Search

Patients with high-risk lymphoma have a poor prognosis when treated with standard chemoimmunotherapy. This retrospective study included 23 high-risk lymphoma patients with a median age at diagnosis of 59 (range, 35-68) years. They received 2 cycles of R-COPADM and 2 cycles of CYVE, completed by ASCT for fit patients. With a median follow-up of 46 (range, 3-78) months, three (13%) patients in the cohort died. Nearly half of the patients had an ECOG performance status of 2 or 3. Most patients in the cohort (91%, n = 21) had Ann Arbor stage III-IV disease, and 88% (n = 20) had an IPI of 3 to 5. LDH levels were elevated in 83% (n = 19) of patients. Overall, 30% of patients were identified as having double-expressor lymphoma and 22% as having DHL, while two patients (9%) had THL. The origin of the lymphoma was GC B-cell-like in 15 patients (65%) and ABC-like in 8 patients (35%). Cumulative incidence of relapse at 46 months was 14% (95% CI, 5-37), while overall survival was 87% (95% CI, 64-95) and progression-free survival was 83% (95% CI, 60-93). These results showed the efficacy and an acceptable safety profile of the R-COPADM/CYVE/ASCT regimen in high-risk lymphoma, including patients with DHL.

Purpose: The study aims to investigate the efficacy/acceptance of photobiomodulation by a quick and easy-to-use device for both preventing oral mucositis (OM) and reducing its severity in the setting of hematopoietic stem cell transplantation (HCT).Methods: Twenty-five consecutive patients underwent autologous HCT for hematological malignancies between November 2020 and October 2021. Prophylactic photobiomodulation (PBM) was used daily from day 1 of conditioning until the day of neutrophil recovery at a dose of 3 J/cm2. Curative PBM was started at a dose of 6 J/cm2 when at least one grade 1 OM had occurred. For each OM case, time of onset, National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 grade for OM, analgesic dose, and time to resolution were reported.Results: The median age of the 25 patients was 58 years (range, 39-74) and 14 (56%) were male. Twenty-one patients (84%) received a high dose melphalan conditioning regimen for multiple myeloma, and 4 (16%) patients received BEAM conditioning for aggressive lymphoma. A total of 178 CareMin650 sessions were performed, with a median of 7 days of application (range, 4-12), with no device-related adverse events (AEs). According to the NCI-CTCAE v5.0 scale, 76% (19 of 25) of patients presented grade 0 or 1 mucositis (no ulcers), five patients (20%) developed small ulcers (grade 2), and only one patient developed grade 4 mucositis. Satisfaction rates were high among patients and users.Conclusion: Photobiomodulation provides excellent safety and tolerance, as well as promising efficacy, both as a preventive and curative strategy, in patients undergoing autologous HCT.

For acute lymphoblastic leukemia (ALL) patients, total body irradiation (TBI)- based conditioning regimens are the first choice specially in young population. However, several studies have shown an equivalence in clinical outcomes with thiotepa-based conditioning regimen. We performed a retrospective study to evaluate the outcome of adult ALL patients who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with a thiotepa-busulfan-fludarabine (TBF) myeloablative conditioning regimen with reduced toxicity. Fifty-five patients received a TBF regimen. The median age of the patients was 51 years (range, 17 to 72.4). Most patients had a diagnosis of B-ALL (93%) with 7% having T-ALL. Two - and 5-year overall survival was 73.2% and 64%, respectively. At 2 years, leukemia-free survival and GVHD-free, relapse-free survival were 59.5% and 57.6%, and at 5 years, 53.4% and 51.8%, respectively. The 5-year non-relapse mortality was 15%. The day 180 cumulative incidence (CI) of grade II-IV acute GVHD and grade III-IV acute GVHD were 38.2% and 5.5%, respectively. At 2 years, the CI of chronic GVHD and extensive chronic GVHD was 16.9% and 1.9%, respectively. Our study results do suggest that using TBF as the conditioning regimen in adult ALL patients is a promising option with acceptable toxicity.

Background Daratumumab (Dara), an anti‐CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells. Methods We analyzed CD38 and PD‐L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara. Results We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well‐known rapid depletion of natural killer cells. Finally, we found that PD‐L1 expression on antigen‐presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase. Conclusion Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD‐L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD‐L1/PD‐1 pathway in patients with MM., Daratumumab have immunomodulatory effects on CD38‐expressing immune cells. Daratumumab prevents PDL1 expression on CD38‐expressing antigen‐presenting cells.

International audience

Objectives Haploidentical haematopoietic cell transplantation (Haplo‐HCT) using peripheral blood stem cell (PBSC) grafts and post‐transplant cyclophosphamide (PTCy) is being increasingly used; however, data on immunological reconstitution (IR) are still scarce. Methods This retrospective study evaluated T‐cell immunological reconstitution in 106 adult patients who underwent allogeneic haematopoietic cell transplantation for haematologic malignancies between 2013 and 2016. Results At D30, while conventional T cells reached similar median counts in Haplo‐HCT recipients (n = 19) and controls (n = 87), γδ and Vδ2+ T‐cell median counts were significantly lower in Haplo‐HCT recipients and it persists at least until D360 for Vδ2+ T cells. PTCy induces a significant reduction in early γδ and Vδ2+ T‐cell proliferation at D 7. At one year, the rate of increase in Epstein–Barr virus (EBV) viral load was significantly higher in Haplo‐HCT recipients as compared to controls (61% versus 34%, P = 0.02). In multivariate analysis, a higher γδ T‐cell count (> 4.63 μL−1) at D30 was the only independent parameter significantly associated with a reduced risk of increase in EBV viral load (RR 0.34; 95% CI, 0.15–0.76, P = 0.009). Conclusion Immunological reconstitution of γδ T cells is significantly delayed after Haplo‐HCT using PTCy and low‐dose ATG and is associated with an increased risk of increase in EBV viral load., In this study, immune reconstitution analyses with flow cytometry observed an impaired γ/δ and Vδ2+ T‐cell reconstitution following haploidentical haematopoietic cell transplantation using peripheral blood stem cell grafts and post‐transplant cyclophosphamide (PTCy). PTCy induces a significant reduction in early proliferation of γ/δ and Vδ2+ T‐cell subsets while impaired γ/δ T‐cell recovery was associated with an increased risk of increase in Epstein–Barr virus load.

This retrospective study evaluated the impact of a pre-emptive rituximab (RTX) strategy for Epstein-Barr virus (EBV) reactivation on immune recovery and outcomes of 219 high-risk recipients undergoing allogeneic stem cell transplantation (allo-SCT) for hematological malignancies or bone marrow failure. One-hundred and seven patients received pre-emptive RTX for EBV reactivation (RTX group) and 112 did not (control group). The median onset time of EBV reactivation was 49 days (range, 14-561), including five patients who developed post-transplant lymphoproliferative disorder (EBV-PTLD). RTX and control groups were pair-matched to assess the impact of RTX on all endpoints. In RTX patients, CD19 + B cells were significantly decreased until 1-year post-transplant, so were immunoglobulin levels. Twenty-one patients (17%) developed RTX-related neutropenia. There was, in the RTX group, a trend towards a lower cumulative incidence of chronic GvHD (P = 0.059). Overall survival, progression-free survival, non-relapse mortality, relapse incidence, and incidence of overall infections at 2 years following allo-SCT were comparable in the two groups. We conclude that pre-emptive RTX, despite inducing a delayed B-cell reconstitution and a high risk of RTX-related neutropenia, may be considered as a worthwhile treatment, given the absence of negative impact on post allo-SCT outcomes and a low incidence of EBV-PTLD.

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As2O3 preferentially inhibited IFN-α secretion as compared to other cytokines such as TNF-α, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As2O3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs’ capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition, and regulatory phenotype induced by As2O3. Collectively, our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature., Graphical abstract High concentrations of As2O3 induce apoptosis of plasmacytoid dendritic cells (pDCs) with increased BAX/BCL-2 ratio. At clinical relevant concentrations, As2O3 preferentially inhibits IFN-α secretion via down-regulation of interferon regulatory factor 7 expression, and down-regulates pDCs’ capacity to induce T and B cell responses. Moreover, the As2O3 effects on pDCs were uncompromised in systemic sclerosis patients.Image 1

Introduction The outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with refractory myeloid malignancies remains poor. Thiotepa-based sequential conditioning has shown promising results for various refractory hematological malignancies (Duléry R et al. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021). However, no study has evaluated the outcome of this sequential approach specifically in refractory myeloid malignancies. The optimal dose of chemotherapeutic agents used in the conditioning regimen and the feasibility of this sequential approach in patients aged 60 years and above also need to be assessed. Methods All consecutive patients with refractory myeloid malignancy who underwent allogeneic HCT with a thiotepa-based sequential conditioning regimen in Saint Antoine hospital between April 2013 and October 2020 were included. The sequential approach consisted of a broad spectrum cytoreduction with thiotepa, etoposide, and cyclophosphamide (TEC) from day -15 to -10. Then, after a 3-day rest, a reduced-intensity conditioning (RIC) regimen was administered with fludarabine 150 mg/m 2, intravenous busulfan 6.4 mg/kg and thymoglobulin 5 mg/kg from day -6 to -2. From 2013 to 2018, doses of thiotepa (10 mg/kg), etoposide (400 mg/m 2) and/or cyclophosphamide (1600 mg/m 2) could be reduced in patients older than 60 years or with comorbidities. Since September 2018, the use of a reduced TEC-RIC regimen (thiotepa at 5 mg/kg, etoposide 300 mg/m 2 and cyclophosphamide 1200 mg/m 2 from day -13 to -10) became the new standard of care for all patients. After transplant, patients could receive a hypomethylating agent or targeted therapy to prevent relapse. Prophylactic donor lymphocyte infusions were given to enhance the graft-versus-leukemia effect, in the absence of contraindication. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil for all patients. Post-transplant cyclophosphamide was added in the case of haploidentical HCT. Results Seventy-one patients (median age 61 years, range 15-76) were included. Diagnoses comprised acute myeloblastic leukemia (n=65) and myelodysplastic syndrome/chronic myelomonocytic leukemia (n=6). Donors were haploidentical (n=36), matched related (n=13), unrelated (n=21) and umbilical cord blood (n=1). A reduced TEC-RIC was administrated to 43 (61%) patients, a full dose TEC-RIC to 18 (25%), and a TEC-RIC with a dose reduction only for thiotepa to 10 (14%). With a median follow-up of 45.4 months (95% CI: 36.7-63.6), the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 51%, 41%, and 24%, respectively. Patients receiving a reduced TEC-RIC had a lower cumulative incidence of acute and chronic GVHD (acute grade II-IV GVHD: 14%, acute grade III-IV GVHD: 0%, chronic GVHD: 19%) than the other patients (acute grade II-IV GVHD: 29%, acute grade III-IV GVHD: 18%, chronic GVHD: 29%). The outcomes were not significantly different according to the TEC dose in terms of relapse incidence, OS, and PFS, although the NRM was lower with the reduced TEC-RIC (21% versus 28%, p=0.72). Most notably, patients aged 60 years and above had a 2-year OS and PFS of 48% and 39%, respectively, with no significant difference compared to patients younger than 60 years (Figure). Conclusion Our findings endorse the feasibility and efficacy of a thiotepa-based sequential approach for refractory myeloid malignancies undergoing HCT. The dose reduction did not compromise disease control and expanded the transplant option to older patients, ineligible for a higher dose regimen. Thus, a reduced TEC-RIC sequential regimen can be proposed for selected patients older than 60 years and allows promising outcomes for the treatment of refractory myeloid malignancies. Figure 1 Figure 1. Disclosures Duléry: Gilead: Other: travel support and meeting fees; Takeda: Consultancy; Novartis: Honoraria. Malard: Therakos/Mallinckrodt: Honoraria; Biocodex: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Legrand: Servier: Consultancy. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

International audience; Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). The majority of aGVHD mouse models are based on radiation conditioning and bone marrow as graft, despite that most allo-HCTs performed now in clinic are based on chemotherapy conditioning and G-CSF mobilized graft. Aiming for a higher translational value, we constructed an MHC major mismatched [C57BL/6 (H-2 Kb) to BALB/c (H-2Kd)] aGVHD mouse model based on busulfan/cyclophosphomide (BU–CY) conditioning and human G-CSF mobilized splenocytes as graft. Allogeneic transplanted mice showed quick and profound donor engraftment. Moreover, there were quick onset (day +7) of typical clinical and histopathological signs of aGVHD, which gradually developed to extensive aGVHD. In addition, CD8+ T cells were the main aGVHD contributing T-cell subtype. No toxicity or GVHD signs were observed in the syngeneic setting. This clinical-relevant model offers a promising platform for future studies on aGVHD.

Career situation of first and presenting author Student for a master or a PhD Introduction Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting Immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases.1 Tfh cells can infiltrate the skin of SSc patients, and induce fibrosis in vitro.2 Objectives The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. Methods Using flow cytometry, we analyzed cTfh cells from 52 SSc patients with no immodulotary treatment and 38 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells from 13 SSc patients and 6 HC were performed for functional analysis. IgG and IgM production were measured by ELISA. BCL-6, Blimp-1, CXCL13 and IL-21 expression were analyzed by RTqPCR. Results We observed that cTfh cell numbers are increased in SSc patients compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from SSc patients present an activated Tfh phenotype, with high expression of BCL-6 and increased capacity to produce IL-21 in comparison to HC. In vitro, cTfh cells from SSc patients had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than cTfh cells from HC. Blocking IL-21 or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells9 capacity to stimulate the plasmablasts and Ig production. Conclusions Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc. References Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014;41(4):529-42. Taylor DK, Mittereder N, Kuta E, Delaney T, Burwell T, Dacosta K, et al. T follicular helper-like cells contribute to skin fibrosis. Sci Transl Med 2018;10(431). Acknowledgements This work was supported by the Aterhit foundation and received grants from 9Groupe Francophone de Recherche sur la Sclerodermie’ (GFRS). Disclosure of Interest None declared

Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity. Herein, we studied Slan-DCs from the BM and blood of MM patients. We performed quantitative and functional analyses of these cells from 54 patients with newly diagnosed, symptomatic MM, 21 patients with MGUS and 24 responding MM patients. We found that circulating Slan-DCs were significantly decreased in MM patients as compared to those of healthy donors or patients with MGUS, while CD14+CD16+ intermediate monocytes accumulate in the BM. Moreover, after activation with TLR7/8 ligand R848, IL-12-producing Slan-DCs from the BM or peripheral blood from MM patients were decreased as compared with healthy donors. We show that MM cell lines or MM cells isolated from patients at diagnosis were able to inhibit the production of IL-12 by Slan-DCs, as well as to shift the phenotype of Slan-DCs towards an intermediate monocyte-like phenotype. Finally, Slan-DCs that have been cultured with MM cells reduced their capacity to induce T cell proliferation and Th1 polarization. We conclude that Slan-DCs represent previously unrecognized players in MM development and may represent a therapeutic target.

Malgre les progres realises dans le traitement des syndromes myelodysplasiques (SMD), notamment lies aux agents hypomethylants, l’allogreffe de cellules souches hematopoietiques (allo-CSH) d’un donneur HLA-compatible reste la therapeutique offrant la meilleure probabilite de remission. Depuis de nombreuses annees, le nombre d’allo-CSH est en augmentation et se developpe chez les patients plus âges, notamment grâce au developpement des conditionnements a intensite reduite [...]

L’amylose systemique a chaines legeres (AL) est caracterisee par des depots toxiques de fibrilles au sein d’organes (reins, foie, cœur, systeme nerveux ou poumons) engendrant une dysfonction progressive parfois severe [1]. Si le traitement initial de l’amylose AL comprend l’association de melphalan et de dexamethasone [2] ou celle de bortezomib, de cyclophosphamide et de dexamethasone [1], il n’existe pas de traitement approuve en situation refractaire ou de rechute malgre [...]

Le traitement de premiere ligne du myelome multiple a pour objectif d’obtenir un taux de reponse globale (RG) eleve pour l’ensemble des patients, permettant une duree de remission et une survie prolongees [1]. Chez les patients atteints de myelome multiple, au diagnostic ou lors d’une rechute, il a ete recemment montre que l’association d’un agent immunomodulateur, le lenalidomide, a un inhibiteur du proteasome, le bortezomib, conduisait a un taux de RG interessant, avec [...]

L’ibrutinib, inhibiteur irreversible de la tyrosine kinase de Bruton et de la kinase inductible par l’interleukine-2, est approuvee pour le traitement de la leucemie lymphoide chronique en situation refractaire ou en rechute. Cette nouvelle molecule a ete autorisee en 2014 par la Food and Drugs Association et les agences europeennes [1] sur la base des resultats de l’etude Resonate, qui rapportait [...]

La greffe allogenique de cellules souches hematopoietiques (allo-CSH) represente une therapeutique efficace dans le cadre de la leucemie lymphoide chronique (LLC) de haut risque. Une etude retrospective recente, colligeant cinquante-deux patients atteints de LLC en rechute apres une allo-CSH, revele des taux de survie globale (SG) de 67 % a deux ans et 38 % a cinq ans [1]. Une alternative [...]

Introduction Arsenic trioxide (As2O3), a well-established drug for acute promyelocytic leukemia, has been recently shown to have therapeutic potential in a number of mouse models of autoimmune diseases such as, systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and chronic graft-versus-host disease. However, the therapeutic mechanism remains largely unknown. Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialized in secreting high level of type I interferons and promote anti-viral responses. Clinically, pDCs have also been reported to be implicated in the pathogenesis of a series of autoimmune diseases characterized by a type I IFN signature, such as SSc. Given the pathogenetic and therapeutic role of As2O3 and pDCs in the same spectrum of diseases, we examined the effects of As2O3 on pDCs viability and functions to better understand the therapeutic mechanism of As2O3 on pDC-related autoimmune diseases. Materials and Methods pDCs cells were isolated from fresh peripheral blood mononuclear cells (PBMCs) by magnetic selection. pDCs were cultured in presence of different concentrations of As2O3 to check for viability and functional changes. pDCs viability and apoptosis were checked by flow cytometry with Fixable Viability Dye-Annexin V staining. Phenotype evaluation was done with surface staining. Bcl-2 and Bax protein expressions, reactive oxygen species (ROS) level, and cytokine production of pDCs were measured by intracellular staining. IRF7 and phospho-IRF7 protein levels were measured with cell signaling staining. Cytokine concentrations in supernatants were quantified by ELISA, and IRF7 expression in pDCs was analyzed by real-time RT-PCR. Naïve CD4+ T and CD19+ B cells were isolated from PBMCs. A pDC/T cell co-culture system was constructed to test As2O3 effect on pDCs in inducing T cell proliferation and polarization. A pDC/B cell co-culture system was used to test As2O3 effect on pDCs in inducing B cell differentiation. Results We first investigated the effect of As2O3 on the viability of human pDCs. We observed that As2O3 decreased dose-dependently the percentages of viable pDCs by inducing cell apoptosis. We then checked the protein expression levels of the apoptosis related Bcl-2 family proteins. As2O3 induced a dramatic upregulation of Bax, while slightly down-regulated the expression of Bcl-2, leading to a significantly decreased Bcl-2 to Bax ratio, which determined cell apoptosis. As2O3 is a well-known inducer of oxidative stress, which is one of the major upstream mediators of cell apoptosis. We first demonstrated that As2O3 induced reactive oxygen species (ROS) within pDCs. However, the anti-oxidant NAC pre-treatment only slightly decreased the percentages of apoptotic cells, indicating that As2O3 could induce pDCs apoptosis independently of ROS generation. Then, we investigated the functional effects of As2O3 on pDCs, and observed that culture for 6h with 5μM of As2O3 almost totally inhibited production of IFN-α from gated pDCs within PBMCs (IFN-α positive cells: 28.56±9,99% without As2O3 vs 1.43±1.65% with 5μM As2O3, p Further studies revealed that As2O3 inhibited the secretion of IFN-α from activated pDCs by potently down-regulating the total protein and mRNA expression, and also phosphorylation level of inteferon regulatory factor 7 (IRF7), a key adaptor of the type I inteferon pathway. Finally, As2O3 inhibited pDCs maturation by decreasing the expressions of CD80, CD86 and HLA-DR, and increasing PD-L1 expression. As2O3 also down-regulated pDCs capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Conclusion Our study demonstrated that As2O3, at different concentrations, negatively affects the viability and functions of human pDCs, suggesting that pDCs could be a target for As2O3 treatment efficacy in autoimmune diseases with type-I interferon signature. We are currently running a prospective multicenter clinical trial testing As2O3 in the setting of chronic GVHD (ClinicalTrials.gov Identifier: NCT02966301). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria.

Background: Allogeneic hematopoietic stem cell transplantation using a related haploidentical donor (Haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. However, use ofperipheral blood stem cell graft (PBSC) is associated with an increased risk of acute GvHD (aGvHD) compared to bone-marrow graft. Therefore, while cyclosporine A (CsA) and mycophenolate mofetil (MMF) are traditionally initiated after completion of PT-Cy at day +5, we decided to initiate them at day -3 before transplant and to add a low dose of ATG to reinforce GvHD prophylaxis in those patients. With this background, we analyze retrospectively the impact of early initiation of CsA and of CsA concentration on patients' outcome in all patients who underwent Haplo-HCT with PBSC grafts and PTCy. Patients and Methods: Sixty-one consecutive patients who underwent Haplo-HCT for hematological malignancies between October 2013 and August 2017 were included in this retrospective single-center study. All patients received G-CSF mobilized PBSC as grafts and post-transplantation immunosuppression with CsA and MMF. CsA was administered at a dose of 3mg/kg by continuous intravenous infusion starting from D -3 and changed to twice daily oral dosing as soon as tolerated.MMF was administered at a fixed oral dose of 2g per day starting from day 6 without adjustment. In the absence of GvHD, MMF and CsA were tapered over 4 weeks starting from day 30 and day 60, respectively. CsA blood trough concentrations were monitored 3 times per week during the intravenous treatment and at least once per week after switch to oral dosing. CsA doses were adjusted to achieve blood levels between 200 and 300 ng/mL and to prevent renal dysfunction. The primary endpoint was to determine the impact of the CsA concentration on the risk of grade II-IV and III-IV aGvHD. Results: Median age was 53 (range, 15-72) years, with 16 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid (64%) or lymphoid malignancies (36%). According to the Disease Risk Index, patients were considered as low-risk, intermediate-risk, high-risk or very-high-risk (respectively 8%, 56%, 31% and 5%). Twenty-five patients (41%) with refractory disease received a sequential conditioning regimen while the remaining (n=36, 59%) received a RIC/RTC regimen based on fludarabine, busulfan and thiotepa. 51 patients (83%) received ATG (2.5-5 mg/Kg total dose) as part of the conditioning regimen. All patients received standard PTCy, nine at D+3 (15%) and 52 at D+3 and D+5 (85%). All patients engrafted at a median of 18 (range: 13-35) days after Haplo-HCT and the median follow-up among surviving patients was 21 (range: 13-53) months. The median concentrations of CsA at 1, 2, 3, and 4 weeks after Haplo-HCT were 272 (range: 114-911), 296 (range: 132-516), 251 (range: 111-485), and 246 (range: 36-375) ng/mL, respectively. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. The CIs of chronic GvHD (cGvHD), extensive cGvHD and relapse were 41%, 19% and 35% at 18 months after Haplo-HCT, respectively. At 18 months after the transplant, the OS, PFS and GPFS rates were respectively 60%, 55% and 48%. In univariate analysis, patients having the lowest CsA concentration in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (49% vs 18%; P= .02), severe grade III-IV aGvHD (26% vs 0%; P = .03), cGvHD (P= .02) and extensive cGvHD (P= .04). We do not find statistically significant correlation between CsA concentration and relapse incidence, NRM, PFS, GPFS or OS. In multivariate logistic regression analysis, higher CsA concentration (> 301 ng/ mL; the cut-off value defined by ROC analysis) during the first week following Haplo-HCT was the only independent parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (respectively P = .04; RR .11; 95% CI, 0.05-0.94; and P < .0001; RR < .001; 95% CI, 0.000007-0.00006). There was no association with extensive cGvHD (P = .14; RR .11; 95% CI, 0.06-1.48). Conclusion: We conclude that achievement of high concentration of CsA early after Haplo-HCT using PBSC graft is associated with a low incidence of aGvHD and that CsA should be initiated at time of transplant with adequate monitoring during the engraftment period to reduce the risk of grade II-IV aGvHD. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria.