[Relapse with HLA loss after hematopoietic stem cell transplantation with non-HLA identical donor: Guidelines from the Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Perte d'hétérozygotie HLA dans les rechutes après greffes de cellules souches hématopoïétiques avec donneur non HLA identique : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Loss of heterozygosity or HLA loss is a genomic-type escape mechanism highlighted in certain types of relapses after allogeneic hematopoietic stem cell transplantation with a non-HLA identical donor, and especially after haplo-identical transplantation. The diagnosis must be made with certainty because the result conditions the therapy. In this article, the different mechanisms and techniques that can be used for the diagnosis of loss of heterozygosity, as well as the therapeutic options are reviewed, making it possible to establish clinico-biological recommendations for the diagnosis confirmation and management of the patients in relapse.

Impact of Calcineurin Inhibitor-Based Immunosuppression Maintenance During the Dialysis Period After Kidney Transplant Failure on the Next Kidney Graft Outcome: A Retrospective Multicenter Study With Propensity Score Analysis.

The impact of immunosuppressive therapy (IS) strategies after kidney transplant failure (KTF) on potential future new grafts is poorly established. We assessed the potential benefit of calcineurin inhibitor (CNI)-based IS maintenance throughout the dialysis period on the outcome of the second kidney transplant (KT). We identified 407 patients who underwent a second KT between January 2008 and December 2018 at four French KT centers. Inverse probability of treatment weighting was used to control for potential confounding. We included 205 patients with similar baseline characteristics at KTF: a total of 53 received at least CNIs on the retransplant day (G-CNI), and 152 did not receive any IS (G-STOP). On the retransplant date, G-STOP patients experienced a longer pretransplant dialysis time, were more often hyperimmunized, and underwent more expanded-criteria donor KTs than G-CNI patients. During the second KT follow-up period, rejection episodes were similar in both groups. The 10-year survival rates without death and dialysis were 98.7% and 59.5% in G-CNI and G-STOP patients, respectively. In the multivariable analysis, CNI-based IS maintenance was associated with better survival (hazard ratio: 0.08; 95% confidence interval: 0.01-0.58, p = 0.01). CNI-based IS maintenance throughout the dialysis period after KTF may improve retransplantation outcomes.

[Definition and standardization of histocompatibility requests depending on patient course and donor type: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society of Histocompatibility and Immunogenetics (SFHI)]. / Définition et standardisation des bilans d'histocompatibilité en fonction du parcours du patient et du type de donneur : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC) et de la Société Francophone d'Histocompatibilité et Immunogénétique (SFHI).

Standardization of histocompatibility tests for allogeneic hematopoietic cell transplants, harmonization of information transmitted to clinicians are part of quality improvement and optimization of human and economic resources. New HLA typing technologies provide high-resolution information within a reasonable time frame. Knowledge of high-resolution HLA typing for the patient and their relatives is essential for a better interpretation of compatibilities. HLA-DPB1 typing must be considered in transplant field regardless of the donor type. The benefits of using search and match programs are considerable. It saves time and reduces additional typing costs by providing rapid information about the likelihood to identify a matched unrelated donor. A backup therapy considering alternative cell sources or treatment can therefore be quickly implemented. The importance of knowledge and consideration of patient immunization for donor choice was explored in previous workshops of the SFGM-TC (2018 and 2019). The published recommendations remain applicable. The routine follow-up protocol and in case of desensitization will be detailed here. This harmonization must be accompanied by the standardization of information to be returned to the clinician regarding the donor finding possibilities for the patient. This will guarantee a similar quality level in every center.

Management of Immunosuppression After Kidney Transplant Failure: Effect on Patient Sensitization.

BACKGROUND: Immunosuppressive treatment is often interrupted in the first months following kidney transplant failure (KTF) to limit side effects. The aim of this study was to assess the effect of prolonged treatment (PT) of more than 3 months' duration after KTF on HLA sensitization and treatment tolerance. METHODS: We performed a retrospective observational study involving 119 patients with KTF in 3 French kidney transplant centers between June 2007 and June 2017. Sensitization was defined as the development of HLA donor-specific antibodies (DSA). RESULTS: In the PT group receiving calcineurin inhibitor (CNI) treatment, 30 of 52 patients (57.7%) were sensitized vs 52 of 67 patients (77.6%) who had early cessation of treatment (P = .02). The results were confirmed by multivariate analysis (odds ratio [OR] = 0.39, 95% confidence interval [CI] [0.16; 0.98], P = .04). The development of de novo DSAs after CNI treatment (n = 63/90 [70.0%]) was significantly more frequent than during CNI treatment, (n = 18/52 [34.6%], P = .01). Panel-reactive antibody ≥85% was lower in the PT group in multivariate analysis (OR = 0.28, 95% CI [0.10; 0.78], P = .02). No differences in the rates of infection, cardiovascular complications, neoplasia, and deaths were observed between the 2 groups. In multivariate analysis, continuation of corticosteroid treatment had no influence on sensitization but was associated with a higher rate of infection (OR = 2.66, 95% CI [1.09; 6.46], P = .03). CONCLUSION: Maintenance of CNI treatment after return to dialysis in patients requesting a repeat transplant could avoid the development of anti-HLA sensitization with a good tolerance.

Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy.

In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma targeted radionuclide therapy (TRT), we explore the interplay between immune system and the melanin ligand [131I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [131I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [131I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [131I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [131I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [131I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p < 0.0001) compared to TRT alone. Specifically, [131I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26 days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.

[Haploidentical hematopoietic stem cell transplant: How to choose the best donor? Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Greffe de cellules souches hématopoïétiques haplo-identiques avec cyclophosphamide en post-greffe : comment choisir le meilleur donneur en 2019 ? Recommandations de la Société francophone de greffe de mœlle et de thérapie cellulaire (SFGM-TC).

Haploidentical hematopoietic stem cell transplantation has been growing steadily since 2012. The SFGM-TC has twice published guidelines concerning T-cell repleted haploidentical grafts with high dose cyclophosphamide post-transplantation. The 2013 workshop recommended using the non-myeloablative Baltimore protocol with bone marrow and developed prospective protocols to evaluate these transplantations. The 2015 workshop reported improved results of reduced conditioning regimens in Hodgkin's lymphoma and intensive conditioning in myeloid hemopathies, and a similar outcome with 10/10 HLA matched donor with the same disease-risk score thus raising the question of the qualifier "alternative" for haploidentical transplants. The current work concerns the criteria for selecting the donor. The main criterion remains the absence of anti-HLA antibodies directed against the donor present in the recipient sera (DSA - Donor Specific Antibodies). In case of DSA and in the absence of an alternative donor, desensitization protocols exist. The other criteria are impossible to prioritize: age, sex, CMV, and blood type. The degree of relatedness and the number of HLA incompatibilities do not seem to be a criterion of choice. The 'ideal' donor would be a young man, CMV-matched, without major ABO incompatibility with a marrow transplant. There is insufficient data for the KIR-ligand and NIMA/NIPA mismatch. Peripheral stem cell grafts appear to yield more acute GVHD than bone marrow grafts after intensive conditioning, but with comparable survival rates. Based on the literature review, the comparison of haploidentical with unrelated donors encourages inclusion in existing national protocols randomizing these different donors.

Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis.

BACKGROUND: Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA). METHODS: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks. RESULTS: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13-9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01-5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01-5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30-674.79; p = 0.034). CONCLUSION: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level. TRIAL REGISTRATION: NCT01126541 ; 18 May 2010.

Vascular endothelial growth factor levels and rheumatic diseases of the elderly.

BACKGROUND: Increasing vascular endothelial growth factor (VEGF) has been reported in remitting symmetrical seronegative synovitis with pitting edema (RS3PE) syndrome, rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). The aim of this study was to compare VEGF levels in patients over 60 years of age who have RS3PE, RA, PMR or GCA so as to determine whether elevated VEGF is specific for a rheumatic disease, the inflammation or edema that occurs with these pathological conditions. METHODS: In this retrospective, multicentric study we assessed serum and plasma levels of VEGF in patients over 60 years of age with rheumatic diseases that were either de novo or of recent onset according to the initial clinical presentation, and we compared these patients with a control group. RESULTS: Serum and plasma VEGF levels were determined in 80 patients (5 with RS3PE, 13 with RA, 44 with PMR, and 18 with GCA) and 37 controls. Edema occurred in five patients with RS3PE, four with RA, and one with PMR, but not patients with GCA. Serum VEGF levels were significantly higher in individuals with rheumatic diseases (849 (405.5-1235.5) pg/ml) relative to the controls (484 (302-555) pg/ml) (p < 0.001). There were no significant differences between patients with RS3PE, RA, PMR, or GCA in terms of the VEGF serum levels (p = 0.60) or plasma levels (p = 0.57). Similarly, the occurrence of edema did not correlate with VEGF levels. CONCLUSION: VEGF increases in rheumatic diseases compared to a control group. This was not associated with specific rheumatic diseases or with edematous rheumatic diseases.

Peanut oral immunotherapy in adolescents: study protocol for a randomized controlled trial.

BACKGROUND: Peanut allergy is an increasingly common health problem. Current treatment guidelines are based on strict avoidance. However, in the last few years, oral immunotherapy protocols have shown promising results yielding increased tolerance to peanut in allergic children. Adolescence is particularly at risk. METHODS/DESIGN: We have designed a randomized, double-blind, placebo-controlled, multicenter study to investigate the efficacy and safety of peanut oral escalating immunotherapy in a 12- to 18-year-old population with proved allergy to peanut. Patients are selected when the threshold of peanut intake is over 100 mg and 2 cumulated g on the first double-blind, placebo-controlled oral food challenge (DBPCOFC). During the build-up placebo-controlled blinded phase, doses containing peanut or placebo will be administered by gradual up-dosing from 10 mg to 2 g with 2-weekly increments. After this first randomized phase, the desensitized participants will continue to intake native peanut in an unblinded process during 13 or 37 weeks following a second randomization. Adverse events are picked up and managed throughout the entire protocol. The main endpoint is the percentage of patients with negative DBPCOFC at the threshold of 2 g of cumulative peanut at the end of the build-up phase of 24 weeks. Secondary endpoints include: (1) desensitization 6 weeks and 6 months after the end of the maintenance phase; (2) adverse effects during the build-up phase; (3) immunological profile confirming peanut desensitization. Immunologic assays will be carried out at every DBPCOFC and at the middle of the build-up phase to evaluate the peanut immunologic profile modifications. DISCUSSION: This double-blind, placebo-controlled study will be, to our knowledge, the first evaluation of a peanut oral immunotherapy protocol in teenagers in the purpose to reduce severe reactions after unexpected intake and to improve quality of life. TRIAL REGISTRATION: ClinicalTrial.gov: NCT02046083 (23 January 2014).