Kurzfassung: Background: ARI0002h is an academic lentiviral autologous second-generation CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA. In pre-clinical studies, ARI0002h has demonstrated potent in vitro and in vivo activity. Here, we report the first safety and efficacy results of the CARTBCMA-HCB-01 multicenter clinical trial for patients with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) who received ARI0002h in 5 Spanish centers. Methods: Patients (pts) aged 18-75 years old with RRMM were eligible for this study if they had measurable disease, as assessed by M-protein or serum free light chain levels, received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug (lenalidomide or pomalidomide) and an anti-CD38 antibody, and were refractory to the last line of treatment. Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m 2) and fludarabine (30 mg/m 2) on days -6 to -3 were used as lymphodepletion regimen. The targeted dose was 3x10 6/kg CAR+cells (range 1.2-3x10 6) and was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A second dose of 3x10 6 CAR+ cells/kg was planned at least 4 months after the first dose in pts who had any response and had not presented MM progression or serious complications after the first administration, with or without repeated lymphodepletion depending on the persistence of CAR-T cells. Primary objectives were overall response rate (ORR; at less partial response -PR-) within 3 months of the first infusion and rate of cytokine release syndrome (CRS) and/or neurological toxicity in the first 30 days. Response was assessed as per IMWG criteria and bone marrow minimal residual disease (MRD) was analyzed by next-generation flow. Adverse events (AEs) were graded using CTCAE v5.0. CRS and neurotoxicity were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Results: As of July 19 th, 35 pts (median age 61 years) with RRMM were included in the trial. Four pts could not receive ARI-0002h due to MM progression before apheresis (2 pts) or treatment (2 pts) and one pt died of a fungal infection. Therefore, 30 pts received ARI0002h cells (modified intention-to-treat population), of which 47% received bridging therapy. The main characteristics of these pts and previous treatments are described in Table 1. Median CAR-T cell production time was 11 days (range 9-14) with a 100% manufacture success. Median follow-up after ARI0002h administration for surviving pts was 8 months (range 2-12). The ORR of 27 evaluable pts at 3 months was 96%, with a stringent complete remission (sCR) rate of 44.4% (Table 1) and very good partial response (VGPR) observed in 18.6% of pts. Median time to first response was one month. All pts achieved at least a PR and only one patient progressed after 4 months exclusively with extramedullary disease. Of 25 MRD-evaluable pts at day +100, 92% were MRD-negative. Median progression-free survival (PFS) and overall survival (OS) were not reached and the 6-month PFS and OS rates were 92.1% (Figure 1) and 95.8%, respectively. AEs reported in & gt;70% of pts were CRS (87%; grade [gr] 3/4 0%; gr 1 73%), neutropenia (97%; gr 3/4 100%), anemia (85%; gr 3/4 43%), and thrombocytopenia (79%; gr 3/4 70%). Median duration of CRS was 4 days (range 1-12). No CAR-T cell-related neurotoxicity cases were reported. Tocilizumab and corticosteroids were administered in 76% (mainly for persistent grade 1 CRS) and 12% of pts, respectively. One death occurred due to unrelated causes (cranial traumatism). ARI0002h cells demonstrated peak expansion on day 14 (range 7-100 days). Among the pts with 3 and 6 months follow-up, 54% and 24% had measurable CAR+ T cells in peripheral blood, respectively. 22 out of 27 eligible pts (81%) have already received the second dose (range 1.2-3x10 6 CAR+ cells/kg). Median time after first infusion was 4 months; 36% received a second lymphodepletion. No relevant toxicities after second infusions were reported. Responses deepened over time and at 6 months, 5 pts who had reached PR achieved VGPR and one improved from VGPR to sCR. Conclusion: ARI0002h is the first European academic CAR T-cell for RRMM that has demonstrated excellent feasibility in a clinical trial, with deep and durable responses and a favorable safety profile, including the absence of neurotoxicity. Figure 1 Figure 1. Disclosures Fernandez de Larrea: Takeda: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Gonzalez-Calle: BMS, Janssen, Amgen: Honoraria. Cabañas: Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Rodriguez-Otero: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Regeneron: Honoraria. Reguera: BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen, Kite/Gilead, Novartis: Speakers Bureau. Corral: Novartis: Consultancy; Gileqd: Honoraria; Gilead: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences. Prósper: BMS-Celgene: Honoraria, Research Funding; Janssen: Honoraria; Oryzon: Honoraria. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Mateos: Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Bluebird bio: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Regeneron: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: Although increasing numbers of allogeneic stem cell transplants are being performed worldwide using reduced intensity conditionings (allo-RIC), most of the current experience and knowledge on the characteristics of graft-versus-host disease (GVHD), especially chronic GVHD (cGVHD), comes from the use of myeloablative conditioning regimens (MCR). We have analyzed the incidence and characteristics of GVHD among 150 consecutive patients undergoing allo-RIC as compared to 88 concomitant patients undergoing MCR. All patients analized received peripheral blood stem cells (PBSC) from an HLA identical sibling and the same GVHD prophylaxis (cyclosporine and methotrexate). Incidences of acute GVHD (aGVHD) were 69% and 47% among MCR and allo-RIC, respectively (p 〈 0.001). Incidences of grades 2–4 aGVHD were 51% vs 33%, respectively (p=0.0009). Regarding organ involvement, no signifficant differences were observed between either subgroups. Skin was the organ most frecuently involved in both subgroups (83 % vs 75.3% cases among MCR and allo-RIC patients, respectively; p=0.08). Regarding response to treatment, no significant differences were observed between both subgroups, with 66.1% vs 52.2% of patients reaching complete remission (CR) after first line therapy. Interestingly, gastrointestinal tract was the organ most frequently involved in treatment failure in both subgroups: 16 (66.6%) and 20 (80%) of MCR and allo-RIC patients (p=0.21) had gut GVHD relapse/progression/no response with or without other organs involvement. Liver was involved in treatment failure in 6 (25%) vs 12 (48%) patients undergoing MCR vs allo-RIC, respectively (p=0.02). In multivariate analysis, only type of conditioning (MCR vs RIC) significantly influenced the incidence of overall aGVHD: HR= 2.16 (95 % CI: 1.52–3.07), p 〈 0.0001. Incidences of chronic GVHD (cGVHD) were 68% and 76% among MCR and allo-RIC patients, respectively (p=0.03), although patients who developed cGVHD, incidence of extensive cGVHD was higher in the MCR group as compared to allo-RIC (88 vs 64%, p=0.01). A higher incidence of severe skin cGVHD involvement was observed among MCR recipients (39.4% vs 9.6%, respectively; p=0.008). As far as response to immunosupressive treatment 41.4% of MCR vs 58.2% of allo-RIC patients reached CR (p=0.43). Among patients who reached CR of cGVHD, a high incidence of cGVHD relapse was observed in both subgroups (58.3% vs 50% among MCR vs allo-RIC patients), with most relapses occurring in the first year after inmunosuppression was stopped. Among patients who developed extensive cGVHD, 83.3% vs 37.9% of patients undergoing MCR vs allo-RIC required systemic immmunosupression 3 years after allogeneic PBSC transplantation (p=0.009). Thus, overall, duration of immunosupression was shorter among allo-RIC patients, since 36 months after transplant 68.8% vs 35.5% of patients receiving MCR vs RIC required systemic immunosupression (p=0.028). In conclusion, the use of reduced intensity conditioning regimens decreases the incidence of both acute and extensive cGVHD after PBSC allogeneic transplantation, thus reducing the immunosupression requirements at the long term follow up.

Kurzfassung: Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%,P  〈  .001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P = .006) and chronic GVHD (5% versus 66.7%, P  〈  .001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P  〈  .001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P = .43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.

Kurzfassung: Abstract 4082 Intoduction. Cytokine gene polymorphisms are well know to be associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. They seem to play an important role in allogeneic stem cell transplantation (allo-SCT), mostly in the incidence and severity of graft-versus -host disease (GVHD) which is one of the most common serious complications of allo-SCT. Interleukin-6 (IL-6) is a proinflamatory cytokine known to be implicated in the pathogenesis of aGVHD with increasing serum levels during the development. The IL6−174 (G/C) single nucleotide polymorphism (SNP), localized in the promoter region (7p21) has been linked to in vitro and in vivo productions, associating the presence of allele G with significantly higher levels of IL-6 and a trend to have higher grades of aGVHD. Objetive. To analyze the influence of Donor (D) and Recipient (R) genotype for the polymorphism IL6−174 (G/C) on the outcome of HLA-identical related stem cell transplantation. Patients and Methods. The study comprised 171 allo-SCT (342 D/R samples) included in the Spanish Group for Haematopoietic Stem cell Transplantation (GETH) DNA bank. Genomic DNA was purified from peripheral blood samples obtained pre-SCT from patients and donors, after written informed consent. The IL6−174 (G/C) SNP genotype was determined by allele-specific PCR (Cavet et al, Blood 98, 2001). Results were analyzed using the Pearson's Chi-square Test and survival estimation by Kaplan-Meier curves. Results. Genotypes for D and R as well as D/R combinations (table 1), were in accordance with previous reports. Homozygous recipients for IL6−174GG polymorphism showed a trend to higher incidence of grade III-IV aGVHD than those with other genotypes (19.9% vs 9.1%) p=0.14. No significant differences were found in terms of cGHVD, relapse or mortality rates. On the other hand, patients transplanted from homozygous GG Donors showed a higher incidence of extense cGVHD (20/52 (38%) vs 21/87 (24%) p=0.07), lower relapse rates (10/59 (23.8%) vs 32/105 (76.2%) p=0.041) and better global mortality rates (23/62 (36.9%) vs 51/106 (69%) p=0.11). Survival analysis with Kaplan-Meier curves in this group of patients (IL6−174GG homozygotes in the Donor) revealed a lower cumulative incidence of relapse (CIR) (NR vs 567 days p=0.028) a better event free survival (EFS) (732 days vs 380 days p=0.02) and showed a trend to a better overall survival (OS) (1235 days vs 836 days p=0.157); (Figure1). Conclusions. IL6 cytokine is known to be implicated in the pathogenesis of aGHVD with increasing serum levels during its development. The presence of allele G for the polymorphism of IL6−174(G/C) which is associated with higher levels of IL6, has shown to influence the outcome of our cohort of HLA-identical related stem cell transplantation. Since acute GHVD is mainly influenced by R genotype and chronic GHVD by D genotype, the present study revealed that homocigous presence in the R of allele G was associated with higher incidence of aGHVD. Moreover when this allele is homozigously present in the D, patients show greater extense cGHVD and better EFS and OS. Genotyping for this polymorphism could aid in D selection or even more interestingly drive a risk-adapted management of transplanted patients. Disclosures: No relevant conflicts of interest to declare.

Kurzfassung: Background The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Chimeric Antigen Receptor T-cell (CAR T-cell) therapy for hematologic malignancies are at risk for poor outcomes after COVID-19 due to their severely immunocompromised state caused by prior cumulative immunochemotherapy, on-target/off-tumor B-cell depletion, hypogammaglobulinemia and ongoing cytopenias. Current data are limited to small case series and case reports. This study describes the clinical characteristics and outcomes of CAR T-cell therapy recipients after developing COVID-19 in the largest cohort to date. Methods In response to the COVID-19 pandemic, the European Society for Blood and Marrow Transplantation (EBMT) developed a special COVID-19 report form to capture data from all patients with COVID-19 after treatment with CAR T-cell therapy for hematologic malignancies. Only PCR positive SARS-CoV-2 diagnosed patients before June 1 st, 2021 were included. The aim of this study was to describe the clinical course after COVID-19 diagnosis and evaluate overall survival. Overall survival probabilities were calculated using the Kaplan Meier method. Factors associated with mortality after COVID-19 diagnosis were examined using a Cox proportional hazard model. Results A total of 57 patients from 11 countries were reported to the EBMT. One patient with incomplete data at diagnosis and without any follow up information had to be excluded from the analysis. The median age of these 56 patients was 57.7 years (min-max 5.2 - 72.8) including 55 adults and one child. Of these patients, 32 were male. CAR T-cell therapy was given to 46 patients with B-cell-non-Hodgkin lymphoma, 7 patients with B-cell acute lymphoblastic leukemia, and 3 patients with multiple myeloma. The median time from CAR T-cell infusion to COVID-19 diagnosis was 7.4 months (min-max 0.03 - 25.3). At the time of COVID-19 diagnosis, 62.5% of patients were in complete remission, 12.5% of patients had a partial response and 25% of patients had relapsed/refractory disease. Forty-five patients (80%) were admitted to hospital (median 26,5 days, min-max 3-171) due to COVID-19. Of the admitted patients, 24 (53%) needed oxygen support. Twenty-two (49%) patients were admitted to the intensive care unit (median 14 days, min - max 2-65) and 16 (73%) of these patients received invasive ventilation. At the time of analysis, 25 of the 56 patients had died (44.6%), most (23/25) due to COVID-19, resulting in a COVID-19 attributable mortality rate of 41%. The Kaplan-Meier estimate of overall survival is shown in Figure 1. The median follow-up from COVID-19 diagnosis was 20.9 weeks. In 1 of the 32 alive patients there was no resolution of COVID-19 at the time of analysis. In multivariate analysis, older age (hazard ratio (HR) 1.50, 95% CI 1.11-2.03, p=0.009) and comorbidities (HR 2.56, 95% CI 1.05-6.23, p=0.001) had a negative impact on overall survival. Better performance status at time of admission (HR 0.72, 95% CI 0.59-0.88, p=0.038) had a positive impact on overall survival. Sex, time from CAR T-cell therapy to COVID-19 diagnosis, disease remission status and the occurrence of neurotoxicity or cytokine release syndrome after CAR T-cell infusion did not have a significant effect on overall survival in the multivariate analysis. Conclusion Patients with COVID-19 after B-cell-targeted CAR T-cell therapy have a very poor outcome. As it remains uncertain whether currently applied vaccination strategies against SARS-CoV-2 are effective after CAR T-cell therapy, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are likely to play the most important role in protecting this vulnerable group of patients. Better treatment strategies are urgently needed. Figure 1 Figure 1. Disclosures Ljungman: OctaPharma: Other: DSMB; Enanta: Other: DSMB; Janssen: Other: Investigator; Takeda: Consultancy, Other: Endpoint committee, speaker; AiCuris: Consultancy; Merck: Other: Investigator, speaker. De La Camara: IQONE: Consultancy; Roche: Consultancy. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Barba: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Sesques: Novartis: Honoraria; Chugai: Honoraria; Kite, a Gilead Company: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Thieblemont: Janssen: 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Nicholson: Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; BMS/Celgene: Consultancy; Pfizer: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Ribera: NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Sanderson: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Ayuk: Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Gilead: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria. 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. Kersten: Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Mielke: DNA Prime SA: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau.

Kurzfassung: Graft versus host disease (GvHD) is the main cause of morbimortality after allogeneic stem cell transplantation (allo-SCT). Several single-nucleotide polymorphisms (SNPs) in in the promoter region of cytokine genes have shown to alter their expression and are therefore associated with donor-recipient alloreactivity and, ultimately, with SCT outcome. Interleukin 17 (IL-17) is secreted by CD4+ T-cells and has been implicated in the pathogenesis of various autoimmune diseases but its importance in SCT is not well-known. Objective To analyse the influence of IL-17A SNP genotypes on the risk and severity of GvHD and other complications after HLA-identical allo-SCT. Patients and Methods Genomic DNA obtained from peripheral blood samples belonging to 546 patients and their HLA-identical sibling donors (Table 1) included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation (GETH). Genotyping of the polymorphisms of interest, rs8193036 (-737C 〉 T), rs2275913 (-197G 〉 A), rs3819024 (-444A 〉 G), rs4711998 (-877A 〉 G), were performed by multiplex primer extension followed by mass spectrometry (MALDI-TOF; Sequenom MassArray). Results Genotype frequencies are shown in Table 2 and the association between IL-17A genotypes and complications after allo-SCT are shown in Table 3. Patients transplanted from donors harboring genotype CC for the SNP rs8193036 show increased risk of grade III-IV acute GvHD (7/26 vs 47/397, p=0.035) and of grade II-IV acute GvHD (13/26 vs 133/409, p=0.048). Patients transplanted from donors harboring allele A in the SNP rs4711998 show increased risk of extensive chronic GvHD (53/161 vs 43/177, p=0.045). Relapse rate was not related with IL-17A SNP genotypes. Finally a higher risk of toxicity-related mortality (TRM) was observed in patients transplanted from donors harboring allele A for SNP rs2275913 (78/293 vs 46/227, p=0.048), donors harboring allele G for SNP rs3819024 (78/279 vs 46/242, p=0.011) and donors harboring allele A for SNP rs4711998 (68/250 vs 55/229, p=0.044). Conclusions IL-17A SNP genotyping might be useful to anticipate complications after sibling HLA-identical allo-SCT and, therefore, to improve the clinical management of transplanted patients. This results further support the idea of a genetic predisposition to certain complications after allo-SCT. Paper presented on behalf of the GvHD/Immunotherapy committee of the Spanish Group for Hematopoietic Transplantation (GETH). Disclosures: No relevant conflicts of interest to declare.

Kurzfassung: Abstract 2446 Poster Board II-423 Donor's hemopoietic progenitor cells leads to myeloid and lymphoid engraftment in the recipient, which is followed not only by a hematological recovery but also by crucial immune and inflammatory reactions. Many studies have focused their interest in the role of donor's genetic characteristics involved in immune responses after allo-SCT. However, very few of them have analysed genes that modulate the intensity of inflammatory response. We have studied the potential influence of polymorphisms in donor's genes involved in TGF-β signalling pathway and in cell growth and proliferation on clinical outcomes after allo-SCT, specifically on the incidence of acute GVHD (aGVHD), transplant related mortality (TRM), relapse, and disease free survival (DFS). The study population consisted of 106 donor-patient pairs undergoing HLA identical sibling allo-SCT in a single institution. Patient median age was 38 years (range, 5-66), and 44% were females. All patients were diagnosed with hematological malignancies; 52% of them were in advanced phase at transplantation. 29% of the patients received a reduced intensity conditioning. Mobilized peripheral blood progenitor cells were the source of hemopoietic stem cells in 98% of the cases. Donor's DNA was genotyped by allelic discrimination PCR for 15 single nucleotide polymorphisms (SNPs) in genes related to TGF-β signaling pathway (SMAD3, EP300, TGFB1, FURIN, PRF1, FNBP3) and in genes involved in regulation of cell growth and proliferation (ATBF1, NFAT5, NM1, CD151, TCIRG1, SH3KBP1, AKT2). Cumulative incidence for aGVHD, TRM and relapse was computed with the cmprsk package for R 2.6.2 software. Competing events were death in the case of aGVHD and relapse, and relapse in the case of TRM. Univariate and multivariate analysis for DFS was performed with actuarial probabilities using Kaplan-Meier with log-rank test and with Cox regression including in the model phase of disease. Multivariate analysis of TRM and relapse was performed using the regression model of Fine and Gray with the cmprsk package. None of the different genotypes analyzed had an association with the incidence of aGVHD. In contrast, different genotypes in NFAT5 and ATBF1 were associated with the incidence of TRM and relapse, respectively. Donor NFAT5 rs6499244 AA dominant genotype was associated with a higher incidence of TRM (p=0.001). At multivariate analysis, this genotype was the most important factor for TRM (RR 3.7, p=0.003). Donor ATBF1 rs719327 AA dominant genotype was associated with a higher incidence of relapse (p=0.03). At multivariate analysis, this genotype retained its significance (RR 1.8, p=0.03). Finally, both SNPs had an association with DFS, showing in the multivariate analysis NFAT5 AA dominant genotype and ATBF1 AA dominant genotype a lower DFS after allo-SCT (RR 1.8, p=0.025 and RR 1.7, p=0.035; respectively). Of them, NFAT5 AA dominant genotype was the most important prognostic factor for DFS. NFAT5 is necessary for optimal T cell development in vivo and ATBF1 inhibits cell proliferation acting as a tumor suppressor gene. In conclusion, donor's genetic variants in NFAT5 and ATBF1 have a strong influence on the clinical outcome of allo-SCT. If confirmed in other series, carrying these SNPs in these genes might be important in donor selection criteria. Disclosures: No relevant conflicts of interest to declare.