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Long-term safety and efficacy of eltrombopag in adults with persitent/chronic primary immune thrombocytopenia (ITP) evaluated in EXTEND study, showed a high response rate (80%) but, in the clinical safety study, it was observed that 6% of the patients presented venous and arterial thrombotic events. In addition, in the course of the disease, autoimmune hemolytic anemia (Evans syndrome, ES) may occur and could increase the risk of thrombosis. We report an interesting case of splenic rupture due to massive intrasplenic arterial thrombosis in the course of ES in a patient with chronic ITP treated with eltrombopag. The purpose of this case report is to highlight the potential increase in thrombotic risk that may involve the use of eltrombopag in hemolysis situations in patients with ITP.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p

Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to 94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage >94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.

Introduction. Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDS) or MDS/MPN unclassifiable cases with relative monocytosis (≥ 10% monocytes) and a total monocyte count of 0.5- Objective. We investigated TET2 mutations in 42 OM-CMML, their diagnostic value and their correlation with immunophenotypic pattern, and compared them with that observed in 54 CMML and 86 MDS. Patients and methods. Samples were collected from 182 patients: 42 OM-CMML, 54 overt CMML, and 86 MDS. Molecular characterization was performed by next-generation sequencing (NGS) using a custom panel (QIAseq Custom DNA Panels, Qiagen) including the whole codifying region of 25 myeloid-associated genes and sequenced using Illumina technology. Multiparametric flow cytometry (FC) analysis of monocyte subsets was performed on whole PB collected on EDTA. Cell surface staining of 2 × 10 6 cells was performed and at least 500 000 total events were acquired per tube (FACS Canto II; BD Biosciences). The FC strategy analysis, the 5-tube experimental panel, and the NGS custom panel are described in Calvo & Garcia-Gisbert, Blood Adv 2020. Results. Patients with multiple TET2 (multi-TET2) mutations (2 or more) were identified with similar percentages in OM-CMML (17/42, 40.5%) and CMML (29/54, 53.7%) while they were infrequent in MDS (5/86, 5.8%) (P10% though they were not considered OM-CMML since the monocyte count was below 500/microL. CMML and OM-CMML patients with multi-TET2 showed predominantly 2 TET2 mutations (CMML: 20/29, 69%; OM-CMML: 14/17, 82%;). The distribution of patients with >2 TET2 mutations was similar in CMML and OM-CMML. We did not observe differences among the frequency of nonsense, frameshift or missense TET2 mutations, nor between early or late-truncating (early: aa 1-1128, late: 1128-1936) TET2 mutations between OM-CMML and CMML.TET2 variant allele frequency (VAF) was significantly lower in MDS (median 11.83%) than in OM-CMML and CMML (P55% or a sum of muti-TET2 mutations VAF above 55% (17 OM, 19 CMML, 2 MDS), we could infer a biallelic alteration in the same clone (Coltro, Leukemia 2020). We did not observe differences in the frequency of OM-CMML showing biallelic TET2 mutations when compared to CMML.The main clinical characteristics of CMML patients (overt and OM-CMML), grouped by TET2 mutational status (unmutated: TET2 WT; 1 TET mutation: TET2 single; ≥2 mutations: multi-TET2) are depicted in Table 1. As shown, we did not observed significant differences when comparing TET2 single to TET2 WT or multi-TET2 Of note, multi-TET2 patients showed a higher percentage of PB and BM monocytes, BM promonocytes and more dysgranulopoiesis than TET2 WT patients.Patients with TET2 WT presented a lower number of mutated genes than TET single and multi-TET2 patients (P=0.019 and P=0.029). In line with previous studies, IDH mutations and TET2 mutations where mutually exclusive (P=0.001). Co-mutation of SRSF2 and TET2, the well-accepted gene signature of CMML, was found in 25/96 patients (26.0%, 13 OM-CMML, 12 CMML) in 10 cases co-mutated with TET2 single and in 15 cases with multi-TET2.We assessed the proportion of OM-CMML patients with MO1>94% since this has been shown as very sensitive and specific feature of CMML. In TET2 mutated OM-CMML, we observed a higher proportion of patients with MO1>94% (90% mut. vs 40% WT; P=0.001) and CD56 expression on monocytes (70% mut. vs 30% WT; P=0.025). We observed a trend (non-significant) difference in the proportion of patients showing these features when comparing TET2 single vs multi-TET2 OM-CMML (single, CD56: 57.1%, MO1>94%: 85.7%; multi-TET2, CD56: 81.3%, MO1>94%: 93.8%). Conclusion. The high occurrence of multiple TET2 mutations in overt and OM-CMML and its infrequency in MDS is a new biological clue for supporting the consideration of OM-CMML in the continuum of CMML. Figure 1 Figure 1. Disclosures Salar: Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Bellosillo: Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Thermofisher Scientific: Consultancy, Speakers Bureau.

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

Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

INTRODUCTION Recent studies have shown that OM-CMML and CMML have a similar clinical and biological profile. Since the proliferative-CMML (P-CMML) is the last-stage of CMML proliferative continuum and shows poor outcomes, it is expected that OM-CMML presents the best outcomes of these entities, as it represents an early-stage of dysplastic-CMML (D-CMML). In this sense, although a high percentage of OM-CMML evolve to CMML, some of them die before evolving. Therefore, identifying predictive factors of evolution into CMML may be valuable since, OM-CMML that evolves to CMML show shorter overall survival (OS) (Calvo X et al. Blood Adv 2020). AIM To analyze clinical outcomes of 41 OM-CMML patients and to compare them to that of 182 overt CMML (141 D-CMML and 41 P-CMML), and to assess predictive factors of evolution of OM-CMML into overt CMML. RESULTS OM-CMML showed longer OS than D-CMML and P-CMML (Figure 1). OM-CMML also showed longer AML-free survival than D-CMML (median OS: 131.8m vs. 43.47m; P=0.001) and P-CMML (median OS: 23m; P As previously commented, OM-CMML patients who evolved to overt CMML showed an inferior OS than did those who did not. At a median follow-up of 42 months, 30% OM-CMML evolved to CMML. Patients with more than 3 mutated genes (HR: 4.24, 95%CI 1.08-16.71, P=0.039) and a proportion of monocytes above 20% in peripheral blood (HR: 3.48, 95%CI 1.05-11.47, P=0.041) showed a significant shorter time to CMML. These two variables were faced in a multivariate analysis and maintained their significance for predicting time to CMML (HR: 4.33, 95%CI 1.23-15.20, P=0.022; and HR:5.82, 95%CI 1.32-25.7 , P=0.02). Moreover, these variables were also independent adverse prognostic factors for OS in our series of 94 patients with available molecular data (41 OM-CMML and 53 CMML) (HR:4.39, 95%CI 1.99-9.68 , P CONCLUSIONS 1. The clinical outcomes of OM-CMML support its consideration as the first step in the proliferative continuum of CMML. 2. OM-CMML with higher molecular complexity and higher relative monocytosis are at greater risk of CMML evolution. Figure 1 Figure 1. Disclosures Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau.

Introduction. Myelodysplastic syndromes (MDS) are clonal heterogeneous disorders in which molecular studies and cytogenetics are essential for diagnosis, classification and prognosis. Cell-free DNA (cfDNA) analysis has been reported as a reliable non-invasive approach for detecting molecular abnormalities in MDS. However, there is limited information about cytogenetic alterations and monitoring in cfDNA from MDS patients. Objective. To assess and monitor the molecular and cytogenetic abnormalities by next generation sequencing (NGS) using cfDNA from patients with MDS. Patients and methods. Bone marrow (BM) aspirates and peripheral blood (PB) samples were collected from 70 newly diagnosed or treatment-naïve patients with MDS (Table). PB samples from 21 healthy controls were also studied. Molecular characterization was performed in paired samples of BM DNA and cfDNA by NGS in all patients. Libraries were prepared using a custom panel including 48 myeloid-associated genes and genomic regions localized at the most frequently altered chromosomes in MDS (QIAseq Custom DNA Panels, Qiagen) and sequenced using Illumina. 20/70 (28.6%) showed cytogenetic/FISH alterations at diagnosis, 2 of them with infrequent alterations in MDS, not covered by the panel (+14, del(9q)). 6 cases presented chromosome Y loss as a single alteration, not covered by the NGS panel. Copy number variant (CNV) analysis was performed by NGS to detect cytogenetic alterations in both cfDNA and BM, and confirmed by chromosomal microarrays (CMA) in BM DNA (CytoScan/OncoScan, ThermoFisher). Results. We obtained a median amount of cfDNA of 58.4 ng/ml in MDS patients that was significantly higher than that obtained in healthy controls (median 32.4 ng/ml, P=0.023). Sequencing of BM DNA and cfDNA showed a comparable mutational profile (187/201 mutations, 93.0% concordance). The most frequently mutated genes were TET2 (44.3%), SF3B1 (37.1%), ASXL1 (20.0%), DNMT3A (20.0%), SRSF2 (15.7%), ZRSR2 (12.9%) and U2AF1 (12.9%). A strong correlation was observed between the VAFs of BM DNA and cfDNA (r s=0.797, P The analysis of cytogenetic alterations by NGS showed abnormalities in 10/70 MDS patients in both BM DNA and cfDNA. Interestingly, in a patient without analyzable metaphases in karyotype, del(20q) was found by NGS and confirmed by CMA. Overall, CMA and NGS were highly concordant to detect chromosomal aberrations although they do not reach the sensitivity achieved by karyotype/FISH (Figure 1). However, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. Molecular and cytogenetic alterations were monitored in sequential samples from 7 cases (median follow up: 13 months, range 10-30). We observed an excellent correlation between the VAF of mutations in BM DNA and ctDNA across multiple matched time points. A decrease in the VAF was detected in patients responding to therapy (either hypomethylating agents or chemotherapy), but not in non-responding patients (Figure 2). Of note, cfDNA analysis also showed cytogenetic evolution in 2 cases not responding to azacitidine (del(12p) and +21). From the two untreated patients, one acquired a subclonal del(7q) not detected by NGS and observed only in few metaphases, and the second patient showed a clonal expansion of the NF1 mutation at the time of AML transformation. Conclusions. Analysis of cfDNA allows the characterization and monitoring of molecular abnormalities in patients with MDS. Cytogenetic alterations were detectable in most cases by NGS in both BM DNA and cfDNA although with a lower detection rate than karyotype/FISH. Acknowledgements. ISCIII-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure/Table legends: Table. MDS patients included, classified by disease subtype. (SLD: single lineage dysplasia; MLD: multilineage dysplasia; RS: ring sideroblasts; EB: excess blasts; MDS-U: MDS-unclassifiable) Figure 1. Detection of cytogenetic alterations by conventional karyotype, FISH, CMA and NGS. Figure 2. Monitoring of molecular and cytogenetic alterations in 7 patients with MDS. 5 patients receiving treatment (3 azacitidine, 1 FLAG-IDA + HCT, 1 inhibitor of hypoxia-inducible factor (HIF)) and 2 untreated cases were included. BM VAF dynamics are shown with a dotted line and cfDNA dynamics are shown with a solid line. Figure 1 Figure 1. Disclosures Besses: Gilead: Research Funding. Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau.

Background: Polycythemia vera (PV), Essential Thrombocytosis (ET) and Primary Myelofibrosis (PMF) are Myeloproliferative Neoplasms (MPNs) with median age at diagnosis of ~56-70 years old. However, around 10%-15% of cases are diagnosed during young adulthood and there are scanty data about their molecular profile and its implications in clinical outcomes. Objective: To analyze the clinical and molecular characteristics of young adult patients (≤45y.o.) with MPNs (Y-MPN) and to correlate them with clinical features and outcomes. Material and Methods: This is a retrospective single-center study including MPN patients diagnosed below the age of 45 years. Molecular characterization was performed using DNA from granulocytes at diagnosis or before the start of cytoreductive therapy. JAK2V617F was assessed by quantitative allele-specific PCR and CALR mutations by fragment analysis of exon 9. Further molecular profiling was performed by next generation sequencing (NGS) with a custom panel of 25 myeloid-associated genes (ASXL1, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NRAS, PRPF8, RUNX1, SETPB1, SF3B1, S2HB3, SRSF2, STAG2, TET2, TP53, U2AF1 and ZRSR2) using Illumina technology. Pathogenic mutations in genes previously related with poor outcomes (ASXL1, EZH2, IDH1, IDH2, SRSF2 and U2AF1) were named as Mutations of Adverse Significance (MAS). Molecular alterations were correlated with diagnosis, progression to PV post ET (PVpET), progression to MF post PV/ET (MFpPV/ET), start of cytoreduction and major thrombotic events (MTE). Time to progression (TTP) and overall survival (OS) were calculated from diagnosis to progression (ELN criteria) and to last visit. Results: From 646 MPN followed in our clinic, 109 (17%) cases were Y-MPN; females 72 (66.1%). At diagnosis the median age was 35 y.o. (9-45). 23 patients (21%) were PV, 91% carried JAK2V617F, 4% (1) carried an exon-12 JAK2 mutation and 1 was JAK2V617F and exon-12 negative. 84 cases (77.1%) were ET, 53.5% (45) JAK2V617F, 25% (21) CALR, (52% type-1 mutation, see table) and 21.4% (18) triple negative (TN). There was 1 PMF with CALR type-1 mutation. No MPL canonical mutations were found. ET was predominantly diagnosed in females (M/F: 26/58). Regarding clinical variables, we found a high proportion of ET-JAK2V617F with high LDH values, higher platelet count for CALR-ET and ET-TN patients (967 and 978 vs 728 for ET-JAK2V617F, p=0.03) and higher frequency of MTE at or before diagnosis for JAKV617F cases (p=0.001). The mean follow-up was 152 months (SD +/-10.4); 16 progressions were registered (PFS 305 months); 8 patients to MFpPV/ET and 8 ET-JAK2V617F to PVpET. An increase in the VAF of JAK2V617F was observed at the time of progression either to PVpET or to MFpET/PV (see table). Seven MTE were registered during this time, 3 in JAK2V617F, 2 in CALR type-1, 1 in exon-12 and 1 in a TN case. 38 (34.8%) cases started cytoreduction, with median time to cytoreductive therapy of 251 (172-330) months; JAK2V617F cases started cytoreduction more often (p=0.04) than patients with other genotypes. No progression to AML nor deaths were recorded. The NGS panel was performed in 102 (93.5%) cases. Pathogenic mutations in non-driver genes were found in 41.2% (42) of cases, being TET2 (7%), ASXL1 (6%) and DNMT3A (5%) the most frequently mutated genes. Also, in 28.4% (29) variants of unknown significance (VUS) were found, involving TET2 (6%), SETBP1 (4%), SH2B3 (5%), and JAK2 (4%) among others. The mutations in SH2B3 (1 pathogenic, 5 VUS) were more frequent in JAK2V617F patients and those in DNMT3A were more common in PV patients. The presence of mutations in non-driver genes (pathogenic or VUS) did not correlate with MTE before or after diagnosis, the start of cytoreduction nor clonal progression. Regarding the 19 TN cases, in 7 (36.8%) one or more non-canonical pathogenic variants implicating MPL, JAK2 and TET2 genes were found. Finally, 8 patients (7.8%) harbored a MAS, of which 3 progressed to MF (2 CALR to MF and 1 ET-JAK2V617F to PVpET); TTP was similar to the rest of the cohort. Conclusions: Our data show that 41% of Y-MPN patients harbor pathogenic mutations in non-driver genes. There was no correlation between their presence and clonal progression, major thrombotic events or overall survival. Mutations of adverse significance did not predict major clinical outcomes. Monitoring of JAK2V617F allele-burden can help to predict progression to MFpPV/ET or PVpET. Disclosures Andrade-Campos: Sanofi-Genzyme: Consultancy, Speakers Bureau; Takeda-Shire: Speakers Bureau; Celgene-BMS: Consultancy. Fernández:Roche: Consultancy, Speakers Bureau. Salar:Janssen: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau. Bellosillo:Qiagen: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau.

Introduction The European LeukemiaNet (ELN) 2017 classification for acute myeloid leukemia (AML) stratifies patients in 3 risk categories, according to genetic features of the disease. ELN classification is commonly used to guide post-remission treatment; favorable risk patients do not seem to benefit from allogeneic hematopoietic transplantation (alloHCT) in first complete remission (CR1) while this procedure is highly recommended in adverse risk patients. Post-remission treatment in intermediate risk patient is still debated. This classification has not been prospectively validated. Herein we analyze the prognostic impact of ELN 2017 classification in patients treated with the same protocol (CETLAM-12), including a well-defined preplanned alloSCT policy according to genetic risk. Methods We analyzed characteristics and outcome of patients diagnosed with de novo AML, included in CETLAM-12 protocol for patients up to 70 years, with an available genetic characterization at diagnosis allowing an accurate ELN 2017 stratification. Genetic risk allocation was based on cytogenetic analysis and pre-specified RT-PCR of determined markers (including CBF-rearrangement, NPM1, FLT3, CEBPA, and MLL-PTD) performed in all patients, and targeted Next Generation Sequencing testing (available in 143 patients). CETLAM-12 protocol defines a genetic risk stratification in three groups, closely similar to that proposed by the ELN 2017 classification, and recommends a post-remission strategy based on this risk assessment. Patients from the favorable group received three courses of consolidation with high-dose cytarabine (HiDAC), whereas alloSCT in CR1 is strongly recommended for intermediate and adverse risk patients following one HiDAC-based consolidation course. Results We included in the study 813 patients (400F/413M; median age 56, 17-76); with a 37 months median estimated follow-up (range 0.1-92). The outcomes of the entire cohort are shown in table 1. Out of all patients, 641 could be classified according to the ELN 2017 classification, due to the presence of risk defining genetic features identified by any of described methods. In the group of .atients allocated in the favorable risk category (n=316; 49%), twenty-seven patients died during induction. Fifty-eight relapses were observed, mostly in patients with NPM1 mutation (n=41). AlloSCT was finally performed in CR1 in 84 patients (27%) due to MRD persistence or reappearance (n=40), overt hematological relapse (n=27), persistent aplasia following chemotherapy (n=3) and protocol deviation (n=14). In the group of patients allocated in the intermediate risk category (n=95; 15%), twelve patients died during induction. AlloSCT in CR1 was performed in 62 patients (67%), with 5 patients receiving an alloSCT in CR2. In the group of patients allocated in the adverse risk category (n=230; 36%), twenty-five patients died during induction. AlloSCT could be finally performed in CR1 in 138 patients (60%) and 88 relapses occurred (42 before alloSCT, 46 after alloSCT). Amongst ELN adverse risk patients, a subgroup with a significant worse outcome has been identified, defined by AML with complex karyotype +/- TP53 mutation or chromosome 3q26/MECOM-GATA2 rearrangement. This group (ELNadv+) presented a lower CR rate, with a higher relapse rate and fewer proportion of patients who receive a pre-planned alloSCT in CR1. OS and EFS of ELNadv+ is significantly lower than ELN adverse patients. In the multivariate analysis for OS including age, sex, WBC count at diagnosis and number of cycles to achieve CR, only age and ELNadv+ status showed independent prognostic value. Outcome data is summarized in table and figures attached. Conclusions The initial risk-adapted post-remission assignment planned in CETLAM-12 could be performed in the majority of patients. Despite this different proposed post-remission treatment, ELN risk classification was able to identify three groups of patients with a markedly different outcome. Interestingly, within the unfavorable ELN category, a very high-risk ELNadv+ subgroup can be distinguished, with a dismal outcome with current approach, warranting the implementation of innovative pre and post-transplant strategies aimed to prevent treatment failure. Figure Disclosures Tormo: MSD: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Salamero:Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Daichii Sankyo: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sierra:Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: 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; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction:Acute myeloid leukemia (AML) real-world incidence has been investigated in a limited number of European countries such as Sweden, Denmark and a few others. These prospective population-based analyses give a more precise idea of AML as a health problem than registry data from cooperative groups or other sources, that usually include selected cases as part of research studies and/or therapy trials. In October 2016, the Autonomous Government of Catalonia funded a project (PERIS SLT002/16/00433) to prospectively collect all AML cases from our territory. Objective:To investigate the incidence, characteristics and treatment decisions in all consecutive AML patients diagnosed in Catalonia between January 2017 and December 2019. Methods:Inclusion criteria were diagnosis of AML according the WHO 2016 criteria, both primary and secondary (APL excluded) with an age >18 years. The project was disseminated to all hospitals from Catalonia regardless of their size, having at least one hematologist. A specific informatics tool was implemented for remote reporting of the cases. All data were anonymized. In parallel, a circuit for centralized bio banking of patients' samples was designed. The database included the main clinical, laboratory data as well as the initial therapeutic approach. Cases included in our CETLAM group cooperative studies were automatically linked to the trial database for collecting detailed information. Statistical analyses were performed with R packages. Results:Assuming an incidence of AML of 4 cases per 100,000 inhabitants (based on previous reported data from others), we expected 912 cases during three years in the 7,6 million population of Catalonia. Our prospective registry included 750 consecutive AML patients, 82% of the expected cases. The remaining 18% could be explained by the exclusion of APL, age below 18 years, or underreporting. Seventy percent of patients (n=527) were diagnosed and treated in the 5 large University Hospitals from Barcelona and the two adjacent cities (Badalona and Hospitalet). Table 1 shows the main characteristics of the patients. Among the 390 patients up to 70 years, 272 (70%) were enrolled in the CETLAM AML-12 protocol that included intensive chemotherapy (ICT) and risk adapted hematopoietic cell transplantation (HCT). Forty-one additional patients (11%) in this age group received other ICT in different clinical trials. A remaining 73 patients (20%) were treated with other intensive or non-intensive approaches outside trials. In the group of 360 patients older than 70 years only a 33% (n= 119) were treated under the risk-adapted CETLAM AML-16 protocol for elderly AML patients. This trial included ICT as in the CETLAM-12 in case of favorable genetic features; this was received by 13 of the 119 patients (11%) enrolled. The remaining patients of CETLAM-16 were treated with low-intensity chemotherapy (oral fludarabine, subcutaneous (SC) cytarabine and G-CSF or azacytidine) and 97 additional elderly patients were included in other clinical trials mostly with targeted and hypomethylating agents (27%). Other active therapies outside trials (usually low-intensity) were administered in 50 additional patients (14%) whereas the remaining 94 patients (26%) only received supportive measures (transfusions, hydroxyurea, antibiotics, palliation, or no treatment), because of one or more of the following: advanced age, poor AML features or severe clinical condition. Overall survival (OS) of the whole series at 2 years was 31±2% (CI: 27-35). Patients younger than 70 years had a 2-year OS of 47±3% (CI: 41-53) compared to 11±3% (CI: 7-17) for those above 70 years (p Conclusions:This prospective study is highly representative of the diagnosis and treatment of AML in Catalonia. The median age at diagnosis was 70 years. Of note, 81% of patients up to 70 years were enrolled in ICT trials. The proportion of patients in trials in the elderly group was lower although still remarkable (60%). In this advanced age group, a 26% of patients were treated with supportive measures only. Despite the high inclusion rate in clinical trials, only one third of newly diagnosed AML patients have the probability to survive at 2 years, with a dismal outcome in those above 70 years. Therefore, the investigation of novel and more effective treatments remains mandatory. This series will be detailed and updated during the meeting. Disclosures Salamero: Pfizer:Consultancy;Jazz Pharmaceuticals:Consultancy, Honoraria;Daichii Sankyo:Honoraria;Novartis:Consultancy, Honoraria;Celgene:Consultancy, Honoraria.Olivera:BAYER:Consultancy;Pfizer:Consultancy, Speakers Bureau;Daiichi Sankyo:Consultancy, Speakers Bureau;Boehringer Ingelheim:Consultancy, Speakers Bureau.Sureda Balari:Celgene:Consultancy, Honoraria;Merck Sharpe and Dohme:Consultancy, Honoraria, Speakers Bureau;Sanofi:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Gilead/Kite:Consultancy, Honoraria;Janssen:Consultancy, Honoraria;Incyte:Consultancy;Roche:Honoraria;BMS:Speakers Bureau;Celgene/Bristol-Myers Squibb:Consultancy, Honoraria;Takeda:Consultancy, Honoraria, Speakers Bureau.Ribera:Pfizer, Amgen:Research Funding;Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau.Sierra:Jazz Pharmaceuticals:Research Funding;Pfizer:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Daiichi Sankyo:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: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;Astellas:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead-Kite:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: AML risk classification is based on genetics (cytogenetics and molecular features) and more recently also on minimal residual disease (MRD) after chemotherapy. These two aspects allow predicting relapse and supporting or not the most anti-leukemia treatment that remains allogeneic hematopoietic cell transplantation (HCT). We prospectively investigated the combined use of the two predictive markers to allocate post-remission therapy with or without HCT. Objectives of the study were testing: a) if this approach was feasible in a multicenter setting; b) the proportion of patients who were allocated to an allogeneic HCT and finally received the procedure; c) the final distribution into the risk categories and their outcome; d) to analyze the outcome of patients with favorable or intermediate genetics moved to the high risk category because of positive MRD. METHODS: Adult patients with primary AML treated at 15 academic hospitals were included between February 2012 and December 2018. Induction chemotherapy consisted of idarubicin 12 mg/m2 days 1-2-3 and cytarabine 200 mg/m2 days 1 to 7. Consolidation courses were high-dose cytarabine (3 g/m2 or 1.5 g/m2 if ≥60 y/o). The number of consolidation courses was based on genetic risk: 3 in favorable genetics category (FGC) (CBF, NPM1mut/FLT3-ITDwild or ratio0.1%) and/or quantitative PCR of the specific transcripts (RUNX1/RUNX1T1, CBFβ/MYH11 and NPM1). RESULTS: Seven hundred forty-five patients (median age: 55, range18-70 y/o, 51% male) were enrolled. Cytogenetics according the revised MRC classification in 707 informative cases was: CBF AML 12%, intermediate 65% (75% of them normal karyotype), and adverse 23%. FLT3-ITD was detected in 28% of patients with intermediate risk cytogenetics and NPM1 mutation in the same group was present in the 48%. Complete remission (CR) was achieved in 81% (n=603) of patients, 82% and 80% in patients up to and above 60 yrs, respectively. Induction death occurred in 9% of patients, 7% and 11% the two age groups, and 10% of patients had refractory leukemia; 542 (90%) of the 603 CR patients completed the consolidation phase and were risk allocated taking into account genetics and MRD. The remaining CR patients were not allocated because of early relapse (n=22), death in CR (n=5), severe toxicity (n=22) or others (n=12). After risk allocation, 208 (38%) patients were in the genetics-MRD combined favorable group (CFG), 103 (19%) in combined intermediate group (CIG) and 231 (43%) in the combined adverse group (CAG). In the latter, 185 (80%) of patients received an allogeneic HCT in first CR. Fifty-seven patients (11%) moved from the genetically FGC or IGC to the CAG because of high MRD at the end of consolidations. Median follow-up in survivors was 25 months. Overall 4-years survival (OS) of the whole series is 48±2%; event-free survival (EFS) is 77+3% in the CFG group, 45+6% in the CIG and 34+4% in the CAG (p CONCLUSION Risk adapted therapy for primary AML based on genetics and MRD is feasible in a cooperative group setting. The proportion of CR was high (>80%) even in patients older than 60 y/o. MRD assessment at the end of consolidation moved 57 patients with favorable or intermediate genetics to the CAG. Avoiding HCT in first CR in the FGC patients associated to EFS above 75% at 4 years. Allogeneic transplantation feasibility was 80% when this was the intended treatment because of adverse genetics and/or MRD positivity. Risk assessment based on genetics and MRD continues separating three groups of patients with different outcomes. Since relapses remain frequent when adverse AML features are present, further approaches after transplantation, such as targeted agents and immune therapies deserve investigation. Disclosures Sierra: Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Salamero:Daichii Sankyo: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Esteve:Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy.

Introduction The majority of prognostic indexes in CMML include information extracted from bone marrow (BM) evaluation. The blast count in BM in CMML includes the blast and promonocyte percentage. In the extent of our knowledge there are no data evaluating whether both cells have an equivalent prognostic weight for predicting survival. Recent data indicate that an accurate diagnosis of CMML could be established by assessing the monocyte population distribution by flow cytometry and by evaluating its molecular profile by targeted next-generation sequencing in PB. Our aim was to analyze which variables from our series had an independent prognostic value in order to assess if their addition to the most common prognostic scores for CMML, CPSS and Mayo prognostic model (Mayo), contributed to increase their predictive capacity; or if they allowed us to create a new one. Methods One hundred and fifty patients diagnosed with CMML from 1975 to 2019 from a single institution were evaluated. All patients met 2017 WHO criteria. Complete information was available for the following: BM blast percentage, BM promonocyte percentage, PB blast percentage, circulating immature myeloid cells (IMC), presence of Auer rods and complete blood count. The median overall survival (OS) was 35 months (CI 95%: 30-40). We performed univariate and multivariate survival analyses to establish the prognostic weight of each one. Both C-index and Somers'D (Dxy) were used to compare the prognostic accuracy of the different models. Results Patients characteristics are depicted in Table 1. The prognostic impact of the following items was reviewed: BM blasts; BM promonocytes; the sum of BM blasts and promonocytes; proliferative CMML (CMML-P); monocyte count ≥ 5 x 109/L; transfusional dependency; Hb < 100 g/L; platelets < 100 x 109/L; IMC; PB blasts; abnormal karyotype; spanish cytogenetic risk classification; sex, and dysmegacaryopoiesis, dysgranylopoiesis and dyserythropoiesis according to WHO criteria. In the univariate analysis for the OS only the following demonstrated an adverse impact: sex (women 50.7m vs men 33.4m, P=0.023), PB blasts (39m vs 11m, P Conclusions The variables with an independent adverse prognostic value for OS in our series were: Hb < 100 g/L, platelets 100 x 109/L and the presence of blasts in PB. The MAR score, a model based on them showed the best predictive capacity for OS in our series. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION The diagnosis of CMML according to WHO 2017 requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB). Establishing an accurate diagnostic is difficult since many clinical situations present persistent monocytosis. The presence of dysplasia is frequent but not always present and cytogenetic aberrations are infrequent in this disease (20-25% of cases). Although 85-90% of CMML patients present ≥1 mutation in TET2, SRSF2 or ASXL1, the use of NGS panels is not widespread. The study of PB monocyte subsets by flow cytometry (FC) has gained interest for CMML diagnosis. The increase of classical monocytes (Mo1) upper 94% presents a high sensitivity (Sn) and specificity (Sp) for CMML diagnosis (Sn 90.6, Sp 95.1; Selimoglu-Buet et al, Blood 2015). The 94% threshold was validated in two studies (Talati C et al, Blood 2017; Tarfi S et al, Blood Cancer J 2018). However, some controversies have recently appeared in the literature. Picot T detected the 95% cutoff as the one with the best Sn (100%) and Sp (97%) (Picot T et al, Front Oncol 2018). Hudson CA found that the presence of < 1.13% (Sn 100, Sp 96) of non-classical monocytes (Mo3) was the best predictor for CMML diagnosis (Hudson CA et al, Am J Clin Pathol 2018). With the exception of the study of Tarfi S, based on 47 CMML, the rest presented a very low number of patients (Talati C: 29; Picot T: 15; Hudson CA: 16) and therefore a bias could be expected specially when studying the Sn of the proposed methods. Moreover, the different series assessing the "monocyte assay" have no molecular data and therefore this could diminish the accuracy of the results since some patients may have received misdiagnoses. The aim of our study was to assess the Sn and Sp of different thresholds of Mo1 and Mo3 in a large series with well-annotated clinical, cytogenetic and molecular data. Moreover, we assessed whether the study of CD2 and CD56 monocyte expression in combination with the %Mo1 >94 test improves the detection of the disease. METHODS 50 CMML, 12 MDS, 11 MPN with ≥1x109/L monocytes and 79 reactive monocytosis with ≥1x109/L monocytes (N = 152) were prospectively studied from 02/2016 to 07/2019. We studied PB monocyte subsets by FC: Mo1 (CD14bright/CD16-), Mo2 (CD14bright/CD16+) and Mo3 (CD14dim or -/CD16bright). In addition, we assessed the expression of CD56 and CD2 in monocytes (positivity ≥ 20%). Finally, targeted NGS of the entire exonic sequence of 25 genes recurrently mutated in myeloid malignancies was performed (VAF sensitivity: 2%). Chi-Square or Fisher exact tests were used as appropriate. ROC curves were developed to explore optimal cutoffs in terms of sensitivity (Sn) and specificity (Sp). Moreover, we plotted the AUC of the subset of Mo1 and Mo3. Finally, the Youden index (YI) was used to detect the threshold of Mo1 and Mo3 with the best balance between Sn and Sp. RESULTS AND DISCUSSION The Sn and Sp of the Mo1>94% test in our series were similar to those reported by the French group (GFM). Our Sn and Sp were 90% and 92% respectively with a YI of 82. The Sn and Sp of the Mo1>93% were 94% and 84% with a YI of 78. Finally, the 95% cutoff proposed by Picot T et al showed a Sn of 81% and a Sp of 96% with a YI of 77. Therefore, the 94% cutoff presented the best balance between Sn and SP of the different thresholds assessed. The Mo3 threshold of 1.13% proposed by Hudson CA et al showed a Sn of 67% and a Sp of 95% with a YI of 62. The best Mo3 cutoff in our series was established in 3.18% with a Sn of 90% and Sp of 83%. The YI of this threshold was 73. The AUC for the percentage (%) of Mo1 (0.937, IC 95%: 0.89-0.99) was better than the AUC of the % of Mo3 (0.924, IC 95%: 0.88-0.97) reinforcing the use of %Mo1 as the item with the best discriminative power for CMML diagnosis. The AUC of the percentage of Mo1 population was similar to that reported by the GFM (Figure 1). The Sn and Sp for CD56 expression in monocytes was 67% and 91% respectively, while CD2 expression showed a Sn of 38% and a Sp of 99%. Finally, the presence of at least one of the following: Mo1 >94%, CD56+ or CD2+ presented the highest Sn (98%) and a Sp of 84%. This method may be a very good screening test due to the low false negative rate expected. This combined approach showed the best balance between Sn and Sp (YI: 82). CONCLUSIONS Our study supports the utility of the Mo1 >94% test as the best flow cytometry assay for establishing accurate diagnoses in CMML. The combined assay of Mo1, CD56 and CD2 may be of high utility as a screening test. Figure 1 Disclosures Bellosillo: Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

INTRODUCTION The 2017 WHO classification requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB) for the diagnosis of CMML. Recently, Geyer et al. defines oligomonocytic CMML (O-CMML) as those MDS cases with relative monocytosis (≥10% monocytes) and monocyte count 0.594% is a highly sensitive and specific diagnostic marker for CMML. In the extent of our knowledge, there are no data about PB monocyte subset distribution by FC in O-CMML. Moreover, CD2 and CD56 expression is common in CMML and rarely observed in MDS, the group where O-CMML are currently included. Furthermore, we compared: the molecular profile; cytogenetic abnormalities; cytopenias; BM dysplasia; BM blast and monocyte percentage; PB monocyte percentage, and monocyte and leukocyte counts. METHODS 50 CMML and 33 O-CMML from a single institution were prospectively studied from 02/2016 to date. Table 1 summarizes morphologic, cytogenetic, molecular and clinical findings. We studied PB monocyte subsets by FC: Mo1 (CD14bright/CD16-), Mo2 (CD14bright/CD16+) and Mo3 (CD14dim or -/CD16bright). In addition, we assessed the expression of CD56 and CD2 in monocytes (positivity ≥ 20%). Finally, targeted NGS of the entire exonic sequence of 25 genes recurrently mutated in myeloid malignancies was performed (VAF sensitivity: 2%). Chi-Square, Fisher exact or Man-Whitney U tests were used as appropriate. RESULTS AND DISCUSSION The Mo1 percentage (%) was significantly inferior in O-CMML (P=0.007), but it is noteworthy that median and mean of Mo1% in O-CMML were upper the cutoff of 94% (median: 96.1 vs 98.1; mean: 94.7 vs 96.9). Moreover, the % of patients with >94% Mo1 was no significantly different when comparing O-CMML and CMML although a clear trend was observed (72% vs 90%; P=0.082). This result is impressive since, as previously reported, the specificity of the Mo1 >94% test is around 90-95% and only 5-10% of false positive rate (FP) should be expected. However, in O-CMML a 72% of FP was observed since following 2017 WHO recommendation these patients should be considered as MDS. No differences were observed neither in the % of patients showing CD56+ monocytes (65.6% vs 66.7%; P=0.923) nor in the % of them showing CD2+ (28.1% vs 37.5%; P=0.53) when comparing O-CMML and CMML. We observed no significant differences in platelet count, hemoglobin, BM dyserythropoiesis, BM dysgranulopoiesis, BM dysmegacaryopoiesis, BM blast %, percentage of abnormal karyotypes, and Spanish cytogenetic risk stratification. The main differences were observed in leukocyte count, monocyte count, PB monocyte %, BM monocyte %, and BM promonocyte percentage. Table 1. There were no differences in the number of mutated genes or in the number of mutations between CMML and O-CMML (Table 1). As expected, TET2 and SRSF2 were the most frequently mutated genes in both groups. Moreover, no significant difference was observed in the presence of TET2/SRSF2 co-mutation, the gene signature of CMML (32% vs 26% in CMML). The genes mutated at a frequency >10% in O-CMML were: TET2 (79%), SRSF2 (36%), SF3B1 (29%), ZRSR2 (25%), DNMT3A (15%), and ASXL1 (14%). The genes mutated at a frequency >10% in CMML were: TET2 (81%), SRSF2 (28%), ASXL1 (23%), CBL (23%), SF3B1 (16%), and NRAS (14%). Only two genes were mutated at a significant different frequency: CBL (4% vs 23% in CMML, P=0.041) and ZRSR2 (25% vs 7% in CMML, P=0.043). As expected, CMML showed a higher % of RAS pathway mutations (CBL, NRAS or KRAS) since these have been associated with proliferative features (4% vs 40%, P=0.001). This is especially evident in proliferative CMML in which genes associated with proliferation are present at higher frequencies: CBL (4% vs 39% in CMML, P=0.01), NRAS (0 vs 23% in CMML, P=0.029) and ASXL1 (14% vs 62% in CMML, P=0.004). A significant lower percentage of O-CMML with ZRSR2mut presented Mo1 >94% (33% vs 86%, P=0.024). As shown, O-CMML without ZRSR2mut showed this feature in a similar percentage than CMML (86% vs 90%). At a median follow-up of 31.2 months, 19% of O-CMML evolved to CMML showing a median time to evolution of 34 months. CONCLUSION Our data support the diagnosis of O-CMML as a distinctive subtype of CMML. Table 1 Disclosures Bellosillo: Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

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.

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 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.

Myelodysplastic syndrome with 5q- (MDS 5q-) is the only cytogenetically defined MDS category recognized by the world Health Organization (WHO) in 2001 and 2008 and is defined as a MDS with isolated deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow (BM). It is well known that for patients with MDS 5q- and transfusion dependence (TD), Lenalidomide is the first choice treatment. However, as far as we know there are no data regarding factors that may impact on the development of TD in these patients or the disease evolution in patients diagnosed without TD. In the present study a retrospective multicenter analysis on patients with low-int 1 MDS 5q- without TD at diagnosis has been performed in order to answer these questions. Patients and methods Data from eighty-four low-Int 1 risk MDS 5q- patients diagnosed between 1980 and 2012 were retrospectively analyzed. Ninety percent of patients had a single 5q deletion and according to IPSS-R 99% were in low and very low risk. Statistical analysis 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 (Lenalidomide or ESA). Patients follow up was updated on March 30, 2013, and all follow up data were censored at that point. Transfusion free survival (TFS), Overall survival (OS) and AML were analyzed using the Kaplan – Meier method. TFS, OS, and Leukemia free survival (LFS) were measured from diagnosis to TD or to last follow up if transfusion free (TFS), death from any cause or last follow up (OS) and evolution to AML or last follow up (LFS). Multivariate analysis was performed using Cox’s proportional hazards regression model. Incidence of progression to AML was analyzed with cumulative incidence competing risk method. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p Results During the study 61 (73%) became TD at a median of 1.7 years from diagnosis. The unique factor associated with poorer TFS was Hb level Disclosures: Díez-Campelo: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen-Cilag: Research Funding. Off Label Use: In the present study we describe Lenalidomide treatment among patients with MDS and del(5q-) receiving this drug, not approval for this use in Europe, patients with anemia and transfusional requirements. Solé:Celgene: Consultancy, Honoraria; Celgene: Consultancy. Consuelo:Celgene Jansen-Cilag Arry Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Abstract 1627 Front line treatment with chemoimmunotherapy in mantle cell lymphoma (MCL) is able to obtain a high CR rate. Regrettably, all patients with MCL eventually relapse, a situation for which no effective therapies are available. Gemcitabine plus Oxaliplatin have shown promising results in “in vitro” and in clinical studies for several types of lymphoma, its activity being improved by the addition of rituximab. Against this background, we conducted a pilot study aimed to assess the efficacy and toxicity of the combination of Rituximab, Gemcitabine and Oxaliplatin (R-GemOx) in pts with relapsed/refractory MCL. Inclusion criteria were age > 18 years and a histologically proved MCL that relapsed or was refractory to previous treatment. Patients were excluded if they had neutrophil count < 1,500 μL, platelet count < 100,000 μL, creatinine > 2.5 mg/dL, > 3 times the upper limit of laboratory normal for AST and ALT, or bilirubin > 3 mg/dL. The regimen consisted of Rituximab 375 mg/m2 day 1, Gemcitabine 1000 mg/ m2 and Oxaliplatin 100 mg/ m2 day 2, every 14 days for a total of 8 cycles. Dose and interval adjustment was done according hematological and extrahematological toxicities. Twenty-eight patients (71% male, median age 68 years, range 41–84 years) were included in this study. Median number of previous treatments was one (range: 1–4). Fifteen (53%) pts had relapsed after previous CR/uCR, 10 (36%) had progressed after a PR, and three (11%) were refractory to the previous treatment. Bone marrow infiltration was observed in 85% of evaluated patients. Median number of cycles administered was 8 (range 2–8). Toxicity was mainly hematological, with a grade 3–4 neutropenia and thrombocytopenia observed in 9 (4.7%) and five (2.6%) cycles, respectively. Main non-hematologic toxicities were hepatotoxicity grade 1–2(21%), sensitive neurotoxicity grade 1–2 (43%), and nefrotoxicity grade 2 (4%). Dose reduction was performed in only two pts for a total of eight cycles, and treatment was delayed in six pts for a total of 17 cycles. After completion of treatment, 21 pts (75%) achieved a CR/uCR, 1 (3.5%) a PR, 1 (3.6%) SD and 5 (17.8%) progressed. Stem-cell transplantation was subsequently performed in nine pts (6 allogeneic and 3 autologous). After a median follow-up of 23 months, 4 patients are alive without progression, 7 relapsed, and 17 died (13 due to progression, 2 due to aGVHD, and 2 due to post-transplant infection). Median PFS and OS of this series were 18 and 30 months, respectively. In conclusion, the R-GemOx combination showed an encouraging efficacy in relapsed/refractory pts with MCL. Hematological and non-hematological toxicity were mild. This is a feasible combination to be employed in salvaging pts prior stem-cell transplantation. Based on the above mentioned data from this pilot study, a national prospective multicenter phase II clinical trial is currently ongoing. Disclosures: No relevant conflicts of interest to declare.