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Background Intestinal fibrosis is a common complication of Crohn’s disease (CD) leading to progressive bowel stricture formation. Mesenchymal stem cells (MSCs), known for their immunomodulatory, anti-inflammatory and anti-fibrotic properties, could be a potential therapy in this frequently fibro-inflammatory condition. In this phase I–II open-label pilot trial, we aimed to assess safety and efficacy of local MSCs injection in CD strictures. Methods: CD patients with a non-passable stricture, length from 2 to 5 cm, accessible by ileocolonoscopy, but without intestinal obstruction, fistulas, or abscess, could be included. A total of 3X107 allogenic bone-marrow derived MSCs were equally injected in the 4 quadrants of the strictured bowel wall during an ileocolonoscopy. Adverse events and clinical scores (Crohn Disease Activity Index, Short Health Scale and Crohn Disease Obstructive Score) were evaluated at each follow-up visit (at week 4, 12, 24 and 48) while endoscopy was performed at baseline, W12 and W48. The main judgement criteria for efficacy was the complete (defined by the ability to pass the ileocolonoscope) or partial (defined by a diameter increase) resolution of the stricture at 12 weeks. Other efficacy criteria included complete or partial resolution of the stricture at 48 weeks as well as the evolution of clinical scores between weeks 0, 12 and 48. Results Between 2018 and 2020, we performed 11 local MSCs injections in 10 CD patients (6 female; aged to 38-65 years; median 45 years old; 70% were smoker). The strictures’ (3 primary, 7 anastomotic) location was as follows: 7 at an ileo-colonic or ileo-rectal anastomosis, 1 colonic and 2 of the ileocecal valve. MSCs injections were well tolerated but a total of 5 hospitalizations for occlusion were reported (2 secondary to a different stricture than the injected one) leading to a surgical resection for one patient and an endoscopic dilatation for another one. Neither intestinal perforation nor intra-abdominal fistula or abscess was reported. At 12 weeks, 5 patients (45%) presented a stricture improvement with a complete resolution for 2 and a partial resolution for 3. Of the 11 MSCs injections, 6 patients were re-evaluated at week 48 (2 patients still undergoing follow-up, 1 operated, 1 dilated, and 1 lost to follow-up), 4 patients had a complete resolution and 1 had a partial resolution. The evolution of clinical scores between weeks 0, 12 and 48 (Figure 1) was not statistically significant. Conclusion Local MSCs injection in non-passable CD stricture was well tolerated over the short term but several occlusions were reported in the follow-up. Combining the effects of MSCs with the proven effect of endoscopic balloon dilatation could possibly improve the outcome of CD stricture.

ispartof: EJHaem vol:1 issue:1 pages:338-341 ispartof: location:United States status: Published online

BackgroundPeripheral T cell lymphomas form a heterogeneous group with a usually dismal prognostic. The place of allogeneic stem cell transplantation to treat PTCL is debated.MethodsWe retrospectively analyzed the overall survival (OS), event-free survival (EFS), relapse, and transplant-related mortality (TRM) and associated variables in 285 adults with non-primary cutaneous PTCL (PCTL-NOS (39%), angioimmunoblastic T cell lymphomas (29%), anaplastic T cell lymphomas (15%), and other subtypes (17%)), who received alloSCT in 34 centers between 2006 and 2014.ResultsAlloSCT was given as part of front-line therapy (n= 138) to 93 patients in first complete response (CR) and 45 in first partial response (PR), and of salvage therapy (n= 147) to 116 patients for second or more CR/PR and 31 for progressive disease. Reduced-intensity conditioning (RIC) was given to 172 patients (62%), while 107 (38%) received myeloablative conditioning (MAC). The median follow-up was 72.4 months. The 2- and 4-year OS were 65% and 59%, respectively, and the cumulative incidence of relapse was 18% after 1 year and 19% after 2 years. TRM was 21% at 1 year, 24% after 2 years, and 28% after 4 years. In multivariate analysis, grade III–IV acute GvHD (HR = 2.57, 95% CI 1.53–4.31;p= 0.00036), low Karnofsky score < 80% (HR = 5.14, 95% CI 2.02–13.06;p= 0.00058), and progressive disease status before transplant (HR = 2.21, 95% CI 1.25–3.89;p =0.0062) were significantly associated with a reduced OS.ConclusionsThe data demonstrate in the largest retrospective cohort of non-cutaneous PTCL so far reported that alloSCT after RIC or MAC is an effective strategy, even in chemoresistant patients.

Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia7g/dL despite hydroxycarbamide, need to maintain transfusion programs longer than six months, and major transfusion difficulties related to red blood cell alloimmunization. In children with an HLA-identical sibling donor, we recommend a myeloablative conditioning regimen associating high dose busulfan, cyclophosphamide and ATG, considering the excellent results of this approach In patients over 15 years of age, we recommend the NIH approach consisting of a reduced intensity conditioning regimen by alemtuzumab, and 3Gy total body irradiation, followed by peripheral hematopoietic stem cells and post-transplant immunosuppression by sirolimus In the absence of HLA-identical sibling donor, there is no definitive data for preferring transplant from unrelated versus haplo-identical donors but we recommend to evaluate these approaches in prospective trials.

Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.

International audience; 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.

Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19-and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively., SCOPUS: re.j, info:eu-repo/semantics/published

International audience; Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia

Poor graft function (PGF) is a rare but serious complication of hematopoietic cell transplantation (HCT). Boost of CD34+stem cells could be a therapeutic option but is not always feasible nor successfull. Due to their hematopoietic support properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after HCT. Here, we conducted a multicenter prospective study to evaluate the efficacy of MSC perfusion to improve PGF after HCT. Thirty patients (median age 51y, range 11 to 70y) received a single IV administration of third-party donor BM-derived MSC (1-2 x 10 exp6/kg body weight) for PGF after allogeneic HCT (median 151 days after HCT, range 62- 430). PGF was defined as (1) at least one cytopenia (Hb < 80 g/L, absolute neutrophil count [ANC] The primary endpoint was response at day +90 after MSC administration. A significant decrease in RBC and platelet transfusion requirements was observed at day + 90 after MSC (median monthly frequencies of 0 and 0 vs. 5 and 4 before MSC, respectively, p ≤0.001). An increase in ANC was also noted (median 2.500 at day 90 vs. 1.767 x 10exp9/L before MSC, p= 0.04), with 2/5 patients with severe neutropenia having recovered an ANC > 0.5 x 10exp9/L. At day 90 post-MSC, 51.8% (95% CI, 33 - 70.7%) of patients resolved at least one of their cytopenias (overall response, OR) and 40.7% (95% CI, 22.2 - 59.3%) achieved a complete haematological recovery (CR: ANC >0.5 x 10exp9/L and transfusion independence). Corresponding response rates increased at day 180, with 69.2% (95% CI, 51.5 - 86.9%) OR and 61.5% (95% CI, 42.8 - 80.2%) CR, respectively. Overall survival at 1 year post-MSC was 70% (95% CI, 53.6 - 86.3%), with all but one of the d90-responders being alive (1 death to relapse of hematological malignancy). No severe adverse event related to MSC administration was reported during the 1-year follow-up. In conclusion , perfusion of BM-derived MSC from a third party donor appeared to be safe and to improve PGF after allogeneic HCT, although spontaneous amelioration cannot be excluded. Further (ideally comparative) studies are warranted to confirme our results. Disclosures Selleslag: Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau.

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

Introduction Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment option in patients with advanced Chronic Myeloid Leukemia (CML) who have disease resistant to tyrosine kinase inhibitors (TKI) or who cannot tolerate these agents. In the absence of a matched sibling donor (MSD), the use of an unrelated donor (UD) is recommended; however, this approach is associated with a higher incidence of both graft-versus-host disease (GvHD) and non-relapse mortality (NRM). Post-transplant cyclophosphamide (PTCy) has been found to result in similar rates of GvHD-free, relapse-free survival (GRFS) in allo-HCT using UD, haploidentical donors (HD) and MSD across a range of haematological malignancies. However, the role of PTCy in allo-HCT using UD and HD in CML is unknown. We here report an observational, retrospective, comparative study on the role of PTCy in UD and HD in CML patients undergoing allo-HCT. Methods Inclusion criteria were age ≥ 18 years, diagnosis of CML, first AlloHCT from 2012 to 2019, and UD and HD. The main endpoints of the study were to compare the one-year GRFS of allo-HCT using UD with standard GvHD prophylaxis (SP), PTCy UD and PTCy HD. Secondary endpoints were 3-year OS, 3-year PFS, 3-year NRM, 3-year RI, Day +100 acute GvHD (aGvHD) and one-year chronic GvHD (cGvHD). The Kaplan-Meier estimator and log-rank test were used for GRFS, OS and PFS, and the crude cumulative incidence estimator and Gray's test were used for competing events (RI/NRM, aGvHD/death before aGvHD and cGvHD/death before cGvHD). Cox proportional hazard regression was used in multivariable analyses (MVA) using patients with complete data with cause-specific models for competing risk outcomes. Results A total of 1,341 CML patients treated in EBMT centers were included. 1,094 patients received allo-HCT from SP UD, 113 from PTCy UD and 134 from PTCy HD. 61% and 54% of patients received an allo-HCT from matched UD in the SP UD and PTCy UD cohort, respectively. SP UD GvHD prophylaxis was calcineurin inhibitor-based in 88% of patients; some form of T-cell depletion was used in 82%, 19% and 9% in the SP UD, PTCy UD, and PTCy HD cohorts, respectively. Further transplant and patient details can be found in Table 1. The median follow-up was 34.9 (IQR 13.2-61.2) months. One-year GRFS was comparable in the three cohorts: 56%, 53% and 48% in SP UD, PTCy UD, and PTCy HD, respectively (log-rank p=0.30). There was no significant difference in the cumulative incidence of aGvHD at D+100 (Gray's test p=0.10) and one-year cGvHD (p=0.40) among cohorts. Conversely, the 3-year relapse incidence (RI) was significantly lower in the SP UD cohort (26%), compared to the PTCy UD (35%) and PTCy HD (34%) cohorts (Gray's test p=0.03) and the 3-year progression-free survival (PFS) was 53% vs 47% vs 45% in the SP UD, PTCy UD and PTCy HD cohorts, respectively (log-rank p=0.05). 3-year NRM was similar among cohorts 20% vs 18% vs 21% in SP UD, PTCy UD and PTCy HD, respectively (Gray's test p=0.80) and the three cohorts had a similar 3-year OS (64%, 60% and 59% in SP UD, PTCy UD and PTCy UD, respectively) (p=0.50). In total 902 patients (68%) had complete data. In MVA, higher age (HR per 10 year increase in age 1.24, 95% CI 1.06-1.45, p=0.007) and high HCT-CI (HR high vs. low 2.43, 1.59-3.71, p Conclusion Based on our results, PTCy resulted in comparable outcomes in UD and HD allo-HCT, when compared to SP UD allo-HCT, as GRFS, PFS, NRM and OS were similar. However, there was a trend to a lower RI and higher PFS in SP UD allo-HCT which may have reached significance in a larger cohort. Furthermore, the findings of this study confirm that PTCy HD allo-HCT in CML is a valid option for patients lacking a MSD or UD. In addition, disease stage pre-transplant remains a major prognostic factor with CP1 patients having better outcomes when compared to those with more advanced phases and ≥CP1 CML. Overall, our results provide information on the efficacy of PTCy in allo-HCT for CML, and show that PTCy UD and PTCy HD are feasible allo-HCT platforms for patients diagnosed with CML. Figure 1 Figure 1. Disclosures Ortí: BMS, Novartis, Incyte, Pfizer: Honoraria, Speakers Bureau. Kulagin: X4 Pharmaceuticals, Alexion, Apellis, Biocad: Research Funding; Novartis, Generium, Sanofi, Roche, Johnson & Johnson, Pfizer: Speakers Bureau. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy in patients with primary or secondary myelofibrosis. Ruxolitinib, a JAK-inhibitor, has been approved in myelofibrosis patients and is effective to alleviate symptoms of the disease in a substantial proportion of patients. In a French phase 2 study, the use of ruxolitinib as a bridge to HSCT was followed by a high transplantation rate, with one third of patients presenting clinical improvement before HSCT (partial response or spleen size reduction) (BMT 2021, Robin et al). The aim of the current study is to compare post-transplantation outcomes between patients who received ruxolitinib before HSCT and those who did not. Methods: This retrospective study includes patients with primary or secondary myelofibrosis registered in the SFGM-TC registry including patients from France, Belgium and Switzerland. Patients who received HSCT between July 2010 and December 2019 with available information regarding ruxolitinib treatment were included. The impact of ruxolitinib was analyzed by multivariable Cox regression and a propensity score. Results: 305 patients could be included, of whom 143 received ruxolitinib prior to HSCT (RuxoG). All patient characteristics are given in RuxoG followed by no ruxolitinib group (noRuxo). The diagnosis before HSCT was primary myelofibrosis (83% vs 75%), secondary myelofibrosis (13% vs 19%) or transformed into AML (4% vs 6%). Karnofsky score at transplant was < 70% in 9% and 11%. In RuxoG. median age was older (60.29 vs. 58.75, p=0.069) and delay from diagnosis longer (20.42 vs 13.26 months, p=0.040). RuxoG patients had less frequently anemia < 10 g/dl (84% vs 98%, p=0.027) or thrombocytopenia < 50 G/L (22% vs 32%, p=0.066) and presented more frequently splenomegaly or pre-graft splenectomy (83% vs 63%, p=0.0007). DIPSS score was well balanced in both groups, being high or intermediate-2 in 100 patients (79% vs 86%, p=0.23), from the 235 patients with available data. Myeloablative conditioning regimen was used in 16% vs 26% (p=0.049), and conditioning regimen consisted of on fludarabine-busulfan in 33% vs 61%, fludarabine-melphalan in 47% vs 22% or other in 20% vs 16% (p Conclusion: Patients who received ruxolitinib before HSCT were at higher risk of acute GVHD and post-transplant mortality, but this was not observed in patients responding to ruxolitinib and it does not translate into higher risk of chronic GVHD. Main hypotheses to explain these finding could be: 1) specific disease, patient or transplant characteristics in RuxoG; 2) the longer delay to transplantation or 3) a specific effect of ruxolitinib. This study suggests that myelofibrosis patients responding to ruxolitinib should have the transplant without waiting disease progression. Figure 1 Figure 1. Disclosures Forcade: Novartis: Other: travel grant. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Duléry: Takeda Gilead Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robin: NEOVII MEDAC NOVARTIS: Research Funding.

INTRODUCTION: Myelodysplastic Syndrome (MDS) is a heterogenous disease which is almost incurable without an allogeneic hematopoietic cell transplantation (allo-HCT). Within the revised international scoring system (R-IPSS), MDS with poor and very poor cytogenetics have a much worse outcome after allo-HCT. The very poor cytogenetic subgroup refers to patients harboring more than 3 abnormalities and is therefore a highly heterogenous group. We have shown in acute myeloid leukemia (AML) that beyond complex karyotype, specific adverse cytogenetic features such as 7q abnormalities (abn7q), 5q abnormalities (abn5q), 17p abnormalities (abn17p) and monosomal karyotype (MK) worsen the outcomes after allo-HCT. We have therefore retrospectively reviewed MDS with very poor cytogenetics and studied the impact of adverse cytogenetic features on outcomes after transplant. METHODS: We selected MDS patients who underwent allo-HCT between 2001 and 2018 from a matched related or unrelated donor, for whom a full cytogenetic report was available in the EBMT registry. We then stratified them according to the presence of abn7q, abn5q, abn17p, MK and the number of abnormalities (≤5, 6-9 and ≥10). Graft-versus-host disease (GvHD) and relapse-free survival (GRFS) was defined as survival without grade II-IV acute GvHD, extensive chronic GvHD or relapse. RESULTS: A total of 154 patients were identified in the registry. One hundred twenty-three patients (81%) had MDS with excess of blasts and 4 (3%) had secondary AML. Median age was 59 years (interquartile range (IQR), 51-64) and the median follow-up was 38 months (95% confidence interval (CI), 34-60). The time from diagnosis to allo-HCT was a median of 6 months (IQR, 4-8). Two thirds of patients received a reduced-intensity conditioning regimen (N = 103, 67%) and 87 patients had a matched unrelated donor (57%). Almost all patients were in first complete remission at time of transplant (N= 149, 97%). Regarding specific cytogenetic features, 87 patients had abn7q (57%), 99 abn5q (64%), 59 abn17p (38%) and 120 MK (78%) with considerable overlap between groups. The 2-year overall survival (OS) and progression-free survival (PFS) was 34% (95% CI 26-42%) and 24% (95% CI 17-31%), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality (NRM) was 59% (95% CI 51-67%) and 18% (95% CI 12-24%), respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 33% (95% CI 25-40%) and 44% (95% CI 36-53%) by day 100 and 2 years respectively. The 2-year GRFS was 12% (95% CI 6-17%). The presence of abn5q was associated with a significantly decreased PFS of 17% (95% CI 9-25%) versus 36% (95% CI 23-49%); p=0.05) and GRFS (6% (95% CI 1-11%) versus 23% (95% CI 11-34%); p=0.04). The presence of abn7q was associated with significantly increased NRM (25% (15-34%) versus 9% (2-16%); p=0.02) which did not translate into OS. There were no specific cytogenetic features that had an independent impact on the cumulative incidence of relapse, but age over 55 years did increase the relapse risk (65: 66% (95% CI 50-83%); p=0.03). A continuous effect was also observed (per decade increase: HR=1.24, 95%CI 1.02-1.52; p=0.03). Patients with an interval of more than 6 months from diagnosis to allo-HCT had almost double the OS (45% (95% CI 32-58%)) compared to patients with an interval less than 6 months (27% (95% CI 17-37%); p=0.04), however a continuous effect was not observed. CONCLUSION: MDS with very poor cytogenetics according to R-IPSS is a very bad group with dismal outcomes after allo-HCT. Within this high-risk group, specific adverse cytogenetic features such as the number of abnormalities, abn7q, abn5q, abn17p or MK did not stratify outcomes further, except for abn5q which was associated with a decreased PFS. Our results might be explained in part by the low number patients and by the over-representation of adverse features within this cohort. Despite that, advancing age was associated with increased relapse. Whilst allo-HCT remains the best therapeutic option for this very high-risk patient group, efforts should focus on post-transplant preemptive intervention strategies to prevent relapse. Disclosures Byrne: Incyte: Honoraria. Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Scheid: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Introduction: Primary mediastinal B cells lymphoma (PMBCL) is a rare subtype of aggressive non Hodgkin lymphoma (NHL). Despite therapeutic progresses, 10 to 30% of PMBCL patients are primary refractory or experience early relapses (R/R). Despite Autologous hematopoietic cell transplantation (auto-HCT) after bridging therapy or new therapies such as PD-1 inhibitors or CAR-T cells, R/R PMBL patients have a very poor outcome. Allogeneic stem cell transplantation (allo-HCT) is thus a potentially curative treatment for patients who relapsed after salvage therapies. Only limited data have been published about allo-SCT in R/R PMBCL (Herrera A. F, BBMT 2019). In the present study conducted on behalf the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the lymphoma study association (LYSA) group, we investigated the outcomes of allo-transplanted adult R/R PMBCL. Methods This multicenter retrospective study included all adult R/R PMBCL patients reported to the SFGM-TC and who underwent an allo-HCT between 1999 and 2018. Data have been obtained through ProMISe (internet-based system shared by all European transplantation centers) and completed by consulting the medical files of the LYSA group centers. All patients have given signed informed consent. Results Thirty-three patients with R/R PMBCL from 19 French (n=29) and 3 Belgium (n=4) centers were included. The median age at transplant was 33 y (18-61), with a predominance of female patients (58%). Majority of patients had a low HCT-CI score [0 = 9/17 (53%), data missing in 16 patients]. Seventy-six percent of patients had an IPI score between 1 and 2 and Ann Harbor score was ≥ 3 in 56.6% at diagnosis. Median number of treatment lines before allo-HCT was 3 (1-6). All patients received poly-chemotherapies with anthracyclines and anti-CD20 as first-line therapy. Most sixty-one percent of patients had previously undergone auto-HCT and one patient received CAR-T before allo-HCT. Forty one percent of patients were primary refractory. At time of transplant, 50% of patients were in complete response, 40% in partial response, and 10% had a progressive disease. Conditioning regimen was reduced intensity regimen in 63%. Stem cell source was PBSC in 88%. Donors were sibling in 42% or matched related donor in 39%. An alternative donor was chosen in 18%. GVHD prophylaxis included antithymocyte globulin in 61%, and calcineurin inhibitor in 97%. Median follow up was 78 months (3.5-157). Considering the whole cohort, 2y OS, DFS, NRM, and cumulative incidence of relapse were 48% (95%CI: 33-70), 60% (95%CI: 44-82), 18% (95%CI: 7-34), and 34% (95%CI: 18-50) respectively. Cumulative incidences of day 100 grade I-II and III-IV acute GVHD 36% and 0%, respectively. Cumulative incidence was 32% among whom 33% had an extensive cGVHD. Patients with progressive disease at transplantation had worst 2y PFS and OS (PFS: HR: 6.12, 95%CI: 1.32-28.31, p=0.02 and OS: HR: 7.04, 95%CI: 1.52-32.75, p=0.013). Conclusion: To our knowledge, this is the largest published study evaluating outcomes of allo-HCT for R/R PMBCL. Although this is a retrospective study with a limited number of patients, the outcomes suggest that allo-HCT is a therapeutic option providing durable remissions for patients with R/R PMBCL. Introduction: Primary mediastinal B cells lymphoma (PMBCL) is a rare subtype of aggressive non Hodgkin lymphoma (NHL). Despite therapeutic progresses, 10 to 30% of PMBCL patients are primary refractory or experience early relapses (R/R). Despite Autologous hematopoietic cell transplantation (auto-HCT) after bridging therapy or new therapies such as PD-1 inhibitors or CAR-T cells, R/R PMBL patients have a very poor outcome. Allogeneic stem cell transplantation (allo-HCT) is thus a potentially curative treatment for patients who relapsed after salvage therapies. Only limited data have been published about allo-SCT in R/R PMBCL (Herrera A. F, BBMT 2019). In the present study conducted on behalf the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the lymphoma study association (LYSA) group, we investigated the outcomes of allo-transplanted adult R/R PMBCL. Methods This multicenter retrospective study included all adult R/R PMBCL patients reported to the SFGM-TC and who underwent an allo-HCT between 1999 and 2018. Data have been obtained through ProMISe (internet-based system shared by all European transplantation centers) and completed by consulting the medical files of the LYSA group centers. All patients have given signed informed consent. Results Thirty-three patients with R/R PMBCL from 19 French (n=29) and 3 Belgium (n=4) centers were included. The median age at transplant was 33 y (18-61), with a predominance of female patients (58%). Majority of patients had a low HCT-CI score [0 = 9/17 (53%), data missing in 16 patients]. Seventy-six percent of patients had an IPI score between 1 and 2 and Ann Harbor score was ≥ 3 in 56.6% at diagnosis. Median number of treatment lines before allo-HCT was 3 (1-6). All patients received poly-chemotherapies with anthracyclines and anti-CD20 as first-line therapy. Most sixty-one percent of patients had previously undergone auto-HCT and one patient received CAR-T before allo-HCT. Forty one percent of patients were primary refractory. At time of transplant, 50% of patients were in complete response, 40% in partial response, and 10% had a progressive disease. Conditioning regimen was reduced intensity regimen in 63%. Stem cell source was PBSC in 88%. Donors were sibling in 42% or matched related donor in 39%. An alternative donor was chosen in 18%. GVHD prophylaxis included antithymocyte globulin in 61%, and calcineurin inhibitor in 97%. Median follow up was 78 months (3.5-157). Considering the whole cohort, 2y OS, DFS, NRM, and cumulative incidence of relapse were 48% (95%CI: 33-70), 60% (95%CI: 44-82), 18% (95%CI: 7-34), and 34% (95%CI: 18-50) respectively. Cumulative incidences of day 100 grade I-II and III-IV acute GVHD 36% and 0%, respectively. Cumulative incidence was 32% among whom 33% had an extensive cGVHD. Patients with progressive disease at transplantation had worst 2y PFS and OS (PFS: HR: 6.12, 95%CI: 1.32-28.31, p=0.02 and OS: HR: 7.04, 95%CI: 1.52-32.75, p=0.013). Conclusion: To our knowledge, this is the largest published study evaluating outcomes of allo-HCT for R/R PMBCL. Although this is a retrospective study with a limited number of patients, the outcomes suggest that allo-HCT is a therapeutic option providing durable remissions for patients with R/R PMBCL. Disclosures Sibon: Abbvie: Consultancy; Takeda: Consultancy; iQone: Consultancy; Roche: Consultancy; Janssen: Consultancy. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .

Venous access device-related bloodstream infections (VAD-BSIs) with coagulase-negative staphylococci (CoNS) are common complications after allogeneic hematopoietic cell transplantation (alloHCT). So far, the standard systemic antimicrobial therapy for uncomplicated VAD-BSIs with methicillin-resistant CoNS consisted of intravenous (IV) vancomycin (vanco). This approach requires hospitalization, necessitates new competent venous access, exposes patients to potential (mainly renal) toxicity and increases the risk of commensal flora dysbiosis with selection of vanco-resistant enterococci. Patients after alloHCT are particularly at risk of iatrogenic and nosocomial complications. In addition, repeated hospitalizations can impact autonomy and quality of life and are associated with significant costs. Minocycline (mino) is an oral antimicrobial agent that has strong in vitro effects on most Gram positive bacteria and potential anti-biofilm activity, and can be used in the clinic for some CoNS infections. Our infectious disease specialists proposed that systemic therapy with oral mino could be used for the management of uncomplicated VAD-BSIs, primarily when the reference treatment with IV vanco was not possible (renal failure or allergy) or when hospitalization was refused by patients. We retrospectively analyzed the results of this mino-based approach. From January 2012 to December 2020, we treated 24 uncomplicated VAD-BSIs with CoNS in 23 alloHCT patients aged 17-72y with oral mino. Uncomplicated VAD-BSIs were defined as 2 or more blood cultures positive for the same CoNS drawn consecutively peripherally and through the VAD, in patients without signs of sepsis, cellulitis or suppurative thrombophlebitis and without endovascular implant or orthopedic material. VAD were implantable ports (n=17), tunneled catheter (n=1) or PICC-lines (n=6). Pathogens were S. epidermidis (n= 21) or S. haemolyticus (n=3). CoNS were in vitro susceptible to mino according to EUCAST guidelines (with MIC Overall, clearance of bacteremia (as assessed by negativity of surveillance peripheral blood cultures with the same CoNS drawn between d+3 and +30 after initiation of systemic therapy) was achieved in all but 1 patient (with port, treated with mino alone) who had persistent bacteremia at day +9. No complication such as suppurative thrombophlebitis, endocarditis or metastatic foci of infection was observed in any patient during the 3-month period after initiation of treatment. Among the 17 patients for whom VAD salvage was attempted, VAD decontamination was successful in 10 cases while 4 patients experienced persistently positive VAD-derived blood cultures during the early (d+3 to +14) surveillance period and 3 patients experienced delayed relapse of VAD-BSIs with the same CoNS 1-3 months later (with 1 patient with cellulitis). All these events led to VAD removal. Treatment with mino was well tolerated with the exception of mild skin rash in one patient. Our results in this retrospective cohort suggest that oral mino can be a promising alternative to standard IV vanco for systemic therapy in VAD-BSIs with CoNS and that a strategy combining oral mino and antibiotic locks may salvage VAD in approximately half of the cases. This remains to be confirmed in prospective studies. Disclosures No relevant conflicts of interest to declare.

While CAR T cell therapy has delivered impressive clinical efficacy in B cell malignancies, similar levels of clinical activity have not been demonstrated in acute myeloid leukemia (AML). One underlying reason for this lack of translation is the relative paucity of validated CAR T targets. Major Histocompatibility Complex Class 1 related proteins MICA and MICB along with the UL16 binding proteins 1-6 (ULBP1-6) are frequently over-expressed on AML and myelodysplastic syndrome (MDS) blasts. The Natural Killer Group 2D (NKG2D) is a single receptor able to bind MICA, MICB and ULBP1-6, thus providing a potentially powerful approach that could be exploited to target this family of targets thereby providing a novel CAR T approach for AML/MDS. Expressing the NKG2D receptor fused to the human CD3z cytoplasmic domain generates a CAR that, when expressed in primary T cells, generates a CAR T product (termed CYAD-01) that showed good anti-tumor activity in preclinical models. In clinical trials, CYAD-01 showed a good tolerability profile but with a disappointing level of clinical activity when combined with cyclophosphamide / fludarabine preconditioning (DEPLETHINK trial, NCT03466320). We hypothesised that the transient expression of MICA/MICB on the CAR T itself may inhibit the activity of the NKG2D CAR through self-targeting and consequent fratricide. We developed a single shRNA able to knockdown both MICA and MICB. Co-expression of this shRNA with the NKG2D CAR generated a second generation CAR T product termed CYAD-02 which was examined in a highly similar AML/MDS patient population and preconditioning regimen as employed in the DEPLETHINK trial. CYAD-02 was evaluated in the the first-in-human CYCLE-1 trial (NCT04167696) in patients with r/r AML/MDS. The dose-escalation phase evaluated three dose-levels (DL) (1x10 8, 3x10 8 and 1x10 9 total cells per infusion), administered as a single infusion after standard preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days) according to a classic 3+3 design. As of July 2021, 11 patients have been treated with CYAD-02 at the different dose-levels (3 at each DL1 and 2 and 5 at DL3). In terms of safety and tolerability, there was no evidence of a differential safety profile of CYAD-02 within the CYCLE-1 trial as compared to that observed in the CYAD-01 clinical trial. Of note, five patients enrolled in all 3 DLs experienced Grade ≥ 3 adverse events (AE) at least possibly related to CYAD-02 (cytokine release syndrome, febrile neutropenia, white blood cell count decreased, infusion related reaction). With respect to clinical activity, seven patients in total achieved stable disease (2 at DL1, 3 at DL2 and 2 at DL3) with 4 demonstrating evidence of transient blast reduction or anti-leukemic activity (decrease of at least 50% of the bone marrow blasts). In addition, two MDS patients at DL3 achieved a marrow complete response. Overall, this suggests dose dependent response to CYAD-02. Furthermore, patients receiving CYAD-02 cells seem to display a greater duration of response and stronger blast reduction as compared to patients who received CYAD-01 in DEPLETHINK. Interestingly, peak engraftment levels were higher for CYAD-02 compared to CYAD-01 at the same dose (DEPLETHINK trial). At DL3, CYAD-02 cells could be readily detected in peripheral blood of 4/5 patients through month 2. In addition, and unlike what is reported in B cell CAR T-cells trials, there was very limited evidence of elevated homeostatic cytokines (IL-7/IL-15) following CyFlu administration with IL-15 not detected in any of the patients and IL-7 showing only a minor increase in 2 patients. The knockdown of MICA/MICB appears to have a positive contribution to the initial clinical activity of CYAD-02 as compared to that achieved with the first generation CYAD-01 CAR T, together with good safety and tolerability. The lack of homeostatic cytokines after preconditioning, likely limiting the engraftment and activity of CAR T cells, may be related to the biology of myeloid malignancies. One approach to further drive the potency of NKG2D-based CAR T cells would likely be armoring the CAR T through using the T cell as a vehicle to secrete cytokines alongside the CAR. Overall, shRNA knockdown technology provides a means to modify CAR T function and here shows that single shRNA can target two independent genes to enhance the phenotype of the CAR Ts. Disclosures Deeren: Alexion: Consultancy; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Sobi: Consultancy; Takeda: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Alcantar-Orozco: Celyad Oncology: Current Employment. Dheur: Celyad Oncology: Current Employment. Breman: Celyad Oncology: Current Employment. Braun: Celyad Oncology: Current Employment. Lonez: Celyad Oncology: Current Employment. Gilham: Celyad Oncology: Current Employment. Flament: Celyad Oncology: Current Employment. Lehmann: Celyad Oncology: Current Employment.

Hematopoietic stem cell transplantation (HSCT) is being increasingly explored as a treatment modality for older patients with acute lymphoblastic leukemia (ALL). Yet, concerns regarding the long term outcome of transplantation in older patients limit the wide spread applicability of this approach. In this analysis we set out to determine the outcome of ALL patients over the age of 60 who underwent reduced intensity HSCT. Herein, we present the experience of the acute leukemia working party (ALWP) of the EBMT in this age group. We analyzed a cohort of 142 patients transplanted in first remission with a median age of 62 (range 60–76 years) and a median follow-up period of 36 months post-transplant. At 3 years, overall survival (OS) and leukemia-free survival were 42% and 35%, respectively. Multivariate analyses identified cytomegalovirus (CMV) donor-recipient matching (CMV D+/R+) to be significantly associated with inferior OS. Patients transplanted from unrelated donors experienced increased grade II-IV acute graft versus host disease compared to those receiving grafts from matched related donors [Hazard ratio (HR) of 3.7, 95% confidence interval (CI), 1.75–7.8; p = 0.0005). Outcome was not impacted by Philadelphia chromosome status. A select subset of older ALL patients will benefit from extended survival and a disease free state following HSCT.

The Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2016 in Lille, France. The objective of our workshop is to discuss chronic graft versus host disease and to provide recommendations for the indications and treatment of this condition.

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant.

Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results. In this review, we will provide a comprehensive overview of the biology of MM bone disease, summarize its current clinical management and discuss preclinical and clinical data on next generation therapies.

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

While performance since the introduction of the JACIE quality management system has been shown to be improved for allogeneic hematopoietic stem cell transplants (HSCT), impact on autologous-HSCT remains unclear in Europe. Our study on 2697 autologous-HSCT performed in adults in 17 Belgian centres (2007-2013) aims at comparing the adjusted 1 and 3-yr survival between the different centres & investigating the impact of 3 centre-related factors on performance (time between JACIE accreditation achievement by the centre and the considered transplant, centre activity volume and type of HSCT performed by centres: exclusively autologous vs both autologous & allogeneic). We showed a relatively homogeneous performance between Belgian centres before national completeness of JACIE implementation. The 3 centre-related factors had a significant impact on the 1-yr survival, while activity volume and type of HSCT impacted the 3-yr survival of autologous-HSCT patients in univariable analyses. Only activity volume (impact on 1-yr survival only) and type of HSCT (impact on 1 and 3-yr survivals) remained significant in multivariable analysis. This is explained by the strong relationship between these 3 variables. An extended transplantation experience, i.e. performing both auto & allo-HSCT, appears to be a newly informative quality indicator potentially conveying a multitude of underlying complex factors., info:eu-repo/semantics/published

The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate. ispartof: BLOOD ADVANCES vol:3 issue:13 pages:1950-1960 ispartof: location:United States status: published

Hemoglobin levels are believed to be regulated as per a set point model of regulation. This model of regulation, by which specific levels of a parameter are targeted and defended by physiological systems, implies a particular population correlation between the parameter and its controlling hormone. Empirical population correlations of other parameters and their controlling hormones, have denied the presence of such set point‐based regulation. To assess if hemoglobin is regulated according to a set point model we performed a systematic search of PubMed/MEDLINE and Web of Science identifying relevant reports published up to November 2018. Population hemoglobin/erythropoietin level correlations were retrieved, and these empirically derived correlations were compared with the positive correlation implied by a set point model of regulation. Authors of papers containing potentially suitable data were contacted with requests for further analyses, and a meta‐analysis was performed. Twelve correlations between hemoglobin and erythropoietin levels from eleven papers were analyzed. None of these correlations were significantly positive, three, restricted to the normal range of hemoglobin, were significantly negative. All but one of the other correlations showed a negative trend. New analyses of previously published data sets resulted in similar findings. In particular a new analysis of large data sets of males (n = 2417) and females (n = 2592) with normal range hemoglobin levels, revealed significantly negative correlations. A meta‐analysis of our results indicated that the data overall are not consistent with a positive relationship between hemoglobin and erythropoietin (P

Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation. ispartof: LEUKEMIA & LYMPHOMA vol:60 issue:10 pages:2404-2414 ispartof: location:United States status: published

Purpose We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). Patients and methods We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. Results Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. Conclusion This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies.

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT., The project was supported by funding from EBMT

Therapy-related myelodysplastic syndrome (t-MDS) after autologous stem cell transplantation (ASCT) is a rare complication with no curative option. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for eligible patients and has been understudied in t-MDS. We report 47 consecutive patients with t-MDS after an ASCT who underwent allo-HSCT with a median age of 58 years (range, 30 to 71 years) at transplantation and a median follow-up of 22 months (range, 0.7 to 107). The median overall survival (OS) was 6.9 months (95% confidence interval [CI], 0 to 19 months). OS rates were 45% (29% to 60%) and 30% (15% to 45%) at 1 and 3 years after transplantation, respectively. On univariate analysis, prior therapy for t-MDS before allo-HSCT (P = .02) and mismatched donors (P = .004) were associated with poor OS. Three-year nonrelapse mortality (NRM) and relapse rates were 44% (25% to 63%) and 41% (22% to 61%), respectively. Mismatched donors (P < .001) were associated with higher NRM and a high-risk MDS (P = .008) with a higher relapse risk. On multivariate analysis, HLA mismatch was associated with higher NRM (hazard ratio, 6.21; 95% CI, 1.63 to 23.62; P = .007). In conclusion, our results suggest that one third of the patients who develop t-MDS after an ASCT for lymphoma are cured after an allo-HSCT. The use of mismatched donors with standard graft-versus-host disease prophylaxis should be avoided in such an indication for allo-HSCT. It will be worthwhile to see if the implementation of cyclophosphamide post-transplantation will improve the outcome with mismatched donors.

Highlights • Seventeen EBMT centers participated to a questionnaire on MSC manufacturing. • 88% of centers manufacture MSC from bone marrow and only 2 centers from umbilical cord. • Human platelet lysate has replaced bovine serum as culture medium supplement. • Release criteria extensively differ among centers. • The results highlight the need to harmonize MSC manufacturing., The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients’ stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.

Allogeneic stem cell transplantation is an alternative for patients with relapsed or refractory Hodgkin lymphoma (HL), but only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 131 adults with HL who underwent UCBT in European Society for Blood and Marrow Transplantation centers from 2003 to 2015. Disease status at UCBT was complete remission (CR) in 59 patients (47%), and almost all patients had received a previous autologous stem cell transplantation. The 4-year progression-free survival (PFS) and overall survival (OS) were 26% (95% confidence interval [CI], 19% to 34%) and 46% (95% CI, 37% to 55%), respectively. Relapse incidence was 44% (95% CI, 36% to 54%), and nonrelapse mortality (NRM) was 31% (95% CI, 23% to 40%) at 4 years. In multivariate analysis refractory/relapsed disease status at UCBT was associated with increased relapse incidence (hazard ratio [HA], 3.14 [95% CI, 1.41 to 7.00], P = .005) and NRM (HR, 3.61 [95% CI, 1.58 to 827], P = .002) and lower PFS (HR, 3.45 [95% CI, 1.95 to 6.10], P < .001) and OS (HR, 3.10 [95% CI, 1.60 to 5.99], P= .001). Conditioning regimen with cyclophosphamide + fludarabine + 2 Gy total body irradiation (Cy+Flu+2GyTBI) was associated with decreased risk of NRM (HR, .26 [95% CI, .10 to .64], P = .004). Moreover, Cy+Flu+2GyTBI conditioning regimen was associated with a better OS (HR, .25 [95% CI, .12 to .50], P < .001) and PFS (HR, .51 [95% CI, .27 to .96], P = .04). UCBT is feasible in heavily pretreated patients with HL The reduced-intensity conditioning regimen with Cy+Flu+2GyTBI is associated with a better OS and NRM. However, outcomes are poor in patients not in CR at UCBT. (C) 2018 American Society for Blood and Marrow Transplantation.

Several approaches have been developed to overcome historical barriers associated with poor outcomes in the setting of HLA-haploidentical allogeneic transplantation (HaploSCT). Here, we examine the outcome of patients with various hematological disorders undergoing HaploSCT with high-dose, post-transplantation cyclophosphamide. We performed a retrospective study on 381 patients from 30 centers between January 2013 and December 2015. At the last follow-up, a total of 1058 infectious episodes were diagnosed, affecting 90.3% of the cohort. Median time to first infection was 13 days for bacterial, 32 days for viral and 20 days for fungal infections. Around 41% of these infections were of bacterial origin and 35% of viral origin, among which 48.8% of patients presented CMV reactivation. Median of GVHD relapse-free survival, progression-free survival and overall survival were 7.1 months, 19.9 months and 33.5 months, respectively. HSCT procedure was the primary or contributing cause of death (55.6%), followed by relapse of the original disease (34.2%). Infections accounted for 45.7% of the HSCT-related deaths. The present multicenter data on a large cohort of patients receiving HaploSCT with PTCy confirmed the feasibility of the procedure with an acceptable incidence of infectious complications, not different as compared to other haploidentical platforms or HLA-matched transplantation.

The detection rates of whole-body combined [

International audience; The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh -/-) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh -/- mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh -/- mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh -/- mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh -/- mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh -/- mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh -/- mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae.

Background T-cells engineered to express a chimeric antigen receptor (CAR) based on the NKG2D receptor (NKG2D CAR) targeting the 8 NKG2D ligands (MICA/B, ULBP1-6) over-expressed by a large variety of malignancies have been developped to treat patients, including patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Previously, CYAD-01, the first generation of NKG2D CAR T-cell products, was evaluated in several Phase I clinical trials and showed initial signals of objective clinical responses in patients with r/r AML and MDS, albeit with short durability. Preclinical data have shown that NKG2D ligands MICA and MICB are transiently upregulated on activated CAR T-cells, and target-dependent killing of CAR T-cells post-infusion can potentially occur, leading to short in vivo persistence. In an effort to increase the persistence and potency of the NKG2D CAR T-cells, CYAD-02 was developed as a next-generation product using a non-gene editing approach to silence the expression of MICA and MICB. Aim MICA and MICB were down-regulated by inserting a single optimized short hairpin RNA (shRNA) targeting both MICA and MICB within the NKG2D CAR construct. This next-generation NKG2D CAR T-cell product is manufactured with the OptimAb process, resulting in CAR T-cells with a higher frequency of early memory T-cells secreting high levels of cytokines upon activation, and is referred to as CYAD-02. Results As compared to CYAD-01, CYAD-02 cell expansion in vitro was 3-fold increased. In an in vivo AML model, CYAD-02 showed 10-fold higher engraftment 1 week after injection and improved anti-tumor activity as compared to CYAD-01 manufactured with the initial mAb process. This led to a 2.6-fold increase of mouse survival as compared to CYAD-01 in a stress-test aggressive AML model where the dose of CYAD-01 was titrated down for minimal activity (figure). The first-in-human study evaluating CYAD-02, the CYCLE-1 study (NCT04167696), has been initiated in early 2020 in patients with r/r AML/MDS. The study evaluates three dose-levels of CYAD-02 (1x108, 3x108 and 1x109 cells/infusion), administered as a single infusion after non-myeloablative preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days, CyFlu) according to a classical Fibonacci 3+3 design. As of August 2020, 6 patients have been treated with CYAD-02 at the dose of 1x108 or 3x108 cells/infusion. To date, the results demonstrate the safety and tolerability for CYAD-02 in patients with r/r AML and MDS with no dose-limiting toxicity observed. The study is currently enrolling at 1x109 cells/infusion. The CYAD-02 safety profile and preliminary clinical activity data together with the pharmacokinetics evaluation from the complete dose escalation segment will be provided at the time of presentation. Conclusion/summary The CYAD-02 is the first autologous CAR T-cell product based on the non-gene edited shRNA technology used to treat patients. This next generation NKG2D CAR T-cell product is currently investigated in the CYCLE-1 Phase I study in r/r AML/MDS patient population, a difficult to target disease due in part to the absence of truly AML-specific surface antigens, its rapid clinical progression and the absence of disease control by the CyFlu preconditioning. Both the anti-MICA and MICB shRNA hairpin and the OptimAb manufacturing process for CYAD-02 aim to improve CAR T-cell persistence and clinical responses. Figure Disclosures Lin: Mateon Therapeutics: Research Funding; Aptevo: Research Funding; Abbvie: Research Funding; Ono Pharmaceutical: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Jazz: Research Funding; Astellas Pharma: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Celyad: Research Funding; Genetech-Roche: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding. Demoulin:Celyad Oncology: Current Employment. Fontaine:Celyad Oncology: Current Employment. Sotiropoulou:Celyad Oncology: Current Employment. Alcantar-Orozco:Celyad Oncology: Current Employment. Breman:Celyad Oncology: Current Employment. Dheur:Celyad Oncology: Current Employment. Braun:Celyad Oncology: Current Employment. Lonez:Celyad Oncology: Current Employment. Gilham:Celyad Oncology: Current Employment. Flament:Celyad Oncology: Current Employment. Lehmann:Celyad Oncology: Current Employment.

The genomic profile of multiple myeloma (MM) has prognostic value by dividing patients into a good prognosis hyperdiploid group and a bad prognosis nonhyperdiploid group with a higher incidence of IGH translocations. This classification, however, is inadequate and many other parameters like mutations, epigenetic modifications, and genomic heterogeneity may influence the prognosis. We performed a genomic study by array-based comparative genomic hybridization on a cohort of 162 patients to evaluate the frequency of genomic gains and losses. We identified a high frequency of X chromosome alterations leading to partial Xq duplication, often associated with inactive X (Xi) deletion in female patients. This partial X duplication could be a cytogenetic marker of aneuploidy as it is correlated with a high number of chromosomal breakages. Patient with high level of chromosomal breakage had reduced survival regardless the region implicated. A higher transcriptional level was shown for genes with potential implication in cancer and located in this altered region. Among these genes, IKBKG and IRAK1 are members of the NFKB pathway which plays an important role in MM and is a target for specific treatments. © 2016 Wiley Periodicals, Inc.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor's immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40-60% of alloHSCT recipients.In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention.A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.

Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of tumor cells in the bone marrow (BM) and is associated with immunosuppression, angiogenesis and osteolysis. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature, immunosuppressive myeloid cells that promote tumor progression through different mechanisms. In this work, we studied the contribution of MDSC subsets to different disease-promoting aspects in MM. We observed an expansion of polymorphonuclear/granulocytic (PMN-)MDSCs in two immunocompetent murine MM models, while this was not observed for monocytic (MO-)MDSCs. Both MDSC subpopulations from MM-bearing mice were immunosuppressive, but PMN-MDSCs displayed a higher suppressive potential. Soluble factors secreted by MM cells increased the viability of MDSCs, whereas the presence of MDSCs did not affect the proliferation of MM cells in vitro or in vivo. Interestingly, we observed a pro-angiogenic effect of PMN-MDSCs in the context of MM using the chick chorioallantoic membrane assay. Consistently, MM-derived PMN-MDSCs showed an up-regulation of angiogenesis-related factors and reduced PMN-MDSC levels were associated with less angiogenesis in vivo. Finally, we identified MO-MDSCs as osteoclast precursors. These results suggest that MDSC subpopulations play diverging roles in MM. We show for the first time that PMN-MDSCs exert a pro-angiogenic role in MM.

Objective Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of self-perceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. Methods In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients' SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients'/primary caregivers' personal relationship characteristics (family tie, support), were assessed. Results Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients' SPB-PC was associated with lower Karnofsky performance (β = −0.135, p = 0.058) and ADL (β = −0.148, p = 0.037) scores, and higher HADS (β = 0.283, p

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P.001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P.001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P.001), and platelet count50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P.001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P.001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT.

// Gregory Ehx 1,* , Muriel Hannon 1,* , Yves Beguin 1,2 , Stephanie Humblet-Baron 1,3,** and Frederic Baron 1,2,** 1 Hematology Research Unit, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA)-I³, University of Liege, Liege, Belgium 2 Department of Medicine, Division of Hematology, CHU of Liege, Liege, Belgium 3 Autoimmune Genetics Laboratory, University of Leuven, Leuven, Belgium * These authors are co-first authors ** These authors are co-senior authors Correspondence to: Gregory Ehx, email: // Keywords : Treg, regulatory T cells, FOXP3, STAT5, IL-2, Immunology and Microbiology Section, Immune response, Immunity Received : September 14, 2015 Accepted : November 26, 2015 Published : December 07, 2015 Abstract BACKGROUND: Regulatory T cells (T regs ) are key players in immune tolerance. They express the transcription factor FOXP3 and are dependent of the STAT5 signaling for their homeostasis. So far, the study of phosphorylated epitopes by flow cytometry required treating the cells with methanol, which is harmful for several epitopes. METHODS: Here we assessed whether the PerFix EXPOSE reagent kit (PFE)(Beckman Coulter) allowed monitoring the phosphorylation level of STAT5 in T reg subpopulations together with complex immunophenotyping. Results observed with the PFE kit were compared to those observed without cell permeabilization for surface markers, with paraformaldehyde permeabilization for non-phosphorylated intracellular epitopes, and with methanol-based permeabilization for phospho STAT5 staining. RESULTS: In human PBMCs, the PFE kit allowed the detection of surface antigens, FOXP3, KI67 and phospho STAT5 in similar proportions to what was observed without permeabilization (for surface antigens), or with PFA or methanol permeabilizations for FOXP3/KI67 and phospho STAT5, respectively. Comparable observations were made with murine splenocytes. Further, the PFE kit allowed determining the response of different human and murine T reg subsets to IL-2. It also allowed demonstrating that human T reg subsets with the highest levels of phospho STAT5 had also the highest suppressive activity in vitro , and that anti-thymocyte glogulin (ATG) induced T reg independently of the STAT5 pathway, both in vitro and in vivo . CONCLUSIONS: We have validated a multicolor staining method that allows monitoring phospho STAT5 levels in T reg subsets. This staining could be useful to monitor responses of various T reg subsets to IL-2 therapy.

International audience; Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft-versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68–48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04–16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17–0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease

This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400 mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p = 0.02, R2 = 0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822 ng/mL vs 1099 ng/mL; Student's t-test, p = 0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p = 0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. In conclusion: in patients treated with imatinib at a fixed daily dose of 400 mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.

Background Post-transplant administration of high-dose cyclophosphamide (PTCy) is one of the most efficient way to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). However, the impact of PTCy on immune-mediated graft-versus-leukemia (GvL) effects has remained debated. Here, we investigated the impact of PTCy administration on xenogeneic GVHD and allogeneic GvL effects in two humanized mouse models. Impact of PTCy on xGVHD A single i.p. injection of cyclophosphamide (100 mg/kg) 3 days after infusion of 2 × 107 human PBMC in NSG mice significantly delayed xGVHD (64 vs 43 days, P Impact of PTCy on GvL effects The impact of PTCy on GvL effects was assessed in NSG-HLA-A2/HHD mice (a strain of NSG mice that express in addition to mouse MHC, the human HLA-A0201). All mice were i.v. injected with the human (HLA-A0201) AML cell line THP-1 transfected with the luciferase gene on day 0, while a second injection of THP-1 cells was administered on day 5. Four groups of mice were compared, a group of mice given only THP-1 cells, a second group given THP-1 cells and PTCy on day 3, a third group given THP-1 cells and human PBMC from a non HLA-A2 donor, and a last group of mice given THP-1 cells, PTCy and human PBMC from the same non HLA-A2 donor. On day 34, none of the THP-1+ PBMC mice had detectable tumors while THP-1 + PTCy + PBMC mice had detectable tumors but to a lesser extent that THP-1 only mice or THP-1+PTCy mice. The best survival was observed in THP-1+PTCy+PBMC mice while THP-1+PBMC mice died from xGVHD whereas THP-1+PTCy as well as THP-1 mice died from leukemia. Conclusions These results suggest that PTCy prevents xGVHD by depleting proliferative T cells and favoring the recovery of Treg. Further, GvL effects (although decreased) were not abrogated by PTCy.

Multiple myeloma is the second most frequent hematological malignancy. Unfortunately, it is still incurable. A better understanding of the myeloma pathophysiology favored the development of new therapeutic molecules that improved both survival and quality of life of patients. Diagnostic and prognostic criteria for myeloma have been reviewed and help to detect multiple myeloma more early and further help to define the best therapeutic strategy. These new regimens are associated with side effects that differ from those of classic molecules and that we have to be able to recognize and to treat appropriately.Le myélome multiple est le second cancer hématologique le plus fréquent. Il reste malheureusement incurable à l’heure actuelle. Pourtant, ces deux dernières décennies ont été marquées par des progrès dans la compréhension de la physiopathologie du myélome, ce qui a permis le développement de nouvelles molécules thérapeutiques, améliorant la survie et la qualité de vie des patients. Les critères diagnostiques et pronostiques du myélome ont été revus et sont maintenant plus performants pour détecter des stades précoces et déterminer ainsi la stratégie thérapeutique à entreprendre. Les nouveaux régimes de traitement sont grevés d’un profil d’effets secondaires différent qu’il faut pouvoir reconnaître et traiter.

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4