Background: MDS comprise a group of disorders characterized by bone marrow (BM) failure, cytogenetic and molecular alterations, and progression to acute myeloid leukemia (AML). Most lower-risk MDS patients (pts) eventually need chronic red blood cell (RBC) transfusions because of impaired hematopoiesis, resulting in iron overload (IO) that damages organ function and contributes to shortened survival. Though iron chelation therapy (ICT) has been consistently shown to improve outcomes in lower-risk MDS pts, most studies had limitations (eg retrospective analyses, registry studies, pts not stratified by performance status). As such, a prospective, controlled study of ICT and survival in Low/Intermediate (Int-1)-risk MDS pts was needed. Aims: TELESTO (NCT00940602) was a Phase II randomized, double-blind study that evaluated event-free survival (EFS) and safety of deferasirox (DFX) vs placebo (PBO) in Low/Int-1-risk MDS pts. Methods : Eligible pts were aged ≥18 yrs, had IPSS Low/Int-1-risk MDS (confirmed by BM examination within 6 months of study entry), serum ferritin (SF) >1000 ng/mL, transfusion history of 15-75 pRBC units, without cardiac, liver and renal abnormalities. Pts were randomized 2:1 to DFX (dispersible tablets; 10-40 mg/kg/day based on dosing guidelines) or PBO. Primary objective was to evaluate DFX and PBO for EFS, measured by a composite primary endpoint of time to first non-fatal event (related to cardiac and liver function and transformation to AML) or death, whichever occurred first; events were confirmed by an independent adjudication committee. With a planned sample size of 210 pts, no hypotheses were planned to be tested; statistical tests are exploratory, P values associated with treatment effect are nominal. Results: 225 pts were randomized to DFX (n=149) or PBO (n=76); 72.4% had Int-1 MDS, 60.9% were male, mean age was 61.0 yrs; baseline characteristics were balanced, but more pts in the DFX arm were aged ≥75 yrs (25.5% vs 17.1%). DFX and PBO pts received a mean of 20.28 and 20.27 international units of pRBC transfusions 6 months prior to randomization. Median time on treatment was longer with DFX vs PBO (587.5 vs 370.5 days); 43.9% and 25.0% of DFX and PBO pts received treatment for ≥2 yrs. Median EFS was prolonged by 349 days with DFX (1440 days; 95%CI 1167-1559) vs PBO (1091 days; 95%CI 820-1348): 36.4% risk reduction in EFS with DFX (P=0.015 [Figure 1]). Estimated EFS at 3 yrs was 61.5% (95%CI 52.2-69.6) with DFX and 47.3% (95%CI 31.8-61.3) with PBO. Events that occurred first with DFX (n=62; 41.6%) and PBO (n=37; 48.7%) included: worsening cardiac function (1.3 vs 2.6%); hospitalization for congestive heart failure (0.7 vs 3.9%); liver function impairment (0.7 vs 1.3%); progression to AML (6.7 vs 7.9%); death (32.2 vs 32.9%). Robustness of the positive treatment effect with DFX was confirmed by various sensitivity analyses, including censoring pts with premature treatment discontinuation and subsequent ICT. Median overall survival (OS) was 1907 days (95%CI: 1440-not estimable) with DFX and 1509 days (95%CI 1095-1804) with PBO; HR 0.832 (95%CI 0.54-1.28, P=0.200). ICT after study treatment discontinuation may have diluted any potential OS difference. SF declined over time with DFX and increased in the PBO arm (Figure 2). Most frequently reported AEs (≥20% in either arm) were diarrhea, pyrexia, upper respiratory tract infection, cough and increased blood creatinine. After adjustment for exposure, rates were: diarrhea (24.7 vs 23.9%), pyrexia (21.8 vs 18.7%), upper respiratory tract infection (16.7 vs 22.7%), cough (12.6 vs 11.3%) and increased blood creatinine (15.9 vs 0.9%) in the DFX and PBO arms, respectively. Most frequently reported severe AEs (≥5% in either arm) were anemia, pyrexia, thrombocytopenia and lung infection. When adjusted for the different exposure time, the rate of all severe AEs per 100 pt-yrs was overall comparable. Summary/conclusions: TELESTO is the first prospective, randomized study in Low/Int-1-risk MDS pts with IO to show ICT with DFX provides clinical benefit across multiple tissues, leading to longer EFS (including cardiac and liver events and transformation to AML) vs PBO. The safety profile was as expected, consistent with previous studies of DFX in adult MDS pts with IO. Considering the current treatment landscape, it is unlikely that a similar, randomized trial can be performed. These results support the use of DFX in Low/Int-1-risk MDS pts with IO. Disclosures Angelucci: Celgene: Honoraria, Other: Chair DMC; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Rodriguez:Novartis: Speakers Bureau. Dong:Novartis: Employment. Ghosh:Novartis: Employment. Bornstein:Novartis: Employment.

INTRODUCTION. The over expresión of the multidrug resistance genes (MDR) specifficaly ABCB1 and ABCG2 correlate with a poor prognosis in patients with ALL. Different drugs specially the chomotherapeutic agents are they substrates. This genes encode a family of different membrane transports that Works with energy specifically the ATP. Metformin is a biguanide whose mechanism of action is the activiation of AMPK and depletes the levels of ATP. PRIMARY OBJECTIVE: Evaluate the efficacy of the use of Metformin on the levels of expression of the MDR genes (ABCB1 y ABCG2) by RQ-PCR in ALL cell lines and patients with ALL during a preinduction treatment with prednisone. RESULTS. In vitro study . The ALL cell lines RS4, ReH, MOLT4 and SUB15 were elavluated. After the addition of Metformin (10uM) the expression level of ABCB1, ABCG2 started to decrease after the 24hrs of culture (mean expression level of 0.3823 ABCB1 and 0.4265 of ABCB2) with a máximum effect at 48 hours (0.2415 ABCB1 and 0.3452 ABCB2) The difference of levels were statystically significant (p= 0.0045). In vivo study . About 108 patients were evaluated, 44 (40.7%) in the arm of prednisone and 64 (59.3%) in the arm of prednisone plus metformin. Fort eh subanalysis of the MDR genes by RQ-PCR we select 25 patients (14 in the prednisone arm and 11 in the metformin arm). The mean levels of the genes was 0.1906 for the ABCB1 gene and 0.3371 of the ABDG2. At the moment of diagnosis about 32% were considerer with high level of expression (n=8), 28% (n=7) of low expression and 40% (n=10) do not express any of the both genes. After the treatment with Metformin 4 patients with high expression at diagnosis change the patter for low expression. Although there is no difference in means of the expression of genes in both arms (p = 0.391 , p = 0. 828) in the group of metformin the prognosis in the high expression group was better than in the prednisone arm (p=0.043). Fort he entire cohort the complete remission rate was higher in the Metformin cohort comparing with prednisone (86.4% versus 67.2%) and the refractoriness was higher in the group of prednisone (n=16, 25%) p=0.002. About the relapse, the addition of Metformin reduce the relapse rate ( 6 vs 21 patients, p = 0.027). Conclusion. The addition of metformin in a controlled enviroment reduce the expression of the MDR genes, but in vivo the impact is primarily on the refractory leukemias and the relapse rate Disclosures No relevant conflicts of interest to declare.

Introduction: Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is a newly recognized entity by the World Health Organization. EBV+ DLBCL, NOS is commonly encountered in Latin American countries and carries a dismal prognosis. Current prognostic models such as the Oyama and the International Prognostic Index (IPI) score have limited prognostic value in this patient population. Therefore, we aim to evaluate the ability of these models to risk stratify patients and propose a novel prognostic model in the largest cohort of Latin American patients with EBV+ DLBCL, NOS. Methods: This retrospective cohort study included patients ≥18 years from six Latin American countries diagnosed and treated at tertiary centers from 2010 to 2020. Hematopathologists at each institution reviewed pathological samples to confirm the diagnosis of EBV+ DLBCL, NOS. We collected clinicopathological data by reviewing the medical records of the patients. The primary endpoint was overall survival (OS), defined as the time from the date of diagnosis until death from any cause or last visit. The secondary endpoint, progression-free survival (PFS), was defined as the time from diagnosis until death, progression, or last visit. Our novel model (Grupo de Estudio Latinomericano de Linfoproliferativos [GELL] Score) includes the Eastern Cooperative Oncology Group (ECOG) performance status ≥2, extranodal involvement >1, serum albumin <3.5 g/dL, serum lactate dehydrogenase (LDH) above the upper limit of normal, and platelet-to-lymphocyte ratio >455. We assigned a value of 1 to each of the abovementioned elements in the score and classified the patients as low (0 points), intermediate (1-2 points), and high (3-5) risk. OS and PFS probabilities were computed with the Kaplan-Meier method and compared with the log-rank test. We used Cox regression to evaluate the proportional hazard ratios (HR) of each score for our study outcomes. The C-index was employed to measure discrimination of each model. We used cross-validation to evaluate the model performance. Results: A total of 154 patients with EBV+ DLBCL, NOS were included in this analysis. The median age at diagnosis was 58 years (range 19-86 years) with a slight male predominance (53%). EBER was positive in all cases (range 1-100%). Clinically, 39% presented ECOG ≥2, 57% had B symptoms, 50% had an extranodal disease as a primary tumor, and 71% had Ann Arbor stage III/IV. Fifty-one percent of the patients had an elevated LDH level, and 43% had albumin <3.5 g/dL. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen was administered in 79% of individuals as first-line treatment. The overall response rate was 80% (62% complete response and 18% partial response). With a median follow-up of 61 months, the 5-year OS and PFS rates were 61% and 47%, respectively. The 5-year OS rates of patients with low, intermediate, and high-risk disease according to the GELL score was 90%, 59%, and 33%, respectively (Fig 1A). The 5-year PFS rates were 82%, 39%, and 23%, respectively (Fig 2A). Table 1 shows the Cox regression and the discrimination analysis for each of the scores. The GELL score has the highest discriminatory index for OS and PFS compared to the IPI, Revised-IPI, National Comprehensive Cancer Network-IPI, and the Oyama score (Figure 1 and 2). Conclusions: This study proposes a novel score for risk stratification of patients with EBV+ DLBCL, NOS. The GELL score appears to better discriminate OS and PFS than previous scores. Our results should be validated in an independent prospective cohort. Figure 1 Figure 1. Disclosures Ramirez-Ibarguen: Asofarma: Consultancy; MSD: Consultancy; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Perini: Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau. Oliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees . Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Background: There are well-established prognostic factors for predicting the overall survival (OS) of patients involved by diffuse large B cell lymphoma (DLBCL). These prognostic factors are age, performance status (PS; ECOG score), high serum lactate dehydrogenase level (LDH), advanced disease (Ann Arbor stage: III, IV) and extranodal sites involved (EN). The patients are distributed in different risk groups according to the score obtained and as established by each research group who developed each international index. However, these prognostic indexes do not explore new markers and just readjust the five known variables since 1993 when The International Non-Hodgkin's Lymphoma Prognostic Factors Project was developed. Serum albumin (SA) has been shown to be a prognostic biomarker in DLBCL prior to R-CHOP treatment (Ngo et al. Leuk Lymph 2008). In another study of patients older than 80 years receiving R-miniCHOP treatment, SA ≤3.5 g/dl was the only factor with a significant effect on OS on (Peyrade et al Lancet Oncol 2011). Studies of non-Hodgkin's lymphoma reported that SA <3.0 g/dl was one of the factors predicting early death from aggressive disease treated with ACVBP (Dumontet et al. Br J Haematol 2002). Another study found that SA <3.7 g/dl is an independent prognostic indicator in DLBCL patients treated with R-CHOP (Dalia et al. Ann Hematol 2014). Aims. The present study evaluates the behavior of IPI, RIPI and NCCN-IPI risk groups obtained from a database of 855 patients involved by DLBCL and explores a cut-off for SA and the addition of it as part of those risk groups. Methods. Seven databases were obtained from different public and private institutions in the country with patients diagnosed with DLBCL. Creating a unique database with 855 patients. Only 811 patients had serum albumin levels in their record (94.8%). Statistical methods: First, we decided to obtain the SA cut-off through the Received Operating Curve because any study has evaluated this (including sensibility, specificity, likelihood ratio positive and negative). Thus, we evaluated the influence of SA in OS. For that, OS was assed using Kaplan-Meier method (KM) and compared between obtained groups using log rank-test. Subsequently, we add SA score to the different risk prognostic index groups and were assed using KM again. Hazard ratio was evaluated using cox-regression model (CRM). Outcomes. From 2008 to 2016 were included from seven different databases in one, 855 patients of different institutions (publics, academics and privates) in different States. Demographic characteristics: Female,51.46%; Median age was 63 y/o (range: 18-96), ≥ 60, 54.8%; PS, ECOG ≥2,31.1%; EN ≥ 1, 32%; LDH > normal, 52.74%. Type of regimen: Rituximab + anthracycline-based regimen= 75%, anthracycline-based regimen=10.5%, rituximab + CVP= 7%, Other treatments=4.5%, No treatment= 3%. All of them were included as intent-to-analyses. The classical variables were evaluated using the CRM, for IPI and RIPI; age and LDH were evaluated according to the proposed cut-off or ratio respectively in the original paper for NCCN-IPI, confirming that all were significant as predictor factors (p <0.0001). The Area under the curve for SA in relation to OS was 0.70 (CI95% = 0.67 to 0.73, p <0.0001) and the cut-off point was <3.2g / dL. However, we observed that SA had two cut-off points with different predictive value that perfectly differentiated two groups. These points were for low group: 3.2 g / dL to 2.5 g / dL (PPV=68%, NPV= 68.1%) and for very low group: ≤2.4 g/dL (PPV=80% , NPV=60.5%). Then, we evaluated its influence in OS, normal SA was 64% ±0.02 vs low group 34%±0.03 (HR=2.6, CI95%=2to3.5) vs. Very low group 16%±0.04 (HR=4.5, CI95%=3to7). For the addition of SA to IPI, RIPI and NCCN-IPI, we gave a 1 point to Low and 2 points to very low; Then, these points were added to the risk scores of the different IPI, which increased the final scores or not. In Table 1, the percentages of OS of each risk group can be compared before and after adding the points according to the SA score. Where adding SA significantly improves the distribution of risk groups. See table 1. Conclusion: SA is an important predictive factor of OS in patients involved by DLBCL. Two risk groups can be observed according to the SA level. The addition of SA to the prognostic indexes improves the distribution of patients and the OS percentage at 5 years of follow-up. Figure. Figure. Disclosures Gomez-Almaguer: AbbVie: Consultancy; Novartis: Consultancy.

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