patients with high‐risk AML is very poor, a significant proportion of patients treated by standard intensive chemotherapy but not HMA are long‐term survivors.

Summary Background Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. Methods In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indesirables Severes des Anticorps Monoclonaux Immunomodulateurs en Cancerologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Reference des Cytopenies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. Findings We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51–75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. Interpretation Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. Funding Gustave Roussy and Gustave Roussy Immunotherapy Program.

Introduction L’anemie hemolytique auto-immune (AHAI) est une maladie rare, pouvant mettre en jeu le pronostic vital avec un taux de mortalite pouvant s’elever jusqu’a 30 % en reanimation. Peu de donnees existent dans la litterature concernant les caracteristiques et l’evolution des patients admis en reanimation pour leur AHAI et les facteurs pronostics associes au deces. Patients et methodes Etude retrospective multicentrique incluant des patients adultes atteints d’AHAI vus entre 2013 et 2020 et hospitalises au moins une fois en reanimation pour la prise en charge de leur AHAI. Les patients atteints d’AHAI admis en reanimation pour une autre raison etaient exclus. Les caracteristiques au diagnostic du groupe de patients hospitalises en reanimation ont ete comparees a celles d’un groupe de patients atteints d’AHAI vus sur la meme periode et non hospitalises en reanimation avec un ratio de 1 pour 2. Resultats Au total, les donnees de 62 patients d’âge median 55 ans (dont 42 % de femmes) provenant de 11 centres participants ont ete recueillies et analysees. Il s’agissait d’AHAI a anticorps « chauds » dans 79 % des cas, d’AHAI « froides » dans 7 %, et de formes d’AHAI dites « mixtes » dans 13 % des cas. Les formes dites secondaires representaient 65 % des cas et dans 26 % des cas l’AHAI s’integrait dans le cadre d’un syndrome d’Evans. Le taux median d’Hb a l’admission en reanimation etait de 4,3 g/dL (3,7–5,1) avec dans 93 % une reticulocytose inadaptee (definie par une index reticulocytaire Conclusion Le taux global de mortalite intra-hospitaliere chez les patients adultes atteints d’AHAI admis en reanimation est de 13 %, soit moindre que precedemment decrit dans la litterature, mais ce taux atteint 30 % a 1 an. Les patients avec une AHAI, un taux d’Hb

Introduction Le Purpura Thrombopenique Immunologique (PTI) est une maladie auto-immune due a une destruction peripherique et a une alteration de la production centrale de plaquettes. Le traitement de premiere intention repose sur les corticoides. Les agonistes des recepteurs de la thrombopoietine (AR-TPO) sont indiques en seconde ligne du PTI, mais peu de facteurs predictifs de reponse sont connus. La realisation d’un medullogramme dans le diagnostic du PTI est discutee. Deux etudes ont suggere une association entre les anomalies morphologiques des megacaryocytes (MK), supposees etre la consequence d’une reaction auto-immune centrale, et la reponse a la corticotherapie dans le PTI primaire [1] , [2] , mais aucune n’a etudie cette association pour les AR-TPO. L’objectif de cette etude etait d’examiner l’association entre les anomalies des MK au medullogramme et la reponse aux AR-TPO chez des patients adultes atteints de PTI primaire. Patients et methodes La source de donnees etait le registre CARMEN (Cytopenies Auto-immunes : Registre Midi-PyreneEN), qui a pour objectif le suivi prospectif de tous les adultes atteints de PTI dans la region Midi-Pyrenees depuis juin 2013. Chaque investigateur suit tous les patients adultes nouvellement diagnostiques pour un PTI et recueille prospectivement des informations detaillees au cours du suivi. Le diagnostic de PTI etait defini par une numeration plaquettaire La population d’etude comprenait les patients inclus dans le registre CARMEN pour un PTI primaire jusqu’a mars 2018, traites par AR-TPO et qui avaient beneficie de la realisation d’un medullogramme avant le debut du traitement. Les criteres d’anomalies morphologiques des MK ont ete etablis en concertation avec 3 cytologistes experts. Un biologiste a analyse tous les MK presents sur chaque frottis. Les MK ont ete classes en fonction de la presence de dysplasie (MK monolobes et/ou a noyaux separes et/ou micromegacaryocytes), et en fonction de leur stade de maturation (basophile, granuleux ou thrombocytogene). Les dossiers medicaux de tous les patients ont ete examines par deux investigateurs (OW et GM) afin de determiner leur reponse aux AR-TPO, definie comme une numeration plaquettaire [3] 30 G/L avec au moins un doublement de la valeur [3] . Dans l’analyse principale, nous avons considere tous les patients de l’etude (traites par romiplostim seul, eltrombopag seul ou les deux successivement). Ils etaient classes comme repondeurs en cas de reponse a au moins un AR-TPO. Nous avons effectue une analyse en sous-groupe pour evaluer uniquement la reponse a l’eltrombopag. Resultats Entre 2013 et mars 2018, 451 patients ont ete inclus dans le registre CARMEN, dont 105 traites par AR-TPO et 65 avec medullogramme. Nous avons exclu 20 patients pour un PTI secondaire, et 7 avec moins de 10 MK analysables au medullogramme. Nous avons finalement inclus 38 patients pour l’analyse, l’âge median au diagnostic etait de 71 ans (inter quartile range–IQR : 31–94) et 34,2 % etaient des femmes. Trente-trois patients ont ete traites par eltrombopag, 17 par romiplostim, 13 par les deux. Le nombre median de MK analyses par patient etait de 137 (IQR : 50–265), dont 6,5 (IQR : 3–13) etaient dysplasiques. Trente-quatre patients (89,4 %) avaient obtenu une reponse aux AR-TPO. Dans l’analyse principale, il n’y avait pas de difference significative dans le pourcentage median de MK dysplasiques chez les repondeurs (4,0 % ; IC 95 % : 2,3–6,4) et les non-repondeurs (4,5 % ; IC 95 % : 0,7–7,1). On observait une tendance a une proportion plus elevee de MK granuleux (4,5 % ; IC 95 % : 3–6) et de MK basophiles (30,1 % ; IC 95 % : 21,9–39,1) chez les non-repondeurs par rapport aux repondeurs (granuleux : 2,0 % ; IC 95 % : 0–4,1 ; basophiles : 21,3 % ; IC 95 % : 11,4–40,7). Les resultats etaient similaires dans le sous-groupe de patients traites par eltrombopag (trop peu patients traites par romiplostim pour realiser des analyses dans ce groupe). Conclusion Dans notre etude, ni les anomalies megacaryocytaires ni les stades de maturation des megacaryocytes n’etaient significativement associes a la reponse aux AR-TPO. Ces resultats ne vont pas dans le sens de la realisation d’un medullogramme systematique chez les patients presentant un tableau de PTI primaire dans le but de predire simplement la reponse aux AR-TPO.

Harnessing or monitoring immune cells is actually a major topic in pre-clinical and clinical studies in acute myeloid leukemia (AML). Mucosal-Associated Invariant T cells (MAIT) constitute one of the largest subset of innate-like, cytotoxic T cell subsets in humans. Despite some papers suggesting a role for MAIT cells in cancer, their specific involvement remains unclear, especially in myeloid malignancies. This prospective monocentric study included 216 patients with a newly diagnosed AML. Circulating MAIT cells were quantified by flow cytometry at diagnosis and during intensive chemotherapy. We observed that circulating MAIT cells show a specific decline in AML patients at diagnosis compared to healthy donors. Post-induction monitored patients presented with a drastic drop in MAIT cell numbers, with recovery after one month. We also found correlation between decrease in MAIT cells number and adverse cytogenetic profile. FLT3-ITD and IDH ½ mutations were associated with higher MAIT cell numbers. Patients with high level of activated MAIT cells are under-represented within patients with a favorable cytogenetic profile, and over-represented among patients with IDH1 mutations or bi-allelic CEBPA mutations. We show for the first time that circulating MAIT cells are affected in newly diagnosed AML patients, suggesting a link between MAIT cells and AML progression. Our work fosters new studies to deepen our knowledge about the role of MAIT cells in cancer.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20% of cases. Immune thrombocytopenia (ITP) is among the reportedly associated diseases, but large studies assessing the association are lacking. It is unclear whether patients with MDS or CMML and ITP have a particular phenotype or require particular management. We, therefore, analyzed the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison to: (i) patients with primary ITP without MDS/CMML and (ii) patients with MDS/CMML without ITP. Forty-one patients with MDS/CMML-associated ITP were included, of whom 26 (63%) had chronic ITP, 30 (73%) had low-risk myelodysplasia and 24 (59%) had CMML. An associated autoimmune disease was noted in ten (24%) patients. In comparison to patients with primary ITP, patients with MDS/CMML-associated ITP had a higher rate of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulins (56%). Patients with primary ITP were more likely to respond to intravenous immunoglobulins than were patients with MDS/CMML-associated ITP. Response rates to second-line therapies were not statistically different between patients with primary ITP or MDS/CMML-associated ITP. Four (10%) of the patients with MDS/CMML-associated ITP had multirefractory ITP whereas none of the primary ITP controls did so. After a median follow-up of 60 months, there was no difference in overall survival between patients with MDS/CMML-associated ITP or primary ITP. Leukemia-free-survival was significantly better in patients with MDS/CMML-associated ITP than in those with MDS/CMML without ITP. In conclusion, it appears that patients with MDS/CMML-associated ITP have a particular phenotype, with more severe bleeding than patients with primary ITP, a higher likelihood of multirefractory disease, but a similar response to primary ITP therapy except for intravenous immunoglobulins. Finally, compared to MDS/CMML patients without ITP, they are less likely to progress to having acute myeloid leukemia.

This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.

Objectives Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. Methods We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet’s syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1–1.5 million units of proleukin/day during 5 days and then every fortnight. Results The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. Conclusion Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.

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.

Resume La maladie residuelle minime (MRD) est de plus en plus utilisee dans le domaine de l’onco-hematologie. Sa mesure par cytometrie en flux ou biologie moleculaire a notamment une place grandissante dans la leucemie lymphoide chronique (LLC) avec l’amelioration importante des resultats des traitements ces dernieres annees. Du fait du benefice en survies sans progression et globale apporte par l’obtention d’une maladie residuelle minime indetectable, sa mesure en post-therapeutique est recommandee comme marqueur de substitution pour l’enregistrement des medicaments cytotoxiques. Cet effet est independant du traitement prealablement recu et pose la question de mesures sequentielles de la maladie residuelle minime en cours de traitement pour envisager un arret precoce en cas de reponse profonde, mais aussi de la poursuite des traitements jusqu’a obtention d’une maladie residuelle minime indetectable (en passant par des schemas associant traitements d’induction puis de maintenance). De plus, un suivi de maladie residuelle minime en post-therapeutique pourrait aider a proposer des traitements preemptifs de la rechute. Des facteurs tels que la cinetique de croissance de la maladie residuelle minime ou la lymphopenie CD4 post-therapeutique permettent d’ameliorer la prediction de la survie sans progression des patients ayant une leucemie lymphoide chronique. Les inhibiteurs de la voie du BCR n’induisent quant a eux pas de maladie residuelle minime indetectable, mais leur association a des traitements cytotoxiques type immunochimiotherapie permet d’augmenter la proportion de patients obtenant une reponse profonde. Les inhibiteurs de BCL2 permettent l’obtention de maladie residuelle minime indetectable chez beaucoup de patients y compris en rechute, ce qui donne a la maladie residuelle minime une place centrale dans l’evaluation des traitements actuellement a l’etude.

Oral isotretinoin, an isomer of retinoic acid, has been used for more than 35 years for the treatment of severe nodular acne. It is also indicated for the treatment of moderate acne that is treatment resistant or for the management of acne that is producing physical scarring or psychological distress.1 Adverse events are well known and frequently dermatologic in nature, including exfoliative cheilitis, diffuse xerosis, delayed wound healing, acne fulminans, or paronychia. Adverse events are mostly of mild intensity and do not generally require dose adjustment. The other main toxicities include depression/mood changes, bone demineralization, transaminitis, dyslipidemia and teratogenic effects.1 Here we report a young female patient who progressively had diffuse painful oral aphthous-like lesions secondary to a severe vitamin B12 deficiency induced by long-term isotretinoin therapy that required discontinuation of the treatment.

Introduction Les syndromes myelodysplasiques (SMD) peuvent s’associer a des manifestations dysimmunes dont le traitement repose habituellement sur les corticoides ou les biotherapies. L’azacitidine (AZA), traitement de reference des SMD avances (haut-risque) semble etre efficace sur ces manifestations « paraneoplasiques ». Le VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome) est un nouveau syndrome auto-inflammatoire monogenique cause par une mutation somatique de UBA1 et dont la prise en charge therapeutique semble difficile. Les premieres series montrent une association frequente avec les SMD. Sur la base d’un registre national francais de 116 patients atteints de VEXAS, nous rapportons l’efficacite et la securite d’un traitement par azacitidine chez 11 patients VEXAS atteints de SMD. Patients et methodes Nous avons collectes les donnees des patients porteur de SMD (selon la classification OMS 2016) ayant recu au moins 1 cycle d’AZA (5 ou 7 jours). Une reponse majeure de la manifestation inflammatoire a etait defini par une reduction de la posologie de corticoide d’au moins 50 % et pour une dose quotidienne 10 mg/j pendant au moins un mois. Resultats Nous avons identifie dans le registre 58 patients porteur d’un SMD (50 %) dont 11 ayant recus au moins un cycle d’AZA pour une manifestation inflammatoire. Il s’agissait d’hommes (100 %) d’âge median de 64 ans (min–max 54–73). La classification OMS du SMD etait : SMD-MLD (n = 6) SMD-SLD (n = 1), SMD-EB1 (n = 4). Le delai median entre le diagnostic de SMD et le debut de l’AZA etait de 8 mois (min–max 0–88). Le phenotype du VEXAS incluait principalement une atteinte cutanee (100 %), de la fievre ou une alteration de l’etat general (91 %). Tous, sauf un, etaient dependant le cortisone a l’initiation de l’AZA et ils avaient recus une mediane d’un immunosuppresseur en plus de la cortisone (min–max 0–6). Les patients avaient recus une mediane de 11 cures d’AZA (min–max 2–35) avec un suivi median de 32 mois (min–max 12–75). Cinq (46 %) patients ont arrete l’AZA avant la fin du suivi (apres 2 a 10 cycles) pour echec (n = 4) ou reponse persistante apres 6 cycles (n = 1). Cinq (46 %) patients ont obtenu une reponse, dont 2 reponses majeures et 3 mineurs, alors que 6 patients n’ont pas repondu a l’AZA. La meilleure reponse etait observe apres 4 cycles (n = 4) ou 6 cycles (n = 1). Parmi les repondeurs, la cortisone a pu etre arretee chez un patient. Les durees de reponses etaient de 6, 8+, 12, 21, 27+ mois. Trois des 5 repondeurs ont recus par la suite un autre immunosuppresseur. Concernant la reponse sur le SMD, 3 des 10 patients anemiques ont obtenu une reponse erythroide alors que 2 des 5 patient thrombopeniques ont obtenu une reponse plaquettaire (criteres IWG 2006 criteria). Deux patients ont presente un evenementiel indesirable grave Durant le traitement par AZA : une pneumocystose, et une colite severe associee a une pneumopathie bacterienne. Conclusion Nos resultats suggerent malgre le faible effectif une efficacite de l’AZA sur les symptomes du VEXAS chez un peu moins de 50 % des patients, permettant une diminution voir un arret de la corticotherapie. L’AZA permet, dans les meme proportions d’obtenir une reponse hematologique est peut etre une option interessante en cas de cytopenies associees. Une etude prospective avec plus de patients est cependant necessaire pour confirmer cette impression.

Background MDS are associated in 10% to 25% of the cases with systemic inflammatory or auto-immune diseases (SIAD). The management of SIADs in this context includes glucocorticoids and biologics with variable response rates, but we and others found that hypomethylating agents, especially azacytidine (AZA), can have some efficacy in SIADs associated with lower risk MDS (Fraison, J.-B. et al. Leuk. Res. 43, 13-17 (2016).). The recently described VEXAS syndrome (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome) (Beck et al, NEJM 2020) an autoinflammatory disease characterized by somatic mutation of the UBA1 gene, is often associated with hematological disorders, especially MDS, and its treatment is often unsuccessful Based on a French nationwide registry of patients with VEXAS syndrome, we described the efficacy and safety of AZA in VEXAS syndrome patients with concomitant MDS. Patients A French nationwide registry of 116 patients with VEXAS syndrome was established in Jan 2021. We collected in this registry patient cases with concomitant MDS (according to WHO 2016) who received at least 1 full cycle of AZA (5 to 7 days). Major response of autoinflammatory disease to AZA was defined by at least 50% steroids dose reduction to less than 10 mg/day during at least one month, and minor response by at least 50% steroid dose reduction but to > 10 mg/day, during at least one month. Results Of the 58 patients with concomitant MDS included in the French VEXAS registry, 11 had received at least 1 cycle of AZA. All patients were males and median age was 64 (range 54-73), WHO : MDS MLD (n=6) , MDS SLD (n=1), MDS EB1 (n=4) ) ,R-IPSS low (n=7), intermediate (n=3) high (n=1). Median time from MDS diagnosis to AZA onset was 8 (range 0-88) months. VEXAS phenotype mostly included skin lesions (100%), fever (91%) and constitutional symptoms (91%). All patients, except one, were steroid dependent at AZA onset. In addition to steroids, patients had received a median of 1 immunosuppressive treatment (IST) (range 0-6). The median number of AZA cycles was 11 (range 2-35). Median follow up from AZA onset was 32 months (range 12-75). Five (46%) patients discontinued AZA before the end of follow-up, after 2 to 10 cycles due to failure (n=4) and persistent response after 6 cycles (n=1). Response of autoinflammatory disease to AZA was achieved in 5 patients (45%) including major response in 2 patients, and minor response in 3, while 6 patients had no response. Best response was observed after 4 cycles (n=4) and after 6 cycles (n=1). In responders, prednisone could be discontinued in 1 patient. Duration of response was 6, 8+, 12, 21, 27+ months (Median 16.5). Three of the 5 responders subsequently received another IST. Of 10 anemic and 5 thrombocytopenic patients,3 obtained erythroid and 2 obtained platelet response, respectively (IWG 2006 criteria). Two patients experienced serious adverse events during AZA treatment, including pneumocystis pneumonia (n=1), severe colitis and bacterial pneumonia (n=1). Conclusions Our results, in a limited patient number, suggest that AZA can improve auto inflammatory symptoms in 45% of patients with VEXAS syndrome and underlying MDS, allowing decrease or even discontinuation of steroids, during a median time > 1 year, with concomitant hematological response in about 50% of the cases and limited side effects. A prospective study with more patients will be needed to confirm those results. Disclosures Comont: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terrier: LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Georgin-Lavialle: Novartis: Membership on an entity's Board of Directors or advisory committees; Soby: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Fenaux: Syros Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.

Background: Systemic autoimmune and inflammatory diseases (SAIDs) occur in 10-15% of MDS or CMML patients. They are often severe, difficult to treat and steroid resistant/dependent disorders. In a retrospective report of 22 patients with steroid-dependent MDS/CMML associated SAID, we observed promising results with azacytidine (AZA) on the SAID component (Fraison et al, Leuk Res, 2016). In this prospective French nationwide trial, we aimed at confirming this effect prospectively. Patients and Methods: This open-label, single-arm multicenter, phase II study included MDS/CMML patients with IPSS/CPSS int 2 or high, or lower IPSS/CPSS but with significant cytopenias, especially ESA resistant anemia (or, for CMML, proliferative features) and SAID with steroid dependence and/or resistance. The primary endpoint was response rate (RR, including CR and PR) of SAID after 6 cycles of AZA. Secondary endpoints included RRof SAID after 3 cycles of AZA, response of MDS, time to MDS progression (including to AML), overall survival (OS) and safety. AZA was used at 75 mg/m²/d x 7 days, every 4 weeks for a minimum of 6 cycles (unless overt disease progression occurred before). At the onset of AZA, prednisone (PRED) was administered at 1 mg/kg during 1 month and then decreased progressively over 6 months. Results: 30 patients were included between July 2017 and June 2020 , 29 of whom received AZA and were considered evaluable: median age 72 [range 68-78], 69% males; WHO: MDS ML (n=11; 41%), CMML (n=11, 41%), MDS-RS (n=2, 7%), EB-1 (n=1) and EB-2 (n=1), unclassified (n=3); IPSS-R : good (n=15, 54%), very good (n=3; 11%, each), intermediate (n=7; 25%) and very poor profile (n=3; 11%) (all CMML had WBC 19 patients (65.5%, IC95% [45.7.82.1]) obtained a SAID response after 6 cycles (including 8 CR and 11 PR), while 17 (58.6% (IC95% [38.9; 76.5]) patients achieved an IWG 2006 hematological response (7 CR, 9 SD with HI and 1 marrow CR). All the 13 patients who received 12 cycles of AZA achieved SAID CR or PR at 12 months, and 10 of them had a hematological response (6 CR, 1PR, 2 HI, 1 marrow CR). The SAID response rate at 12 month was at 72.4% (IC95% : [51.3;85.6]). SAIDs complete/partial response occurred in 3/9 (33%) UBAI-positive versus 8/19 (42%) non-mutated cases. No significant prognostic factor of SAID response after 6 cycles, including sex, age, WHO classification, IPSS-R, UBA1 and TET-2 mutation status was found. With a median follow-up of 18.5 months [11.8; 24.3], 9 (31%) patients had died, with a 1-year OS of 82.3% (IC95% [69.4; 97.7]. At least one SAE occurred in 23 patients, with a median of 2 events/patient [1.5; 5.5]. Death was due to infection (n=5, two of them in patients with good IPSS-R, but severe steroid dependent SAID), MDS progression (n=2), or unrelated causes (n=2). Conclusion We confirmed prospectively an effect of AZA on the autoimmune/inflammatory component in two thirds of MDS/CMML patients with steroid dependent / refractory concomitant systemic autoimmune/inflammatory disease. No significant difference in AZA response was noted between UBA1 mutated and unmutated MDS patients. The adverse events and mortality rates, often from infectious origin, appear to be those expected in such an MDS population, potentially worsened by the associated SAID and background of immunosuppressive treatment (especially steroids) Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Ades: ABBVIE: Honoraria; TAKEDA: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Introduction : Adult' autoimmune hemolytic anemia (AIHA) can be life-threatening with an overall mortality rate of 8-10% which can rise up to 30% for patients admitted in intensive care unit (ICU). The factors associated with the need of management in ICU are partially unknown as only few data are available in the literature. To better describe the baseline characteristics and outcome of severe adult'AIHA admitted in ICU and to identify some prognostic factors, an observational multicentre study was set up by the French reference center of adult' immune cytopenias. Patients and Methods : This was an observational retrospective multicentre study. Patients had to fulfill the following inclusion criteria : 1) Age ≥ 18 years at time of AIHA onset ; 2) Definite diagnosis of primary or secondary warm (wAIHA), cold (cAIHA) or mixed AIHA ; 3) At least one admission in ICU specifically for the management of AIHA. Patients with AIHA admitted in ICU for another reason than the severity of AIHA were excluded. Patients' baseline characteristics at time of admission in ICU were recorded by means of a standardized form including the Charlson comorbidity score, the Knaus score, the Sequential Organ Failure Assessment (SOFA) and the Simplified Acute Physiology Score (SAPS II). Categorical variables were expressed as number (percentage) and quantitative variable as median [interquartile range]. To identify factors associated with death in ICU or after 1 year of follow-up, patients' characteristics were compared using usual tests. In order to identify some parameters associated with the risk of admission in ICU, the main characteristics of the patients were compared to those of controls (1 to 2 ratio) diagnosed with AIHA and followed over the same period who were never admitted in ICU. Univariate logistic regressions analyses were performed followed by a multivariate logistic regression using a backward stepwise selection procedure. A p-value Results : In total, 62 patients (42% of females) from 11 centers fulfilling the inclusion criteria were included for a total of 69 admissions in ICU (see table for baseline characteristics). Of note, 57/62 patients (92%) had a low (< 121) bone marrow reticulocytes index (BMRI) reflecting an impaired erythropoiesis. The mortality rate in ICU was 13%; 3 patients died from massive pulmonary embolism. Compared to the 54 survivors the 8 patients who died in ICU had: a higher CRP level (p value = 0.011); a higher need for transfusion (median number of packed red cells was 12 versus 4, p value = 0.008); higher SOFA and IGS scores (p value = 0.006); a higher number of organ failures on admission (p value < 0.001), thrombotic events (p value = 0.024) and sepsis during the stay in ICU (p value = 0.019). Among the survivors, 9/49 (5 lost of follow-up) eventually died within a year after the admission in ICU leading to an overall mortality rate of 30% at 1 year. For the management of AIHA in ICU, 56 patients (90%) were transfused (median number of packed red cells = 4 [2-7]); recombinant Epo was administered to 14 patients (22.5%) and 5 patients (8%) had plasma exchange. In ICU, 58 patients (95%) were treated with corticosteroids, 29 (46%) received at least one other treatment line including mostly : rituximab (n = 22), intravenous immunoglobulin (n = 10), iv cyclophosphamide (n = 5), cyclosporin (n = 3). Other treatment lines including chemotherapy-based regimen (n=8) were given afterwards. The characteristics of the 62 patients were compared to those of 138 controls with AIHA who were never admitted in ICU. In univariate analyses, younger age, Evans' syndrome, Hb level < 6 g/dl; reticulocytes count < 100 x 10 9/L, BMRI Conclusion : Based on this retrospective study, the mortality rate of adult patients admitted in ICU for AIHA was lower than expected (13%) but the 1 year mortality rate in this population of patients rose up to 30%. Patients with AIHA and a Hb level < 6g/dl, a high bilirubin level and/or an inadequate reticulocytes count must be treated promptly and monitored closely beyond the initial phase of the disease in order to reduce the mortality rate. The treatment of severe refractory cases is not consensual and should be harmonized. Figure 1 Figure 1. Disclosures Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Haioun: Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Godeau: Amgen: Consultancy; Sobi: Consultancy; Novartis: Consultancy; Grifols: Consultancy. Michel: Amgen: Consultancy; Rigel: Honoraria; Alexion: Honoraria; UCB: Honoraria; Argenx: Honoraria; Novartis: Consultancy. OffLabel Disclosure: rituximab is commonly used off-label as a second line for adult' AIHA

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease due to peripheral destruction but also impaired central production of platelets. Autoimmune reaction directed against megakaryocytes (MKs) has been described, and may explain morphological abnormalities of MKs observed in some patients with primary ITP. Thrombopoietin receptor agonists (TPO-RAs) are indicated as second-line treatments for ITP, but no predictive factors of response used in clinical routine practice has been demonstrated. The utility of systematic bone marrow smears (BMS) at ITP diagnosis is discussed. Howerer, it is usually recommended before second-line treatments. Two studies have suggested an association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for TPO-RAs. This study aimed to investigate the association between MK abnormalities and response to TPO-RAs in adult patients with primary ITP. Methods: The source of population was the CARMEN registry. The CARMEN (Cytopénies Auto-immunes: Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) with incident ITP in routine visit or hospital stay. ITP was defined by international definition (platelet count Results: During the study period, 451 patients with incident ITP were included in CARMEN-registry. Among them, 105 had been treated by TPO-RAs, including 65 with BMS before the exposure to TPORA. We then excluded 20 patients with secondary ITP and 7 with less than 10 MKs on the BMS. We finally included 38 patients in the analysis. Median age at diagnosis was 71 years (interquartile range - IQR: 31 - 94) and 34.2% were women. Thirty-three patients were treated with eltrombopag, 17 with romiplostim including 13 who were exposed to both TPORAs. Thirty-four (89.4%) achieved response. The median number of MKs analyzed per patient was 137 (IQR: 50 - 265). All results are presented in Table 1. In the main analysis, there was no significant difference in the median percentage of dysplastic MKs in responders (4.0%, 95% confidence interval - CI: 2.3 - 6.4) and non-responders (4.5%, 95% CI: 0.7 - 7.1). There was a trend for a higher proportion of granular MKs (4.5%, 95% CI: 3 - 6) and basophilic MKs (30.1%, 95% CI: 21.9 - 39.1) in non-responders comparing to responders (granular: 2.0%, 95% CI: 0 - 4.1; basophilic: 21.3%, 95% CI: 11.4 - 40.7). Results were similar in the subgroup of patients treated with eltrombopag (data not shown; the low number of patients treated with romiplostim precluded any analysis). Conclusion: In this study, neither MK abnormalities nor the pattern of MK maturation stages were significantly associated with response to TPO-RAs. These results do not support a systematic bone marrow smear in patients with primary ITP to look for morphological predictive factors of response to TPO-RA. Figure 1 Figure 1. Disclosures Comont: AstraZeneca: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees.

Introduction Although splenectomy is still considered as the most effective curative treatment for primary immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the emergence of thrombopoietin receptor agonist (TPO-RAs) and anti-CD20 monoclonal antibodies 1-3. The main objective of our study was to evaluate if splenectomy was still as effective in the modern era, particularly for patients who failed to respond to TPO-RAs and rituximab. One of the secondary objectives was to assess, among patients who did not respond to or relapse after splenectomy, the pattern of response to subsequent intervention with treatments used before splenectomy and particularly TPO-RAs. Methods This multicentre retrospective observational study involved adults who underwent surgical splenectomy for primary ITP in France from 2011 (authorization of TPO-RAs in France) to 2020. To be included in the study, patients had to fulfil the following criteria : age ³18 years, primary ITP diagnosis defined according to the usual international criteria 2. Patients with abnormal spleen histology (other than reactional lymphoid hyperplasia, white-pulp hypoplasia or red pulp hyperplasia) or yet definite secondary ITP were excluded. Response was defined according to international criteria 4. Sustained response was defined as the absence of ITP relapse at last visit. We performed univariable and multivariable logistic regression procedures to calculates the odds ratio associated with a sustained response. Results In total,185 patients, 98 (53 %) women, with median age at splenectomy of 43.3 [interquartile range 27.6-64.3] years, were included in 18 French university and general hospitals from the French reference center network. Most of the patients were splenectomised at the chronic phase of ITP (n=150, 81.1%) and only two patients had undergone surgery within 3 months after ITP onset. Of note, 100 (54.1%) and 135 (73.0%) patients received TPO-RAs and/or rituximab prior to the splenectomy, respectively. The median time of follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) of patients had an initial response and 23 patients (12.4%) relapsed during follow-up leading to an overall rate of sustained response of 65.4%, similar to the one observed in the pre-TPO-RA's era 1. Characteristics of patients according to the period during which occurred the splenectomy is available in Table 1. Among the 14 patients who failed to respond to both eltrombopag and romiplostim prior to splenectomy a sustained response after splenectomy was observed in 7 (50%). Among the 13 patients who had failed after both TPO-RAs and rituximab, we observed a sustained response in 6 (46%). In the multivariate analysis, an older age (60-75 years: OR 0,39 [0,17-0,86], p=0.02; >75 years: OR 0,28 [0,10-0,75], p=0.013) and a history of more than 4 treatment lines for ITP before splenectomy (OR 0.25 [0.08-0.66], p=0.010) were significantly associated with a lack of sustained response after splenectomy. TPO-RAs were used for 57/64 (89.1%) patients who failed to respond to splenectomy. Among them, 21 were treated with one TPO-RA (i.e. eltrombopag or romiplostim) which was previously used before splenectomy without any efficacy and a response was observed in 13 (62%) of them. Conclusions In conclusion, splenectomy seems to be still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients who fail to respond or relapse after splenectomy should be re-challenged with TPO-RAs. 1. Kojouri, K., Vesely, S. K., Terrell, D. R. & George, J. N. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term 2. Provan, D. et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 3.Neunert, C. et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 3, 3829-3866 (2019). 4. Rodeghiero, F. et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113, 2386-2393 (2009). Figure 1 Figure 1. Disclosures Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ebbo: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Attendance Grant; Sobi: Other: Attendance Grant. Viallard: Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy; LFB: Consultancy. Jeandel: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for congress; Sobi: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Support for congress; GSK: Other: Support for congress; Pharming: Other: support for congress. Michel: Amgen: Consultancy; Novartis: Consultancy; Rigel: Honoraria; UCB: Honoraria; Alexion: Honoraria; Argenx: Honoraria. Godeau: Grifols: Consultancy; Sobi: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Comont: Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

The pathophysiology of myelodysplastic syndromes (MDSs) is complex and often includes immune dysregulation of both the innate and adaptive immune systems. Whereas clonal selection mainly involves smoldering inflammation, a cellular immunity dysfunction leads to increased apoptosis and blast proliferation. Addressing immune dysregulations in MDS is a recent concept that has allowed the identification of new therapeutic targets. Several approaches targeting the different actors of the immune system have therefore been developed. However, the results are very heterogeneous, indicating the need to improve our understanding of the disease and interactions between chronic inflammation, adaptive dysfunction, and somatic mutations. This review highlights current knowledge of the role of immune dysregulation in MDS pathophysiology and the field of new drugs.