ALBERT

Description: INTRODUCTION Anemia is the most frequent cytopenia in lower-risk MDS. Erythropoietic-stimulating agents (ESAs) are commonly used in these patients. The use of ÒclassicalÓ parameters (EPO and ferritin levels) and the revised IPSS (IPSS-R) has been proposed1 (SantiniÕs score) to predict response to ESAs and overall survival (OS) among patients with lower risk MDS by IPSS and a favorable Nordic group score2. OBJECTIVES The main objective of the study was to evaluate overall response rate (ORR) to ESAs and OS according to the proposed SantiniÕs score in an independent and large cohort of anemic lower risk MDS patients receiving treatment with ESAs. METHODS Data from 530 anemic patients with low/int1 risk IPSS de novo MDS (according to FAB and WHO criteria) and sufficient follow-up data available were recorded in Spresas3 (SPanish Registry of Erythropoietic Stimulating Agents Study from GESMD). Two hundred and twenty six patients (42.6% of the patients) were selected according to specific criteria regarding the published SantiniÕs score1: Hb level 350 ng/mL(=1) and IPSS-R very low=0, low=1, intermediate=2 and high=3) yielded a score ranging from 0 to 5. ESAs response rate and overall survival were analysed according to these score. Response to treatment was evaluated according to IWG 2006 response criteria and a multivariate logistic regression analysis was used to identify independent predictors of erythroid response (ER). OS were defined as the time between diagnosis and the corresponding event or last follow up (Feb 2015) and were analyzed using univariable and multivariable Cox proportional hazards regression methods. RESULTS Median age was 77 years (interquartile range [IQR] 25%-75%: 71-83 y), median Hb level at start of treatment was 10 g/dL (IQR25-75: 9-10), median EPO level was 90 (IQR25-75: 27,25-108) and median ferritin level was 338,5 (IQR25-75: 146,5-568,75). Among 139 patients with this data available, 85 patients (61,1%) were RBC transfusion dependent before ESAs treatment. Median time from diagnosis to ESAs treatment was 82 (IQR25-75: 27-353) days. According to the IPSS, 68.6% (N=155) and 31.4% (N=71) were in low and Int-1 risk groups, respectively. Regarding IPSS-R, 23% (N=52), 66.8% (N=151), 9.7% (N=22) and 0.4% (N=1) were in very low, low, intermediate and high risk, respectively. ORR to ESA treatment was 71.2% (N=161), with a median duration of response of 2.06 years. Prognosis factors of ER showed a trend toward to a higher ER among patients in the lower IPSS-R (P〉0.05), low IPSS (p=0.039) and lower EPO levels (p

Description: Introduction: Micro-RNAs (miRNAs) are 19-24 nucleotide non-coding RNAs that regulate gene expression through the inactivation of their messenger RNA. Previous studies have demonstrated the important role of some miRNAs in the development of cancer. Specifically, in diffuse large B cell lymphoma (DLBCL), miRNAs involved in lymphomagenesis were identified but understanding their biological function continues to be a challenge. Nevertheless, the pathogenesis effects of some miRNAs such as miR-125a, miR-17-92 cluster or mi-R-155 are well characterized. Some studies suggest that miRNAs also possess a prognostic potential role in DLBCL. For this reason, our objective was to analyze the different miRNAs involved in the chemo-sensitivity or resistance to the first line treatment, their correlation with standard prognostic factors at diagnosis and the role of these miRNAs in survival in patients with DLBCL. Material and methods: Patients homogeneously treated with R-CHOP from 1999-2013 were reviewed from 3 Spanish centers. They were retrospectively obtained from Pathology Department registry to avoid selection bias. We included those patients with valid genomic material in formalin-fixed-paraffin-embedded tissue and with available clinical data. Samples were processed using the miRNA 4 Affymetrix microarrays kit in a discovery group that included 2 cohorts (patients with durable complete remission (CR) versus refractory or early relapsing patients). Those miRNAs with differential expression were validated in the whole series with quantitative RT-PCR. We also analyzed the role of these miRNAs as predictors of event-free survival (EFS) and overall survival (OS) and their relationship with standard prognostic factors in DLBCL. Results: We identified 156 patients homogeneously treated with R-CHOP. Finally, 96 samples were obtained with valid material for RNA extraction. To identify those miRNAs with prognostic implication, a discovery cohort of 12 patients was used in which all the cases had poor prognosis with high tumor load and advance disease (III-IV stage and unfavorable R-IPI). On this basis of poor prognosis, 2 groups were defined totally opposed from the point of view of the treatment response and evolution: chemo-resistance group (n=6) including refractory or relapsed (RR) patients (first 12 months) and chemo-sensitive group (n=6) including patients with at least 3 years of CR. A hierarchical clustering was performed in which 26 miRNAs differentially expressed were identified. A screening of miRNAs was carried out based on the fold-change and pathways involved and finally we obtained 10 miRNAs differentially expressed in RR group. The validation of these miRNAs was performed with quantitative RT-PCR in the whole series which finally included 68 samples with valid material. A univariate survival analysis including clinical prognostic factors and the selected 10 miRNAs was performed. We confirmed that 7 of them (miR-20b-5p, miR-1244, miR-6840-3p, miR-1231, miR-193b-5p, miR-6860-5p y miR-199a-5p) significantly influenced EFS and 6 of them (miR-1244, miR-1231, miR-193b-5p, miR-885-3p, miR-182-5p y miR-199a-5p) on OS. From these 10 miRNAs, only 3 had a significant prognosis role not only for EFS but also for OS and progression-free survival (PFS): miR-1244, miR-193b-5p and miR-1231. The overexpression of miR-1244 and miR-193-5p were associated with advance stage and worse clinical prognosis factors (p15% were independently associated with worse SG and EFS (Figure 1). In previously reported studies, these 3 miRNAs have been related with proliferative events such as the overexpression of myc or anti-apoptosis. Also, the miR-1231 may be related with new lymphomagenesis pathways associated to viral infections. Conclusions: Through a discovery group focused on progression/refractoriness, a group of new miRNAs differentially expressed on chemo-resistant patients with DLBCL was identified. The overexpression of miR-1244 and miR-193-5p was associated with more extensive disease and worse clinical prognostic factors. The high R-IPI, reduction of 〉15% RDI and the overexpression of miR-1231 were independently associated with worse EFS and OS. Disclosures Sánchez-González: Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Salar:Roche: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy.

Description: Abstract 1886 Poster Board I-909 Background: Approximately 30% of patients with multiple myeloma (MM) present with baseline renal impairement, with 1% to 13% having renal failure requiring dialysis support. The severity of renal impairment significantly affects the prognosis of patients with MM and has been associated with shorter survival or early death. Lenalidomide is an immunomodulating agent indicated for the treatment of MM patients after one prior therapy. Lenalidomide is primarily excreted unchanged by the kidney, adjustements to the starting dose are recommended in patients with moderate or severe renal impairement and in patients on dialysis. For patients with end stage renal disease (CLCr 〈 30 mL/min) requiring dialysis, the recommended starting dose is 5 mg/day. However, experience in patients with MM and dialysis support is limited. To further examine the safety and activity of lenalidomide-based therapy in these patients, we underwent a retrospective analysis in patients with MM who required dialysis at the time of lenalidomide administration. Methods: Fifteen patients (10 M/5 F; median age, 70 years, range 55–77) with relapsed MM from 10 Spanish hospitals received lenalidomide-based therapy between 2007 and 2009. All patients were on dialysis at the time of lenalidomide administration. Median (range) number of therapies previously administered was 2 (1–4) and median time between diagnosis and lenalidomide treatment was 14 months (range, 5–50). Eighty-seven percent of patients received lenalidomide at a dose of 15 mg/day three times weekly after dialysis given in combination with dexamethasone. Patients were given a median of seven 28-day cycles (range, 1–22 cycles) of lenalidomide treatment. Antithrombotic prophylaxis was administrated in fourteen patientes and consisted of low molecular weight heparin (five cases, 36%), oral anticoagulation (four cases, 29%), antiplatelet therapy (three cases, 21%), and combination of the above agents (two cases, 14%). Results: Overall, 13 (87%) patients experienced adverse events, with grade 3 neutropenia as the most common (8 patients). Seven patients (47%) developed grade 3–4 infectious complications (3 bacteremias, 1 infection of arterio-venous fistula, 1 septic arthritis, 1 central venous line infection, and two pneumonias in the remaining patient). No patient developed thromboembolic complications. Fourteen patients were evaluable for response: 4 had complete response (29%), 1 a very good partial response (7%), and 3 partial response (21%). In addition, 4 patients had stable disease (29%) and 2 (14%) did not respond. One patient became independent of dialysis following lenalidomide-based treatment. As of July 2009, seven (47%) patients have died, four due to infectious complications and three as a result of progressive disease. Eight patients are still alive, six of them continue on lenalidomide treatment and two discontinued therapy due to liver toxicity (1 case) and progressive disease (1 case). Conclusion〉: These results suggest that lenalidomide-based regimens can be used in MM patients requiring dialysis, with a good response rate. The high incidence of neutropenia and infectious complications highlights the need of a close monitoring of these patients. Currently ongoing studies will more formally evaluate the impact of lenalidomide-based regimens in this patient population. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4845 Hodgkin lymphoma (HL) represents 10–15% of all types of lymphoma. At present, more than 70% of patients can be cured with current strategies based on chemotherapy with or without radiotherapy. However, one third of the cases finally relapses and needs salvage regimens usually consolidated with high dose chemotherapy and autologous stem cell transplantation. The number of regimens and drugs available are limited and new protocols that increase the efficacy with manageable toxicity are needed. In the present communication we report the results of a retrospective study using the GemOx schema that combines the efficacy of gemcitabine in Hodgkin lymphoma with oxaliplatin, a less toxic and effective platinum-based drug. Patients and methods: Patients were eligible for this retrospective study, according to the following criteria: diagnosis of HL, which relapsed or failed to achieve complete remission after induction treatment. They received GemOx regimen that consisted of gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 on day 1. Treatment was given every 15 days if feasible or every 21 days. To evaluate response and toxicity Cheson criteria and OMS toxicity scale were used respectively. Results: Between 2003 and 2012, 29 patients with Hodgkin lymphoma were retrospectively included in this study. All patients had recurrent (n=17) or refractory (n=12) disease. Median age was 24 (14–76) years and 50% had an International Prognosis Score (IPS) higher than 2. Patients received a mean of 2.79 previous regimens and 79% more than 1 regimen before GemOx with 48% relapsing after a prior autologous stem cell transplant (ASCT). Median follow-up was 41 months. 76% of patients responded (31% complete responses; CR). Responses were better in the relapsed setting or partial response (PR) (85% with a 45% of CR) compared to the truly refractory cases (55% PR) (p=0.037). Main prognostic factors for HL were assessed to view their impact on survival. Factors related with progression- free survival (PFS) and overall survival (OS) were age lower than 45 years, response to GemOx and consolidation with stem cell transplantation (p=0.001). Presence of B-symptoms at diagnosis also influenced OS. Neurologic toxicity was present in 9% of patients, all of them grade I or II. Hematologic toxicity was also common, including grade 3 or 4 neutropenia in 23% of patients, and grade 3 or 4 thrombocytopenia in 33%. Nausea and vomiting occurred in all the patients at grade 2, or lower. At last follow-up, 13 patients (45%) are alive and remain free of progression. However, 16 patients (54%) had died: 12 (41%) due to progression of disease, 3 (10%) due to complications due to a subsequent allogenic transplant (graft versus host disease, thrombotic thrombocytopenic purpura and bleeding) and 1 due to pneumonia. PFS was better in patients consolidated with autologous or allogeneic transplantation (100%) compared with patients not consolidated (14%) (p=0.009). PBSC collection after GemOx and G-CSF was successful for all of candidates. Conclusions: 1) GemOx regimen is effective in relapsed or refractory Hodgkin lymphoma with manageable toxicity; 2) Results are better in relapsed or chemosensitive disease compared to truly refractory cases; 3) No mobilization failures were observed; 4) Consolidation after response is needed. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction The best strategy for the follow-up of patients with Hodgkin Lymphoma (HL) in complete remission (CR) after the first line of treatment is not established. The NCCN guidelines recommend follow-up computed tomography scan (CT) at 6, 12 and 24 months after the end of treatment. Several clinical trials of relevance require the follow-up with quarterly CT during the first year after treatment, and every 6 months thereafter. However, these recommendations are based on expert opinion rather than evidence. The aim of our study is to evaluate the different follow-up strategies after 1st line of treatment in patients with diagnosis of LH who achieved CR, and to identify the best follow-up strategy. Materials and methods This is a multicenter, retrospective study. We analysed 604 patients from 11 GELTAMO group centers, diagnosed with HL between 2007 and 2016 that had positron emission tomography-computed tomography scan (PET-CT) for initial staging, and at the end of induction treatment. Patients were grouped according to the different follow-up strategies in: 1) only clinical (clinical history, blood test (BT) and physical examination), 2) CT 3) PET-CT. The study was approved by the ethics committee of the Gregorio Marañón hospital. Medians, ranges and percentages were used for the descriptive analysis and the X2 test, Fisher's test and the Mann-Whitney U test for the comparison of variables. Results: Patients and disease characteristics and treatment information are included in Table 1. Table 2 shows the number of radiological images performed, the number of visits and the suspicion of relapse according to the used strategy. The median follow-up was 64 months (24-180). Of 90 suspicions, 59 relapses were confirmed. Relapse was identified in 64% of the patients by some clinical data that suggested it, 17% of patients had only symptoms, 25% had only abnormal physical examinations, 2% had only abnormal BT and 20% presented a combination of all the clinical variables. Regarding laboratory assessment at relapse time, 62% of the patients had a normal blood test at the time of relapse, 18% had elevated ESR, 8% elevated LDH and 9% abnormal blood count. Regardless of the strategy, 55% of relapses had at least one accessible lesion on physical examination. Comparing the used strategy, the median time to relapse was 19 months (p25-75 = 8-39) for the clinical follow-up, 18 months (p25-75 = 9-41) with CT follow-up and 13 months (p25-75 = 2-23) with PET-CT, with not statistical significance differences among them (p = 0.57) (Figure 1). Overall survival was not different using any of the strategies (Figure 2). Conclusions: In our study, the use of CT and PET-CT for the follow-up of patients with HL does not significantly reduce the time to identify the relapse and has no impact on survival. In addition, these strategies expose patients to radiation and have a high cost with not clear benefit. Our next step is to confirm this results with a prospective study. Disclosures Vidal Maceñido: GILEAD SCIENCES: Research Funding. Perez De Oteyza:Celgene: Speakers Bureau.

Description: INTRODUCTION: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed or refractory aggressive B-cell lymphoma, and is frequently used as part of first-line therapy in patients with peripheral T-cell lymphoma (PTCL). However, long-term remission rates with this strategy are inferior to 50%, so novel approaches are required. We have designed a prospective multicenter phase II study to evaluate the safety and efficacy of bendamustine as part of conditioning regimen in patients with aggressive lymphomas undergoing ASCT. METHODS: Inclusion criteria were: histologic diagnosis of i) relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or grade 3B follicular lymphoma (FL) in partial response (PR) or complete remission (CR) after salvage therapy, or ii) transformed DLBCL or peripheral T-cell lymphoma (PTCL) in first or subsequent PR or CR. Conditioning regimen consisted of bendamustine (200 mg/m2, days -7 and -6), etoposide (200 mg/m2, days -5 to -2), cytarabine (400 mg/m2, days -5 to -2), and melphalan (140 mg/m2, day -1) (BendaEAM regimen). Primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints were toxicity, response to transplant at 3 months, and overall survival (OS). This trial was registered at EMEA (EUDRACT number 2010-020926-17). RESULTS: Sixty patients (median age 54 years, range 27-70) from 22 Spanish hospitals were included since May 2011 to November 2012. Histologies were: 40 DLBCL, 3 grade 3B FL, 13 transformed DLBCL, and 7 PTCL. 82% of patients have received ³2 lines of treatment prior to ASCT. 37 patients (62%) were in CR at the time of transplant and 23 (38%) in PR. A median number of 4.05 x 106/Kg (range: 1.69-19.80) CD34+ cells were reinfused. All patients (except one who died early) engrafted after a median of 11 (range: 9 to 72) and 14 (range: 4 to 53) days, respectively, to achieve 〉0.5 x109/L neutrophils and 〉20 x109/L platelets. 39 serious adverse events (SAEs) were reported before day +100, including 14 infectious episodes, 2 of them resulting in respiratory failure and death (3.3% of transplant related mortality). Another major SAE was renal toxicity developed by 5 patients (8.3%) after bendamustine administration, reversible in all cases (3 of these patients had developed mild renal failure during previous salvage therapy). Non-relapse mortality after day +100 was 3.3% (1 patient died because of Wernicke's encephalopathy, and 1 patient from infectious complications). Concerning response to transplant, 44 patients (73.3%) achieved CR, 7 (11.7%) PR, and 6 patients (10%) did not respond. Univariate analysis showed that patients who received more than 2 lines of treatment prior to transplant (1 line: 100% of CR post-transplant; 2 lines: 71%; 〉2 lines: 50%; p=0.013), and those who were in PR at transplant (48% vs 89%, p0.1). At the time of analysis, 13 patients (22%) had disease progression and 8 patients (13%) have died (4 from lymphoma, and 4 from other causes). With a median follow-up of 18.9 (9.5 to 32.3) months, the estimated 2-year PFS and OS were 73% and 88%, respectively. CONCLUSIONS: The BendaEAM conditioning regimen is feasible and active in patients with aggressive lymphomas. Toxicity profile is similar to that commonly observed in the ASCT setting, but renal toxicity can occur and should be carefully monitored, especially in patients with prior history of renal failure. Longer follow-up is needed to assess the long-term toxicity and the efficacy of this regimen, although patients who are not in CR before transplant seem to have poorer outcomes. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (CHOP14) or intensity (CHOEP, ACVBP, autologous stem cell transplantation) without obtaining benefit in terms of survival. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients. RDI is an important issue to consider when treating malignancies. Although this a well-known prognostic factor in Hodgkin lymphoma, scarce information has been published in DLBCL. Objective: The purpose of this study is further analyzing the prognostic impact of RDI in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14, to evaluate its differential impact when increasing dose density. Material and methods: All patients diagnosed of DLBCL from January-1999 to June-2013 at University Hospital Son Espases were retrospectively identified from Pathology Department registry to avoid selection bias. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included (N=115). To increase the R-CHOP14 cohort we added also all patients treated with R-CHOP14 in the same time period in two additional hospitals (Hospital Son Llatzer of Palma and Hospital del Mar of Barcelona) identified from their Pharmacy registries to avoid selection bias (N=42). Other regimes, consolidations or maintenance were excluded. Table 1 shows main characteristics of the global series (N=157). RDI represents the ratio of the amount of a drug actually administered to the amount planned for a fixed time period. RDI was calculated as previously described. Briefly, RDI of each drug was obtained followed by an average of RDI in CHOP consisting in the sume of RDI of the 3 drugs divided by 3. Main prognostic factors at diagnosis in DLBCL were obtained, including international prognostic index (IPI) factors. Evaluations were carried out following standard guidelines. Results: Overall response and complete response rates were similar in both groups:86% and 76% for R-CHOP21 and 94% and 74% for R-CHOP14(p=0.17 and p=0.85, respectively). Median follow-up for alive patients was 68 months (4-156). There were no differences between the two cohorts in terms of either OS or PFS (Figure 1). In the R-CHOP21, both a reduction higher than 15% in RDI [RR 7.41 (2.51-21.83); (p 1 17 (23%) 18 (22%) 0.85 Ann Arbor stage III-IV 40 (54%) 48 (58%) 0.75 B-symptoms 25 (34%) 26 (31%) 0.86 Elevated LDH 33 (46%) 40 (49%) 0.75 〉 1 extranodal site 8 (11%) 19 (23%) 0.057 Bulky disease 23 (31%) 34 (41%) 0.24 R-IPI unfavorable 24 (32%) 26 (32%) 1 NCCN-IPI: - Low - Low-intermediate - High-intermediate - High 9 (13%) 27 (39%) 26 (38%) 7 (10%) 17 (21%) 35 (44%) 24 (30%) 4 (5%) 0.31 Elevated Beta-2-microglobulin 32 (49%) 31 (39%) 0.24 Radiotherapy 27 (36%) 27 (32%) 0.62 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Introduction DLBCL is the most common non-Hodgkin lymphoma and a heterogeneous subtype from the biological and clinical point of view. 20-40% of the patients relapse so it is important to identify a high risk population that could benefit from different therapeutic approaches. For this purpose, several scores have been developed. The IPI has been the most widely used but lacks the ability to identify this very high risk population in Rituximab era. Low absolute lymphocyte count and high levels of blood monocytes have shown to be unfavorable risk factors. The red cell distribution width (RDW) has been associated with aging and active inflammatory processes and beta-2-microglobulin (B2M) with tumor load and proliferation as well as comorbidities such as kidney failure. All these variables are easily obtainable at the time of diagnosis. Patients and methods From the national database of GELTAMO-IPI Project, we selected those patients with DLBCL homogeneously treated with R-CHOP ± radiotherapy. The complete blood count (CBC) values were standardized using the normal reference values of each centre. The survival analysis was estimated with Kaplan-Meier method. The comparison between variables was performed through Log-Rank test and multivariate analysis with Cox regression. The CBC quantitative variables cut points were calculated through MAXSTAT. A new prognosis score was generated taking into account the results of multivariate analysis for progression free survival (PFS), spliting the sample in two cohorts (discovery and validation). Results Nine hundred and ninety-two patients with DLBCL were retrospectively analyzed with a median follow up of 55 months (12-185). The characteristic of the patients are summarized in table 1. In the multivariate analysis, age, ECOG, stage, bulky mass, B2M, RDW and lymphocytes/monocytes ratio (LMR) were significantly independent variables for PFS. A new prognosis score was generated with these variables including age categorized in 3 groups (18-64, 65-80 y 〉80) with 0, 1 y 2 points, ECOG〉3-4 with 2 points, stage III-IV, bulky mass, high B2M, LMR0.96 with 1 point each for a maximum of 9. This score could improve the discrimination of a very high risk subgroup with a 5-year PFS of 17% (Figure 1) versus 45%, 52%, 32% or 29% of R-IPI, NCCN-IPI, R-TS and GELTAMO-IPI, respectively and 5-year overall survival (OS) of 20% (Figure 2) versus 59%, 46%, 45% and 40% for R-IPI, NCCN-IPI, R-TS and GELTAMO-IPI. Conclusion A new prognosis score including easily obtainable CBC variables (LMR and RDW) and B2M is presented. This score identifies a high risk population both for PFS and OS in comparison with other scores for DLBCL. The addition of other biological or image markers could improve these results. Disclosures Martín: Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Sancho:SERVIER: Honoraria; JANSSEN: Honoraria, Speakers Bureau; MUNDIPHARMA: Honoraria; SANOFI: Honoraria; GILEAD: Honoraria, Research Funding; KERN FHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria; ROCHE: Honoraria, Speakers Bureau.