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Introduction: Commonly accepted standardized sets of outcomes to be measured in clinical trials are still limited. In accordance, outcome measures vary widely between clinical trials even within defined hematological malignancy (HM) entities. Definition of a core outcome set (COS), which represents a standardized agreed set of outcomes that should be measured and reported in all trials for the respective disease of interest may improve this situation. Furthermore, respective COS should address the need of all stakeholders, i.e. not only the views of physicians and industry running the trials, but also the interests of patients and regulators. To perform a task like this, HARMONY - Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms in Hematology - a private-public partnership established in January 2017, including 53 partners and 43 associated partners in 18 different European countries and also 6 patient organizations, poses an optimal platform to define COS for HMs. Methods: To define COS for 5 selected HMs, it was decided to use the Delphi survey method provided by COMET initiative. Since HARMONY has members of several important stakeholder groups (clinicians, industry, health authorities and patient groups) it was decided to include all stakeholders to participate in the Delphi surveys. A pilot study was implemented for the COS for acute myeloid leukemia (AML) based on which additional Delphi surveys were developed for myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL). As starting point preliminary outcome lists were generated based on published reports and available guidelines. Surveys were performed with representatives from each stakeholder group to agree within a pre-defined and iterative process on a COS for each HM. Conditions and criteria were defined in study protocols. Each outcome was rated into 3 categories (1-3 "not important", 4-6 "important but not critical" and 7-9 "critical"). A "consensus-in criterion" was defined if 70 % or more respondents scored the outcome as critically important (7-9) and 15% or fewer rated the outcome as limited important (1-3). To make sure that the patients' voice was heard within the consensus process, a special "patient-important criterion" had been implemented during data analysis. Outcomes ranked with a median of 7 or higher in the patient group were highlighted, showing these are really important for patients. According to a bottom-up-approach, an overarching COS was then created based on the individual survey results. Results: For the Delphi surveys a total of 365 individuals participated including 126 clinicians (35%), 46 EFPIA members (13%), 177 patients/patient advocates (48%) and 16 regulators (4%). While there was a large overlap of outcomes among HMs, there were also many disease specific outcomes such as leukemia-free survival (LFS) for AML, very good partial response (VGPR) for MM to name only few. In addition, there were sometimes major differences in the assessment of individual stakeholders within an outcome, e.g. between clinicians and patients. Finally, the general COS applicable to all HMs included core outcomes that met the consensus-in criterion for all HMs. Conclusion: Using Delphi surveys to define specific COS for HMs revealed meaningful results. Based on the bottom-up-approach not only disease specific HM COS could be defined, but also an overarching COS applicable to all HMs. This overarching COS will subsequently not only allow to compare results more easily within a distinct HM subgroup but also results across different HMs. To our knowledge, this is the first multidisciplinary approach to define COS across four different stakeholder groups. These COS should now be a starting point to further refine COS and to apply them within future clinical trials, thereby reducing inconsistencies and bias in outcome-reporting. Results of COS based clinical trials will simplify the development of novel clinical recommendations, which will improve future patient management and clinical patient care in the real-world setting. Figure 1 Figure 1. Disclosures Lang: Roche: Honoraria. Ossenkoppele: Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Döhner: Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Astellas: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Salles: Genmab: Consultancy; Incyte: Consultancy; Velosbio: Consultancy; Genentech/Roche: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Debiopharm: Consultancy; Allogene: Consultancy; Rapt: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Kite/Gilead: Consultancy; Ipsen: Consultancy; Takeda: Consultancy; Regeneron: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Dreyling: Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Sonneveld: Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Fenaux: Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Santini: Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Guillevic: BMS: Current Employment. Calado: Novartis: Current Employment. Sanz: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Hernández-Rivas: Pfizer: 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/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Barbus: Abbvie: Current Employment. Schulze-Rath: Bayer: Current Employment. Bullinger: Menarini: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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.

Background: The development of new genetic profiling techniques such as Next Generation Sequencing (NGS) have helped to unravel the genomic landscape of a large number of hematological diseases. In acute myeloblastic leukemia (AML), many mutations have been found at diagnosis or during the course of the disease, either alone or in combination. Nevertheless, the clinical significance of most of them has not been well established. That is particularly true regarding infrequent gene mutations and their co-mutations as they are underrepresented in most case series that have been analyzed so far. The big data platform of HARMONY alliance provides the excellent basis for addressing this problem as it assimilates clinical and genomic information about AML patients from over 100 organisations in 18 European countries comprising more than 5000 patients. Anonymised and harmonized using OMOP standards, data collected in HARMONY are optimal for studying the impact of gene-gene-interactions overcoming differences related to data providers. Aims: To identify clinically significant genetic patterns of 2 or more concurrent mutations using the Harmony alliance AML database Methods: From the HARMONY alliance database, we selected ~3600 AML patients with NGS molecular panel analysis. We first performed survival analysis between each gene combination and then we rendered those with statistically significant differences in one easy-to-read graph using the Gephi platform (Fig. A). We then highlighted promising or unexpected associations and analyzed them one by one in greater detail. Finally, these results were validated on an independent cohort. Results: We found that the co-mutation of RAD21 (RAD21mut) in DNMT3A mutated (DNMT3Amut) AML impacted outcome compared to DNMT3Amut alone patients (Fig. B, 3-year survival, 81% vs 52%, p=0.016). However, this effect was exclusively seen in allogeneic transplant recipients. In order to identify possible bias that could be generated if RAD21mut were associated with other well-known favorable prognosis mutations, we compared the frequency of each mutation in our DNMT3Amut / RAD21mut subgroup with the global AML cohort. NPM1 co-mutation was more frequent in the DNMT3Amut / RAD21mut group (Fig. C 3, 84% of patients with NPM1 mutation (NPM1mut) vs 26% in the global cohort), potentially explaining the higher survival. Next, we tried to isolate the positive effect of NPM1 on outcome by comparing DNMT3Amut / NPM1mut patients with and without the RAD21 co-mutation. This analysis showed a favorable outcome only in RAD21mut patients compared to RAD21 wildtype (Fig. D, 3-year survival, 83% in RAD21mut / DNMT3Amut / NPM1mut vs 50% in DNMT3Amut / NPM1mut with RAD21 wildtype, p=0.016), one more time only in allogeneic transplant recipients. Finally in order to validate our results we reproduced this study from the beginning using an independent cohort of 3125 AML patients. The Gephi graph confirmed an association of DNMT3Amut / RAD21mut patients with better survival over DNMT3A alone (3 year-survival, 75% vs 37%, p Conclusions: Using the HARMONY alliance database we tested for potential gene co-mutations in AML patients, often very infrequently represented in other studies. Our data suggest that RAD21mut has a positive effect on outcome in patients receiving an allogeneic transplant with concurrent mutation of DNMT3A and NPM1. Even though NPM1mut is much more frequent in the DNMT3Amut / RAD21mut group, its association with favourable outcome seems to depend on the presence of an additional RAD21mut Keywords: AML , gene combinations, RAD21, DNMT3A, NPM1, HARMONY, big data. Figure: Graphical results. A. View obtained from the Gephi platform with the gene combinations and their effect on survival. B. Survival curves respectively of the DNMT3A+RAD21 cohort and the DNMT3A-only one. 1. Representation of the proportions of each mutation in the overall cohort (red) compared to the DNMT3A+RAD21 cohort (blue). D. Survival curves respectively of the NPM1+DNMT3A+RAD21 cohort and the NPM1+DNMT3A one. Figure 1 Figure 1. Disclosures Sobas: Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding. Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria; BMS-Celgene: Honoraria. Sierra: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS Celgene: Honoraria, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria; Roche: Other: Educational grant; Janssen: Other: Educational grant; Amgen: Other: Educational grant; Alexion: Other: Educational grant. Mayer: Principia: Research Funding. Voso: Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Sanz: Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Gilead Sciences: Other: Travel, accommodations, and expenses; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Calado: Novartis: Current Employment. Döhner: Janssen: Honoraria, Other: Advisory Board; Jazz Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Research Funding; Agios and Astex: Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Heuser: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; BergenBio: Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Bayer Pharma AG: Research Funding. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Turki: Jazz Pharma: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; CSL Behring: Consultancy. Schulze-Rath: Bayer: Current Employment. Hernández Rivas: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Bullinger: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Hexal: Consultancy; Gilead: Consultancy; Abbvie: Consultancy, Honoraria; Menarini: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Research Funding. Döhner: Jazz: Honoraria, Research Funding; Janssen: Honoraria; GEMoaB: Honoraria; Astellas: Honoraria, Research Funding; Astex: Honoraria; Agios: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria; Pfizer: Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedicals: Honoraria; Helsinn: Honoraria; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Amgen: Honoraria, Research Funding. Ossenkoppele: Servier: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Background: The Revised International Prognostic Scoring System (IPSS-R) classifies pts with MDS into risk categories, from very low-risk (vLR) to very high-risk (vHR), which guide treatment (tx) options. Pts with intermediate-risk MDS (IR-MDS) are heterogenous and real-world tx practices and outcomes for these pts are unknown. In Spain, the GESMD is an MDS registry containing more than 16,000 pts registered from 142 study sites which represent the country. We evaluated the real-world tx patterns and survival outcomes of pts with MDS from this registry across IPSS-R risk groups (with a focus on IR-MDS) and explored factors driving tx decisions among pts with IR-MDS. Methods: We analyzed the data collected by the GESMD registry from January 2008 to June 2020. Pts included were adults diagnosed with MDS, with informed consent and ≥6-mo follow up if the pt was alive. Pts who did not have available data on their MDS risk score or their use of hypomethylating agent for MDS were excluded. Prior to inclusion in the registry, a curation process was performed to ensure that each pt had the minimum data set and to avoid duplication and errors. Data queries were responded to by physicians at study sites, and the final data included were reviewed by the investigators. Descriptive statistics were used to summarize demographics, clinical, and tx characteristics overall and by risk groups. Overall survival (OS) was analyzed by risk group and tx type using the Kaplan-Meier estimator and 95% confidence intervals (CIs) were calculated. In pts with IR-MDS, a number of baseline variables (including sex, diagnosis year, transfusion status, risk score, age, and blood and blast counts) were explored to assess their relationship with tx selection between either azacitidine (AZA) or best supportive care (BSC) only (eg, transfusions, growth factors). Results: In total, 4,604 pts were included in this analysis. The median age of enrolled pts was 76 y and 39% were female. Other baseline characteristics are seen in Table 1. Seven hundred sixty-one pts (16.5%) were classified as IR-MDS with similar distribution across IPSS-R risk score subgroups 3.5, 4.0, and 4.5. Txs received by pts in the cohort included AZA, chemotherapy, allogeneic stem cell transplant (alloSCT), BSC, and others (eg, immunosuppressors, androgens; Table 2). The majority of pts with IR-MDS were treated with BSC (61%) and AZA (38%). The median time from diagnosis to start of AZA tx ranged from 1 mo in pts with high-risk (HR) and vHR-MDS to 26 mo in pts with vLR-MDS; pts with IR-MDS started AZA at a median of 3 mo from diagnosis. Survival analysis by IPSS-R group shows that median OS decreased with increased risk score (vLR: 81.3 mo [95% CI, 73.6-89.0], low-risk (LR): 59.0 mo [95% CI, 55.2- 62.8], IR: 29.4 mo [95% CI, 27.0-31.8], HR: 15.2 mo [95% CI, 13.3-17.1], vHR: 9.4 mo [95% CI, 7.7-11.1]). When analyzed by tx type, pts with IR-MDS had longer median OS when treated with AZA or chemotherapy ± alloSCT than with BSC (AZA: 30.1 mo [95% CI, 27.3-32.9], chemotherapy ± alloSCT: 30.1 mo [95% CI, 23.8-36.4], BSC: 24.6 mo [95% CI, 18.5-30.7]; Figure 1). No relevant factors associated with decision to treat pts with IR-MDS with AZA or BSC were identified. Conclusions: This study shows that more than one-third of pts with IR-MDS were treated with AZA shortly after their diagnosis, similar to the HR/vHR group. This cohort represents what we know about MDS and its distribution by risk group, while bringing new information on the use of AZA and its potential value in improving the OS of pts with IR-MDS. It is possible that other factors not included in the analysis (comorbidities, distance to the hospital, social and familial support) might have had an influence on the decision to treat pts with IR-MDS with AZA or offer BSC instead. Selection bias, misclassification, and confounding might occur when using registry data and this may limit the interpretation; however, the study shows important insights into the use of real-world therapies for pts with MDS, especially IR-MDS. The COVID-19 pandemic had an impact on the study, delaying the availability and curation process of data from recent years. Analysis of length of AZA tx in relation to response to tx is ongoing. Figure 1 Figure 1. Disclosures Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sasse: Novartis: Current Employment, Current holder of stock options in a privately-held company. Wormser: Roche: Current equity holder in publicly-traded company; Novartis: Current Employment, Current equity holder in publicly-traded company. Hernandez Donoso: Novartis: Current Employment, Current holder of stock options in a privately-held company. Colicino: Novartis: Current Employment, Current holder of stock options in a privately-held company. Tormo: Astellas, Novartis, Jazz, Pfizer, Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sanz: Gilead Sciences: Other: Travel, accommodations, and expenses; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Díaz-Beyá: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: 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. Jerez: Novartis: Consultancy; BMS: Consultancy; GILEAD: Research Funding. Valcárcel: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizzer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

'MDS with isolated del(5q)' is a subtype of Myelodysplastic Syndrome (MDS) with characteristic morphological and genomic features. Clinically, MDS with isolated del(5q) is uniquely responsive to immunomodulatory agents, with lenalidomide (LEN) approved for treating anemia in this indication. Erythropoiesis Stimulating Agents (ESA) and red cell transfusion (RBCT) are other options for anemia management. The EUMDS Registry is an international prospective registry of newly diagnosed patients (within 100 days of diagnosis) with IPSS Low/Int-1-risk MDS (plus higher-risk MDS from 2017) recruiting since 1 st April 2008, currently at 146 sites in 17 countries. We describe the largest prospective Registry series of 'MDS with del(5q)' patients, with data from diagnosis. Methods Comparative analyses of baseline characteristics for categorical variables compared different groups by chi 2 test, and for continuous variables by Kruskal-Wallis test. p values are given with Bonferonni correction applied. Results Baseline characteristics Of 2469 EUMDS patients, 197 (8%) met the WHO 2016 classification criteria for 'MDS with isolated del5q'. Median follow up is 4.3 yrs. 77% were female (34% for all EUMDS patients), and median age was 73y. In comparison to EUMDS patients lacking del(5q), patients with MDS with isolated del(5q) were lower risk at diagnosis (IPSS and IPSS-R, p Interventional management To date, 168/197 patients received active intervention and the following sequence of interventions was observed, in order of frequency of initial intervention, RBCT>ESA>LEN: RBCT (n=96), - then ESA (42) then LEN (21) - then LEN (32) then ESA (5) ESA (n=55), - then RBCT (30) then LEN (13) - then LEN (9) then RBCT (6) LEN (n=17), - then ESA (3) then RBCT (2) - then RBCT (2) then ESA (2) Ninety-two patients have received LEN. In comparison with those not (yet) treated with LEN, LEN treated patients were younger (mean 70y vs 75y, p Adverse events were considered but proved too difficult to evaluate from the Registry data. For example, anticoagulant treatment data was collected, but not the specific indication. Outcome No difference in outcome (OS or PFS) was noted for patients treated with LEN vs. not (Figure, OS - adjusted Hazard Ratio, age and sex, 95% Confidence Interval: 0.67 [95% CI:0.35-1.29], lenalidomide treatment as a time-dependent variable). Conclusion EUMDS is uniquely placed to describe 'real-world' management of patients with 'MDS with isolated del(5q)' from diagnosis. To date, the largest (retrospective) case series reported had a median age 5 years younger than EUMDS, most likely representing referral bias(1). EUMDS demonstrates that most patients with MDS with isolated del(5q) require interventional therapy, and that more than half of transfusion dependent patients have received LEN. Further analysis of interventions and response will be presented. 1. Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P, et al. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study. Leukemia 2012;26(6):1286-92. Figure 1 Figure 1. Disclosures Fenaux: Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Symeonidis: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; 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, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; Astellas: Consultancy, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis: Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Genesis: Consultancy, Other: NONE; Astellas: Other: NONE, Research Funding, Speakers Bureau. Mittelman: Janssen · Roche · Novartis · Takeda · Medison / Amgen · Neopharm / Celgene / BMS · Abbvie · Gilead: Research Funding; Novartis · Takeda · Fibrogen · Celgene / BMS · Onconova · Geron: Other: Clini; Onconova · Novartis · Takeda · Silence: Membership on an entity's Board of Directors or advisory committees; MDS HUB: Consultancy; Celgene / BMS · Novartis: Speakers Bureau. Sanz: Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Gilead Sciences: Other: Travel, accommodations, and expenses; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Jazz Pharmaceuticals: Honoraria. van Marrewijk: EUMDS Registry: Current Employment; Novartis: Other: Educational Grants; BV Oncology Europe: Other: Educational Grants; Amgen Limited: Other: Educational Grants; Celgene International: Other: educational grants; Janssen Pharmaceuticals: Other: educational grants; Takeda Pharmaceuticals: Other: educational grants; MDS-RIGHT: Other: project budgets. de Witte: Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Janssen: Research Funding.

Background: Pts with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes and limited survival with single-agent hypomethylating agent (HMA) therapy. Novel treatments that provide durable responses and clinically meaningful survival benefit for pts with HR-MDS are needed. TIM-3 is a promising target in myeloid malignancies as it regulates innate and adaptive immune cells and is expressed on leukemic stem cells (LSCs) and blasts but not normal hematopoietic stem cells. Sabatolimab (MBG453) is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating antileukemic immune activation and phagocytic killing of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of LSCs via inhibition of TIM3-galectin-9. In an early phase (ph) trial (NCT03066648) sabatolimab + HMA therapy showed a durable clinical benefit and was well tolerated in pts with HR-MDS (Wei, EHA 2021). Study Design and Methods: The STIMULUS immuno-myeloid clinical trial program is investigating the safety, efficacy, and durability of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. Additional exploration of the mechanism of action of sabatolimab and identification of potential biomarkers predictive of response is planned. This abstract summarizes the design of the 4 ongoing STIMULUS trials in previously untreated adult pts with HR-MDS who are not eligible for intensive chemotherapy (IC) or HSCT. STIMULUS-MDS1 (NCT03946670) is an international, randomized, double-blind, placebo-controlled Ph II trial evaluating sabatolimab + HMA therapy in pts with very-high, high-, or intermediate-risk (vH/H/IR)-MDS which has completed enrollment (N=127). The primary endpoints of STIMULUS-MDS1 are complete response (CR) and progression-free survival (PFS). STIMULUS-MDS2 (NCT04266301) is an ongoing, international, randomized, double-blind, placebo-controlled, Ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2. Target enrollment is ~500 pts. The primary endpoint in this trial is overall survival (OS). Key secondary endpoints are time to definitive deterioration of fatigue; duration of RBC transfusion-free interval; and improvement of fatigue, physical functioning, and emotional functioning. Other endpoints include CR, marrow CR (mCR), partial remission (PR), PFS, and leukemia-free survival (LFS). STIMULUS-MDS2 is a trial that aims to determine if sabatolimab + HMA has a statistically significant and clinically meaningful benefit in OS and quality of life vs HMA alone. STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, Ph II trial investigating sabatolimab + HMAs of investigators' choice (AZA intravenous [IV] or subcutaneous, decitabine IV or oral decitabine) in pts with vH/H/IR-MDS. Target enrollment is 90 pts. Primary endpoint is safety, which will be evaluated via incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints include CR, PFS, LFS, and OS. This trial will provide further understanding of sabatolimab + HMA therapy with additional insight into the safety and efficacy of sabatolimab + oral HMA. STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, Ph II trial that explores triplet therapy of sabatolimab combined with AZA and the BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS. Part 1 of this trial is a safety run-in comprising 2 safety cohorts with ~6 pts receiving sabatolimab 400 mg + AZA + VEN and ~12 pts receiving sabatolimab 800 mg + AZA + VEN. Primary endpoint of part 1 is safety (dose-limiting toxicities between cycle 1 day 8 and end of cycle 2). If (both 400 and 800 mg) sabatolimab + AZA and VEN are safe, the trial will progress to an expansion cohort (~58 pts) of sabatolimab 800 mg Q4W + AZA + VEN. The primary endpoint is CR. Secondary endpoints include CR + mCR rate, overall response rate (CR + mCR + PR + hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy, safety, and improved quality of life of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. The goal of ongoing STIMULUS-MDS trials is to gain insight into the promising durable benefit of sabatolimab combination therapies in pts with HR-MDS. Figure 1 Figure 1. Disclosures Zeidan: Jazz: Consultancy; Jasper: Consultancy; Pfizer: Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cluzeau: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Astellas: Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Takeda: Other: travel, accommodations, expenses. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Esteve: Jazz: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Takeda: Honoraria. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy. Santini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Sanz: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Van Hoef: Novartis Pharma: Current Employment. Nourry-Boulot: Novartis: Current Employment. Sadek: Novartis: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sabo: Novartis: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Introduction: De novo myelodysplastic syndromes (MDS) usually present in the elderly, within the context of the progressive acquisition of somatic mutations throughout the patient's life. On the other hand, MDS in children and younger adults are often associated with predisposing germline mutations. Early-onset MDS in adults (16-60 years old) accounts for »10% of all MDS cases. We aim to depict profiles of co-occurrence between germline and acquired variants in a Spanish multicenter cohort of patients with data from paired tumor-germinal whole exome sequencing (WES). Methods: Prospective cohort study (2014-2021) of 197 patients from 25 Spanish Group of Myelodysplastic Syndrome (GESMD) centers with a de novo diagnosis of MDS and chronic myelomonocytic leukemia (CMML) between 16-60 yo, without prior organ dysfunction. In each case, we annotated 107 clinical variables in relation to family and personal history, diagnosis, treatment, HSCT and disease evolution. WES was performed in paired tumor-germline samples with 100x average depth, 150 million reads per sample, and >95% Phred Quality Score 30(Q30 a). WES libraries were prepared using SureSelectXT Target Enrichment System for Illumina Version B.2 and sequenced on a HiSeq4000-NovaSeq6000-Illumina platform. The analysis of the variants was carried out by means of an in-house pipeline. The germline variants were categorized according to American College of Medical Genetics and Genomics (ACMG) criteria. Results: The median age of the cohort at diagnosis was 49 years old (16-60) with the following WHO 2017 diagnoses: 13.7% MDS with single lineage dysplasia, 10.4% MDS with ring sideroblasts, 30.6% MDS with multilineage dysplasia, 17.9% MDS with excess blasts, 6% MDS with isolated del(5q), 2.2% MDS-unclassifiable, and 9.3% CMML. We found germline variants categorized as pathogenic (P), likely pathogenic (LP) or uncertain significance (VUS) in 83.2% (n=162) of 197 patients, with 24.4% (n=48) harboring LP and/or P variants. A gene pathway-driven classification of germline variants (VUS+LP+P) categorized carrier patients as follows: 38.1% (n=75) with, at least, a variant in DNA damage response pathway (DDR), 2% (n=4) in telomere function maintenance (TF), 9.6% (n=19) in hematopoiesis regulators (HR), 6.1%(n=12) in ribosome function (RB), 14.7%(n=29) in immune response (IR), 13.3%(n=13) in chromatin modifiers, 14.2%(n=28) in cell cycle and proliferation (CP), 12.7%(n=25) in platelet function (PF), 7.1%(n=14) in erythroid synthesis (ES), and 22.8%(n=45) in signaling activation (SA) genes. Remarkably, out of 56 patients with germline variants in the DDR pathways other than MMR variants [DDRw/MMR GERM], 33 patients presented, at least, one somatic mutation. Twelve (36%) of these 33 cases involved an acquired variant in the TP53gene (TP53SOM). Within the DDR group, patients harboring germline variants in mismatch repair genes [MMR GERM](n=26) acquired, at least, one somatic mutation in 13 cases. In nine of these cases, the somatic variant was included included in the of chromatin modifying genes (ChrMod SOM) group. Considering only pathogenic variants (LP+P): 8% (n=16) of patients showed, at least, a variant in DDR, 2% (n=1) in TF, 3% (n=6) in HR, 1.5% (n=3) in RB , 3.5%(n=7) in IR, 25% (n=5) in CP, 1% (n=2) in PF, 1%(n=2) in ES, and 3.5%(n=7) in SA genes. Within the DDR group, patients harboring MMR GERM variants (n=6) acquired, at least, one somatic mutation in 3 cases, of which 2 (67%) affected genes that were included in ChrMod SOMgenes, Those patients with DDR GERM(VUS+LP+P)+TP53SOM variants showed lower levels of hemoglobin (9 g/dl vs. 11 g/dl, p=0.011), platelets (61x10 9/L vs 10 9x10 9/L, p=0.023) and a higher percentage of blasts in the BM (6% vs 3%, p=0.010). Moreover, they presented a worse outcome when applying a multivariate analysis with a dichotomized IPSS-R (≤3.5 vs >3.5): a shorter median time to AML (6 months vs. non-reached, p Conclusions: Young adult patients diagnosed with de novo MDS, without any previous organ dysfunction, show a germline profile enriched in variants affecting genes of the DDR pathways, frequently associated with TP53 acquired mutations, and showing significant clinical differences. Figure 1 Figure 1. Disclosures Tormo: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sanz: Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Valcarcel: ASTELLAS: Consultancy, Honoraria, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; NOVARTIS: Consultancy, Honoraria, Speakers Bureau; JAZZ: Consultancy, Honoraria, Speakers Bureau; SANOFI: Consultancy, Honoraria, Speakers Bureau; SOBI: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; CELGENE: Consultancy, Honoraria, Speakers Bureau. Diez-Campelo: Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jerez: GILEAD: Research Funding; BMS: Consultancy; Novartis: Consultancy.

BACKGROUND: An important progress has been made in understanding the pathophysiology of lower risk MDS in recent years. This progress has been more relevant in some specific subtypes such as del(5q) MDS or MDS with RS (>15% RS in BM or >5% RS + SF3B1 mut). In fact, for the latter subtype, in-depth knowledge of its pathophysiology has led to the recent development of new therapeutic strategies (luspatercept). In this regard, new WHO 2017 classification identify in the lower risk MDS setting 2 categories of patients with different clinical and biological features: those without RS (15% of RS and those with 5% of RS and the presence of SF3B1 mutations. Unfortunately, no clear data regarding disease characteristics and outcome have been analyzed to identify these 3 new subgroups of patients, are those with 5-15RS really like those with >15RS? Therefore, improving knowledge in real life setting of these subgroups of patients will lead to optimize the therapeutic management and the potential development of new therapeutic strategies. AIMS: Our aim was to describe baseline clinical characteristics and their implication in overall survival (OS), progression free survival (PFS) and transfusion free survival (TfFS) among LR-MDS according to the presence of RS. We compare 3 sub-categories within the current WHO classification. METHODS: A retrospective study from the Spanish MDS registry was performed in which patients diagnosed with low-risk MDS (Very low to int risk IPSS-R) were selected. MDS with excess of blasts, del(5q) and/or MDS/MPS were excluded. Finally, 2250 patients were selected which were classified according to the percentage of RS into three groups: 1) patients without RS (defined as less than 5% RS, 15RS) (n=1098). Descriptive analysis and survival estimation was done according to classical definitions (OS, PFS). Transfusion free survival (TfS) was defined from diagnosis to the development of transfusion dependency. RESULTS: In 15RS patients. Ferritin level at diagnosis was also lower for 15RS group and as expected, erythroid cellularity was lower in 15RS. Regarding single or multiline dysplasia, patients with 15RS (47%). Median blast% was higher in patients with Median follow-up was 4.1 years. Interestingly, median OS and range (p25-p75) for 15RS pts (7.66 yr 3.7-12.3) p15RS groups respectively (p=0.002). In this sense, PFS for LR-MDS with 15RS pts (7.01 yr (3.5-12.3) (p15RS (2.4 yr 0.1-7.6) patients (Figure2, p=0.02). SUMMARY: Clinical and biological characteristics of LR-MDS patients according to RS are different and impact on survival, disease evolution and need of treatment. Patients with 5-15RS are in an intermediate situation from 15RS regarding clinical and biological variables and with poorer outcome than >15RS patients. A better understanding of these subgroups could help us to personalize therapeutic options in this heterogeneous subset of patients. Figure 1 Figure 1. Disclosures Sanz: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Gilead Sciences: Other: Travel, accommodations, and expenses; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Valcárcel: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizzer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background: Guadecitabine (G) is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a large global randomized phase 3 study (ASTRAL-2) of G vs TC in AML patients who were either refractory to or relapsed (r/r) after prior anthracycline-based intensive chemotherapy with or without hematopoietic cell transplant (HCT). Methods: r/r AML patients were randomized to G (60 mg/m 2 SC/d for 10 days in first 1-2 cycles followed by 5-day cycles Q 28 days) vs Treatment Choice (TC). TC were preselected prior to randomization to either low intensity (LI) treatment; high intensity (HI) chemotherapy; or Best Supportive Care (BSC). LI choices were other HMAs of azacitidine or decitabine, or low-dose Ara-C (LDAC) at their standard doses. HI choices were high-dose Ara-C (HiDAC), MEC, or FLAG± Ida combination chemotherapy at standard doses. Primary endpoint was overall survival (OS) based on ITT analysis with secondary endpoints including 12 and 24-month survival rates, complete response (CR), event-free survival (EFS), and safety. P values for secondary endpoints and subgroups are nominal as there was no adjustment of p values for multiple analyses. Results: 302 patients were randomized to G (148) or TC (154). Preselected TCs were mainly LI (77%) predominantly HMAs (86% of the patients randomized to LI), or HI (21%), with only 6 patients (2%) in the BSC subset. Baseline variables were well balanced across the 2 treatment arms. For G vs TC respectively, age ≥65 y in 51.4% vs 40.3% with median age 65y vs 63y, ECOG PS 2 in 15.5% vs 20.8%, poor risk cytogenetics in 44.6% vs 42.2%, refractory AML in 44.6% vs 33.1%, prior HCT in 18.2% vs 26%, a majority of patients were in second or subsequent relapse after ≥ 2 prior therapies (54.7% vs 56.5%). Median number of treatment cycles was short (3 cycles for G vs 2 cycles for TC). Median follow up was 21.6 months. Most common causes of treatment discontinuation were disease progression (35.2% for G vs 38.1% for TC), or death (15.2% for G vs 18.4% for TC). Median OS on G was 6.4 months vs 5.4 months for TC and not statistically significant (OS HR 0.88, 95% CI 0.67, 1.14, log rank p value 0.3). There was no significant difference in OS between G and each of the LI and HI preselected subsets. However, several other planned prospective subgroups favored G with OS HR 95% CI upper limit ≤ 1.0 including patients Adverse events (AEs) of grade ≥3, regardless of relationship to treatment, were 89% on G vs 84% on TC. Most common Grade ≥3 AEs for G vs TC respectively were febrile neutropenia (38.6% vs 38.1%); neutropenia (32.4% vs 17%); thrombocytopenia (28.3% vs 29.9%); anemia (21.4% vs 24.5%); pneumonia (18.6% vs 20.4%); and sepsis (11.7 vs 10.9%). None of the differences were significant except for neutropenia (p 0.003). Summary/Conclusions: In this randomized study in r/r AML after intensive chemotherapy, G did not significantly improve OS compared to standard of care TC composed mainly of LI treatment with other HMAs. The data suggest that G may be better than TC in in some of the secondary endpoints (24-month survival rate, EFS, CR, CR+CRh, and CRc). Prospective subgroup analyses of OS suggest that younger ( Disclosures Roboz: Actinium: Consultancy; Mesoblast: Consultancy; Janssen: Research Funding; AbbVie: Consultancy; Astex: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Agios: Consultancy; Glaxo SmithKline: Consultancy; Blueprint Medicines: Consultancy; Janssen: Consultancy; Jasper Therapeutics: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Helsinn: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Sanz: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding. Griffiths: Novartis: Honoraria; Abbvie: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Boston Biomedical: Consultancy; Alexion Pharmaceuticals: Consultancy, Research Funding; Takeda Oncology: Consultancy, Honoraria. Yee: Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; TaiHo: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Tolero: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Geron: Research Funding; Janssen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Kantarjian: Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Jazz: Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Recher: Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne: Karyopharm: Research Funding. Patkowska: Astellas Pharma, Inc.: Consultancy, Other: Travel fees; KCR US, Inc.: Consultancy; Bristol-Myers Squibb: Other: Travel fees; Jazz Pharmaceuticals: Other: Travel fees; Angelini Pharma: Honoraria, Other: Travel fees; Novartis: Honoraria, Other: Travel fees; Servier: Honoraria, Other: Travel fees; Pfizer: Other: Travel fees; AMGEN: Honoraria. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Illes: Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses. Fenaux: Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Miyazaki: Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Chugai: Honoraria; Janssen: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Astellas: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Honoraria; Takeda: Honoraria; Kyowa-Kirin: Honoraria; Sanofi: Honoraria. Yamauchi: Daiichi Sankyo: Research Funding; Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Solasia Pharma: Research Funding. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Dohner: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria; Agios: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; GEMoaB: Honoraria; Gilead: Honoraria; Helsinn: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria.

Introduction: Lenalidomide is a potent drug with pleiotropic effects in patients with myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 [del(5q)]. The clinical efficacy of lenalidomide in MDS patients has been extensively reviewed and although the mechanisms of action in del(5q) clone have been previously described, in vivo sequential studies of modulatory effect on T lymphocytes are lacking. Our study was conducted in patients included in the Sintra-REV Clinical Trial: Lenalidomide (Revlimid) phase III, multicenter, randomized, double-blind study versus placebo in patients with low-risk MDS (low and intermediate IPSS-1) with del(5q), with anemia (HB≤12gr/dl) and without transfusion needs. Aim: The aim of this study was to explore the effect of lenalidomide in T-lymphocytes in MDS patients with del(5q) and without transfusion dependence. Materials and Methods: Sequential study was carried out in 26 samples from 13 paired MDS patients with del (5q). Seven out 13 were treated with lenalidomide and achieved a major erythroid and cytogenetic response. Peripheral blood (PB) samples were collected before and one month after treatment in treated-patients and at the same time points for non-treated patients. CD3+ cells were collected from PB samples and total RNA was isolated. SureSelect Strand Specific RNA library (Agilent Technologies) was applied to study changes in RNA levels. Raw reads were aligned against the Human genome GRCh37 using the STAR aligner. Counts were assigned to Ensembl gene IDs through HTseq using its UNION version. Differential gene expression was determined with DESeq2, considering as statistically significant those genes with FDR < 0.05. Pathway over-representation analysis (ORA) was conducted in the Webgestalt suite. Results: 332 genes were differentially expressed in CD3+ lymphocytes one month after lenalidomide treatment in our cohort of patients; 199 of them were over-expressed after the administration of this drug (Fig 1a). Of note, none of them were observed in non-treated patients after one month. The ORA revealed significant differences in the gene expression profile of sixteen cytokines and enrichment of genes of the cell cycle pathway (35 genes). The most relevant up-regulated cytokines were: IL10, TNFSF10, IFNGand IL6. These data explain lenalidomide-induced activation of an antileukemic immune response and secretion of anti-inflammatory cytokines. Although lenalidomide has been reported to reduce the expression of IL6 secreted by myeloid cell derived from MDS clon, we have observed upregulation of this gene in T-lymphocytes. Moreover, our study showed a downregulation of MBP6 that may help to correct the anemia and also attenuate inflammation signaling in MDS patients with del(5q) (Fig 1b). In addition, the most represented up-regulated genes related to cell cycle pathway were: cyclines (CCNB1, CCNB2, CDK1), centromere genes (CENPE, CENPM, CENPU), kinesin family members (KIF18A, KIF23, KIF2C), BUB1 mitotic checkpoint genes (BUB1, BUB1B), and genes involved in cell division (CDC6, CDC7,CDC25A). It has been described that lenalidomide inhibits CDC25A selectively in the del(5q) clone resulting in G2/M arrest and apoptosis. By contrast, our study showed that this gene was upregulated in T-lymphocytes promoting cell cycle and proliferation of these cells (Fig 1b). Conclusions: The immunomodulatory properties of lenalidomide can be summarized in two: a) regulation of antileukemic and anti-inflammatory cytokines production, b) activation of cell cycle and proliferation in T cells. To our knowledge, this is the first report describing RNA expression profiles in PB CD3+ lymphocytes collected from lenalidomide-treated del(5q) patients, contributing to overall understanding of lenalidomide action. Disclosures Sanz: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Diez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Lenalidomide was administered in anemic but not transfusion-dependence patients with low-risk MDS and del(5q)

Introduction Sex represents a major source of diversity among patients in terms of pathophysiology, clinical presentation, prognosis and response to therapy, and therefore sex (gender)-informed medicine is becoming a new paradigm to refine clinical decision making process in different human diseases. Myelodysplastic syndromes (MDS) are heterogeneous disease characterized by ineffective hematopoiesis and risk of leukemic evolution. We aimed to study clinical effect of sex in MDS as a basis to improve patient prognostication and personalized treatment. Material and Methods We analysed three MDS populations from disease-specific registries (Italian registry n=3015, Dusseldorf registry, n=1185 and Spanish registry, n=7678). Results We first analysed the association of sex with clinical and biological disease-specific features. These analyses were conducted on Italian MDS cohort. Considering WHO categories, female patients showed higher prevalence of single lineage dysplasia and MDS with del(5q), while males were characterized by higher frequency of multilineage dysplasia and excess blasts (P We analysed mutations in 47 MDS-associated genes. Males presented higher prevalence of mutations with respect to females (82.2% vs. 76.2%, P Overall survival was significantly worse for male vs. female patients (P Competitive risk analysis showed higher prevalence of non-leukemic vs. leukemic deaths (P As a final step we aimed to integrate the prognostic value of sex into currently available prognostic systems (IPSS-R). We used random effects Cox proportional-hazards multistate modelling for developing an innovative personalized prognostic model ("Sex and age-adjusted IPSS-R", IPSS-RAS). All the three study populations were included (n=11.878). The predicted and observed outcomes correlate well in internal cross-validation. IPSS-RAS substantially improved predictive accuracy of original IPSS-R (concordance 0.68 vs. 0.62), especially in patients with early disease stage. Interestingly, demographic factors (age and sex) accounted for >30% of whole prognostic power. Conclusion In MDS, sex captures additional prognostic information at individual patient level, possibly reflecting a different molecular background and, most importantly, a sex-specific interaction between disease-related factors and comorbidity. Our results strengthen the rationale to include sex in personalized prognostic assessment in these diseases. Table 1 Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; BMS: Speakers Bureau. Santoro:Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Arqule, Sanofi: Consultancy; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees. Santini:Menarini: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Acceleron: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Johnson & Johnson: Honoraria. Sanz:Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction : The 20q deletion [del(20q)] is a recurrent chromosomal aberration in myelodysplastic syndromes (MDS) and, as a single abnormality, is associated according to the Revised International Prognostic Scoring System (IPSS-R) with a favorable outcome. However, the breakpoint of del(20q) is very heterogeneous and may cause deletion of the ASXL1 gene (20q11.21). This gene is an important epigenetic regulator of hematopoiesis and its mutations have been associated in MDS with a shorter overall survival (OS) and a lower response to azacitidine (AZA). Aim: To assess the incidence, prognostic value and impact on response to AZA of ASXL1 chromosomal alterations and genetic mutations in MDS patients with del(20q). Methods: We studied 153 patients diagnosed with MDS and del(20q) as a sole abnormality (n=93), with an additional chromosomal abnormality (n=27) or in a complex karyotype (n=33). Response to AZA therapy was assessed using the 2006 International Working Group (IWG) criteria. Analysis of ASXL1 chromosome alterations was performed by FISH (Empire Genomics probe). Samples with ASXL1 alterations by FISH were analyzed using the Agilent SurePrint G3 Human CGH 8x60K Microarray. Mutations of ASXL1 were detected by Sanger sequencing. SF3B1, SRSF2, U2AF1, DNMT3A, IDH1, IDH2, TP53, RUNX1, and SETBP1 mutations were screened by high-resolution melting and positives were confirmed by Sanger sequencing. An in vitro assay of the response to AZA in HAP1 and HAP1 ASXL1 knockout cell lines (Horizon) was also performed. The association of the clinical characteristics with the molecular findings was analyzed with the SPSS statistical program (v.20.0) and P values Results: Main patient characteristics are shown in Table 1.ASXL1 chromosomal alterations were detected by FISH in 44 patients (29%; Fig. 1): 34 patients (22%) with gene deletion (ASXL1DEL) and 10 cases (6.5%) with additional gene copies (ASXL1GAIN). All 44 cases were analyzed by microarray, and alterations in centromeric KIF3B gene (20q11.21) were also identified in 24 patients (16%). Patients with ASXL1DEL showed a lower platelet count (median, 68x109/L vs. 103x109/L, P=0.046), a poorer response to AZA (response, 9% vs. 43%, P= 0.040) and a trend towards a lower OS (34 vs. 65 months, P=0.057). ASXL1 and KIF3B chromosomal gains were associated with complex karyotypes (ASXL1GAIN, 80% vs. 23%, P Conclusion: In MDS patients with del(20q), the alteration of ASXL1 by chromosome deletion or somatic mutation was associated with adverse clinical features and a poorer response to AZA. Its detection at diagnosis would allow the rapid identification of a subgroup of MDS patients with a poor prognosis that could benefit of earlier and more effective therapies. Disclosures Sanz: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees. Tormo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees.

Background: Most IPSS low and int1 (lower) risk MDS patients with isolated del(5q) develop RBC TD or need treatment for symptomatic anemia early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). Lenalidomide (LEN) is a reference treatment in MDS-del(5q) but approved in many countries only when RBC-TD occurs. LEN directly targets the del(5q) clone improving anemia and quality of life. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015), but no randomized trial has assessed the efficacy and tolerance of early LEN treatment in this MDS subset. Material: The Sintra-Rev clinical trial is a phase III European multicenter study in low-risk MDS-del(5q) patients with anemia (Hb Results: Main clinical characteristics of the 61 patients (ITT population) included (Feb-2010 to Feb-2018) are summarized in Table 1: 82% females, median age 72 years (range 37-89), median time since diagnosis 3.6 months, median Hb at inclusion 9.8 g/dL (7.1 - 11.7) g/dL and 93% patients had isolated del(5q). Four patients were excluded due either to screening failure (1 pat) or failure to complete at least 12w of treatment (3 pat). Fifty-seven patients were included in the ITT evaluable population for efficacy and 59 for safety (2 patients did not receive any drug). Median time on treatment was 66 weeks (3-121), 95w in the LEN arm and 42w in the placebo arm (p=0.392). Forty-seven percent patients in the LEN arm successfully completed the study compared to 33% in the placebo arm. After a median follow up of 25.6 months (Q1 16-Q3 39), median OS was not achieved. Among the 57 patients evaluable for efficacy, median time to TD was 75.7 mo for the LEN patients and 25.9 mo for the placebo arm (HR 2.703, 95CI1.162-6.286, p=0.021, figure 1). HI-E response was observed in 72.5% of LEN patients compared to 0% in the placebo arm (p Fifty-eight patients developed at least one adverse event (AE) during the trial (no differences between the LEN and placebo arm), related to the drug 86.8% in the LEN and 33.3% in the placebo arm, respectively (p Conclusions: In this interim analysis we confirm that low dose LEN (5 mg) in anemic non-TD low risk MDS del(5q) patients prolongs the period of time to TD (75.7 mo vs 25.9 mo), improves Hb levels (72.5% of ER) and induces clonal responses (70% complete CyR), ie potentially more responses than in historical series of MDS del(5q) treated with LEN at time of TD, with a manageable safety profile, and no increased progression rate. Longer follow up will be required to assess the effect of early treatment with LEN, and particularly the effect of the early reduction of the del(5q) clone size, on long-term outcomes. Disclosures Hernandez-Rivas: Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Sanz:LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Platzbecker:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Götze:Celgene: Research Funding. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Diez-Campelo:Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: LEN IN ANEMIC BUT NOT TD PATIENTS WITH LOW RISK MDS AND DEL(5Q)

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials. © 2016 by The American Society of Hematology.

In myelodysplastic syndromes (MDSs), the evolution of risk for disease progression or death has not been systematically investigated despite being crucial for correct interpretation of prognostic risk scores. In a multicenter retrospective study, we described changes in risk over time, the consequences for basal prognostic scores, and their potential clinical implications. Major MDS prognostic risk scoring systems and their constituent individual predictors were analyzed in 7212 primary untreated MDS patients from the International Working Group for Prognosis in MDS database. Changes in risk of mortality and of leukemic transformation over time from diagnosis were described. Hazards regarding mortality and acute myeloid leukemia transformation diminished over time from diagnosis in higher-risk MDS patients, whereas they remained stable in lower-risk patients. After approximately 3.5 years, hazards in the separate risk groups became similar and were essentially equivalent after 5 years. This fact led to loss of prognostic power of different scoring systems considered, which was more pronounced for survival. Inclusion of age resulted in increased initial prognostic power for survival and less attenuation in hazards. If needed for practicability in clinical management, the differing development of risks suggested a reasonable division into lower- and higher-risk MDS based on the IPSS-R at a cutoff of 3.5 points. Our data regarding time-dependent performance of prognostic scores reflect the disparate change of risks in MDS subpopulations. Lower-risk patients at diagnosis remain lower risk whereas initially high-risk patients demonstrate decreasing risk over time. This change of risk should be considered in clinical decision making.

We studied the effect of allele-level matching at human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 in 1568 single umbilical cord blood (UCB) transplantations for hematologic malignancy. The primary end point was nonrelapse mortality (NRM). Only 7% of units were allele matched at HLA-A, -B, -C, and -DRB1; 15% were mismatched at 1, 26% at 2, 30% at 3, 16% at 4, and 5% at 5 alleles. In a subset, allele-level HLA match was assigned using imputation; concordance between HLA-match assignment and outcome correlation was confirmed between the actual and imputed HLA-match groups. Compared with HLA-matched units, neutrophil recovery was lower with mismatches at 3, 4, or 5, but not 1 or 2 alleles. NRM was higher with units mismatched at 1, 2, 3, 4, or 5 alleles compared with HLA-matched units. The observed effects are independent of cell dose and patient age. These data support allele-level HLA matching in the selection of single UCB units.

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adult populations include several rare hematologic malignancies with similar clinicopathologic features that have a significant impact on patient QOL and lead to increased risk of infection, hemorrhage, anemia and transformation to AML (e.g. CMML, aCML, MDS/MPN-RST, and MDS/MPN-U). The only approved therapies for any of the MDS/MPNs are DNA methyltransferase inhibitors (DNMTis) for patients (pts) with CMML. Due to both the rarity and the heterogeneity of MDS/MPNs, it has been challenging to study in dedicated, prospective studies and thus refining treatment strategies has been difficult and optimal salvage treatments in pts who fail DNMTis have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation providing the framework for clinical trials for MDS/MPN, and explore clinical-pathologic biomarkers. Study Design and Methods: The first study within ABNL-MARRO, ABNL MARRO 001 (AM-001), is an open label, randomized phase 1-2 study that will test 3 novel oral treatment combinations in MDS/MPNs, with each of 3 treatment arms including a novel targeted agent and ASTX727, a fixed dose combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine oral bioavailability. The novel agents combined with ASTX727 are: a selective JAK1 inhibitor itacitinib, pan PIM inhibitor INCB053914 and LSD1 inhibitor, INCB059872. Each combination will be tested first in a safety run-in (Phase 1b) to determine the RP2D and schedule of each combination therapy using a 3+3 de-escalation design, and a maximum of four dose decrements will be allowed. After the RP2D and schedule has been determined for a given novel drug combination, efficacy of that combination therapy in MDS/MPN pts will then be evaluated in phase 2 using a Simon's Two-Stage design to allow early discontinuation of any futile treatment regimen and to pursue potentially beneficial combinations in larger cohorts of pts. While each of the targeted agents either has undergone or is currently undergoing safety testing in combination with the DNMTi in myeloid diseases, clear rates of expected responses in MDS/MPN are not known. Retrospective studies of DAC or AZA reveal overall response rates (ORR) from 10-56% in CMML (Helbig et al, 2019; Duchman et al, 2018; Coston et al, 2019). The ORR from the ASTX727 single agent phase I study was 30%, but this included only 14% CMML (remainder MDS pts) and 45% of pts with previous treatment with AZA or DAC (Savona et al, 2019). Finally, and importantly, there are insufficient clinical trial data available for pts non-CMML MDS/MPN syndromes. Thus, the criteria for the Simon's Two-Stage design for each arm are based on best estimation from results of above studies. Accordingly, the null hypothesis that the ORR, as per the MDS/MPN Proposed Response Criteria (Savona et al, 2015; combined CR+MR+PR+Clinical benefit - CB), is 35%, will be tested against a one-sided alternative. In the first stage, 14 DNMTI-treatment naïve (TN) pts will be accrued in each AM-001 Arm and will receive treatment at the RP2D and schedule of the novel targeted agent and of ASTX727, as determined in the phase 1. If there are 5 or fewer responses in these 14 pts before the 7th cycle of therapy, the Arm will be stopped for futility. Otherwise, 30 additional pts (including both TN subjects and subjects relapsed after/refractory to other DNMTI-containing therapies) will be accrued for a total of 44. The null hypothesis will be rejected if 21 or more responses are observed in 44 pts before the 7th cycle of therapy. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 55%. The probability of early termination and expected sample size of any arm is 64% and 25 pts, respectively, assuming low (35% RR) efficacy Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will establish the ABNL MARRO infrastructure that leverages the expertise of the MDS/MPN international working group (IWG) for future prospective studies; will forge innovative scientific research that will improve our understanding of pathogenetic etiologies; and will inform the clinical application of diagnosis, risk stratification tools, and response assessments in MDS/MPNs. Disclosures Savona: AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Padron:Incyte: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria. OffLabel Disclosure: ASTX727, LSD1 inh, PIM inh, JAK1 inh in MDS/MPN

Background Chronic myelomonocytic leukemia (CMML) is an ultrarare stem cell disorder defined by the presence of monocytosis (≥1.0 G/l, ≥10%). Depending on white blood cell (WBC) count, CMML can be divided into a myelodysplastic (MD) (WBC ≤13 G/l) and a myeloproliferative (MP) variant (WBC >13 G/l). Although hypomethylating agents (HMA) have been shown to prolong overall survival (OS) in MDS patients (pts) in prospective, randomized phase III trials, only 6-14 MD-CMML pts were included, and MP-CMML pts were excluded [Silverman 2002; Kantarjian 2006; Fenaux 2009]. EMA approval of azacitidine (AZA) in CMML is thus based on limited experience and restricted to MD-CMML with 10-29% bone marrow blasts (BMB), whereas decitabine (DAC) is not approved for treatment (trt) of CMML in the EU. Smaller analyses and single-arm trials of HMA in CMML exist [Wijermans 2008; Ades 2013; Pleyer 2014; Zeidan 2017; Duchmann 2018; Santini 2018; Coston 2019; Diamantopoulos 2019], but it is still unclear whether HMA provide a benefit in CMML (subgroups) compared with other trts. Aim Evaluate the impact of HMA and hydroxyurea (HU) trt on OS and time to next trt (TTNT). Methods Data were collected from 7 European study groups and 2 US MDS Centers of Excellence; database lock 27.05.19; Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.3. Of 1657 CMML pts, only those who received trt (n=950), with documented WBC and BMB at 1st line, were included in these analyses (n=845, cohort 1). Pts were stratified according to the EMA approved AZA indication, and inclusion/exclusion criteria of the GFM-DAC-CMML trial assessing DAC +/- HU vs HU (NCT02214407) (diagnosis of CMML, no prior trt [except supportive care, erythropoietin or ≤6 weeks HU], WBC ≥13 G/l and ≥2 of the following: BMB ≥5%, clonal cytogenetic abnormality [other than -Y], hemoglobin 16 G/l, platelet count 2 excluded) (n=486; cohort 2). Results In cohort 1, pts receiving HMA 1st line (n=375) had longer OS (19.8 vs 16.3 months [mo], P=0.0102) and TTNT (13.2 vs 6.7 mo, P=0.0001) than pts treated with non-HMA 1st line (n=470). Survival benefit was longer when comparing pts who received HMA (any time) (AZA [n=442], DAC [n=37], both [n=27]) with those that never received HMA (never HMA; n=339) (23.0 vs 13.0 mo, P The following were significantly less common in pts treated with HMA vs those that were not: diagnosis in the pre-HMA era (8 vs 43%), MP-CMML (48 vs 66%), splenomegaly (27 vs 36%), ECOG≥2 (12 vs 24%), 1 trt line (43 vs 74%). WHO subtype, karyotype, transfusion dependence, LDH, CPSS score, AML transformation and therapy-related CMML were comparable between cohorts. HMA are not approved in the EU for CMML pts with HMA are also unapproved in the EU for MP-CMML pts with ≥10% BMB. In pts with ≥10% BMB (n=257), median OS was longer for MD-CMML vs MP-CMML (19.4 vs 11.2 mo, P=0.0023) and for pts who received HMA vs never HMA (18.3 vs 7.0 mo, P In cohort 2, 1st line trts were HU (n=214), HMA (n=187) and others (n=85). Comparing HMA vs HU 1st line, median OS was 15.6 vs 14.5 mo (P=0.0307) and median TTNT was 8.8 vs 6.5 mo (P=0.0452; Fig G). OS and TTNT were comparable for HU vs other trts (Fig G). Similar observations were made in the larger cohort 1 (Fig H). Conclusions HMA show promising results with survival benefits of +11.4, +10.8 and +9.3 mo in pts with MP-CMML Disclosures Pleyer: Abbvie: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Celgene: Other: Advisory board; Agios: Other: Advisory board. Leisch:Novartis: Honoraria, Other: Travel support; Bristol-Myers-Squibb: Honoraria; Celgene: Other: Travel support. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Heibl:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria; Daiichi Sankyo: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: 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. Geissler:Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Ratiopharm: Honoraria. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Medina de Almeida:Novartis: Speakers Bureau; Celgene: Speakers Bureau. Jerez:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greil:Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML or CMML with

Background and Aim: The entity defined by the WHO 2017 classification as myeloid neoplasms with germinal predisposition without preexisting disorder or organ dysfunction is particularly interesting within myelodysplastic syndromes (MDS) for three main reasons: i) in myeloid disease derived from congenital bone marrow failure, therapeutic strategies (e.g., type of conditioning regimen) are defined; it is not the case within the group of young patients with MDS harbouring germinal variants, actually a group candidate for allogeneic transplantation of hematopoietic progenitors, ii) its incidence exceeds the cases secondary to congenital bone marrow failure, and iii) the implications of genetic counseling to patients and relatives are yet to be defined and have not been addressed at the time of diagnosis of MDS. Methods: Whole exome sequencing (WES) was performed on 118 tumour and 73 paired germinal DNA from patients of 16 Spanish Group of MDS (GESMD) centers, diagnosed with de novo MDS between 16-60 years old without previous organ dysfunction. WES libraries were sequenced on a HiSeq4000-NovaSeq6000-Illumina platform, mean number of reads per sample was 144,429,985 with a Phred Quality Score >30 in 94% of bases and a 100x average depth. To identify potential germline-predisposing mutations, a selection tool incorporating 279 genes associated with cause or predisposition to bone marrow failure or cancer was implemented. The analysis of the variants was carried out by means of an in house pipeline: filtering out intronic, synonymous, and those variants with minor allele frequency (MAF) in the general population >1% (ExAC, 1000 Genomes-phase3, TOPmed), and requiring the presence both in tumour and germline DNA with a VAF>37%. In 45 cases without germline material the last requirement was substituted by not being reported as somatic in COSMIC in any cancer. To determine pathogenicity we followed conservative criteria: a CADD Phred score ≥20 and to be considered deleterious in, at least, three out of six used algorithm. Results: In 118 patients, the median age at diagnosis was 47 years with the following WHO 2017 diagnoses: 12% MDS-SLD, 9% MDS-RS, 34% MDS-MLD, 30% MDS-EB, 3% MDS-del(5q), 1%MDS-U, 11% CMML. We found deleterious/pathogenic germ variants in 68 of 118 patients. Strikingly, we found a higher frequency than expected, for this specific subset, in genes not yet considered in the category of myeloid neoplasms with germline predisposition: MSH6 (n=5;4.2%), ATR (n=5;4.2%), ERCC6L2 (n=4;3.4%), PMS2 (n=2; 1.6%), MLH1 (n=3;3.5%), HCLS1 (n=2;1.7%), ITGB3 (n=2;1.7%), LYST (n=4; 3.4%), SAMD9 (n=1;0.8%), MSH2(n=1;0.8%). In genes already considered in the category of myeloid neoplasms with germline predisposition: MPL (n=2;1.7%), DDX41 (n= 2;1.7%), RUNX1 (n=1; 0.8%), ANKRD26 (n=1;0.8%). We also detected 10 cases with deleterious germline variants in genes related to Fanconi anemia (BRIP1, FANCC, FANCD2, FANCG, FANCM, SLX4, XRCC2, RAD51C and BRCA2), 2 cases with a germline variant in a Shwachman-Diamond gene DNAJC21 (1.7%), and 3 cases with germline variant in a telomere biology gene (RTEL1, CTC1 and TERT). We then focused on the characterization of the variants found in 5 genes not considered to date as predisposing to MDS: MSH6, MSH2, MLH1, ATR and PMS2 involved in the instability of microsatellites and whose alteration determines genomic instability and predisposition to a different number of solid tumors. The frequency of patients carrying these variants (13.5%) is much higher than the frequency of DDX41 (1.7%) or CEBPA (not found in our cohort), the two genes currently considered in the category with germline predisposition without a preexisting disorder or organ dysfunction. The sixteen patients carrying these mutations were characterized by a median age of 47 (16-60) years with the following diagnoses, 33% MDS-MLD, 27% MDS-EB1 and 40% CMML, presenting up to 40% with decrease cellularity in the bone marrow. Conclusions: We describe, for the first time, a high frequency of germinal variants in genes that drive genomic instability by modulating the microsatellite pathway, in young adults diagnosed with MDS without previous organ dysfunction. Their frequency and high pathogenicity index warrant functional validation experiments and pose them as potential candidates to be included in future classifications and to be considered in clinical, therapeutic and genetic counseling strategies. Disclosures Díez-Campelo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jerez:Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Dusseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.

The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) into one subgroup assuming all tMDS had the same poor prognosis. We have put together a database including 2032 patients with a diagnosis of tMDS from several different IWG centers and the MDS clinical research consortium. With the idea of developing an individual scoring system for tMDS, we decided to start by optimizing the cytogenetic part of the IPSSR. First, we did an extensive review of karyotypes. Finally, 1245 patients had complete data and correct ISCN formula to be used for score development. We could show regarding karyotypes there are very limited differences between primary and tMDS. Mainly the distribution of risk groups differs with complex occurring more (37%) and normal karyotypes occurring less frequent, although still accounting for 30%. There are few exceptions that are relatively special for tMDS, like translocations including 11q23. A few karyotypes are less frequent; therefore, we could not evaluate the value of IPSS-R cytogenetics for all karyotypes. However, if we apply IPSS-R cytogenetics to our patient cohort, we can separate 5 different risk groups as in pMDS. We tested the performance of the score by using the Dxy. As main endpoint we chose transformation-free survival giving better information about the severity of the disease compared to the single endpoints survival and AML transformation that where calculated for completeness as well. The Dxy for the IPSS-R cytogenetic part is 0.31 for transformation-free survival. This indicates an effective prognostic performance although not as good as in pMDS. Several attempts were done to develop a tMDS specific cytogenetic score. The best draft scoring component achieves a Dxy of 0.33. Counting the number of aberrations achieves a score of 0.30. If normal clone present or not is added, the performance of this very simple model is improved with a Dxy of 0.32. As we could show, all these different approaches lead to a comparable performance. One can argue that still regarding a few karyotypes the prognostic impact is slightly different between p and tMDS (e.g. +8). On the other hand, the most practical approach seems to be to adopt the original cytogenetic part of the IPSS-R for further score development since clinicians do not need to use different scoring systems for different MDS subtypes. While the final analyses for the development of a tMDS specific risk score are currently under way, extensive calculations regarding the performance of different scores like WHO- (Dxy 0.24), FAB-classification (Dxy 0.19), WPSS-R (Dxy 0.35), IPSS-R (Dxy 0.37), and IPSS-R+age (Dxy 0.36), show all these systems can separate different risk groups within our cohort. However, these results also show an inferior performance of the scoring systems in t compared to pMDS. There are multiple possible reasons for this. The most important seem to be tMDS patients are often not cured from the primary disease and its disease specific risk of death should ideally be considered. Unfortunately, we don't have that data. And second, we included treated as well as untreated patients. It seems not to be feasible otherwise since the selection bias for old unfit patients would be unacceptable. We could show already in pMDS that the score performances are considerably worse if we analyze treated patients and the score performance in our cohort is better if limited to untreated patients. To conclude, we can say existing classification and scoring systems work in tMDS and can separate groups with clearly different risk for death and transformation. Although we could not develop a tMDS specific cytogenetic score this could be seen positively since it underlines tMDS do not seem to be much different regarding disease specific risk. This should initiate a discussion of a revision of the WHO-classification and encourage clinicians to use the existing tools for risk assessment and treatment decisions. A simple solution could be to use the WHO classification for pMDS and precede each subgroup with a t, like tMDS-SLD, and so on. Such an approach would be of importance for patients falsely classified as tMDS. After all this classification is done according to anamnestic information only and sporadic cases cannot be excluded. Until now, in the first analyzes performed with the final tMDS-database, we did not find any indication that risk factors established in pMDS would lose or change their meaning in tMDS. Figure. Figure. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Research Funding. Roboz:Orsenix: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Döhner:Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Valent:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Platzbecker:Celgene: Research Funding. Lübbert:TEVA: Other: Study drug; Celgene: Other: Travel Support; Cheplapharm: Other: Study drug; Janssen: Honoraria, Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Background: Lenalidomide (LEN) is a reference treatment in IPSS low and in1 (lower) risk MDS patients with isolated de(5q) (MDS-del(5q)) and RBC - TD. Most low risk MDS-del(5q) patients with anemia and independent of transfusions develop TD or need of treatment for symptomatic anemia very early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). LEN directly targets the del(5q) clone improving anemia, quality of life and survival in this subset of patients. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015). However no prospective randomized study of LEN has been performed in this group of patients. Material: The Sintra-Rev clinical trial is a phase III European multicenter study, in low-risk MDS-del(5q) patients, with anemia (Hb Results: Main clinical characteristics of the 58 patients included are summarized in Table 1: 81% were females, median age was 72 years (37-89), median Hb at inclusion 9.8 g/dL(7.1 - 11.7) g/dL and most patients (86%) had isolated del(5q) cytogenetic abnormality. Three patients were excluded due to screening failures and 58 were finally included in the trial. Seven patients discontinued before 12 weeks: Three developed disease progression (defined as TD), two withdrew consent, one due to changes in patient's status and it was not specified in the remaining patient. Therefore, fifty-four patients were finally evaluable for efficacy and 58 for safety at w12. HI-E was observed in 20/54 patients (37%), minor HI-ER in 6/54 (11%), stable disease in 25/54 (46%) and TD (transfusion dependency) in 3 (6%). In the 26 patients achieving HI-E or minor HI-E, the median Hb level rise was 2.2 g/dL (range 1-4.4) and median Hb level was 12.5 g/dL (9.8-14.2). Cytogenetic response (CyR) was available in 41/54 patients: complete in 16 (30%), partial in 9 (17%), no CyR in 16 (30%) and no available in 13 (23%) patients. 54 patients developed adverse events (AE) in the first 12w, most of them hematological and probably related to the treatment. Hematological toxicity occurred in 74% of patients (neutropenia or thrombocytopenia) and only one third was grade 3/4 (neutropenia 35% or thrombocytopenia 3%). Non-hematological adverse events potentially related to the investigational drug were described in 19 patients (35%) but only 2/19 (11%) were grade 3. Nine serious AE were reported in 7 patients: congestive heart failure (2), vestibular neuritis, polyarthritis, arterial hypertensive crisis, carpal arthritis, respiratory infection, chronic obstructive pulmonary disease exacerbation and blurred vision. Only the last one (blurred vision) was potentially related with the study drug Conclusions: In this preliminary and blinded analysis we confirm a high rate of erythroid and cytogenetic responses early (w12) after study treatment with an adequate safety profile. Unblinded data will be presented at the meeting. Disclosures Platzbecker: Celgene: Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Díez-Campelo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background Data on causes of death (COD) in patients with lower-risk (LR-MDS) is limited and sometimes conflicting. In contrast to higher-risk MDS, many LR-MDS patients die from conditions associated with advanced age, not directly associated with the underlying disease. Infections and cardiovascular disorders (CVD) have been reported as frequent COD in LR-MDS, but whether the incidence is higher than in age-matched population, is not known. The EUMDS Registry has been collecting prospective observational data on LR-MDS since 2008. The comprehensive clinical and laboratory data provides a unique chance to assess the impact of LR-MDS on survival either by causes related to MDS or indirectly related to MDS by aggravation of co-morbidities. Objectives To assess the impact of MDS and associated co-morbidities on COD in patients with LR-MDS and to evaluate the COD in the whole group and across participating countries. Methods: We evaluated clinical and laboratory data of LR-MDS patients registered in EUMDS registry from 2008 to 2018. Data were obtained by 145 centers from 16 European countries and Israel. MDS related causes of death were defined as infection, bleeding, MDS progression and AML transformation. Overall survival(OS) and relative survival(RS) were estimated using the Stata program 'strel' with age, sex and country specific background obtained from national life tables for the CONCORD program. RS is a standard approach used to take into account competing causes of death by adjusting for the age and sex specific mortality in the general population, estimating the excess mortality in these patients compared to that seen in the general population of each country. Results Overall data on 2235 LR-MDS patients was available in the EUMDS registry. Of these, 822 (36,7%) patients had died at the time of analysis. Median age was 77 years and 65% of the patients were male. Nearly half of them (46.9%) were diagnosed as IPPS low risk. The MDS-Comorbidity Index was low, intermediate and high in 55.7%, 37.5% and 6.8% of patients respectively. The most common COD were those considered as related to MDS 41.7% (Table 1). Deaths due to cardiovascular and pulmonary diseases were reported in 10.1% and 4.9% respectively. Other reasons (e.g. liver, renal failure, second malignancy) were found in 18.2%. In 25% of patients, the precise reason of death remained unknown. The proportion of MDS related COD were different between participating countries with lower rates in Germany (30%), France (31.3%) and higher in Portugal (55%), Greece (55.2%) and Romania (63.1%). Median follow-up was 2.1 years (0.1-10 years). Five-year overall survival in the whole cohort was 47.1% (95% CI: 44.1%-49.9%) and 5-year relative survival (attributed to MDS/AML only) was 59.1% (95% CI:55.4%-62.5%)(Figure 1). One year overall and relative survival was 90.4% (95% CI:89.1%-91.6%) and 94.4% (95% CI:93%-95.5%) respectively. Conclusions: MDS- related complications are the most common causes of death in LR-MDS patients. Comparison of overall and relative survival supports that observation and indicates that excess mortality in LR-MDS patients can be mainly explained by MDS/AML related causes. Interestingly, the strongest influence of MDS/AML attributable deaths was observed during the first year from diagnosis. Disclosures Fenaux: Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Otsuka: Honoraria, Research Funding. Stauder:Teva: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. de Witte:Novartis: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Gilead Sciences: Consultancy; Novartis: Research Funding.

Background: Myelodysplastic syndromes (MDS) are diagnosed with a bone marrow examination (BME), an invasive procedure that patients (pts) would rather avoid. Earlier (Oster et al, Leuk Lymph 2018) we developed a logistic regression (LoR) model to diagnose MDS by incorporating 6 variables (age, gender, Hb, WBC, PLT, MCV) into a formula (Figure 1A). We improved the model using data from 178 MDS pts (47 from Tel Aviv, 131 from the EUMDS registry), and 178 controls (ASH 2017). Here we significantly improve the model using a much larger dataset (501 pts; 501 controls) and additional variables. Methods: The EUMDS registry contains data on 2600 BME-proven MDS pts. A random sample of 501 MDS pts from the registry was combined with 501 controls with no MDS (ruled out with BME). Gradient-boosted models (GBM) were used to predict having or not having MDS, using the variables age, gender, Hb, WBC, PLT, MCV, neutrophils, monocytes, glucose, and creatinine (Figure 1B). Area under the ROC curve (AUC), sensitivity and specificity were used to evaluate the models, and model performance was validated by using 100 times 5-fold cross-validation. Model stability was also assessed by repeating the fit of the models using different randomly chosen groups of 501 EUMDS pts as cases. Results: The AUC was 0.97 (95% CI 0.96-0.98, Figure 2), compared with an AUC of 0.87 (0.84-0.91) achieved previously. Under cross-validation, AUC was 89%. Maximizing the sum of sensitivity and specificity led to sensitivity of 88% and specificity of 95%. This means we can calculate a threshold "GBM score," assigning a subject to "MDS" or "no MDS" status with a specificity of 95% and a sensitivity of 88%. Alternatively, we can set two GBM score thresholds G1 & G2, where a GBM score > G2 provides 95% specificity and a score < G1 provides 95% sensitivity. A score between these two cutoffs gives an indeterminate probability of disease. Only 24% of our MDS patients and 15% of our control patients fall into this indeterminate region, compared with about 50% in our earlier model. The most influential variables were MCV, creatinine and neutrophils. Repeated random choice of cases from the EUMDS registry led to stable results. Conclusions: Using easily accessible parameters, MDS can be diagnosed or excluded non-invasively with high accuracy in a substantially large portion of patients. While the Logistic Regression model (Figure 1A) can be used with a relatively simple formula, the Gradient Boosted Model (Figure 1B) is more complex. The GBM combines the variables and the interactions among them, achieving an AUC that represents an excellent predictive ability and a considerable improvement over the previous model. Adding peripheral blood cytogenetic/genetic information could further improve non-invasive MDS diagnosis, and obviate the need for bone marrow examination in many patients. We continue to improve and validate the model. An on-line calculator/app for use in a clinical setting is being developed and will be presented. Disclosures Smith: Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Fenaux:Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria.

Introduction Risk assessment is essential for guiding therapy in patients with myelodysplastic syndromes (MDS). Currently, the most widely used prognostic scoring models are the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). The prognostic relevance of the percentage of erythroid precursors (EP) in bone marrow (BM) and its relationship with other biological characteristics has been poorly studied, although it has been proposed that a very low percentage of EP in BM may represent a cohort of patients with potentially adverse outcome. Our main aim was to analyze the biological and clinical features of MDS patients according to the percentage of EP in BM at diagnosis and evaluate its prognostic value on survival. Patients and Methods Data from 4,791 de novo MDS patients from the MDS Spanish Registry with available cytogenetics were collected. All patients included were diagnosed based on the 2008 WHO criteria and risk stratification was performed following the IPSS-R. Patients were distributed, according to the percentage of EP in BM, into three groups: less than 15% (EP49%). Proportions were compared by the Chi-square test. Survival curves were constructed by Kaplan-Meier method and differences between curves were evaluated by log rank tests. Multivariable analysis of survival was performed using Cox's proportional hazards regression model. P-values Results The 4,791 cases were grouped according to the percentage of erythroid cells in BM at diagnosis. In Table 1 are displayed the clinical and biological characteristics of the patients in the whole series and in the three groups based on the EP percentage in BM. The group with EP49% group presented higher rates of patients with refractory anemia with ring sideroblasts (RARS), lower number of PB and BM blasts, and more frequent high-risk cytogenetics. Conversely, the intermediate EP group with EP 15-49% showed less number of cytopenias, higher frequency of good-prognosis cytogenetics, and lower percentage of patients in higher-risk IPSS-R categories. Survival analyses confirmed that age, blast percentage in PB and BM, and IPSS-R cytogenetics are significantly associated with worse survival. A striking difference in survival within groups according to percentage of EP was also found, recognizing EP percentage as an independent risk factor for survival of MDS patients in multivariate analysis. Patients with EP50% in BM had also worse survival than the intermediate group, showing a median survival of 47 months (hazard ratio, 0.79; 95% CI, 0.67 to 0.93; P < 0.005). Conclusions Our study proves the prognostic impact of the percentage of erythroid precursors in bone marrow in MDS patients, providing evidence that the presence of EP Disclosures Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction Nicotinamide-expanded cord blood (NiCord) is a promising alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-matched donor is unavailable. A phase 1/2 trial with standalone NiCord HCT showed rapid neutrophil engraftment (median 11 days) and platelet engraftment (median 34 days). However, successful CD4+ immune reconstitution (IR) has shown to be crucial for infectious and relapse control associated with favorable survival (Admiraal JACI 2017). We performed unique in-depth immune monitoring to evaluate and compare the recovery of immune subsets after NiCord and conventional HCT. Methods In the phase1/2 multicenter trial, patients (n=36) with hematologic malignancies received NiCord-HCT after myeloablative (MA) conditioning without antithymocyte globulin (ATG). Immune monitoring was performed (harmonized sampling, handling and analyses in a central lab) in a random subgroup. The primary endpoint was probability of achieving CD4+ IR (>50*106/L within 100 days). Secondary endpoints were subset recovery over time of B-cells, CD4+ and CD8+ T-cells, natural killer (NK), monocytes, and dendritic cells (DC), during 7-365 days after HCT. In addition, TREC analyses are pending and will be available at the meeting. Data were compared with IR in cohorts of adolescent and young adult (AYA) patients at the UMC Utrecht receiving either unmanipulated cord blood transplantation (unCBT) or T-repleted unrelated bone marrow transplantation (BMT) for hematological malignancy after MA conditioning without ATG. Linear-mixed effects modelling in LOESS-regression curves and two-sided log-rank test for univariate comparisons in cumulative incidence plots were used. Results 24 NiCord recipients (median 41.5; 13.4-61.7 yrs) had blood samples available for in-depth early immune monitoring. NiCord cell dose consisted of median 6.4*106 CD34+/kg, and 2.3*106 CD3+T-cells/kg of the co-infused negative fraction (following CD133+-selection). 91% of patients achieved successful early CD4+ IR after NiCord (Fig 1). When comparing the NiCord with 27 unCBT (median age 15.4; range 12.2-22.1 yrs) and 20 BMT (median age 14.3; range 12.1-19.7 yrs), no difference in probability of early CD4+ IR was noted (p=0.76: Fig 1). Overall T-cell reconstitution was similar; CD3+ (p=0.99), CD4+ (p=0.71), CD8+ (p=0.08), although effector and central memory CD4+ and CD8+ T-cells, Tregs, gamma-delta T-cells, Th2, and Th17 recovered somewhat faster after NiCord. Recovery of conventional- (p=0.41) and plasmacytoid DCs (p=0.52) was similar as well. Overall reconstitution of NK-cells (p Conclusions In-depth immune monitoring reveals rapid and robust immune reconstitution in NiCord recipients, with high early CD4+ IR probability, and comparable recovery of T-cell-, NK-cell-, monocyte-, and DC-subsets to AYA controls receiving unCBT and BMT. Interestingly, B-cell recovery consisted of markedly higher follicular B-cell, memory B-cell, and plasma cell levels in NiCord recipients. Next to higher B-cell recovery, monocyte and NK-cells also recovered faster after NiCord transplantation, despite the younger age of the AYA cohort (expected to reconstituted faster). This may be explained by the higher stem cell dose and higher proliferative capacity of the NiCord- expanded product. Optimal comparison of IR in NiCord vs. unCBT in a randomized phase 3 trial is underway. Disclosures Horwitz: Gamida Cell: Research Funding. Jagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Wagner:Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding. Cilloni:Janssen: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees. Nierkens:Gamida: Research Funding.

Background: The 2016 reviewed classification of the World Health Organisation (WHO) defines a group of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) including the chronic myelomonocytic leukemia (CMML), the myelodyplastic syndrome with ring sideroblasts and thrombocytosis (MDS-RS-T) and the MDS/MPN unclassifiable (MDS/MPN-U). The presence of typical clinical characteristics of MDS and MPN hinders the diagnosis and the prognosis of MDS/MPN-U. Aim: The objective of this study was to compare the clinical characteristics and the prognosis of a series of patients with MDS/MPN such as CMML, MDS-RS-T and MDS/NPM-U from the Spanish registry of MDS. Method: We analized 107 patients diagnosed with MDS/MPN (MDS-RS-T, MDS/NPM-U and CMML) according to the 2016 WHO classification. A comparison of the clinical characteristics, overall survival (OS) and cumulative incidence of progression (CIP) was performed. Results: Median (range) age was 74 (23-93) years and 68/107 (64%) were males. The number of patients in each group was: MDS-RS-T (n=45), MDS/MPN-U (n=29) and CMML (n=33). The main clinical characteristics of the three groups are described in Table 1. There were significant statistical differences in hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts between the three groups. With a median (range) of follow-up of 3.1 (0.3-19.3), 3.7(0.7-10.4) and 4 (1.8-8.5) years for MDS-RS-T, MDS/MPN-U, and CMML, respectively, the OS (95%CI) at 5 years was significantly better in patients with MDS-RS-T (61% [42%; 80%]) compared to MDS/MPN-U and CMML patients (21% [1%; 41%] and 19% [3%; 35%], p=0.002) (Figure 1). The CIP (95%CI) at 5 years between the three groups was significantly different: MDS/MPN-U and CMML (40% [18%; 61%] and 32% (14%-52%, respectively) vs. MDS/RS-T 8% [0.4%; 30%]) (p=0.005) (Figure 2). Conclusions: 1) In this series of patients with MDS/MPN (MDS-RS-T, MDS/MPN-U and CMML) according to the 2016 WHO classification clinical characteristics were similar except for hemoglobin and lactate dehydrogenase levels and leukocyte, monocyte and platelet counts. 2) Patients with MDS-RS-T had longer OS and less CIP than those with MDS/MPN-U and CMML; 3) The prognosis of MDS/MPN-U and CMML were similar. Supported by grants from: AGAUR 9015-470120/2015, 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and "La Caixa" Foundation. Disclosures No relevant conflicts of interest to declare.

Background and Aim:It is increasingly recognized that patients with a de novomyelodysplastic syndrome (MDS) onset as young adults, lacking any other feature of a congenital disorder, may share a pathogenic overlap due to the presence of both germline and somatic variants. Identifying an inherited pathogenic variant has important therapeutic implications beyond family counselling: adapting the selection of sibling donor, the use of highly cytotoxic therapy and the monitoring for other cancer development. However, most studies have focused on patients with suspected inherited disorders based on the presence of physical abnormalities and/or family history. In addition, a mixture of pediatric and adult cases is usually reported. The aim of this study is to characterize the germline and tumor variants in a group of adult MDS patients without accompanying congenital physical anomalies and or family antecedent of bone marrow failure. Methods: We included 72 patients from 15 Spanish centers with a diagnosis of MDS between 18 and 60 years old (y.o). Patients with a previously diagnosed or suspected (one physical anomaly or family history) congenital syndrome were excluded. Diagnoses were made in accordance with the WHO 2016 classification. Whole-exome sequencing (WES) libraries were prepared using SureSelectXT Target Enrichment and sequenced on a HiSeq4000 platform (IlluminaInc.). Mean number of reads per sample was 138,726,017 with a Phred Quality Score >30 in 95.05% of bases. Read mapping sequence alignment and variant calling were performed using Biomedical Workbench (Qiagen). WES was performed on 72 tumor and 32 paired germinal DNA (buccal swab). To identify potential germline-causal mutations, a selection tool was implemented incorporating 239 genes associated with cause or predisposition to bone marrow failure or cancer. Variants with an ExAC, TOPMed and/or European 1000 Genomes minor allele frequency ≥0.01 were discarded. Results: The median age at diagnosis was 49 y.o. The cohort was categorised into two groups, less or equal 50 y.o. (62.5%) and between 50 and 60 y.o. (37.5%). In the first group, the frequency according to the WHO classification were 12% MDS with single lineage dyplasia (MDS-SLD), 8% MDS with ring sideroblasts (MDS-RS), 11% MDS with multilineage dyplasia (MDS-MLD), 24% MDS with excess blasts(MD-EB), 4% MDS with isolated del(5q)(MDS-del5q), 4% MDS unclassifiable and 4% chronic myelomonocytic leukemia (CMML). Meanwhile, in the group with age more than 50 y.o., the subtypes were 3.7% MDS-SLD, 7.4% MDS-RS, 29.6% MDS-MLD, 40.7% MD-EB, 3.7% MDS-del5q, and 14.8% CMML.Patients less or equal 50 y.o. were stratified based on IPSS-R as very low (4%), low (64%), intermediate (20%), high (12%) and very high (0%); and the group of more than 50 y.o. as very low (14.8%), low (33.3%), intermediate (29.6%), high (11.1%) and very high (11.1%).The mean number of somatic mutations was 0.68 in patients with less or equal 50 y.o. and 1.37 in those between 50 and 60 y.o., p=0.033 (U Mann-Whitney); and regarding germline variants, the first group mean number was 2.44 (p25-75, 1-3) and the second group showed a mean of 1.85 (QI 25-75, 1-3), p= 0,331.In the whole cohort, germline variants were found in 62 out of 72 patients, with the following frequencies: ATR(N=5, 6.9%), followed by BARD1(N=5, 6.9%), ERCC6L2(N=4, 5.6%), MSH6(N=4, 5.6%), TCIRG1(N=4, 5.6%), NBEAL2(N=4, 5.6%), ASXL1(N=3, 4.2%), ATM(N=3, 4.2%), MPL(N=3, 4.2%), NF1(N=3, 4.2%), RECQL4(N=3, 4.2%), SAMD9L(N=3, 4.2%), WRN(N=3, 4.2%).Among germline variants, those reported previously as pathogenic or likely pathogenic, or involving genes associated with familial MDS/AML included: ERCC6L2(N=4, 5.6%), SAMD9L(N=3, 4.2%), and one case mutated for DDX41, FANCC, JAK2, MSH6, SETBP1, MUTYH, BRCA1and RECQL4. In the whole cohort, somatic variants were found in 38 patients, with the following frequencies: TP53(N=7, 9.7%), ASXL1(N=7, 9.7%), SETBP1(N=5, 6.9%), NF1(N=5, 6.9%), SRSF2(N=4, 5.5%). Conclusion:In this subset of young adults with de novo MDS without congenital anomalies and/or familial history suggesting the presence of an undiagnosed congenital syndrome, 18% of the cohort harbored a likely causative germline variant. In addition, we noted a predominance of variants affecting genes with a cancer predisposition limited to the hematopoietic system, rather than classical telomere, DNA damage genes with an established mendelian link. Table. Table. Disclosures Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background: Delayed or failed engraftment after adult UCBT is a major contributor to the morbidity, mortality and resource utilization associated with this procedure. Increasing the number of hematopoietic stem and progenitor cells within the cord blood graft may overcome this limitation. NiCord, developed and manufactured by Gamida Cell, is an ex vivo-expanded, cryopreserved graft derived from an entire cord blood unit (CBU). In a pilot study, NiCord transplanted with a second, unmanipulated CBU was shown to shorten time to neutrophil engraftment and provide long-term hematopoiesis (Horwitz M, JCI 2014). In another study, NiCord UCBT demonstrated clinical benefit by reducing the incidence of severe infections as well as the duration of hospitalization during the first 100 days following transplantation (Anand S BBMT 2017). With confirmation that NiCord expands both hematopoietic stem and progenitor cells, we conducted a multicenter study using NiCord as a single stem cell graft. Methods: The study objective was to assess safety and efficacy of NiCord as a single, ex vivo expanded stem cell graft. The primary endpoint was to assess the cumulative incidence of NiCord-derived neutrophil engraftment. Thirty-five evaluable patients, median age 44 (13-63) with ALL (n=9), AML (n=16), MDS (n=7), CML (n=2) or Hodgkin lymphoma (n=1) were transplanted at 10 sites in the USA, EU, and Singapore. 79% had intermediate-high risk disease by Disease Risk Index. All patients received myeloablative conditioning with a TBI-based (n=14) or chemotherapy-only (n=21) regimen. Graft vs. host disease (GvHD) prophylaxis consisted of MMF for a minimum of 60 days and tacrolimus or cyclosporine for a minimum of 180 days. HLA matching was 4/6 (n=25), 5/6 (n=8) or 6/6 (n=2). Results: NiCord processing resulted in a median 32-fold (20-52 fold) increase in CD34+ cells relative to that reported by the cord blood bank prior to cryopreservation. This translated to a median CD34+ cell dose of 6.3 x 106/kg (1.4-14.9 x 106/kg). The cumulative incidence of engraftment at day 42 was 94%. Two patients experienced secondary graft failure; one at day 40 due to HHV6 infection, and another at day 260 due to an overwhelming, lethal adenovirus infection. Neutrophil engraftment occurred at a median of 11 days (95% CI: 9-13 days)(Figure 1). Platelet engraftment occurred at a median 34 days (95% CI:32-42 days)(Figure 2). Full donor whole blood chimerism (≥ 95%) was observed in 100% of engrafted patients by day 100 following transplantation. The incidence of grade II-IV and grade III/IV acute GvHD was 48.6% and 12.2%, respectively. Cumulative incidence of all chronic GvHD was 45%, and moderate/severe cGvHD 11.5% at 1 year following transplantation. Median CD3+, CD4+, and CD19+ lymphocyte counts were 286/µl, 183/µl, and 147/µl at day 100, and 479/µl, 290/µl, and 446/µl at 6 months, respectively. The incidence of grade 2-3 bacterial (n=9) or grade 3 fungal (n=0) infections was 23.9% by day 100. With a median follow-up of 13 months (range 1-35 months), the 6-month and 2-year non-relapse mortality was 12.8% and 20.3%, respectively. The cumulative incidence of relapse was 27% at 2 years. The Kaplan-Meier estimate of overall survival at 6 months and 2 years was 80.5% and 50.8%, respectively. Conclusions: The rapid engraftment kinetic coupled with a low graft failure rate and durable hematopoiesis suggests a favorable safety profile of NiCord as a single umbilical cord blood graft. Ex vivo expansion of the CBU resulted in a CD34+ cell dose comparable to adult mobilized peripheral blood stem cell grafts. Compared to a recently reported multi-center phase II study of adult, unmanipulated myeloablative double UCBT (Barker J, Br. J. Haem 2014), NiCord markedly reduced the median time to neutrophil recovery (11 days vs. 22 days) and platelet recovery (34 days vs. 49 days). Transplantation of NiCord appears not to adversely affect cellular immune recovery. Quantitative assessment of neutrophil, T-cell, and B-cell recovery is comparable to that observed following adult matched unrelated donor transplantation. We conclude that UCBT using NiCord has the potential to broaden accessibility to stem cell transplantation and to become a graft of choice for patients without a matched donor. A global randomized phase III study of NiCord vs. standard UCBT is ongoing (NCT02730299). Figure 1 Figure 1. Disclosures Jagasia: Therakos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Mallinckrodt: Consultancy. Wagner: Magenta Therapeutics: Research Funding; Novartis: Research Funding. Kuball: Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding; Miltenyi: Research Funding. Majhail: Anthem, Inc.: Consultancy; Sanofi: Honoraria. Montesinos: Celgene Corporation: Honoraria, Research Funding. Kurtzberg: Gamida Cell: Research Funding. Sanz: Gamida Cell: Research Funding.

The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults remains unclear. This study reports the results of UD-CBT in 22 adults with hematologic malignancies following conditioning with thiotepa, busulfan, cyclophosphamide, and antithymocyte globulin in 21, with thiotepa, fludarabine, and antithymocyte globulin in 1, and graft-versus-host disease (GVHD) prophylaxis with cyclosporine and prednisone. Median age was 29 years (range, 18-46 years), and median weight was 69.5 kg (range, 41-85 kg). HLA match was 6 of 6 in 1 case, 5 of 6 in 13 cases, and 4 of 6 in 8 cases. Median number of nucleated cells infused was 1.71 × 107/kg (range, 1.01 × 107/kg to 4.96 × 107/kg). All 20 patients surviving more than 30 days had myeloid engraftment, and only 1, who received the lowest cell dose, developed secondary graft failure. Median time to reach an absolute neutrophil count of at least 0.5 × 109/L was 22 days (range, 13-52 days). Median time to platelets numbered at least 20 × 109/L was 69 days (range, 49-153 days). Seven patients (32%) developed acute GVHD above grade II, and 9 of 10 patients at risk developed chronic GVHD, which became extensive in 4 patients. Twelve patients remained alive and disease-free 3 to 45 months after transplantation. Disease-free survival (DFS) at 1 year was 53%. Age strongly influenced DFS (P = .01). For patients aged 30 years or younger, the DFS at 1 year was 73%. These preliminary results suggest that UD-CBT should be considered a reasonable alternative in young adults with hematologic malignancy and no appropriate bone marrow donor.

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients. MethodsThe EUMDS registry, prospectively collects observational data on LR-MDS patients from 142 centers in 16 countries in Europe and Israel. Three iron chelators are available in Europe for treatment of secondary iron overload, but availability varies between countries. We first assessed the impact of treatment of the three iron chelators on OS. Secondly, we compared the chelated patients with a contemporary control group within the EUMDS registry. The control group consisted of patients who met the eligibility criteria for using ICT (≥15 RBC units, RBCT intensity of ≥1 RBC unit/month during a six-month period between visits, or serum ferritin ≥1000 µg/L), but who did not receive ICT. A Cox proportional hazards model was used, treating receipt of ICT as an time-varying variable. Finally, all transfused chelated and non-chelated patients were compared with a propensity-score matched model (3:1 nearest matching with replacement) in which more confounding factors could be added to Cox model in order to deal with confounding as adequately as possible. ResultsThe EUMDS registry included 2205 patients as of July 2017. At this point, 205 patients received ICT. Table 1 shows the follow-up duration for all patients. Of the chelated patients, 154 received deferasirox as initial chelator, 39 deferoxamine, and 12 deferiprone. Nineteen patients switched from one chelator to another, but usually the treatment period of the 2nd chelator was short compared to the 1st chelator (data not shown). The median time on chelation for all 205 patients was 13 months (range 3-42). Patients receiving ICT were on average younger, had better performance scores and less comorbidities compared to the control group (table 2). Comparison of three iron chelators The OS from the start of ICT for 154 patients treated with deferasirox is not significantly different compared to deferoxamine (n=39; p=0.058). The Hazard Ratio (HR) and 95% confidence intervals (CI) for OS (deferasirox as reference group) adjusted for age, sex, comorbidity, performance status, and cumulative number of RBCT for deferoxamine was 1.95 (0.85-4.50) and for deferiprone 0.38 (0.04-4.06) (Table 2). Comparison with non-chelated control group The control group consisted of 657 non-chelated patients (table 2). The crude HR and 95% CI for OS for all chelated patients was 0.66 (0.52-0.85) (non-chelated group as reference). After adjusting for age, sex, comorbidity, performance status, RBCT intensity, cumulative number of RBCT, and IPSS-R, the HR was 0.75 (0.50-1.15). When the analysis was restricted to the patients treated with deferasirox, the crude HR was 0.61 (0.46-0.81) and the adjusted HR was 0.79 (0.51-1.22). Propensity-matched model The chelated and non-chelated patients were matched for age, RBCT intensity, ferritin level, comorbidity, and performance status. 128 chelated patients and 223 controls could be matched, the overlap of propensity scores in both groups was good (data not shown). The crude HR and 95% CI for OS for the chelated group (non-chelated group as reference) was 0.77 (0.55-1.07). When correcting for age, sex, comorbidity, performance status, RBCT intensity, cumulative RBCT number, and IPSS-R, the HR was 0.62 (0.39-0.98). When we again restricted the analysis to deferasirox, the crude HR was 0.71 (0.48-1.06) and the adjusted HR was 0.58 (0.33-1.01). Conclusion OS of LR-MDS patients treated with ICT, was better compared to a large, control group and significantly better in a propensity-score matched model. In the absence of randomized, controlled trials proving the survival advantage of ICT, our large, prospective, observational study of clinical practice in Europe and Israel provides sound evidence of a beneficial effect of ICT on OS. Disclosures Fenaux: Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sanz: Gamida Cell: Research Funding. skov-Holm: Celgene: Research Funding. Almeida: Alexion: Honoraria; Bristol Meyer Squibb: Honoraria; Servier: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Itzykson: Janssen: Research Funding; Novartis: Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau.

Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia ( In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION MDS are a heterogeneous group, and it is necessary an adequate prognostic stratification in order to the best management. The new revised international prognostic scoring system (IPSS-R) has improved prognostic ability for survival and AML evolution comparing with the previous prognostic indexes. But, it is not clear the prognosis of patients included in the intermediate group, 20% of MDS, patients with a median OS of 3 years according to Greenberg et al, are they in the high or in the low risk category? The aims of the present study were to describe characteristics of patients included in this intermediate group of the IPSS-R in the Spanish MDS cohort and to identify which factors could have an impact on survival. A new score prognostic system (GESMDi score) in order to a better stratification should be proposed in this subset of patients that will be useful for determine the best therapeutic approach for them. METHODS: All patients were included in the GESMD, diagnosed of Primary MSD and Intermediate IPSS-R. The Statistical analyzes were performed using SPSS version 21, Cox models and Kaplan-Meier curves were used to demonstrate clinical outcomes. Regarding the new score proposed, GESMDi score, modeling of prognostic risk was based on multivariate analysis of survival time. Cox model for survival was built to derive the relative weights within the score. RESULTS: Data from 957 patients of 69 centers of GESMD were evaluated. Their median age was 73.9 years (p25/p75 66-80), 61.6% males (N=590), and median follow-up 21,4 months (p25-p75 de 11-41). Regarding WHO 2001 classification: 31% were RAEB-1, 21% CMML, 18% RCMD, 14% RAEB-2, 3% RCMD-RS, 3.1% RARS, 2.5% RA, 2% 5q-syndrome, 2% AML, 1% unclassified. Median hemoglobin at diagnosis was 9.8 g/dL (p25/p75:8.3-11.6), median bone marrow (BM) blasts 6% (p25/p75:3-8) and median platelet count 99x109/L (p25/p75:66-180). According to IPSS, 5% of patients were classified as low risk, 78% as intermediate-1, 16% as intermediate-2 and 1% as high risk. Cytogenetic were very good in 2% of patients, good in 76%, intermediate in 17%, poor in 5% and in 1% very poor. IPSS-R score classified patients in 3 different groups, with a punctuation of≤ 3.5 (35.6%), >3.5 and ≤ 4 (35.8%) and> 4 and ≤ 4.5 (28.5%). Median OS was 30.1 months, the estimated 1-year and 2-y OS were 79.2% and 57.8%, respectively. In the univariate analysis for OS older age (>74y, p500 ng/ml, p=0.002), and higher IPSS-R score (>3.5 and ≤ 4 and >4 and ≤ 4.5, p=0.023 and p=0.004, figure 1) had a deleterious impact on survival. In the multivariate analysis, only age, Hb level, PB blast, ferritine level and IPSS-R value retained statistical significant impact on OS (table 1a). In the multivariate analysis, Hazard ratio, a new score system (GESMDi score) was established for all patients. Patients with adverse features were added points in order to stratify the risk of death: age500 ng/ml and/or IPSS-R of >3.5 (1 point), table 1a. The GESMDi score was performed in 685 patients with all data available and 7 groups of patients were defined with different median OS (p30 months) and high risk patients ( CONCLUSIONS: GESMDi score, a proposed prognostic score system from patients with intermediate IPSS-R, allow us to establish a better prognosis stratification in this heterogeneous MDS population. Treatment and management should be better established for those patients nowadays according to this novel stratification. Table 1 a) Univariate and multivariate analysis for OS among patients with Intermediate IPSS-R b) OS according to the GESMDi score proposed Table 1. a) Univariate and multivariate analysis for OS among patients with Intermediate IPSS-R b) OS according to the GESMDi score proposed Figure 1 OS according to IPSS-R value in the intermediate group (≤3.5, ≤4 and ≤4.5) Figure 1. OS according to IPSS-R value in the intermediate group (≤3.5, ≤4 and ≤4.5) Figure 2 OS according the GESMDi score proposed in the intermediate IPSS-R group: low and high risk patients (n=685) Figure 2. OS according the GESMDi score proposed in the intermediate IPSS-R group: low and high risk patients (n=685) Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; janssen: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Díez Campelo:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Introduction Intensive consolidation chemotherapy in acute myeloid leukemia (AML) patients induces important hematologic toxicity with potential life-threatening infections that can lead to delays in further treatment or death in complete remission (CR). Recent single and multi-center studies (Guo et al. Blood 2011, JCO 2012, ASH 2015) have shown that the infusion of HLA-mismatched peripheral stem cell without immunosuppressive prophylaxis can accelerate hematologic recovery after chemotherapy, without developing graft versus host disease (GVHD). Objectives The primary objective of this phase I-II trial is to confirm the safety (absence of GVHD) and efficacy (reduction of neutropenia duration) of HLA-mismatched stem cells infusion after consolidation chemotherapy with idarubicine and cytarabine (3+7) in 50 younger patients with intermediate/high-risk AML. Herein we present the preliminary results of the phase I trial with 9 adult patients (safety cohort). Methods Patients younger than 65 years old with AML in CR after induction therapy that were assigned to receive consolidation course with idarubicin (12 mg/m2/day IV 1-3) and cytarabine (200 mg/m2/day IV 1-7) according to PETHEMA protocol were enrolled in this study in a single Spanish institution. To determine safety of HLA-mismatched stem cells infusion a standard 3+3 design was used in this preliminary study: cohorts of 3 patients were established with decreasing immunosuppressive prophylaxis, 3 additional patients would be enrolled with the same immunosuppression if limiting toxicity (LT) was observed in 1 out of 3 patients. LT was defined as global GVHD>grade 2 or grade 4 infusion related reactions. The first cohort of 3 patients was assigned to receive immunosuppression with cyclosporine (1-1.5 mg/kg/bid) and prednisone (0.5 mg/kg/qid), the second cohort to receive only prednisone (0.5 mg/kg/qid), and the third would not receive immunosuppressive treatment. The immunosuppression resulting of this phase would be used in an expansion cohort. Stem cells were obtained after mobilization with G-CSF and apheresis from HLA-mismatched family-related donors and were infused the day 9 of the consolidation course. The donor and recipient HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 alleles were genotyped using a PCR-SSP method. Hematologic recovery was defined as days from start of chemotherapy to neutrophil count >0.5x109/L and to platelet count >50x109/L. G-CSF was administered only in case of severe infection. This study was approved by the Ethical Committee, and inform consent was obtained from all patients and donors. Results From March 2015 to June 2016, 9 patients were enrolled in this study. Median age was 46 (28-64) and 6 were male. All were in CR after induction therapy, 6 had intermediate risk cytogenetic, and 3 high risk cytogenetic/molecular AML. All the donors were family-related and HLA compatibility was 3/6 for 8 patients and 5/6 in one patient. HLA-mismatched stem cells infusion characteristics were: median number of mononuclear cells, CD34+ and CD3+ T cells infused per course was 4.5 (2.1-6.6)x108/kg, 3.3 (0.7-4.9)x106/kg and 1.7 (0.8-2.3)x108/kg, respectively. LT was not reached and no diagnosis of GVHD was made. Two patients developed cytarabine related rash and other 2 patients infectious diarrhea. No patient needed further immunosuppressive treatment. Median duration of neutropenia and thrombocytopenia was 30 (27-50) and 44 (22-51) days, respectively. 3 patients received G-CSF and 2 developed severe infections. Median blood cell unit and platelet units transfused was 4 (2-20) and 8 (2-32). These results are similar to those observed in a historical cohort (non-matched) of 59 patients with AML who received consolidation with 3+7 at the same institution between January 2010 to January 2015 (median duration of neutropenia and thrombocytopenia was 29 (17-57) and 36 (18-206) days, respectively). Conclusion The infusion of HLA-mismatched stem cell is safe after consolidation with idarubicin and cytarabine in younger patients. The methodology and in consequence the results of our safety cohort (with immunosuppressive prophylaxis) are not comparable to the previous experience reported by other groups. The reduction of hematologic recovery remains to be confirmed with this schedule in a larger cohort without immunosuppressive prophylaxis. Research granted by IIS La Fe (2014/0368) Disclosures Boluda: Instituto de Investigación Sanitaria La Fe: Employment.

Background: Prognostic scoring systems for allogeneic stem cell transplantation (HSCT) are of clinical value when determining a leukemic patient's suitability for this curative, but risky, procedure. Several such scores have been developed over the years for HSCT from sibling or unrelated donors, but no predictive score has been developed specifically for umbilical cord blood transplantation (UCBT). Although individual parameters have been identified to be associated with UCBT outcomes in acute leukemia (AL) patients, integrative tools for risk evaluation in this setting are lacking. We sought to develop a prediction model for overall survival (OS) (primary objective) and leukemia free survival (LFS) (secondary objective) at 2 years following UCBT in acute leukemia patients. Methods: A retrospective, international registry-based study, of 3140 acute leukemia patients who underwent UCBT from 2004 through 2014. Inclusion criteria were patients with AL receiving single or double cord blood units transplantation. Median follow up was 30 months. The dataset was geographically split into a derivation (65%) and validation set (35%). A Random Survival Forest was utilized to identify predictive factors. Top predictors were introduced into a Cox regression model, and a risk score was constructed according to each variable's hazard. Results: The median age at UCBT was 21.9 years. The 2 years OS rate was 47.7% (95% CI: 45.8-49.6). After identifying the top predictive variables, the UCBT risk score (Table 1) was constructed using 9 variables (disease status, diagnosis, cryopreserved cell dose, age, center experience, recipient cytomegalovirus sero-status, degree of HLA mismatch, previous autograft and anti thymocyte globulin administration). Over the derivation and validation datasets, a higher score was associated with decreasing probabilities for 2 years OS and LFS, ranging over the validation set from 0.72 (0.64-0.8, 95% CI) and 0.68 (0.6-0.76, 95% CI) to 0.13 (0.06-0.27, 95% CI) and 0.14 (0.07-0.28, 95% CI), respectively (Figure 1). An increasing score was also associated with increasing hazard of the predictive outcomes (Table 2). The score's discrimination (AUC) over the validation set for 2 years OS and LFS was 68.26 (64.25-72.27, 95% CI) and 66.95 (62.88-71.02, 95% CI), respectively. Calibration was excellent. Conclusion: We have developed the first integrative score for prediction of overall survival and leukemia free survival in acute leukemia patients undergoing a UCBT. The score is simple and stratifies patients into distinct risk groups. Table 1 The UCBT Risk Score Table 1. The UCBT Risk Score Table 2 Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Table 2. Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Figure 1 Overall survival stratified by the UCBT risk score over the validation data set Figure 1. Overall survival stratified by the UCBT risk score over the validation data set Disclosures Bader: Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Medac: Consultancy, Research Funding; Novartis: Consultancy, Honoraria.

To develop a prognostic scoring system tailored for therapy-related myelodysplastic syndromes (tMDS), we put together a database containing 1933 patients (pts) with tMDS from Spanish, German, Swiss, Austrian, US, Italian, and Dutch centers diagnosed between 1975-2015. Complete data to calculate the IPSS and IPSS-R were available in 1603 pts. Examining different scoring systems, we found that IPSS and IPSS-R do not risk stratify tMDS as well as they do primary MDS (pMDS), thereby supporting the need for a tMDS-specific score (Kuendgen et al., ASH 2015). The current analysis focuses on cytogenetic information as a potential component of a refined tMDS score, based on this large, unique patient cohort. Of the 1933 pts, 477 had normal karyotype (KT), 197 had missing cytogenetics, while 467 had a karyotype not readily interpretable. Incomplete karyotype descriptions will be reedited for the final evaluation. Of the remaining 1269 pts the most frequent cytogenetic abnormalities (abn) were: -7, del(5q), +mar, +8, del(7q), -5, del(20q), -17, -18, -Y, del(12p), -20, and +1 with >30 cases each. Frequencies are shown in Table 1. Some abn were observed mostly or solely within complex KTs, such as monosomies, except -7. Others, like del(20q) or -Y, are mainly seen as single or double abn, while del(5q), -7, or del(7q) are seen in complex as well as non-complex KTs. The cytogenetic profile overlapped with that of pMDS (most frequent abn: del(5q), -7/del(7q), +8, -18/del(18q), del(20q), -5, -Y, -17/del(17p), +21, and inv(3)/t(3q) (Schanz et al, JCO 2011)), with notable differences including overrepresentation of complete monosomies, a higher frequency of -7 or t(11q23), and a more frequent occurrence of cytogenetic subtypes in complex KTs, which was especially evident in del(5q) occurring as a single abn in 16%, compared to 70% within a complex KT. IPSS-R cytogenetic groups were distributed as follows: Very Good (2%), Good (35%), Int (17%), Poor (15%), Very Poor (32%). Regarding the number of abn (including incomplete KT descriptions) roughly 30% had a normal KT, 20% 1, 10% 2, and 40% ≥3 abn, compared to pMDS: 55% normal KT, 29% 1, 10% 2, and 6% ≥3 abn. To be evaluable for prognostic information, abn should occur in a minimum of 10 pts. As a single aberration this was the case for -7, +8, del(5q), del(20q), del(7q), -Y, and t(11;varia) (q23;varia). Of particular interest, there was no apparent prognostic difference between -7 and del(7q); del(5q) as a single abn was associated with a relatively good survival, while the prognosis was poor with the first additional abn; t(11q23) occurred primarily as a single abn and was associated with an extremely poor prognosis, and prognosis of pts with ≥4 abn was dismal independent of composition (Table 1). To develop a more biologically meaningful scoring system containing homogeneous and prognostically stable groups, we will further combine subgroups with different abn leading to the same cytogenetic consequences. For example, deletions, unbalanced translocations, derivative chromosomes, dicentric chromosomes of 17p, and possibly -17 all lead to a loss of genetic material at the short arm of this respective chromosome affecting TP53. Further information might be derived from analyses of the minimal common deleted regions. For some abn, like del(11q), del(3p), and del(9q), this can be refined to one chromosome band only (table 1). Conclusion: Development of a robust scoring system for all subtypes of tMDS is challenging using existing variables. This focused analysis on the cytogenetic score component shows that favorable KTs are evident in a substantial proportion of pts, in contrast to historic data describing unfavorable cytogenetics in the majority of pts. Although complex and monosomal KTs are overrepresented, this suggests the existence of distinct tMDS-subtypes, although some of these cases might not be truly therapy-induced despite a history of cytotoxic treatment. The next steps will be to analyze the prognosis of the different groups, develop a tMDS cytogenetic score, and examine minimal deleted regions to identify candidate genes for development of tMDS, as well as to describe the possible influence of different primary diseases and treatments (radio- vs chemotherapy, different drugs) on induction of cytogenetic subtypes. Our detailed analysis of tMDS cytogenetics should reveal important prognostic information and is likely to help understand mechanisms of MDS development. Disclosures Komrokji: Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sole:Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Steensma:Amgen: Consultancy; Genoptix: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Millenium/Takeda: Consultancy; Ariad: Equity Ownership. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Valent:Amgen: Honoraria; Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Deciphera Pharmaceuticals: Research Funding. Giagounidis:Celgene Corporation: Consultancy. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Lübbert:Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding; Ratiopharm: Other: Study drug valproic acid.

Introduction: As showed in a recent study of our group, considering bone marrow (BM) blasts from nonerythroid cellularity (NECs) improves the prognostic evaluation of MDS (Arenillas et al, J Clin Oncol 2016). By enumerating blasts from NECs, 12% of MDS patients diagnosed within WHO categories with less than 5% BM blasts were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in the initial categories. Refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) have shown an special good outcome in different studies. As MDS with ring sideroblasts (MDS-RS) usually present a high percentage of BM erythroblasts, considering BM blasts from NECs could imply a risk overestimation of this subset of patients. Aim: we evaluated the relevance of considering BM blasts from NECs or from total nucleated cells (TNCs) on classification and prognostication of the group of patients diagnosed with MDS-RS. Methods: We retrospectively analyzed 3,924 de novo MDS diagnosed according to WHO 2001 and 2008 classifications from the MDS Spanish registry. 1,045 patients presented less than 5% BM blasts from TNCs and equal or greater than 15% BM ring sideroblasts, fulfilling current definition for RARS (WHO 2001 and 2008) and RCMD-RS (WHO 2001). Moreover 1,233 patients with equal or greater than 5% BM ring sideroblasts and less than 5% BM blasts were analyzed in order to explore the future definition of WHO 2016, that considered as MDS-RS those patients with 5%- Results: Median age at diagnosis of MDS-RS was 76y (25-101) and 59% were males. Estimated median follow-up, as calculated by reverse Kaplan-Meier method, was 50.1 months (95% CI, 45.5-54.7) and median OS was 96.5 months. By enumerating blasts from NECs, 10% of MDS-RS patients were reclassified into categories with equal or greater than 5% BM blasts and showed a poorer overall survival (OS) than did those who remained in initial categories (median OS, 68.1 vs 97.6 months, P=0.025; Hazard ratio (HR): 1.41; 95%CI: 1.04-1.91; p=0.026). After adjusting the survival analysis by IPSS cytogenetic risk groups, the prognostic impact of BM blasts considered from NECs maintained its significance (HR: 1.37; 95%CI: 1.01-1.85; p=0.045). Similar results were observed applying this method to the group of MDS patients with equal or greater than 5% BM ring sideroblasts and less than 5% BM blasts. By considering blasts from NECs, 10% of this subset of patients were reclassified into categories with equal or greater than 5% BM blasts and showed a poorer OS than did those who remained in initial categories (median OS, 60.2 vs 85.8 months, P=0.003; HR: 1.51; 95%CI: 1.15-1.97; p=0.003; HR adjusted for IPSS cytogenetics: 1.46; 95%CI: 1.12-1.92; p=0.006). Conclusion: considering bone marrow blasts from nonerythroid cells improves the prognostic evaluation of MDS with ring sideroblasts. Written on behalf of the Grupo Español de Síndromes Mielodisplasicos (GESMD). Disclosures No relevant conflicts of interest to declare.

Background Loss of chromosome Y (-Y) is observed in 4-10% of male MDS patients as a single cytogenetic abnormality, and is associated to a better outcome. -Y is also known to be an age related phenomenon occurring in 8-10% of elderly men. The clinical significance of -Y in MDS has been a matter of discussion. However, there is increasing evidence that -Y involves the clonal population in MDS cases, and is more likely to be associated with a hematological malignancy when it involves a greater number of metaphases. Aims In this study we aimed to 1) analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, 2) evaluate the clinical significance of the percentage of metaphases with isolated -Y, 3) test whether finding -Y may predispose to over diagnose MDS in patients with borderline morphological features. Methods We evaluated 3581 male patients from the Spanish Registry of MDS with a diagnosis of MDS or CMML (WHO 2001). Patients with isolated -Y and normal karyotype by conventional cytogenetic analysis were selected. The main study outcomes were survival from diagnosis and transformation into acute myeloid leukemia (AML). Survival curves were drawn using the Kaplan-Meyer method and compared by log-rank test. The cumulative incidence of AML was estimated by taking non AML-related death as a competing risk. Statistical comparisons were done by the Mann-Whitney U-test for continuous data, and the chi-square test for categorical factors. Stata, version 11, software (www.stata.org) was used for the statistical analysis. Results Isolated -Y was identified in 177 patients (-Y group) and compared with the 2246 male patients with normal karyotype (46,XY group). The median age for the whole series was 74 years old (IQR 67-80). -Y patients were found to be older than patients in the 46,XY group with a median (IQR) of 78 (74-83) versus 74 (66-79) years old, respectively (n=0.0001). There was no difference between both groups in terms of hemoglobin concentration, neutrophil and platelet counts at diagnosis. Percentage of bone marrow (BM) blasts was significantly lower in the -Y group (median (IQR): 2(0-3) vs. 2(1-5), respectively; p=0.003). Differences in distribution by WHO 2001 classification of MDS were not found between the two groups. After a follow-up of 2,190 patient-years, 1684 (69.5%) patients had died and the median actuarial survival was 3.6 years (95% C.I, 3.3-3.9). A trend towards a larger median survival in the -Y group versus 46,XY group was observed, since it not reached statistical significance (5.2 years [95% CI, 3.89 to 6.40] versus 4.26 years [95% CI, 3.89 to 4.59], respectively) (P=0. 17; Fig. 1A). After a median follow-up of 1.6 years (IQR: 0.8 - 3.7) from MDS diagnosis, 296 patients had progressed to AML, 901 had died without AML, and 1224 were censored alive without transformation. -Y was associated with a decreased incidence of AML at univariate analysis (figure 1B), and after adjustment for the percentage of BM blasts (SHR: 0.46; 95%CI: 0.24-0.88; p=0.02). Within the -Y group, neither survival nor the risk of leukemic transformation were influenced by the percentage of aberrant metaphases (>75% vs, ≤ 75%). From the whole series, only 6.4% of the cases were classified as not having a "MDS strong phenotype", defined by the presence of megakaryocytic dysplasia, more than 5% blasts in the bone marrow, or more than 15% ring sideroblasts. These cases were uniformly distributed between the two groups, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. Conclusions Our results derived from the largest series of patients with loss of chromosome Y support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against AML progression. Disclosures No relevant conflicts of interest to declare.

Introduction: The MDS are a group of clonal hematopoietic disorders characterized by blood cytopenias and increased risk of transformation into acute myeloid leukemia (AML). The MDS predominate in old people (median age at diagnosis > 70 years) so that a fraction of the observed mortality would be driven by age-related factors shared with the general population rather than the MDS. Distinguishing between the MDS-related and unrelated mortality rates will help better assessment of the population health impact of the MDS and more accurate prognostication. This study was aimed at quantifying the MDS-attributable mortality and its relationship with the IPSSR risk categories. Methods: The database of the GESMD was queried for patients diagnosed with primary MDS after 1980 according to the WHO 2001 classification. Patients with CMML, younger than 16 years or who lacked the basic demographic or follow-up data were excluded. Relative survival and MDS-attributable mortality were calculated by the cohort method and statistically compared by Poisson multivariate regression as described by Dickman (Stat Med 2004; 23: 51). Three main parameters were calculated: the observed (all-cause) mortality, the MDS-attributable mortality (both as percentage of the initial cohort), and the fraction of the observed mortality attributed to the MDS. Results: In total, 7408 patients met the inclusion criteria and constitute the basis for this study. Among these patients, 5307 had enough data to be classified according to the IPSSR. Median age was 74 (IQR: 16-99) years and 58 % were males. The most frequent WHO categories were RAEB, type I or II (29% of cases), RCMD (28%), and RA with ring sideroblasts (16%). Most patients (72%) were classified within the very low and low risk categories of the IPSSR. At the study closing date (December 2014), 1022 patients had progressed to AML, 3198 had died (974 after AML) and 3210 were censored alive. The median actuarial survival for the whole series was 4.8 (95% CI: 4.6-5.1) years and 30% of patients are projected to survive longer than 10 years. The overall MDS-attributable mortality at 5 years from diagnosis was 39%, which accounted for three-quarters of the observed mortality (51%, figure). The corresponding figures at 10 years for the MDS-attributable and observed mortality were 55% and 71%, respectively. According to the IPSSR, the 5-year MDS-attributable mortality rates was 19% for the very low risk category, 39% (low risk), 70% (intermediate risk), 78% (high risk), and 92% (very high risk). On average, the incidence rate ratio for the MDS-attributable mortality increased 1.9 times (95% CI: 1.7-2.3, p Conclusions: About three-quarters of the mortality observed in patients with MDS is caused by the disease, the remaining one-quarter being due to MDS-independent factors shared with the general population. The MDS-attributable mortality increases with the IPSSR risk category, from half the observed mortality in the very low risk to nearly all the mortality observed in the high and very high risk groups. Half the MDS-attributable mortality is driven by factors unrelated to leukemic transformation, a proportion that keeps constant across the five IPSSR risk categories. Disclosures Valcarcel: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ramos:AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

INTRODUCTION Anemia is the most frequent cytopenia in lower-risk MDS. Erythropoietic-stimulating agents (ESAs) are commonly used in these patients. The use of ÒclassicalÓ parameters (EPO and ferritin levels) and the revised IPSS (IPSS-R) has been proposed1 (SantiniÕs score) to predict response to ESAs and overall survival (OS) among patients with lower risk MDS by IPSS and a favorable Nordic group score2. OBJECTIVES The main objective of the study was to evaluate overall response rate (ORR) to ESAs and OS according to the proposed SantiniÕs score in an independent and large cohort of anemic lower risk MDS patients receiving treatment with ESAs. METHODS Data from 530 anemic patients with low/int1 risk IPSS de novo MDS (according to FAB and WHO criteria) and sufficient follow-up data available were recorded in Spresas3 (SPanish Registry of Erythropoietic Stimulating Agents Study from GESMD). Two hundred and twenty six patients (42.6% of the patients) were selected according to specific criteria regarding the published SantiniÕs score1: Hb level 200mU/mL(=1), serum ferritin (SF) >350 ng/mL(=1) and IPSS-R very low=0, low=1, intermediate=2 and high=3) yielded a score ranging from 0 to 5. ESAs response rate and overall survival were analysed according to these score. Response to treatment was evaluated according to IWG 2006 response criteria and a multivariate logistic regression analysis was used to identify independent predictors of erythroid response (ER). OS were defined as the time between diagnosis and the corresponding event or last follow up (Feb 2015) and were analyzed using univariable and multivariable Cox proportional hazards regression methods. RESULTS Median age was 77 years (interquartile range [IQR] 25%-75%: 71-83 y), median Hb level at start of treatment was 10 g/dL (IQR25-75: 9-10), median EPO level was 90 (IQR25-75: 27,25-108) and median ferritin level was 338,5 (IQR25-75: 146,5-568,75). Among 139 patients with this data available, 85 patients (61,1%) were RBC transfusion dependent before ESAs treatment. Median time from diagnosis to ESAs treatment was 82 (IQR25-75: 27-353) days. According to the IPSS, 68.6% (N=155) and 31.4% (N=71) were in low and Int-1 risk groups, respectively. Regarding IPSS-R, 23% (N=52), 66.8% (N=151), 9.7% (N=22) and 0.4% (N=1) were in very low, low, intermediate and high risk, respectively. ORR to ESA treatment was 71.2% (N=161), with a median duration of response of 2.06 years. Prognosis factors of ER showed a trend toward to a higher ER among patients in the lower IPSS-R (P>0.05), low IPSS (p=0.039) and lower EPO levels (p According to SantiniÕs score, 11.5%(N=26), 42.9%(N=97), 25.8%(N=81), 8%(N=18) and 1.8%(N=4) of the patients were in the 0, 1, 2 3 and 4 score. Erythroid response was better for patients in the lower scores, with response rates of 73.1%, 82.5%, 65.4%, 50% and 0%, for patients in 0, 1, 2, 3 and 4 score, respectively (p CONCLUSIONS The present study confirms that SantiniÕs score is useful to identify patients with a higher probability of response to ESAs and better OS among lower risk MDS patients with an expected favorable response to ESA according to Nordic group score. Spresas study was partly supported by Janssen 1.-Santini et al, Blood 122(13), 2013. 2.-Hellstršm-Lindberg, Br J Haematol 120(6), 2003. 3.-D'ez Campelo, EHA 2015 meeting, P244. Disclosures Díez Campelo: Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau. Off Label Use: Use of erythropoietic stimulating agents for anemia in patients with myelodysplastic syndromes. Ramos:JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Falantes:Celgene: Honoraria. Garcia:Celgene: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau.

Introduction: Since its implementation in 2012, the IPSS-R (Greenberg et al., 2012), defines the latest standard in risk stratification of patients with Myelodysplastic Syndromes (MDS). However, the prognostic impact of rare abnormalities remains unclear as yet because the number of these aberrations was too low to allow a valid statistical analysis. Hence, rare abnormalities were coalesced in one group in the IPSS and IPSS-R and, due to the unknown prognosis of these abnormalities, classified as prognostically intermediate. The main goal of the study presented here was to analyse the type, frequency and prognosis of rare single abnormalities in a large cohort of patients with primary, untreated MDS and integrate them in the existing IPSS-R in order to refine its predictive power. Methods: The data set analyzed was derived from the IPSS-R database and extended by additional data from European centers. In total, 7245 patients with primary, untreated MDS were included. Of these, we identified 410 (6%) pts. with rare single abnormalities. An aberration was defined as rare when it occurred in less than 10 patients in the cytogenetic scoring system that was the basis for the IPSS-R (Schanz et al., 2012). Additionally, further cytogenetic abnormalities not considered in this score were detected. A specific cytogenetic subgroup was defined as having at least n=5 cases with the same abnormality. Survival analyses was performed in cytogenetic subgroups with a minimum number of n=10 exclusively. The participating centers (in numerical order) were: Spain (n=110; 26.8%), MD Anderson Cancer Center (69; 16.8%), Düsseldorf (44; 10.8%), IMRAW (41; 10.0%), France (32; 7.8%), Pavia (21; 5.1%), Vienna (19; 4.6%), Japan (13; 3.2%), Vienna Medical University (12; 2.9%) Italy (11; 2.7%), Cleveland (10; 2.4%), Dundee (9; 2.2%), Brazil (8; 2.0%), Netherlands (5; 1.2%), Czech (2, 0.5%), Freiburg (1; 0.2%), Innsbruck (1; 0.2%), Sweden (1; 0.2%), and Russia (1; 0.2%). The median overall- (OS) and AML-free survival (AFS) was calculated for any specific cytogenetic subgroup. Results: Rare single abnormalities detected were: der(1;7)(n=24; 5.9%), partial or total monosomy 13 (22; 5.4%), partial or total monosomy 9 (22; 5.4%), +21 (20; 4.9%), +mar (14; 3.4%), del(3p) (12; 2.9%), total or partial monosomy 21 (11; 2.7%), total or partial monosomy X (11; 2.7%), total or partial monosomy 18 (10; 2.4%), +1/+1q (10; 2.4%), del(17p) (9; 2.2%), total or partial monosomy 14 (9; 2.2%), total or partial monosomy 16 (9; 2.2%), total or partial monosomy 6 (9; 2.2%), total or partial monosomy 1 (8; 2.0%), t(11q23;varia) (7; 1.7%), total or partial monosomy 19 (6; 1.5%), +11/+11q (6; 1.5%), +13 (6; 1.5%), +14 (6; 1.5%), del(5p) (5; 1.2%), total or partial monosomy 2 (5; 1.2%), +15 (5; 1.2%) and +X (5; 1.2%) The remaining 159 patients (38.7%) showed very rare abnormalities occurring in less than 5 patients each. The median overall survival as well as the AML-free survival in each category will be presented in detail. Furthermore, a multivariate model including all relevant confounders and a proposal to integrate these abnormalities in the cytogenetic module of the IPSS-R will be suggested. Conclusions: In order to overcome the problem of their extremely low frequency, knowledge about rare single abnormalities in MDS can only be gained by large, international cooperative projects. The present study was performed to identify and comprehensively analyze rare abnormalities occurring in MDS, uninfluenced by therapy or additional abnormalities. The results will lead to a further refinement of the cytogenetic prognostic classification in patients with MDS. The study was supported by a grant from the European Leukemia Net (ELN) Disclosures Schanz: Novartis: Honoraria, Other: Travel Grant; Celgene: Honoraria, Research Funding; Alexion: Other: Travel Grant; Lilly: Other: Travel Grant. Sole:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fenaux:Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Valent:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Ohyashiki:Kyowa Kirin KK: Honoraria; Novartis Pharma KK: Honoraria, Research Funding, Speakers Bureau; Celegen KK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jansen Pharma KK: Honoraria, Research Funding, Speakers Bureau; Chugai Pharna KK: Research Funding; Bristol Meyer Squib KK: Research Funding; Taiho Yakuhin KK: Research Funding; Asahikasei: Research Funding; Teijin Pharma KK: Research Funding; Alexion Pharma KK: Research Funding; Asteras: Research Funding; Shinbaio Pharma KK: Honoraria; Toyama Kagaku KK: Speakers Bureau; MSD KK: Honoraria; Nippo Shinyaku KK: Speakers Bureau; Sumitomo Dainippon: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.