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Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R&D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

Introduction Failure to respond to steroid therapy for intestinal acute graft-versus-host disease (aGvHD) is associated with limited further therapeutic options. Fecal microbiotherapy is defined as the perfusion of treated stool from one or several healthy donors via the upper or lower gastrointestinal (GI) route aiming at improving microbial diversity and functionality. Here we report clinical outcomes from a 76-patient cohort with steroid refractory (SR) GI-aGvHD treated with the pooled allogenic fecal microbiotherapeutic MaaT013. Twenty-four patients were treated in the prospective, single-arm, phase IIa, HERACLES study (NCT03359980) while 52 patients were treated in an expanded access program (EAP). Patients and methods For HERACLES, 24 patients with grade III-IV SR-GI-aGvHD were treated with MaaT013 in 26 European sites, as a 2 nd line therapy after SR diagnosis and evaluable for treatment response. In EAP, 52 patients with steroid-dependent or SR-GI-aGvHD (classical n=41, late onset n=3, overlap syndrome n=8) were treated. These patients had previously received and failed 1 to 6 lines (median 3; 40/52 received ruxolitinib) of GvHD systemic treatments. GI-GvHD response was evaluated weekly and 28 days after day (D) 0 (inclusion for HERACLES or 1st dose for EAP). For all patients, GI-overall response rate (ORR) at D28 was defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR) or partial response (PR), compared to D0, without the use of additional systemic therapy. Other endpoints included the best overall response (BOR) achieved at any time, and overall survival (OS). Prepared under GMP, MaaT013 is characterized by a highly consistent richness of 455 ±3% OTUs and an Inverse Simpson index > 20. Treatment comprised 3 MaaT013 doses, each composed of 30 g of feces in 150 mL volume of inoculum (total 90 g of feces from 4 to 8 healthy donors) administered by enema (except for 2 EAP patients by nasogastric tube). All patients received at least 1 MaaT013 dose, 92% (HERACLES) and 87% (EAP) at least 2 doses, and 50% (HERACLES) and 71% (EAP) the full treatment course. In HERACLES, the reasons for not applying the 3 rd dose were death (n=5), physician decision to introduce salvage therapy (n=5), and ICU hospitalization (n=2)). Results In HERACLES, the GI-ORR was 38% including 5 CR, 2 VGPR and 2 PR. In EAP, positive GI-response was achieved in 31/52 patients (60% with 16 CR, 11 VGPR and 4 PR). Considering the GI-BOR, 13/24 (54%) and 35/52 (67%) achieved at least a PR in HERACLES and EAP respectively. In HERACLES, OS was 29% at month (M) 6 and 25% at M12. OS was significantly higher in responding (R) patients (achieving at least PR at D28) compared to non-responding (NR) (44% vs 20% at M6 and 44% vs 13% at M12, logrank p=0.047). In EAP, OS was 48% at M6 and 37% at M12, and significantly higher in R patients compared to NR (71% vs 17% at M6 and 62% vs 6% at M12, logrank p In HERACLES, treatment with MaaT013 was characterized by excellent tolerance: 252 Treatment-Emergent Adverse Events (TEAE) were reported for the 24 patients, the majority being infections (79%) and GI disorders (62%), as expected in GvHD patients. Of these 252 TEAE, only 2% (5 serious events in 2 patients) could not reasonably be excluded from being related to MaaT013 by the investigators. Shotgun sequencing in these 5 TEAE revealed that the causative infectious agents could not be detected in the administered MaaT013. In EAP, the safety profile of MaaT013 was considered satisfactory for all patients. 16S microbiome analyses were performed in the HERACLES population and showed that MaaT013 produced an early increase in α-diversity at genus level with a significant increase in Richness index at all evaluated timepoints (p Conclusion We herein report the treatment of 76 SR-GI-aGvHD patients using a full ecosystem, pooled-donor, high-richness biotherapeutic. The D28 GI-ORR was 38% and 60% in HERACLES and EAP respectively and this clinical benefit positively and significantly impacted OS (44% and 62% M12 in HERACLES and EAP R patients respectively). MaaT013 was shown to be safe and effective in these heavily immunocompromised patients, warranting further exploration of this approach. Figure 1 Figure 1. Disclosures Malard: JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Astellas: Honoraria; Biocodex: Honoraria; Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria. Loschi: CELGENE/BMS: Honoraria; AbbVie: Ended employment in the past 24 months, 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. Cluzeau: Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Takeda: Other: travel, accommodations, expenses. Huynh: Jazz Pharmaceuticals: Honoraria. Holler: MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vehreschild: SocraTec R&D GmbH: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Takeda Pharmaceutical: Research Funding; Seres Therapeutics: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; 3M: Research Funding. Gasc: MaaT Pharma: Current Employment. Plantamura: MaaT Pharma: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Background:Because bacterial infections are a common complication during neutropenia and a major cause for morbidity and mortality, patients with Acute Myeloid Leukaemia (AML) often receive prolonged courses of broad-spectrum antibiotics during induction chemotherapy. This extended exposure to antibiotics deeply disrupts the gut microbiota and may result in its colonization by resistant, opportunistic and potentially pathogenic microbes.Clostridioides difficile (C.difficile)is one such bacteria often found in patients whose microbiota has been strongly disrupted. Aim:The purpose of this study was to measure the incidence ofC. difficileinfection (CDI) in newly diagnosed AML patients who received induction chemotherapy and to evaluate the association between CDI and the use of antibiotics. Methods:We retrospectively studied the medical history of patients treated from 01/2016 to 12/2018 at the Department of Internal Medicine I of the University Hospital Cologne. The observational period was defined as 100 successive days after onset of induction chemotherapy or from onset of induction chemotherapy until microbiological confirmed CDI, or until death, whichever event occurred first. The diagnosis of CDI was confirmed by microbiological findings indicating the presence of toxin-producingC. difficilein stool isolates of symptomatic patients. The associations between therapeutic and prophylactic antibiotics and CDI were determined by use of a multivariable backward-stepwise binary logistic regression model. Findings:133 patients were included in the study. 30 patients developed CDI during the study period. 5 patients had two episodes or more. The incidence rate for CDI per 10,000 patient days in the observational period was 29.9. The incidence rates of CDI for the period after onset of induction chemotherapy reached 10.5% (n=14) at 8 weeks and 18.8% (n=25) at 120 days. In the analysis, we could not identify a specific antibiotic as risk factor for CDI but the result may be biased by the different mean observational periods for the group with and without CDI (the observational period for the group with CDI ends at the day of CDI). Conclusions:CDI is a frequent comorbidity affecting patients with newly diagnosed AML and receiving induction chemotherapy and deserves the attention of the medical teams in charge of the patients for adequate prevention and treatment approaches. Disclosures Bauquet: Da Volterra:Current Employment.Buffet:Da Volterra:Current Employment;Alfa Collaborative Group:Current Employment.Vehreschild:Berlin Chemie:Consultancy, Honoraria;Organobalance:Research Funding, Speakers Bureau;Pfizer:Research Funding, Speakers Bureau;Da Volterra:Research Funding;Seres Therapeutics:Research Funding;Astellas Pharma:Consultancy, Honoraria, Research Funding, Speakers Bureau;3M:Research Funding;Gilead:Research Funding, Speakers Bureau;MSD/Merck:Consultancy, Honoraria, Research Funding, Speakers Bureau;Basilea:Speakers Bureau.Vehreschild:Rigshospitalet Copenhagen:Research Funding;Academy for Infectious Medicine:Honoraria;University Manchester:Honoraria;German Society for Infectious Diseases (DGI):Honoraria;Ärztekammer Nordrhein:Honoraria;University Hospital Aachen:Honoraria;Back Bay Strategies:Honoraria;German Society for Internal Medicine (DGIM):Honoraria;Merck / MSD:Research Funding;Gilead:Research Funding;Pfizer:Research Funding;Astellas Pharma:Research Funding;Basilea:Research Funding;German Centre for Infection Research (DZIF):Research Funding;), German Federal Ministry of Education and Research (BMBF):Research Funding;(PJ-T: DLR):Research Funding;University of Bristol:Research Funding;Merck/MSD:Honoraria;Gilead:Honoraria;Pfizer:Honoraria;Astellas Pharma:Honoraria;Basilea:Honoraria;German Centre for Infection Research (DZIF):Honoraria;University Hospital Freiburg/ Congress and Communication:Honoraria.

Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction and/or consolidation therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can specifically apply to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial (NCT01540812) from the Spanish PETHEMA Group was to evaluate response of HR Ph-neg adult ALL patients to a different post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (centrally assessed by 8-color flow cytometry [FCM]) at the end of induction (week 5) and consolidation therapy (week 17).. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60y, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or KMT2A rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or in those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD Results: On April 2019, 307 HR ALL pts were evaluable. Median (range) age was 40 (15-60) y, 192 were males, 211 precursor B-ALL and 96 T-ALL, with a median WBC count of 12.9 (0.2-564) x109/L. Results of Induction-1 (n=304, 3 on induction): therapy-related death: 12(4%), resistance: 39(13%), CR: 253(83%). MRD Conclusions: This trial, in which post-induction therapy was only based on MRD results assessed by FCM, suggests that avoiding alloHSCT does not hamper the outcome of HR Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation. Better post-remission alternative therapies are specially needed for patients with poor MRD clearance. Supported by grants PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. Disclosures Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy.

INTRODUCTION Secondary Acute Myeloid Leukemia (s-AML) evolves from a previous hematopoietic clonal disease such as Myelodysplastic Syndromes (MDS/AML), myeloproliferative neoplasia (NPM/AML), medullary insufficiencies - aplastic anemia - (AA/AML) or exposure to chemo or radiotherapy (t-AML). The objective of this work is to describe and highlight the demographic, pathophysiologic and clinical-therapeutic characteristics of s-AML patients compared with p-AML. METHODS This is a retrospective cohort study based on the casuistry from 34 reference centers in Latin America during a period of 10 years (JAN10'-MAY19'). Patients ≥18 years old with primary AML, excluding the promyelocytic subtype (p-AML), and s-AML were admitted. Age, gender, performance status, comorbidity, cytogenetics, mutations, AML subtypes, extramedullary compromise, treatments and overall survival (OS) were analyzed. Statistically, Graph Pad Prism version 5.00 and, SPSS version 17 were used. RESULTS One thousand eleven patients with newly diagnosed AML were recruited, 693 (68.5%) corresponded to p-AML and 318 (31.5%) to s-AML. The demographic differences between p-AML and s-AML are shown on Table 1. Subtypes of s-AML: t-AML (18.5%), MDS/AML (58.2%), NMP/AML (13.5%), AA/AML (5.7%) and others s-AML (4.1%). Global median age was 58 years (R 18-93) and male 52%. Extramedullary compromise in CNS (3.2%) and other organs (5.5%). Seven hundred ninety-three cytogenetic studies were evaluable (based on MRC classification): High (22.3%), Intermediate (68.3%) and Low Risk (9.3%). FLT3 mutation was more frequently found in p-AML. In s-AML, the multivariate study showed short overall survival associated with ECOG ≥2 (HR:2.0), white blood count ≥ 50x109/L at diagnosis (HR:1.9), poor risk karyotype (HR:1.6) and age over 60 years (HR:1.5). At least, 883 patients received treatment (Table 2). During this study period, 211 patients (21%) were transplanted; 49 (23%) were s-AML; histoidentical related donor (46%), haploidentical (39%), non-related (8%) and autologous (7%). The median survival for all AML was 11.0 months with a statistically significant difference in favor of the p-AML (Figure 1). CONCLUSION Performance status (by ECOG ≥2), age ≥60, level of leukocytes a ≥50x109/L, poor risk karyotype and s-AML subtype at diagnosis had a significant worse impact on overall survival. Most patients with s-AML came from MDS, they were older and their incidence increased as the population aged. They presented more comorbidities and worse performance status. Undoubtedly, our findings showed that s-AML is a distinct high risk subset of myeloid disorder with adverse prognosis and represents a therapeutic challenge. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION Cell free tumor DNA (cftDNA) based targeted next generation sequencing (NGS) is a novel tool that enables accurate and minimally invasive tumor genotyping. MATERIAL AND METHODS Here we have performed cftDNA targeted NGS for the molecular diagnosis of a series of 92 peripheral blood samples obtained at diagnosis in patients included in a phase II randomized clinical trial comparing standard RCHOP versus BRCAP as first line treatment in patients with poor IPI (aaIPI2-3 or aaIPI1 with high b2m, age 18-71, NCT01848132). Centralized histopathological review of diagnostic tissue samples confirmed the diagnosis: 83 DLBCL (68%, 55/81 GCB, 32%, 26/81 non-GCB, according to Hans immunohistochemical algorithm), 4 TCHRBCL, 3 PMBCL, 1 concurrent DLBCL and FL3A, 1 FL 3B. 7 out of 83 cases had DLBCL morphology and DH by FISH (6 MYC/BCL2 and 1 MYC/BCL6, all GCB-type by IHC). A targeted NGS approach using amplicon-based chemistry (Truseq, Illumina) that interrogates exonic regions of 35 relevant genes in DLBCL (1458 amplicons analyzed) was used for library generation from plasma derived DNA. Germline DNA from peripheral blood granulocytes from 89 out of 92 patients was sequenced in parallel and used as control DNA for variant calling. Only somatic variants with a read depth above 100 and Variant Allele Frequency > 5% were considered. RESULTS cftDNA concentration (hGE/mL) was associated with LDH levels (U/mL) at diagnosis. Mean cftDNA concentration was lower in patients with low LDH (U Mann whitney p= 0.005). Somatic mutations were identified in 74% (68 out of 92) patient plasma samples. 242 somatic mutations were considered after filtering. Mean of 3.6 mutations per patient. 10 genes were mutated in >10% of the patients, including: FAT2 (19.6%), ARID1A (18%), NOTCH1 (17.4%), NOTCH2 (15.2%), KMT2D (14.13%), SMARCA4 (14%), ATM (13%), EP300 (13%), EZH2 (13%), PLCG2 (13%). Recurrent mutations were found in EZH2 (2 patients). Mutations in BCR/TLR pathway genes were found in less than 10% of the cases (CARD11, 7.6%; MYD88, 4.4%; CD79A, 5.4%; CD79B, 1%; BTK, 4.4%). NOTCH1 mutations were found preferentially in GCB type DLBCL (12/55 GCB vs 1/26 nonGCB, Chi square p value DISCUSSION cftDNA targeted NGS captures the mutational profile in a significant fraction of DLBCL patients and enables tumor genotyping in the clinical trial setting. In contrast with previously published data mutations in NOTCH pathway, including NOTCH1, NOTCH2 and SGK1 were relatively frequent in our series of poor IPI patients, outnumbering the frequency of mutations in BCR/TLR pathway. NOTCH pathway mutations were also preferentially found in GCB-type DLBCL-NOS, PMBCL and 1 case of TCHRBCL. In summary cftDNA genotyping based on targeted NGS can provide potentially useful information for therapy selection in DLBCL patients. Disclosures Martín: Roche: Consultancy, Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses. Gonzalez-Barca:Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; Celtrion: Consultancy. Montes-Moreno:TAKEDA: Consultancy; Roche: Consultancy.

Introduction DLBCL is the most common non-Hodgkin lymphoma and a heterogeneous subtype from the biological and clinical point of view. 20-40% of the patients relapse so it is important to identify a high risk population that could benefit from different therapeutic approaches. For this purpose, several scores have been developed. The IPI has been the most widely used but lacks the ability to identify this very high risk population in Rituximab era. Low absolute lymphocyte count and high levels of blood monocytes have shown to be unfavorable risk factors. The red cell distribution width (RDW) has been associated with aging and active inflammatory processes and beta-2-microglobulin (B2M) with tumor load and proliferation as well as comorbidities such as kidney failure. All these variables are easily obtainable at the time of diagnosis. Patients and methods From the national database of GELTAMO-IPI Project, we selected those patients with DLBCL homogeneously treated with R-CHOP ± radiotherapy. The complete blood count (CBC) values were standardized using the normal reference values of each centre. The survival analysis was estimated with Kaplan-Meier method. The comparison between variables was performed through Log-Rank test and multivariate analysis with Cox regression. The CBC quantitative variables cut points were calculated through MAXSTAT. A new prognosis score was generated taking into account the results of multivariate analysis for progression free survival (PFS), spliting the sample in two cohorts (discovery and validation). Results Nine hundred and ninety-two patients with DLBCL were retrospectively analyzed with a median follow up of 55 months (12-185). The characteristic of the patients are summarized in table 1. In the multivariate analysis, age, ECOG, stage, bulky mass, B2M, RDW and lymphocytes/monocytes ratio (LMR) were significantly independent variables for PFS. A new prognosis score was generated with these variables including age categorized in 3 groups (18-64, 65-80 y >80) with 0, 1 y 2 points, ECOG>3-4 with 2 points, stage III-IV, bulky mass, high B2M, LMR0.96 with 1 point each for a maximum of 9. This score could improve the discrimination of a very high risk subgroup with a 5-year PFS of 17% (Figure 1) versus 45%, 52%, 32% or 29% of R-IPI, NCCN-IPI, R-TS and GELTAMO-IPI, respectively and 5-year overall survival (OS) of 20% (Figure 2) versus 59%, 46%, 45% and 40% for R-IPI, NCCN-IPI, R-TS and GELTAMO-IPI. Conclusion A new prognosis score including easily obtainable CBC variables (LMR and RDW) and B2M is presented. This score identifies a high risk population both for PFS and OS in comparison with other scores for DLBCL. The addition of other biological or image markers could improve these results. Disclosures Martín: Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Sancho:SERVIER: Honoraria; JANSSEN: Honoraria, Speakers Bureau; MUNDIPHARMA: Honoraria; SANOFI: Honoraria; GILEAD: Honoraria, Research Funding; KERN FHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria; ROCHE: Honoraria, Speakers Bureau.