Abstract: This is an Italian multicentric cohort study evaluating efficacy and safety of venetoclax + hypomethylating agents (HMA) in a real‐life setting of newly diagnosed, relapsed, and refractory patients with acute myeloid leukemia (AML). The data show that the combination of venetoclax and HMA offers an expectation of remission and long‐term survival not only to newly diagnosed but also to relapsed or refractory elderly patients with AML.

Abstract: Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P 〈 0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P 〈 0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).

Abstract: Introduction In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287). Patients and Methods Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation. Results The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P 〈 0.0001), while 3-years DFS was 73%, 28% and 13% (P 〈 0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P 〈 0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002). Conclusions Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

Abstract: Background The outcome of primary refractory (PRF) acute myeloid leukemia (AML) patients is poor with a minor proportion rescued by allogeneic hematopoietic stem cell transplantation (HSCT). The identification of pre-HSCT variables may help to identify PRF AML most likely to benefit from HSCT. The EBMT group reported factors predicting the outcome of 168 patients with PRF AML receiving an unrelated donor stem cell transplantation; 5-years OS was 22% and factors associated to an improved survival were the numbers of chemotherapy cycles ( 〈 3), bone marrow blast infiltration 〈 38% and patient CMVseropositivity. These clinical findings allowed to define 4 prognostic groups with survival rates ranging between 44% and 0% {Craddock, 2011). We performed a similar analysis focusing on PRF AML patients transplanted in Italy between 1999-2012 with a stem cell graft obtained by a sibling, unrelated donor and cord blood unit. Patients and study design We analyzed the clinical outcome of 242 patients transplanted in 26 GITMO centers. Patients disease status at HCST included PRF AML defined as failure to achieve a complete response (CR) after one or more chemotherapy cycles containing active drugs on AML. The cytogenetic and molecular risk was defined according to the European LeukemiaNet. The main clinical and outcome follow up data were retrieved from the GITMO database. The main end-points of the study were overall survival (OS) and leukemia-free survival (LFS). Results The median age at HSCT was 49 years (18-72) and 55% of patients were male. Before HSCT, 58% received ≤ 2 chemotherapy cycles. Median time from diagnosis to HSCT was 6 months (1-19) and in 85% was ≥ 3 months. An intermediate-II/adverse karyotype was detected in 58% of patients, 〉 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 60% and a pre-HSCT Karnofsky score 〈 90 was present in 43%. Donors were HLA identical sibling in 48% and matched unrelated in 19%, related mismatched in 19%, unrelated mismatched in 3% and cord blood in 11%. Anti-CMV antibodies were present in 87% of patients and in 65% of the donors. Conditioning regimen intensity was myeloablative or reduced in 69% and 31%, respectively; 49% of patients received T cell depletion (92% in vivo and 8% ex vivo). Neutrophils and platelets engraftment was achieved in 87% of patients after a median of 17 (9-52) and 17 (3-150) days, respectively. In all, 35 (14%) patients died within 30 days from HSCT. Of 207 patients evaluable for response, 138 (66%) achieved CR after a median time of 32 days (range 16-130) from HSCT and 69 did not (33%). Median survival of patient who achieved CR was 10 months while it was 2 months for those who did not. Seventy patients (51%) relapsed after a median time of 3 months (1-31), 64 died of disease, 6 survived and 2 of these latter reachieved CR. Sixty-eight patients (49%) maintained CR, 34(50%) died and 34 survived. A t the last follow up 42 patients were alive, 36 in CR and 6 with disease with a median follow up of 27 months (range 1,8-14). The median OS of the whole patient cohort was 5,7 months. At 3-years, the OS and LFS was 15% and 23% respectively. AGvHD was registered in 39% of patients (grade 〉 2 in 30% of cases) while cGVHD occurred in 29% (extended in 44% of cases). The 3-years cumulative incidence of NRM was 17%. By univariate analysis, the number of chemotherapy cycles to achieve CR (≤ 2), the time to HSCT ( 〈 3 months), the cytogenetics risk favorable/intermediate I, the number of marrow blasts 〈 25% or the absence of blasts in the peripheral blood, the PS ≥ 90 and the lack of any form of T cell depletion, were all associated to a better survival. By multivariate analysis, the number of chemotherapy cycles, (Hazard Ratio (HR): 1.51; 95% confidence interval (CI): 1.04–2.19; P=0.029), the lack of T cell depletion (HR: 1.66; 95% CI: 1.15–2.40; P=0.007), the degree of BM or PB blast infiltration (HR: 1.59; 95% CI: 1.01–2.25; P=0.043), and the PS (HR: 1.46; 95% CI: 1.00–2.14; P=0.048) remained significantly associated with survival. On the basis of this multivariate analysis, we set up a new score predicting a different 3 years OS: score 0 (0 or 1 adverse prognostic factor, with 28% survival), score 1 (2 adverse prognostic factor, 17% survival); score 2 (2 or 3 adverse prognostic factors, 10% survival) (Figure 1) Conclusion The clinical outcome of PRF AML remains poor. The new simple clinical GITMO score helps indentifying patients most likely will benefit or not from the HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Background This non-interventional retrospective study, is intended to analyze toxicity and effectiveness of venetoclax of a large cohort of R/R and de novo AML patients treated in Italy since 2015 outside clinical trials with the ultimate goal of improving the knowledge related to venetoclax treatment in the real-life setting. Interim analysis on first 59 patients enrolled is presented here. Aims The aim of this study is to collect data on safety and efficacy of venetoclax in a large cohort of AML patients treated in Italy from 2015 to 2020 in a real-life setting (out of clinical trials). Methods This is a multicenter, retrospective, observational study. All patients with AML treated outside clinical trials with venetoclax as single agent or in combination with other drugs from 1 January 2015 to 1 April 2020 in 40 Italian Hematology Units will be considered for enrollment. Data are collected in accordance with GCP and Helsinky declaration. For this interim analysis data registered into eCRF at 30 June 2020 have been considered. Adverse events (AEs) are graded according to CTCAE v4.03. Survival is estimated with Kaplan-Meyer method. Results The study started on August 2019 and will be completed on August 2021. Up to 30 June 2020 (first data cut off) 30 sites have been activated and 59 AML patients have been registered, 27 males (46%) and 32 females (54%), with a median age of 64 years (range 35 - 83). At the time of venetoclax initiation, 14/59 (24%) patients had a refractory disease, 31 (52.5%) had relapsed disease (14 first relapse and 17 a second or further relapse), eight patients (15%) were newly diagnosed and received venetoclax as first line therapy while in six patients disease status was missing at the time of data cut off. At diagnosis, 52 patients (88%) had bone marrow involvement, of which four (7%) had extramedullary involvement (skin or subcutaneous and deep muscular localization) and one had CNS involvement. 35/59 (59%) patients were classified as fit for intensive chemotherapy, 16 (27%) unfit and two (3%) frail according to SIE, SIES and GITMO group. For six patients fitness status was missing at the time of data cut off. 45/59 (76%) patients had received previous therapy for AML, eight patients were treatment naïve at the time of venetoclax initiation. while for six patients data regarding previous AML therapy were missing at the time of data cut off. In the R/R setting (n=45), the median number of previous therapy lines were 2 (range 1-7). Nine patients had relapse after stem cell transplantation (SCT) and one of them had received double transplant. For 42/45 R/R AML patients the data regarding treatment with venetoclax were available at the time of data cut off. Three out of 42(7%) patients received venetoclax as single agents, 32 (76%) in combination with HMAs (31 Azacitidine and 1 Decitabine), and six with high or intermediate dose ARA-C. In the cohort of R/R patients treated with combination of venetoclax and HMA, in 29/32 patients venetoclax was started as a ramp up phase. The median number of venetoclax cycles was 2 (range 1-13) and the median dose administered was 400 mg daily (range 100-600). Regarding toxicity, 72 adverse events (AEs) were recorded of which 49 were grade III-IV (39 hematologic toxicities, 4 pneumonia, 2 sepsis and 4 other) and 2 fatal (sepsis). For 25 out of 32 patients treated with venetoclax and HMAs combination, a response evaluation was available at the time of data cut off. 15 patients had an evaluable response within 2 months, 7 within 4-months and for 3 the date was missing. 14 (56%) patients obtained composite complete remission (CR=9; 5 =CRi), three patients had a partial response (PR), one stable disease (SD) while seven patients were refractory. Overall, six out of 32 (19%) patients underwent allogenic transplantation after venetoclax-HMAs combination. Median OS of R/R patients treated with venetoclax plus HMA was 182 days (95% C.I 85-421.). Conclusions These preliminary data show that venetoclax in combination with HMAs has an acceptable toxicity profile and is effective in this setting of R/R patients with unfavorable prognosis. Data from more than 100 patients treated in real life setting with venetoclax in Italy since 2015 is expected by the end of 2020, and further analysis on RR patients is ongoing. Data on newly diagnosed patients treated with venetoclax alone or in combination with HMA or chemotherapy will be analyzed. *G.M. and C.C. contributed equally as last author Disclosures Todisco: Jannsen, Abbvie, Jazz:Membership on an entity's Board of Directors or advisory committees.Fracchiolla:Amgen:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;ABBVIE:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses;Gilead:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau.Papayannidis:Abbvie, Janssen, Novartis, Amgen, Pfizer:Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.Martelli:Pfizer:Membership on an entity's Board of Directors or advisory committees;Novartis:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;AbbVie:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Di Renzo:BerGenBio ASA:Research Funding.Tarella:ADC Therapeutics:Membership on an entity's Board of Directors or advisory committees, Research Funding;ImmunoGen:Research Funding;TG-therapeutics:Research Funding.Rossi:Jazz:Membership on an entity's Board of Directors or advisory committees;Abbvie:Membership on an entity's Board of Directors or advisory committees;Astellas:Membership on an entity's Board of Directors or advisory committees;Novartis:Other: Advisory board;Amgen:Honoraria;Pfizer:Membership on an entity's Board of Directors or advisory committees;Janssen:Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Consultancy, Honoraria;Takeda:Honoraria, Membership on an entity's Board of Directors or advisory committees;Alexion:Membership on an entity's Board of Directors or advisory committees;Celgene:Membership on an entity's Board of Directors or advisory committees;Sanofi:Honoraria.

Abstract: Abstract 2005 Background and Aim The dismal prognosis of AML patients undergoing allogeneic stem cell transplantation not in complete remission at time of conditioning poses challenging clinical decisions. In these patients, a recent, large retrospective analysis conducted by the CIBMTR showed that a myeloablative HCST can induce an overall 19% long term survival. Based on five adverse pretransplantation variables (first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics) this analysis allowed to set up a pre-HSCT score (from 0 to ≥3) able to identify four risk groups defining a 3-years overall survival (OS) probability ranging from 6% up to 42% (Duval M, JCO 2010). However, this CIBMTR analysis was limited to patients with the following characteristics: a) de novo AML or secondary AML to a previous MDS b) patients receiving a TBI or busulfan based myeloablative conditioning regimens (MAC) and a BM or PB derived stem cell graft. Here we report data obtained in Italy in a similar cohort of AML patients that also included those receiving a reduced-intensity conditioning (RIC) regimen and those grafted with a cord blood unit. Study design, patients and transplants characteristics We retrospectively analyzed data reported to the GITMO registry by 20 Italian centers on 523 AML patients who underwent a first HSCT being not in complete remission (CR) at time of conditioning, between 1999 and 2010. The median age at HSCT was 47,6 years (18–72), the male/female ratio 50%. At diagnosis 71,5% were de novo AML, 23% were secondary to a previous MDS/CMML, while in 5,5% the AML was therapy related or secondary to a previous CMN. Before HSCT conditioning, patients were primary refractory (PIF) in 34%, in first or subsequent untreated relapse in 45% and 16%, respectively or an untreated MDS to AML evolution in 5%. Before HSCT, 79% of PIF received ≥2 chemotherapy cycles and for relapsed patients the duration of the first CR was 〈 6 months in 50%. An intermediate-II or adverse karyotype was detected in 43% of patients, a greater than 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 53% and a pre-HSCT Karnofsky score less than 90 was present in 38%. The stem cell source was the PB in 65%, the bone marrow in 28% and the cord blood in 6%. Donors were HLA identical sibling or matched unrelated donor in 69%, a family or unrelated mismatched in 25% and a cord blood unit in 6%. Anti-CMV antibodies were present in 87% of patients and in 66% of the donors, while donor-recipient pair were sex-matched in 50% of the cases. More than 60% patients received a MAC and 37% a RIC program. Results After HSCT, a myeloid and platelets engraftment was achieved in 87% of patients after a median of 17 (9–63) and 18 (2–117) days, respectively. Acute GVHD (grade ≥2 60%) was registered in 46% while chronic GVHD developed in 31%. The median follow up of the whole patients cohort was 5,36 months (0.09–133) while that of survivors was 26 months (1–133) with 96 patients alive and 77 leukemia-free. A multivariate analysis identified 7 pre-HSCT adverse variables that significantly influenced survival: an AML secondary to a previous chronic myeloproliferative neoplasm or a therapy related AML (HR 1,83, 95%CI 1,14–2,96, p 0,013), a relapsed AML with a first CR duration 〈 6 months (HR 1,39, 95%CI 1,06–1,82, p 0,018), an AML with a PIF after ≥2 chemotherapy cycles pre-HSCT (HR 1,74, 95%CI 1,11–2,74, p 0,016), an intermediate II/adverse cytogenetics (HR1,71, 95%CI 1,11–2,62, p 0,015), BM blasts ≥25% or any level of PB at HSCT (HR 1,65, 95%CI, 1,31–2,07, p 0.000) and a mismatched related/unrelated donor (HR 1,56, 95%CI, 1,23–1,98, p 0.000). At 3-years, the OS and LFS of our patients was 16% and 21%. Interestingly, when applied to our results, the CIBMTR score was fully validated in our patients with a 3-year survival rate decreased from 40% (score 0, HR1) to 26% (score 1, HR 1,39; 95%CI 0.88–2,12, p 0,142), to 18% (score 2, HR 1,58; 95%CI 1–2,43, p 0,04) to 5% (score 3, HR 2,83; 95%CI 1,71–4,16, p 0,000) (Figure 1). Conclusions Our results confirm that a) HSCT is a potentially curative option for a significant proportion of AML patients undergoing transplant not in remission, b) these patients may benefit from either a MAC or a RIC conditioning regimens and c) the CIBMTR score applied to this poor prognosis AML cohort is a useful tool for patient counseling and for planning the HSCT activity. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction Patients with secondary acute myeloid leukemia (sAML) after myelodysplastic (MDS) or myeloproliferative neoplasms (MPN) treated with chemotherapy show poorer outcomes compared with de novo AML; consequently, these cases should be allocated to allogeneic stem cell transplant (alloSCT) whenever possible (Döhner H, Blood 2017). Some recent evidence suggested the potential of molecular characterization for implementing the current WHO definition (Arber DA, Blood 2016), since chromatin-splicing mutations have been reported to be highly specific for sAML (Lindsley RC, Blood 2015). However, this molecular signature has also been recognized in some clinically defined de novo AML cases (Papaemmanuil E, NEJM 2016). Based on this background, we assessed the clinical impact of chromatin-splicing mutational signature in clinically defined de novo AML patients enrolled into the prospective NILG 02/06 trial [ClinicalTrials.gov Identifier: NCT00495287]. Patients and Methods The trial (Bassan R, Blood Advances 2019) randomized 574 newly diagnosed AML patients to receive induction (standard vs high-dose) followed by consolidative chemotherapy and/or alloSCT. For the present analysis, only patients with de novo AML (n=313) and WHO-defined sAML after MDS or MPN (n=101) with a full genetic characterization have been considered. Studies performed at diagnosis included conventional karyotype (n=412) and molecular analysis (n=414) and/or targeted NGS (this latter performed on 197 patients with normal karyotype). Patients with WHO-sAML were defined by the presence of an antecedent history of MDS or MPN (n=21) and/or cytogenetic WHO criteria of AML with MDS-related changes (n=80). Chromatin-splicing mutational signature defined the molecular-sAML group and comprised ASXL1, STAG2, BCOR, KMT2A-PTD, EZH2, PHF6, SRSF2, SF3B1, U2AF1, ZRS2 and RUNX1, excluding patients with WHO recurrent abnormalities. Results Chromatin-splicing mutations were scored in 55/313 (17.6%) de novo AML patients (hereafter named molecular-sAML). The most frequently reported were KMT2A-PTD (45.5%), RUNX1 (44.4%) and ASXL1 (22.2%), while other mutations in the signature accounted for 5-17.5% of cases. Compared to de novo AML without chromatin-splicing mutations, patients with molecular-sAML and WHO-sAML were older (P & lt;0.0001) and presented with lower white blood cell counts (WBC) (P & lt;0.0001). The 3 groups were balanced in regards to induction regimen (P=0.5) and proportion of patients allocated to a consolidative alloSCT (31% in de novo AML, 30% in WHO-sAML and 33% in molecular-sAML, P=0.8). Complete remission (CR) after 1 or 2 induction cycles was achieved in 93% of de novo AML, 85% of molecular-sAML and 58% of WHO-sAML. In terms of 5-years overall survival (OS) and disease free survival (DFS), de novo AML patients did markedly better than both molecular and WHO-sAML patients (OS: 61%, P & lt;0.0001; DFS: 54%, P & lt;0.0009). Considering sAML patients, WHO-sAML had the worst OS when compared with molecular-sAML (18% vs 30%, P=0.02), but an overlapping DFS (22% vs 26%, P & lt;0.3) (Figure 1). The negative impact of chromatin-splicing mutations was independently confirmed by multivariate analysis accounting for age, performance status, WBC and induction regimen [HR 2.2 (CI 95% 1.48-3.25), P=0.0001]. Among chromatin-splicing mutations, only RUNX1 and U2AF1 significantly affected OS [HR 3.55 (CI 95% 1.28-9.87), P=0.01 and HR 6.87 (CI 95% 1.71-27.55), P=0.006] . Finally, a consolidative alloSCT improved survival in all patients groups, most significantly in molecular and WHO-sAML (48% vs 24%, P=0.07 and 38% vs 8%, P=0.0001, respectively). Conclusions Chromatin-splicing mutational signature identifies a distinct high-risk group within de novo AML patients, which shows clinical characteristics and outcomes closer to sAML than to de novo AML patients. These data highlight the need to detect this molecular signature at diagnosis and support a molecular definition of sAML. Disclosures Ferrero: Novartis: Honoraria. Corradini:Celgene: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Bassan:Incyte: Honoraria; Amgen Inc.: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Rambaldi:Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support.