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Clinical practice; Myelodysplastic syndrome; Treatment Pràctica clínica; Síndrome mielodisplàstica; Tractament Práctica clínica; Síndrome mielodisplásico; Tratamiento Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases without a care standard and show variability in treatment outcomes. This Spanish, observational, prospective study ERASME (CEL-SMD-2012-01) assessed the evolution of newly diagnosed and treatment-naïve high-risk MDS patients (according to IPPS-R). 204 patients were included: median age 73.0 years, 54.4% males, 69.6% 0-1 ECOG, and 94.6% with comorbidities. Active treatment was the most common strategy (52.0%) vs. stem cell transplantation (25.5%) and supportive care/watchful-waiting (22.5%). Overall (median) event-free survival was 7.9 months (9.1, 8.3, and 5.3); progression-free survival: 10.1 months (12.9, 12.8, and 4.3); and overall survival: 13.8 months (15.4, 14.9; 8.4), respectively, with significant differences among groups. Adverse events (AEs) of ≥3 grade were reported in 72.6% of patients; serious AEs reported in 60.6%. 33.1% of patients died due to AEs. Three patients developed second primary malignant neoplasms (median: 8.2 months). Our study showed better outcomes in patients receiving active therapy early after diagnosis.

Acute myeloid leukemia (AML) predominantly affects the elderly, and prognosis declines with age. Induction chemotherapy plus consolidation therapy is standard of care for fit patients; options for unfit patients include hypomethylating agents (HMA), low-dose cytarabine (LDAC), targeted therapies, and best supportive care (BSC). This retrospective chart review evaluated clinical outcomes in unfit patients with AML who initiated first-line treatment or BSC 01/01/2015-12/31/2018. Overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), and response rates were assessed. Of 1762 patients, 1310 received systemic therapies: 809 HMA, 199 LDAC, and 302 other therapies; 452 received BSC. Median OS was 9.9, 7.9, 5.4, and 2.5 months for HMA, LDAC, other, and BSC, respectively. Median PFS was 7.5, 5.3, 4.1, and 2.1 months for HMA, LDAC, other, and BSC, respectively; median TTF was 4.9, 2.1, 2.2, and 2.1 months, respectively. Our findings highlight the unmet need for novel therapies for unfit patients.

Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the CD33 rs12459419 CC genotype might benefit from the addition of GO to intensive treatment in contrast to patients with CT/TT genotypes. Nevertheless, contradictory results have been reported. We sought to shed light on the prediction of GO response in AML patients with rs12459419 polymorphism who were treated with GO in the consolidation ( n = 70 ) or reinduction ( n = 20 ) phase. The frequency distribution of the rs12459419 polymorphism in the complete cohort of patients was 44.4% ( n = 40 ), 50% ( n = 45 ), and 5.6% ( n = 5 ) for CC, CT, and TT genotypes, respectively. Regarding the patients treated with GO for consolidation, we performed a Kaplan-Meier analysis of overall survival and relapse-free survival according to the rs12459419 polymorphism (CC vs. CT/TT patients) and genetic risk using the European Leukemia Net (ELN) 2010 risk score. We also carried out a Cox regression analysis for the prediction of overall survival, with age and ELN 2010 as covariates. We found no statistical significance in the univariate or multivariate analysis. Additionally, we performed a global Kaplan-Meier analysis for the patients treated with GO for reinduction and did not find significant differences; however, our cohort was too small to draw any conclusion from this analysis. The use of GO in consolidation treatment is included in the approval of the compound; however, evidence regarding its efficacy in this setting is lacking. Rs12459419 polymorphism could help in the selection of patients who might benefit from GO. Regrettably, in our cohort, the rs12459419 polymorphism does not seem to be an adequate tool for the selection of patients who might benefit from the addition of GO in consolidation cycles.

BACKGROUND: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments. METHODS: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, =20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407). FINDINGS: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with

Gemtuzumab ozogamicin (GO) is a conjugate of a monoclonal antibody and calicheamicin, which has been reapproved for the treatment of acute myeloid leukemia (AML). AML patients with the

This retrospective chart review examined real-world healthcare resource utilization (HRU) in patients with AML ineligible for intensive therapy who received first-line systemic therapy or best supportive care (BSC).Data were collected anonymously on patients with AML who initiated first-line hypomethylating agents (HMA), low-dose cytarabine (LDAC), other systemic therapy, or BSC. HRU endpoints included hospitalizations, outpatient consultations, transfusions, and supportive care.Of 1762 patients included, 46% received HMA, 11% received LDAC, 17% received other systemic therapy, 26% received BSC; median treatment durations were 118, 35, 33, and 57 days, respectively. Most patients were hospitalized, most commonly for treatment administration, transfusion, or infection (HMA 82%, LDAC 93%, other systemic therapy 83%, BSC 83%). A median number of hospitalizations were 2-6 across systemic groups and two for BSC, with median durations of 8-18 days. Transfusion rates and outpatient consultations were highest for HMA (80% and 79%) versus LDAC (57% and 53%), other systemic therapy (57% and 63%), and BSC (71% and 66%). Antivirals/antibiotics and antifungals were used more frequently than growth factors (72-92%, 34-63%, and 7-27%, respectively).Patients with AML ineligible for intensive therapy have high HRU; novel therapies are needed to alleviate this burden.

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workup. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly-diagnosed AML patients. Presence of dysplasia according to MFC and WHO criteria had no prognostic value in the elderly. NGS of dysplastic cells and blasts isolated at diagnosis identified three evolutionary patterns: stable (n=12/21), branching (n=4/21) and clonal evolution (n=5/21). In patients achieving complete response, integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in approximately 80% of newly diagnosed AML patients, using techniques other than single-cell multiomics. ACKNOWLEDGEMENTS: The authors acknowledge the patients, caregivers, and the biobank of the University of Navarra. This work was supported by grants from the Área de Oncología del Instituto de Salud Carlos III, Centro de Investigacion Biom ´ edica en ´ Red (CIBER-ONC) (CB16/12/00369, CB16/12/00233, CB16/12/ 00489, and CB16/12/00284), Instituto de Salud Carlos III/Subdireccion General de Investigaci ´ on Sanitaria (FIS numbers PI16/ ´ 01661, PI16/00517, and PI19/01518), and the Plan de Investigacion´ de la Universidad de Navarra (PIUNA 2014-18). This work was supported internationally by the Cancer Research UK, FCAECC, and AIRC under the Accelerator Award Program (EDITOR).

Despite the irruption of massive sequencing technologies in clinical routine, the genetic diagnosis of T-cell acute lymphoblastic leukemia (T-ALL) continues to be based on traditional techniques. The integration of old and new technologies with diagnostic and prognostic purposes represents a major challenge.A High-Throughput Sequencing (HTS) approach was applied to analyze the genetic landscape of two patients diagnosed with T-ALL and one early T cell precursor acute leukemia. Orthogonal standard techniques were used to confirm the findings of NGS analysis.By using a single test, a complete genetic map including 2 previously unreported missense mutations in BCL11B gene are reported. Cooperating oncogenic lesions including CDKN2A/B deletions, SIL-TAL1 rearrangement and FLT3 amplification were also captured by using a single test.HTS is a useful approach that allows simultaneously analyzing mutations, CNVs and the clonal repertoire in T-ALL patients. This approach may simplify the genetic assessment of ALL.

Background: Evaluation of MRD is standard in patients with AML. However, the role of decentralized MRD assessment for risk stratification in AML remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using MFC. Aim: To evaluate the role of decentralized MRD assessment using MFC for risk stratification and putative treatment individualization of patients with AML. Methods: This study was performed on 1,076 AML patients in complete remission (CR) after 7+3 induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories over a period of 20 years in the PETHEMA group. We conducted a survey of technical aspects of MFC based MRD testing in the laboratories of the 60 participating Hospitals, to determine the impact of methodological heterogeneity in the prognostic value of MFC. Results: We first investigated the most effective MRD cutoff to stratify patients' risk at first remission. Patients were segmented into progressively higher cutoffs, starting at 0.01% followed by 0.05%, 0.1%, 0.5% and 1%. Our results showed that 0.1% reached higher statistical significance to discriminate patients with different relapse-free survival (RFS, HR: 0.77; P = .001) and overall survival (OS, HR: 0.73; P = .001). In multivariate analyses together with patients' age, WBC, genetic risk and post-consolidation therapy, MRD status was selected as an independent prognostic factor for OS. To further define the utility of "real-world" MRD assessment using MFC in risk stratification of AML, recursive partitioning was performed using the prognostic and treatment related factors selected in the multivariate Cox model for OS. Of the four variables evaluated, hematopoietic stem cell transplantation (HSCT, regardless of autologous or allogeneic source) vs no transplant emerged as the best single discriminator for OS, followed by genetic risk, age and MRD status. There were two branching points defined by MRD status; the first in patients ≤60 years with intermediate genetic risk who were not transplanted and the second in patients with adverse genetics who were not transplanted, in whom Forty-nine of the 60 hospitals (82%) responded to the survey on questions regarding the measurement of MRD using MFC in the PETHEMA LMA 1999, 2007 and 2010 protocols, providing information corresponding to 966 of the 1,076 (90%) patients regarding the number of markers, preparation of samples, instruments, approach (ie, LAIP, DfN or LAIP+DfN), number of cells to define a cluster, etc. The survey revealed significant heterogeneity intra- and inter-protocols that reflected improvement in MFC assessment of MRD over time, in the absence of harmonization nor standardization at the national level. Accordingly, we investigated if the heterogeneity in methodological, interpretation and reporting aspects of MFC based MRD testing were hampering its ability to predict outcome independently of other patient and treatment related factors. Strikingly, our results showed that except for the denominator used to calculate MRD burden (ie, total nucleated cells vs leukocytes), lack of standardization in all other parameters had an impact on the ability of MFC to predict outcomes in AML (Figure). Namely, panels with ≤4 markers or ≤2 combinations failed to identify patients with significantly different RFS according to MRD status, and MFC-based MRD monitoring was prognostic only when >500,000 cells were measured. Only MRD assessment using patient-specific panels was predictive of outcome. Conclusions: We report here one of the largest studies investigating the role of MRD monitoring using MFC. Our results confirmed that detection of MRD identifies patients in CR/CRi with inferior survival, but uncovered that decentralized MRD testing lacks significance when compared to other baseline risk factors and in the context of risk-adapted post-consolidation strategies. Thus, while this study demonstrated that "real-world" decentralized assessment of MRD using MFC does provide prognostic information in AML patients at first remission, our results question its readiness for risk stratification towards clinical decisions outside trials, at least until adequate standardization of this technique is achieved. Figure Disclosures Paiva: SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Alonso Dominguez:Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding. Martinez-Lopez:Janssen: Speakers Bureau; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Sossa:Astellas: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novo: Honoraria. San-Miguel:Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.

SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil >1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte >1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.

Myeloid neoplasms (MN) are usually sporadic late-onset cancers; nevertheless, growing evidence suggests that ∼5% of the cases could emerge as a consequence of inherited predisposition. Distinguishing somatic from germline variants is of vital importance, in order to establish an appropriate individualized management and counsel the patients and their relatives. Since many of the genes associated with myeloid neoplasm germline predisposition (MNGP) are also affected in sporadic MN, we intended to design a strategy to identify potentially inherited variants in a tumor only NGS panel in a cohort of 299 patients with a variety of MN. We considered as indicative of potential inherited origin, variants detected in BM sample at a ∼50% VAF classified as pathogenic, likely pathogenic or of unknown significance detected in MNGP-related genes. A total of 104 suspicious variants from 90 patients were filtered-in in tumor samples. Mutational patterns, follow-up data, and sequencing of a range of non-myeloid tissues were used for narrowing down the list of suspicious variants, and ultimately discriminate their nature. Our data supports the importance of considering variants found upon tumor-only sequencing as potentially of germline origin, and we offer a pipeline to define the nature of the variants.

Selection of elderly patients (aged =60 years) for intensive chemotherapy treatment of acute myeloblastic leukaemia (AML) remains challenging. Several cooperative groups such as Acute Leukaemia French Association (ALFA), Haematological Oncology Clinical Studies Group (HOCSG) and MD Anderson Cancer Center (MDACC) have developed predictive models to select those patients who can benefit from intensive chemotherapy. Our purpose is to validate and compare these three models in a cohort of patients treated in real-life setting. For this, a total of 1724 elderly AML patients and treated with intensive chemotherapy regimens were identified in the PETHEMA registry. Median age was 67.2 years (range, 60-84,9) and median overall survival [OS] 9 months (95 % confidence interval [CI], 8.2-9.7). Taking into account the ALFA group's model, patients likely to benefit from intensive chemotherapy had longer OS (14 months, 95 % CI 12.3-15.7) than those unlikely to benefit (5 months, 95 % CI 4.1-5.9; p

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51-0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31-46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. 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. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; Karyopharm: 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, Speakers Bureau; Pfizer: 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; 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: 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 Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are a common choice for initial treatment in elderly patients with acute myeloid leukemia (AML). However, about 60% of patients are resistant and most will relapse after a complete response (including CR/CRi). Although relapse or refractoriness to HMAs is very common, very little is known about the therapeutic management of these relapsed or refractory AML (RR-AML) patients after HMAs. METHODS We conducted a retrospective study to describe and compare salvage treatment patterns and real-life clinical outcomes of those AML patients treated upfront with AZA or DEC included in the PETHEMA-AML Registry. RESULTS Between 2006 and 2019, we included 626 AML patients treated in first-line with HMAs, 487 (78%) received AZA and 139 (22%) received DEC. Overall response rate (CR/CRi+PR) was 33.7%, 32% in the AZA vs 39.5% in the DEC group (p=0.120). Patients treated with DEC had a higher median relapse free survival than those treated with AZA (25.6 vs. 17.5 months, p=0.027). No differences were observed in the overall survival between AZA and DEC. We observed 59.7% resistance after HMAs, 60% after AZA and 58.8% after DEC; and 6.5% had other type of response (< PR), 7.9% with AZA and 1.6% with DEC. In addition, 76/121 patients who achieved CR/CRi (62.8%) relapsed, 66/90 in the AZA group (73.3%) vs 10/31 in the DEC group (32.3%) (p=0.000). After relapse or resistance, 74.5% of patients received supportive care only (BSC), which included patients receiving transfusions and other supportive measures, including oral agents to control the white blood cell counts; 71.5% of patients in the AZA group and 84.3% of patients in DEC group (p= 0.004). No differences were observed in baseline characteristics at diagnosis of patients treated with BSC only, except for a higher proportion of patients with adverse cytogenetic risk in the AZA group (46.6% vs. 33.7%, p=0.039). Only 135 patients received a salvage therapy, 116 in the AZA group and 19 in the DEC group. Thirty-five out of 135 RR-AML treated patients (26%) continued receiving HMAs: 31 (26%) in the AZA group and 4 (22%) in the DEC group. In the AZA group, 19 (16%) patients continued with AZA and 12 (10%) switched to DEC, while in the DEC group 2 patients (11%) continued with DEC and 2 (11%) switched to AZA. Fifty-one patients (37.8%) received FLUGA (fludarabine and Ara-C), FLAG-IDA-Lite (fludarabine, Ara-C and idarubicin), Low-dose Ara-C or other non-intensive regimens, 43 patients (37%) in the AZA group and 8 (42%) in the DEC group. Other salvage therapies were administered in 34% of patients (33% in the AZA group and 37% in the DEC group). Salvage therapy was not available in 1% of patients. Response assessment was available in 113/135 of RR-AML treated patients, 98 in the AZA group and 15 in the DEC group. In the AZA group, 13.2% of the patients achieved a CR (n=13), 5.1% achieved CRi (n=5), 6.1% achieved a PR (n=6), 65.3% resistance (n=64) and 8.1% died (n=8). However, no patients in the decitabine group responded to salvage therapy, 86.7% resistance (n=13) and 13.3% died (n=2). If we exclude those patients who died before response was evaluated, the ORR (CR/CRi+PR) after salvage therapy was statistically significant between AZA (n=24/90, 26.7%) and DEC group (n=0/13, 0%), p=0.035. CONCLUSIONS This study shows and compares, for the first time to our knowledge, the patterns of salvage therapy in patients with RR-AML treated upfront with HMAs. Despite the similar response rate with both HMAs, the relapse free survival was lower after AZA. The absence of responses in patients with RR-AML initially treated with DEC could justify the similar OS between AZA and DEC observed. However, we should be very cautious due to the low number of RR-AML patients treated. Disclosures de la Fuente: BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: 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. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, 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; Janssen: 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; Karyopharm: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: 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.

Background: Genetic information has become critical to understand the development of T-cell acute lymphoblastic leukemia (T-ALL) and to elucidate the origin of disease relapse. Several genetic markers, together with measurable residual disease (MRD), are considered strong predictors of patient outcome. However, the prognostic significance of genetic markers can varie according to treatment. Aim: We used targeted deep sequencing to analyze the genetic profile of 125 T-ALL patients enrolled in three consecutive MRD-oriented trials from the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genomic information was analyzed together with the main clinical and biologic data in a subset of 111 patients with detailed clinical and outcome data to determine the prognostic significance for overall survival (OS) and cumulative incidence of relapse (CIR). Methods: Genetic mutations were detected using a custom gene panel and sequenced on a MiSeq platform. Alignment, variant calling, filtration and annotation of variants were done using standardized pipelines. OS curves were plotted by the Kaplan-Meier method and compared by the log-rank test. CIR was estimated using cumulative incidence functions by competing risks analysis. A Cox proportional hazard regression model was used to identify predictive factors for OS. Statistical significance was set at (two-sided) p-values Results: Recurrently mutated genes found in ≥4/125 patients involved transcription factor tumor suppressor genes (PTEN, BCL11B, RUNX1, GATA3, ETV6), epigenetic regulators (PHF6, DNMT3A, EP300, KMT2C, EZH2, TET2), DNA mismatch repair genes (MSH2), ribosomal (RPL5) and RNA splicing (U2AF1) genes, and genes involved in the RAS/MAPK (NRAS), WNT (FAT1, FAT3), IL7R-JAK-STAT (JAK3, JAK1, IL7R) and NOTCH1 signaling pathways, respectively. Mutations in the latest pathway (NOTCH1 & FBXW7) was found in 88/125 (70%) patients. Clinical-genetic correlations revealed that patients with mutations in JAK3, DNMT3A, N/KRAS, IL7R, MSH2 or in U2AF1 were associated with lower OS (vs unmutated patients). None of the mutated genes had impact on CIR. Upon grouping the mutated genes according to their functional role and potential biological impact on T-ALL, two gene signatures were defined. These included the aging gene signature (DNMT3A and U2AF1) characterized by mutations in genes identified in clonal hematopoiesis of indeterminate potential (CHIP); and the treatment resistance gene signature (JAK3, N/KRAS, IL7R and MSH2), defined by mutations in genes involved in resistance to the ALL therapy. Both clusters identified patients with poorer response to therapy (poorer blast clearance on day 14 of induction treatment and lower CR rates). Therefore, we considered together (worse outcome genetics [WOG] signature) for univariate and multivariate analyses. WOG and MRD level (0.1% cut-off) on day 35 after induction therapy (+35d MRD) showed significant prognostic impact in the univariable and multivariable analyses for OS (3y) with a hazard ratio (95% CI) of 2.4 (1.2; 4.8) and 2.7 (1.4; 5.1), respectively (Table 1). OS according to these two variables allowed risk stratification of T-ALL into low, intermediate- and high-risk (HR) patients with significantly different outcomes (p Conclusion: A genetic signature with independent prognostic significance of MRD has been identified in this cohort of patients included in MRD-oriented trials. This gene signature (WOG) together with MRD could help to improve risk-stratification of adult T-ALL patients and would be of interest in the search for new therapies for HR patients Funding: Support from AECC (GC16173697BIGA); ISCIII (PI19/01828 and PI19/01183), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future", CERCA/Generalitat de Catalunya SGR 2017 288 (GRC)/ C González-Gil was supported by AGAUR grant (2020 FI_B2 00210). Figure 1 Figure 1. Disclosures Diaz-Beyá: Jazz: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tormo: Astellas: 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; 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. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Maciejewski: Regeneron: Consultancy; Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Alexion: Consultancy. Ribera: ARIAD: Consultancy, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau.

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.

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.

Introduction and objective. Despite a high complete remission (CR) rate obtained with frontline therapy most adults with T-ALL eventually relapse. Although promising therapies are emerging, salvage options for T-ALL are currently limited. Little is known about outcome of patients (pts) with relapsed T-ALL (R T-ALL) treated with contemporary MRD-oriented trials. Our goal was to analyze the outcome of pts with R T-ALL included in two successive MRD-oriented trials (ALL-AR-03 and ALL-HR-11) from the Spanish PETHEMA Group. Methods. Retrospective study of R T-ALL adults diagnosed between 2003 and 2019 and included in the protocols ALL-AR-03 (NCT00853008) and ALL-HR-11 (NCT01540812). The clinical characteristics at baseline and at relapse, salvage therapies and outcomes (CR and OS) were analyzed and a study of prognostic factors for OS was performed. Results Forty-nine patients were identified (ALL-AR-03 [n=27], ALL-HR-11 [n=22]). Median age (range) at diagnosis was 29 (16-58) yrs, 38 males (78%), CNS involvement 6 (12%), mediastinal mass 30 (61%), WBC count 40.8 x109/L (0.6-351.0), early T-cell precursor 11 (23%), pre-T 8 (16%), cortical 16 (33%), mature 9 (18%), T unspecified 5 (10%). Post-induction-1 MRD level ≥0.1%: 14/42 (33%), ≥0.01%: 17/39 (44%). Nine pts (18%) required 2nd induction therapy (resistant disease after induction-1 [n=5], MRD≥0.1% after induction-1 [n=4]). Allogeneic HSCT in CR1: 8 pts. Interval CR1-relapse: 11.2 [0.1-36.7] months. Relapse was located in BM (n=20, 41%), BM+extramedullary (n=16, 33%) and extramedullary (n=13, 26%). CNS at relapse was involved in 18 pts (37%, isolated in 8 cases). Median number of rescue lineages was 2 (range 1-5). The most frequent first salvage schedules were FLAG-Ida (n=24, 49%), HyperCVAD (n=8, 16%) and nelarabine (n=4, 8%) (other schedules in 13 pts). Second CR was attained in 21/48 pts (44%). The patients with poor morphologic and/or poor MRD response after Induction-1 in first line therapy (n=9) did not respond to first salvage therapy (0/9 vs. 21/39, p=0.003). AlloHSCT was performed in 19 pts (15 in CR2) (HLA-identical sibling: 9, URD: 9, haploidentical: 1, myeloablative conditioning: 16). Thirty-nine pts died (progression: 27, toxicity of rescue regimens: 7, TRM: 5) and 9/10 alive patients were submitted to HSCT (the remaining is on rescue therapy). Median OS (95%CI) was 6.1 (4.9-7.2) months, 5yr OS probability 21% (9%-33%) (Figure 1). By multivariable analysis, only the CR after first salvage regimen emerged as favorable prognostic factor for OS (HR 3.110, 95%CI: 1.579-6.124) (Figure 2). Conclusion. This study shows poor outcome of adults with R T-ALL, with CR to first salvage therapy of 44% and a median OS of 6 months. Poor early response to first line therapy correlated with poor response to salvage-1. The only independent predictor for better survival was CR to first salvage regimen. This study highlights the unmet need for novel effective therapies for T-ALL. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation; ISCIII (PI19/01828), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future". Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Barba:Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire: Consultancy; Amgen, Celgene, Novartis, Pfizer: Speakers Bureau. Tormo: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; Janssen: 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. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Giménez Conca:AbbVie: Honoraria, Speakers Bureau.

7533 Background: Effective AML maintenance treatment (Tx) should decrease the risk of relapse and prolong survival without compromising HRQoL. In the placebo (PBO)-controlled phase III QUAZAR AML-001 trial (NCT01757535), CC-486, an oral hypomethylating agent, provided significant improvements in overall (OS) and relapse-free survival (RFS) in patients (pts) with AML in first remission following IC. Here we present pt-reported HRQoL outcomes from that study. Methods: Eligible pts were ≥ 55 yrs of age with intermediate- or poor-risk cytogenetics and ECOG PS ≤ 3, and in CR/CRi after IC ± consolidation. Pts were randomized 1:1 to CC-486 300 mg or PBO QD on days (d) 1–14 of 28d Tx cycles. HRQoL was assessed by FACIT-Fatigue scale and EQ-5D-3L health utility index, completed on d1 of each cycle and at end of Tx (EOT). Endpoints include Tx differences in mean changes from baseline (BL), and proportions of pts with clinically meaningful change from BL (improvement, no change, deterioration). Evaluable pts had an HRQoL assessment at BL and ≥ 1 post-BL visit. Stratified ANCOVA models included Tx and BL scores as covariates. Results: In all, 225/238 pts (95%) in the CC-486 arm were evaluable for FACIT-Fatigue and EQ-5D-3L, and 219/234 pts (94%) in the PBO arm were evaluable for FACIT-Fatigue and 217 (93%) for EQ-5D-3L. Pt characteristics were comparable between Tx arms. Most pts (61%) were 65-74 yrs of age. Median number of CC-486 Tx cycles was 12 and PBO cycles was 7. Compliance rates were > 95% at BL and remained high ( > 85%) at all post-BL visits except for EOT. At BL, pts in both Tx arms had comparable low levels of fatigue and generally good HRQoL relative to an age-matched general population. There were no meaningful differences between CC-486 and PBO in mean changes from BL in FACIT-Fatigue or EQ-5D-3L scores at any post-BL visit. There was no statistically significant difference between Tx arms in proportion of pts with a clinically meaningful deterioration in FACIT-Fatigue score at any post-BL visit except at cycle 29 (likely due to chance; no adjustment made for multiple testing), or in EQ-5D-3L at any visit. Median time to deterioration was not significantly different between CC-486 and PBO on the FACIT-Fatigue scale (41 vs 44 weeks, respectively; P = 0.70) or the EQ-5D-3L (200 vs 164 weeks; P = 0.63). Conclusions: HRQoL and low levels of fatigue were preserved with CC-486 maintenance Tx. CC-486 significantly improved OS and RFS while maintaining HRQoL comparable to PBO. Clinical trial information: NCT01757535 .

Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a phase 1/2 trial of patients (pts) with FLT3mut+ relapsed/refractory AML (Perl AE, et al. Lancet Oncol. 2017). Gilteritinib plus azacitidine (AZA) synergistically induced apoptosis and inhibited growth in the MV4-11 cell line and in MV4-11 tumors (Ueno Y, et al. Blood. 2016). The safety, tolerability, and efficacy of gilteritinib alone, gilteritinib plus AZA, or AZA alone is being evaluated in pts with newly diagnosed FLT3mut+ AML ineligible for intensive induction chemotherapy; this abstract presents data from the Safety Cohort which evaluated only gilteritinib plus AZA. Methods: Adults with newly diagnosed FLT3mut+ (FLT3-ITD or FLT3-TKD) AML are being enrolled in this ongoing clinical trial (NCT02752035). Prior to initiation of the randomized portion of the study, the appropriate gilteritinib dose for combination therapy was assessed in a Safety Cohort. Patients enrolled in this cohort received escalating doses of oral gilteritinib (80 or 120 mg/day) on Days 1-28 in combination with subcutaneous or intravenous AZA (75 mg/m2/day) on Days 1-7. Observations of dose-limiting toxicities (DLTs) were collected through Cycle 1; treatment was continued in 28-day cycles until lack of clinical benefit or unacceptable toxicity. Safety and tolerability were the primary endpoints of the Safety Cohort; antileukemic response rates (ie, complete remission [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematological recovery [CRi], partial remission [PR], and overall response rate [ORR]) were also assessed. Results: A total of 15 adult pts (median age, 76 [range: 65-86]) were enrolled into the Safety Cohort (n=9, 80 mg gilteritinib; n=6, 120 mg gilteritinib); 14 pts were FLT3mut+ (ITD alone, n=10; TKD alone, n=3; ITD and TKD, n=1) and 1 pt had no FLT3 mutation. As of 25 June 2018, more than half (n=8/15; 56%, Figure) of the pts had a treatment duration of >6 mo, while 9 pts discontinued treatment (death, n=4; relapse; adverse event [AE]; physician decision; sponsor decision; subject withdrawal, n=1 each) and 6 pts remained on treatment. During the DLT observation period, 1 DLT (tumor lysis syndrome) was observed in a pt who received 80 mg gilteritinib plus AZA; no DLTs were reported in pts who received 120 mg gilteritinib plus AZA. One or more AEs were seen in all 15 pts; 12 (80%) experienced AEs considered at least possibly related to treatment. Adverse events occurring in ≥25% of pts were anemia (n=7), febrile neutropenia and nausea (n=6 each), increased ALT and AST, constipation, diarrhea, neutropenia, thrombocytopenia, and pyrexia (n=5 each), and decreased appetite, fatigue, increased blood creatinine, and hypocalcemia (n=4 each). Grade ≥3 AEs occurring in ≥25% of pts were febrile neutropenia (n=6), anemia and neutropenia (n=5 each), and thrombocytopenia (n=4). Serious AEs occurring in >2 pts were febrile neutropenia (n=5), and anemia and pyrexia (n=3 each). Of the 8 pts with fatal AEs, none of which were related to treatment, 3 occurred early in treatment: septic shock (Day 2), respiratory failure (Day 6), and cerebral hemorrhage in the setting of acute kidney injury and uremia (Day 17). None of the 13 pts with post-baseline lab data had any potentially clinically significant AST/ALT (>3 X ULN) and total bilirubin (>2 X ULN) values; none of the pts had a maximum post-baseline QTcF interval >500 msec. Across the Safety Cohort, a composite complete remission rate of 67% (n=10/15) was observed; 4 pts achieved a best overall response of CR and 6 achieved CRi (Figure). Two additional pts (13%) achieved a best overall response of PR, giving an ORR of 80%. One DLT from the 11 DLT evaluable pts (defined as pts who experienced a DLT, or in the absence of DLT, received at least 23 of 28 doses of gilteritinib and at least 5 of 7 doses of AZA during the DLT observation period) informed the decision to proceed to the randomized portion at a dose of 120 mg gilteritinib for the combination treatment arm. Conclusions: Gilteritinib and AZA were generally well tolerated with no unexpected AEs. This combination therapy induced antileukemic responses in newly diagnosed FLT3mut+ AML pts unfit to receive standard induction chemotherapy. Based on these results, pts are being enrolled into the randomized portion of the study with a dose of 120 mg gilteritinib for the combination treatment arm. Disclosures Wang: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Laribi:Amgen: Other: Personal fees; Takeda: Other: Grant and personal fees; Sandoz: Other: Grant; Novartis: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Hospira: Other: Grant; Roche: Other: Grant. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Liu:Astellas Pharma: Employment. Rich:Astellas Pharma: Employment. Bahceci:Astellas Pharma: Employment.

[Background] Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia-related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (≥65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC., [Methods] We compared clinical outcomes for patients with AML-MRC treated with azacitidine or conventional care regimens (CCR; induction chemotherapy, low-dose cytarabine, or supportive care only) overall and within patient subgroups defined by cytogenetic risk (intermediate or poor) and age (65–74 years or ≥75 years). The same analyses were used to compare azacitidine with low-dose cytarabine in patients who had been preselected to low-dose cytarabine before they were randomized to receive azacitidine or CCR (ie, low-dose cytarabine)., [Results] Median overall survival was significantly prolonged with azacitidine (n = 129) versus CCR (n = 133): 8.9 versus 4.9 months (hazard ratio 0.74, [95%CI 0.57, 0.97]). Among patients with intermediate-risk cytogenetics, median overall survival with azacitidine was 16.4 months, and with CCR was 8.9 months (hazard ratio 0.73 [95%CI 0.48, 1.10]). Median overall survival was significantly improved for patients ages 65–74 years treated with azacitidine compared with those who received CCR (14.2 versus 7.3 months, respectively; hazard ratio 0.64 [95%CI 0.42, 0.97]). Within the subgroup of patients preselected to low-dose cytarabine before randomization, median overall survival with azacitidine was 9.5 months versus 4.6 months with low-dose cytarabine (hazard ratio 0.77 [95%CI 0.55, 1.09]). Within the low-dose cytarabine preselection group, patients with intermediate-risk cytogenetics who received azacitidine had a median overall survival of 14.1 months versus 6.4 months with low-dose cytarabine, and patients aged 65–74 years had median survival of 14.9 months versus 5.2 months, respectively. Overall response rates were similar with azacitidine and CCR (24.8% and 17.3%, respectively), but higher with azacitidine versus low-dose cytarabine (27.2% and 13.9%). Adverse events were generally comparable between the treatment arms., [Conclusions] Azacitidine may be the preferred treatment for patients with AML-MRC who are not candidates for intensive chemotherapy, particularly patients ages 65–74 years and those with intermediate-risk cytogenetics., [Trial registration] This study was registered at clinicalTrials.gov on February 16, 2010 (NCT01074047)., This study was funded by Celgene Corporation.

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001). RESULTS There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001). To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, 12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients. Disclosures Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau.

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.

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.

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.

TPS7068 Background: Gilteritinib, a highly selective, potent FLT3/AXL inhibitor, showed antileukemic activity with favorable tolerability in a Phase 1/2 trial of FLT3 mutation-positive (FLT3mut+) relapsed/refractory AML. In FLT3mut+ AML cell lines, gilteritinib plus azacitidine (AZA) inhibited growth, and induced apoptosis and differentiation. This ongoing Phase 2/3 trial will examine the efficacy, safety, and tolerability of gilteritinib alone, gilteritinib plus AZA or AZA alone in newly diagnosed FLT3mut+AML patients ineligible for intensive induction chemotherapy. Methods: This open-label, 3-arm, 2-stage randomized trial (NCT02752035) will enroll ~540 newly diagnosed adults with FLT3mut+ (FLT3-ITD or -TKD) AML; those with APL, BCR-ABL+, or active CNS leukemia will be excluded. Before initiation, the safety and tolerability of gilteritinib plus AZA will be assessed in a Safety Cohort to establish the appropriate gilteritinib dose for combination therapy. Subjects will then be randomized 1:1:1 to receive oral gilteritinib alone (120 mg daily; Days 1–28), AZA alone (75 mg/m2 by subcutaneous injection or intravenous infusion on Days 1–7), or AZA (75 mg/m2; Days 1–7) plus oral gilteritinib (daily on Days 1–28 at the dose determined from the Safety Cohort), and stratified by age ( < 75 vs ≥75 years). Subjects will continue treatment until a discontinuation event occurs. The primary endpoint is overall survival of subjects receiving gilteritinib or gilteritinib plus AZA versus AZA alone; the key secondary endpoint is event-free survival. Additional secondary endpoints: complete remission rate, leukemia-free survival, remission duration, composite remission rate, tolerability, and fatigue. Dose changes and interruptions are allowed in all treatment arms. A formal interim futility analysis by an Independent Data Monitoring Committee is planned when ~50 subjects in each treatment arm have either discontinued therapy or completed 2 treatment cycles. Enrollment began on November 21, 2016; as of January 31, 2017, the Safety Cohort is ongoing. Clinical trial information: NCT02752035.

Background: Karyotype is the strongest independent prognostic factor for survival in AML. The randomized phase 3 AZA-AML-001 study of older patients with AML showed AZA prolonged overall survival (OS) compared with CCR (10.4 vs 6.5 months, respectively; P=0.101) (Dombret et al, Blood, 2015). In a prospective subanalysis of the study, AZA was shown to meaningfully prolong OS by 3.2 months compared with CCR (P=0.0185) in the subgroup of patients with NCCN-defined poor-risk cytogenetics (Döhner et al, Blood, 2014: Abstract 621). Aim: This analysis evaluates treatment effects of AZA vs CCR on OS in subgroups of patients with specific cytogenetic abnormalities as well as in patient subgroups defined by cytogenetic risk per modified European LeukemiaNet (ELN) recommendations (not considering molecular markers) (Döhner et al, Blood, 2010). Methods: Patients aged ≥65 years with newly diagnosed AML (>30% bone marrow [BM] blasts), ECOG performance status score ≤2, intermediate- or poor-risk cytogenetics per NCCN 2009 criteria, and WBC count ≤15x109/L were randomized to receive AZA (75 mg/m2/day [d] x7d/28d) or CCR: intensive chemotherapy (cytarabine 100-200mg/m2IV x7d + anthracycline IV x3d induction), low-dose ara-C (20mg SC BID x10d/28d), or best supportive care only. Karyotypes obtained from BM were reviewed centrally by an independent cytogeneticist. OS was evaluated in subgroups of patients with frequent specific abnormalities, including -5/del(5q), -7, -7/del(7q), abnormal (17p) or complex karyotype (based on specific abnormalities, patients may have been evaluated in more than one category). OS was also assessed for patients in ELN-defined karyotype risk subgroups: Intermediate (Int)-I (normal karyotype), Int-II (all abnormalities not classified as Favorable or Adverse), and Adverse karyotype. OS was assessed using Kaplan-Meier methods and compared using a weighted log-rank test. Results: Centrally reviewed cytogenetic data were available for 485/488 patients (99.4%). In all, 220 patients (45.4%; AZA n=114, CCR n=106) had Int-I karyotype, 111 patients (22.9%; AZA n=53, CCR n=58) had Int-II karyotype, and 154 patients (31.8%, AZA n=73, CCR n=81) had Adverse karyotype (Figure 1). OS was comparable between AZA and CCR in patients with Int-I karyotype (14.1 vs 10.1 months, respectively; hazard ratio [HR] 0.83, 95%CI 0.60, 1.1; P=0.44) and patients with Int-II karyotype (8.9 vs 9.6 months; HR 1.19, 95%CI 0.79, 1.8; P=0.78). There was a significant 2.4-month median OS difference in favor of AZA in patients with Adverse karyotype (5.3 vs 2.9 months with CCR; HR 0.71, 95%CI 0.51, 0.99; P=0.046; Figure 2), with 1-year survival rates of 29.1% vs 14.7% for AZA and CCR, respectively. AZA was associated with longer median OS and higher 1-year survival compared with CCR for all subgroups of patients with the specific cytogenetic abnormalities under study: -5/del(5q), -7, -7/del(7q), abnormal (17p), and complex karyotype, with HRs ranging from 0.54 to 0.69(Table). Median OS in the CCR arm was less than 3 months for each of these subgroups. Similar to what has been reported in MDS (Ravandi et al, Cancer, 2009), AML patients with chromosome 7 abnormalities responded particularly well to AZA, with an improvement in median OS of 4.1 months over CCR. Patients with complex karyotypes also had meaningful improvements in OS, with ~15% more AZA-treated patients alive at 1 year than CCR patients. Conclusions: Prognosis is dismal for older AML patients with adverse karyotypes, and is especially poor for patients with complex karyotypes. Median OS and 1-year survival in patients with ELN-defined Adverse karyotype treated with AZA were almost double those of patients treated with CCR. AZA-treated patients with the specific cytogenetic abnormalities and/or complex karyotype in this analysis had a 31-46% reduction in risk of death vs CCR, and proportions of patients alive at 1 year were 11-22% greater with AZA. These data suggest AZA should be the preferred treatment for older patients with AML and adverse karyotypes. Disclosures Seymour: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: 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. Santini:Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Stone:Celator: Consultancy; Novartis: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Morrill:Celgene: Employment, Equity Ownership. Songer:Celgene: Employment, Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Dombret:Agios: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Menarini: Honoraria; Menarini: Honoraria; Servier: Honoraria; Sunesis: Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding.

Background: Overall survival (OS) in older patients (pts) with AML and poor-risk cytogenetics is only ~2-3 months (mos) (Burnett, Cancer, 2007). Often these pts receive only palliative treatment (Tx) with best supportive care (BSC). Low-dose Ara-C (LDAC) provides no OS benefit in pts with poor cytogenetics (Döhner, Blood, 2010). Typically, intensive chemotherapy (IC) is either not suitable for older AML pts with poor cytogenetics or, when it is used, provides no OS benefit (Kantarjian, Blood, 2010). The phase 3, multicenter, randomized, open-label AZA-AML-001 trial showed azacitidine (AZA) Tx in older pts with newly diagnosed AML (>30% bone marrow [BM] blasts) prolonged median OS by ~4 mos vs conventional care regimens (CCR) (10.4 vs 6.5 mos; p=0.1009) and improved 1-year survival (46.5% vs 34.2%) (Dombret, EHA, 2014). Cytogenetic risk is a prognostic indicator in elderly AML and a frequent determinant of Tx approach and outcomes. Objective: To determine the effect of Tx with AZA vs CCR on OS and 1-year survival in AZA-AML-001 pt subgroups based on cytogenetic risk classification. Methods: Pts aged ≥65 years with newly diagnosed de novo or secondary AML who were ineligible for transplant, with intermediate- or poor-risk cytogenetics (pts with favorable cytogenetics were excluded from study), ECOG performance status 0-2, and WBC count ≤15x109/L, were eligible. Before randomization, each pt was preselected to receive 1 of 3 commonly used CCR for older pts with AML, per investigator choice: IC (standard 7+3 regimen), LDAC (20 mg SC BID x 10 days/28-day cycle), or BSC only. Pts were then randomized to AZA (75 mg/m2/day SC x 7 days/28-day cycle) or to CCR, in which case they received their preselected Tx. The primary endpoint was OS. Cytogenetic risk groups were assessed per NCCN criteria by central review: intermediate (INT; all cases), intermediate with normal karyotype (cytogenetic normal [CN]), and poor. Survival at 1 year was compared between Tx. Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and p values by log-rank test. Results: In all, 488 pts were randomized, 241 to AZA and 247 to CCR. Cytogenetic risk was balanced between Tx groups: 315 pts had INT-risk cytogenetics (AZA n=155 [64%], CCR n=160 [65%]), including 218 who were CN (AZA n=113 [73%], CCR n=105 [66%]), and 170 pts had poor-risk cytogenetics (AZA n=85 [35%], CCR n=85 [34%]). Within each of the 3 cytogenetic risk subgroups, the distribution of pts receiving individual CCR was very consistent: ~18% of each cytogenetic risk subgroup received BSC, ~64% received LDAC, and ~18% received IC. Baseline characteristics were generally balanced among the AZA and CCR Tx arms and the 3 cytogenetic risk groups (Table). At baseline, proportionately more pts with poor-risk cytogenetics in the AZA group were aged ≥75 years (57.6% vs 47.1% with CCR) and more pts in the CCR group had AML with myelodysplastic changes (45.9% vs 37.6% with AZA). Median OS (95%CI) in poor-risk pts was significantly prolonged with AZA vs CCR: 6.4 mos (4.2, 8.1) vs 3.2 mos (2.2, 4.7), respectively; HR=0.68 (0.50, 0.94), p=0.019 (Figure). Median OS in INT-risk pts was 13.0 mos (11.2, 16.3) vs 10.1 mos (7.1, 13.3) with AZA vs CCR; HR=0.90 (0.70, 1.16), p=0.41. Median OS in the CN subgroup was 14.1 mos (12.6, 19.5) vs 10.0 mos (6.4, 13.3); HR=0.81 (0.59, 1.10), p=0.18. Estimated 1-year survival was higher with AZA vs CCR in all cytogenetic risk subgroups. Twice the proportion of AZA-treated pts in the poor-risk subgroup were alive at 1 year vs. CCR pts (30.9% vs 14.0%, respectively), a clinically meaningful difference of 16.9% (95%CI 4.4, 29.5). Similarly, in the CN subgroup, 60.7% vs 44.1% of pts were alive at 1 year in the AZA and CCR groups, a difference of 16.5% (3.2, 29.8). AZA effect on 1-year survival in the INT-risk subgroup was also favorable (55.2% vs 45.5% with CCR) (difference 9.7% [-1.4, 20.8]). Grade 3-4 hematologic adverse event rates with AZA were consistent with previous reports (Santini, Eur J Haematol, 2010), with no meaningful differences among all cytogenetic risk groups. Conclusions: Median OS in older pts with AML and poor-risk cytogenetics was meaningfully improved with AZA compared with the CCR currently used for AML, with those pts receiving AZA twice as likely to be alive at 1 year as those treated with CCR. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Döhner: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30%. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: AML is characterized by molecular heterogeneity; morphology and genetic alterations are important prognostic factors (Weinberg, 2009). In the large, phase 3, multicenter, randomized AZA-AML-001 study, AZA treatment (Tx) prolonged median overall survival (OS) vs CCR by ~4 months (10.4 vs 6.5 mo; p=0.1009) in older pts with newly diagnosed AML (>30% BM blasts). About 33% of patients (pts) in AZA-AML-001 had AML with morphologic dysplastic changes (AML-MDC). Aim: Determine effects of AZA vs CCR on OS, response, and safety in the subset of pts with AML-MDC in the AZA-AML-001 trial; and further analyze OS in AML-MDC pts who had been preselected to receive low-dose cytarabine (LDAC) before randomization to AZA or CCR. Methods: Eligible pts were age ≥65 years (yrs), had AML with >30% BM blasts, ECOG performance status (PS) 0-2, WBC count ≤15x109/L, and intermediate- or poor-risk cytogenetics. This analysis includes pts who, based on local assessment, had AML-MDC.Before randomization, investigators preselected the preferred Tx option for each pt from 3 CCR: intensive chemotherapy (IC; standard 7 + 3 regimen), LDAC (20mg SC BID x 10 days [d]/28d cycle), or best supportive care (BSC) only. Pts were then randomized to AZA (75mg/m2/d x 7 d/28d cycle) or CCR, and then received the preselected CCR. Median OS (Kaplan-Meier method) and percent of pts alive at 1 yr were compared between AZA vs CCR for all pts with AML-MDC, and between AZA vs LDAC specifically in pts with AML-MDC preselected to LDAC before randomization. Response was assessed by IWG AML criteria (Cheson, 2003). Transfusion independence (TI) was defined as no transfusion for 56 consecutive days for transfusion dependent (TD) pts at baseline (ie, ≥1 transfusion in 56d before randomization). Overall response was defined as complete remission (CR) + morphologic CR with incomplete blood count recovery (CRi). Adverse events (AEs) were graded by NCI-CTCAE v4. Hazard ratios (HR) and 95% confidence intervals (95%CI) were determined by unstratified Cox proportional hazards model and p values from log-rank or Fisher's exact test. Results: Of 488 pts in AZA-AML-001, 158 (32.4%) had AML-MDC and are included in these analyses. Baseline characteristics were generally balanced between Tx arms (AZA n=75, CCR n=83 [IC n=13, LDAC n=50, and BSC n=20]). Median (range) ages were 76 (65, 86) and 74 (66, 87) yrs in the AZA and CCR groups, respectively. Higher proportions of pts in the AZA arm were age ≥75 yrs (59% vs 48% of CCR) and had prior MDS (47% vs 37%). In the AZA and CCR arms, 43% and 47% of pts had poor-risk cytogenetics, and 24% and 25% had ECOG PS score of 2. Median (range) %BM blasts (central review) in the AZA and CCR arms was 67% (4, 99) and 73% (9, 100). Mediannumber of Tx cycles with AZA, IC, and LDAC were 6 (1, 28), 1 (1, 3), and 3 (1, 23). Median exposure to BSC was 79 d (8, 535). Median OS in pts with AML-MDC was prolonged 2-fold with AZA vs CCR: 12.7 mo (95%CI 7.2, 14.1) vs 6.3 mo (4.3, 9.6); HR=0.69 (0.48, 0.98), p=0.0357 (Figure). Similarly, 1-yr survival was greater with AZA: 50.7% vs 33.8% with CCR (16.9% difference [95%CI 1.5, 32.2]). Rates of CR+CRi were 26.7% with AZA vs 19.3% with CCR (Table). Most pts with AML-MDC (n=99, 63%) were preselected to receive LDAC (AZA n=49, LDAC n=50). Median OS in the preselected LDAC group with AZA vs LDAC, respectively, was 13.2 mo vs 6.3 mo, a 6.8-mo improvement with AZA (HR=0.76 [95%CI 0.49, 1.19], p=0.23). Further, 1-yr survival with AZA vs LDAC was 55% vs 31% (24% difference [95%CI 5.0, 43.0]). In the overall AML-MDC group with baseline-TD, 16/51 (31%) and 14/58 (24%) attained RBC TI in the AZA and CCR groups, and 10/26 (39%) and 12/33 (36%) attained platelet TI. Grade 3-4 anemia, neutropenia, febrile neutropenia, and thrombocytopenia rates, respectively, were: AZA 12%, 30%, 30%, 28%; IC 15%, 46%, 39%, 31%; LDAC 16%, 29%, 35%, 27%; and BSC 6%, 11%, 44%, 11%. Conclusions: AZA prolonged median OS 2-fold to >1 yr in this older, poor-risk subgroup of pts with AML-MDC. More than one-half of AZA-treated pts with AML-MDC remained alive at 1 yr. Notably, median OS in pts preselected to LDAC, but who were randomized to AZA, was more than doubled vs pts who did receive LDAC. AZA safety profile was consistent with that seen in the entire AZA-AML-001 population (Dombret, 2014). Compared with commonly used CCR, AZA was safe, effective and well- tolerated in this subset of pts with AML. These data suggest AZA may be a beneficial initial Tx as an alternative to LDAC in pts with AML-MDC. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Seymour: Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of azacitidine in AML with blast count >30%. Döhner:Celgene: Consultancy. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Agios: Consultancy; AbbVie: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

We report a case of acute myeloid leukemia (AML) with trisomy 10 as the sole abnormality. We have observed this case among 202 de novo and untreated AML examined cytogenetically in our laboratory during the last 10 years. The patient was an adult man diagnosed with AML-M2. An interesting morphologic finding was the presence in light microscopy and ultrastructural studies of prominent giant “Chediak-Higashi-like” granules in some of the leukemic cells. Cell marker studies showed positivity for CD7 and CD33, as seen in the six previously reported cases. The prognosis has been moderate-good, with a survival of 33 months. Trisomy 10 in AML appears to be a rare recurring numeric chromosomal abnormality and probably linked to a myeloblast subset with a CD33+ and CD7+ phenotype.

Abstract 4408 Chronic transfusion dependence increases the risk of developing iron overload which potentially could have a negative impact on the patient. It has not yet been studied in depth the profile of chronic transfusion-dependent patients, and their therapeutic management. Our objective was to describe the clinical characteristics of chronic transfusion-dependent patients in Spain. An epidemiologic, cross-sectional and multicenter study was performed in 41 Haematology Services according to clinical practice. Patients ≥18 years old, who started to be chronically transfused after January 2007 and who had received at least 10 red blood cell (RBC) units at the time of inclusion were enrolled in the study. A total of 631 patients were analyzed, 56.2% were men with mean age of 65.0 years (deviation standard=17.0). The principal cause of transfusion dependence was of haematological nature (92.9%), being myelodysplasic syndromes (35.8%) the most frequent cause, followed by acute myeloid leukaemia (28.8%), medullary aplasia (6.3%) and myeloproliferative syndromes (6.0%). 15.5% of patients with non-haematological causes of transfusion dependence was observed, being neoplasia the most frequent cause (6.7%). A median of 22 RBC units were transfused in total to the population in study and a median of 14 RBC units were transfused in the last year. 59.3% of patients received ≥20 RBC units. Regarding iron overload, median serum ferritin (SF) level was 1,173.5 ng/ml and 48.7% of patients had SF ≥1000 ng/ml. SF level was not available in 16.3% of patients. Moreover, 18.7% of patients had their last SF measurement done before the study initiation while 64.8% of the SF measurements were performed during the study. The concomitant diseases reported were mainly cardiovascular (24.4%), urogenital (11.7%) and endocrine (10.1%). A higher number of comorbidities was observed in the group of patients with SF ≥1000ng/ml, specially cardiovascular, hepatic and endocrine disease. Of all patients with chronic transfusion dependence, 14.1% received chelation therapy, being deferasirox the most commonly used drug (89.0%). The reason for not receiving chelation treatment was unknown in 28.2% of patients. 13.2% of patients with iron overload did not receive chelation therapy due to present concomitant diseases: neoplasias (6.7%) and renal and urinary disorders (3.0%). A good correlation between transfused RBC units and SF levels was observed in the study (59.3% received ≥20 RBC units, and 48.7% had SF levels ≥1000ng/ml). It was noted that monitoring of iron overload by SF levels is not followed properly in patients with chronic transfusion dependence. 16.3% of patients did not have any SF measurement and in 18.7% of patients the last SF determination was prior to the study. These data may be related to the fact that 28.2% of patients did not receive chelation therapy due to unknown causes. Disclosures: No relevant conflicts of interest to declare.