ALBERT

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: Introduction : Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that represents 15-30% of all newly diagnosed lymphomas. It is characterized by a high rate of response followed by continuous relapses being considered incurable with standard immunochemotherapy regimens (Ardeshna et al. Lancet. 2003). The combination of immunochemotherapy and rituximab maintenance (Rm) improves progression free survival (PFS) when compared with a cohort without Rm (51% vs 35%) (Salles G. et al. ASH, 2017), being the standard for many centers. This improvement may have changed the risk assessment in FL. However, there is a need for identifying those patients with a poor prognosis with standard Rm-based therapy and candidates to receive alternative approaches using new drugs such as obinutuzumab with better reported results in this frontline setting (Gallium trial) (Marcus et al., 2017). Methods : From February-2002 to October-2016, all newly diagnosed FL patients with the intention to treat with immunochemotherapy and Rm where included. The participant centers were Son Espases University Hospital and Hospital del Mar of Barcelona. Clinical data were retrospectively collected from clinical histories and standard prognostic variables were evaluated at diagnosis including FLIPI and FLIPI-2. Another prognostic markers were defined: POD12 (progression of disease at 12 months), POD24 (progression of disease at 24 months) and POD30 (progression of disease at 30 months). The regimen effectiveness was evaluated based on the CT or PET/CT findings. Overall survival (OS) and PFS were determined from the date of the first cycle and they were estimated through Kaplan-Meier. Results: A total of 96 patients were included in the study with a median follow-up of 68 months. Main characteristics of the sample are shown in Tables 1. Briefly, median age was 61 years old, 88% where diagnosed in an advanced stage (III-IV), 36% and 38% presented with high risk (3-5) FLIPI and FLIPI2. Five-year OS and PFS was of 94% and 78% respectively. Univariate survival analysis proved that ECOG and response rate affected PFS and that stage and response influenced OS. In this analysis, no significant relation was found between the studied variables and POD12, POD24 or POD30 except beta2-microglobuline in POD30. Conclusions: Frontline Rm significantly improves outcomes of FL patients. It seems that it is not possible to predict only with clinical variables which patients are in high risk of failure to a standard approach with immunochemotherapy followed by Rm. Additional prognostic factors such as molecular markers may help to identify these patients at risk of failure at the beginning of a first line of immunochemotherapy followed by Rm, and candidates for alternative approaches. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION The standard first line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) independently of cell origin subtype. Retrospective studies have shown that non-germinal center (NGC) subtype is associated with a worse progression free survival (PFS) and overall survival (OS) compared to germinal center subtype. In phase II studies the combination of lenalidomide (lena) or bortezomib (bor) with R-CHOP in this lymphoma subtype has shown better results in comparison to R-CHOP alone. For this reason, the aim of our study is to analyze the efficacy and toxicity of R-CHOP plus lena/bor in comparison with R-CHOP alone in patients with NGC DLBCL. PATIENTS AND METHODS In order to avoid selection bias, all patients with NGC DLBCL (confirmed by immunohistochemistry with Hans algorithm) who received R-CHOP or R-CHOP-lena/bor (25mg lenalidomide daily from day 1 to 10 / bortezomib 1.3mg/m2 days 1 and 4) were retrospectively selected from the Pharmacy Registry. Patients in our center received R-CHOP from March 2002 to June 2013, R-CHOP-bor from June 2013 to July 2015 and R-CHOP-lena from November 2014 until now. Cheson and Lugano criteria were used to confirm response rates. Toxicity was checked with CTCAE v4-5 criteria. RESULTS Fifty-five patients with NGC DLBCL were identified from 2002 to 2018, 18 of whom were treated with R-CHOP-lena/bor and 33 with R-CHOP. Baseline characteristics are specified in Table 1. Overall response rate was similar in both treatment regimens, 94% versus 87%, respectively. 12.5% progression/stable disease cases were identified with R-CHOP alone compared to 5.3% with R-CHOP-lena/bor. With a median follow-up of 45 months (6-126) for R-CHOP and 22 months (6-59) for R-CHOP-lena/bor, the median PFS was 65 months for R-CHOP and was not reached for R-CHOP-lena/bor. 47% versus 9% of progressions were observed in R-CHOP and R-CHOP-lena/bor, respectively (p=0.006). Regarding OS, the death rate in the R-CHOP group was 45% in comparison with 23% in R-CHOP-lena/bor group (p=0.015). Higher hematological toxicity was observed in the R-CHOP-lena/bor group comparing with R-CHOP: neutropenia (95% versus 68%), grade 3-4 neutropenia (81% versus 37%) and anemia (81% vs 56%) (p

Description: Introduction: Six percent of all non-Hodgkin lymphomas (NHL) cases are mantle cell lymphoma (MCL). MCL has a poor prognosis and is considered incurable with current strategies. Intensive approaches are not applicable to most these patients considering the median age at diagnosis (70 years old). Due to the molecular events that drive MCL to be a lymphoma with an aggressive and indolent behavior as well as a tendency to clonal evolution (dysfunction of cell cycle, response to cellular damage and apoptosis), we present a global therapeutic approach which includes an effective induction with a low toxic profile, as well as consolidation and maintenance with the final aim of increasing and maintaining responses. Methods: From December-2008 to January-2018 all MCL patients treated in first line in our center were included. The therapeutic approach was based on an induction with R-GemOx (rituximab, gemcitabine and oxaliplatin) followed by consolidation with autologous stem cell transplant or ibritumomab tiuxetan followed by rituximab maintenance (Rm) (every 2 months for 2-3 years). Since 2016, all patients with less than complete response after induction/consolidation, received Ibrutinib 560 mg daily added to Rm. Standard prognostic variables were collected at diagnosis including MIPI; the response evaluation and follow-up was made considering Cheson criteria; for toxicity assessment, we used OMS grading scales of toxicity criteria. Overall survival (OS) and progression free survival (PFS) were estimated from the beginning of the treatment with the Kaplan-Meier method. Results: Thirteen treatment-naïve MCL patients were included from December-2008 to January-2018. Main characteristics of patients are shown in Table 1. Briefly, this is an old high risk series with a median age at diagnosis of 71 years old and poor prognosis (31% and 69% belong to intermediate and high risk MIPI groups, respectively). Two cases were refractory to R-GemOx induction (a blastic MCL and another case with high MIPI (7.7)). Four cases relapsed between 30 and 66 months after treatment was started. All cases with CR or PR after induction (n=11; 85%), obtained a CR at the end of the maintenance. One of the refractory cases after a second line followed by rituximab and ibrutinib maintenance also reached CR. Only 2 patients died (15%): one disease progression and another non-related pulmonary thromboembolism. The median follow-up was 51 months. Four-years OS was of 83% with a median PFS of 58 months (Figure 1). R-GemOx toxicity profile was manageable: most of them grade 1-2 neutropenia (43%), vomits (100%), diarrhea (30%) and anemia (30%). Grade 3-4 toxicity was scarce (neutropenia 14% and thrombocytopenia 36%). Conclusions: R-GemOx followed by consolidation and Rm should was an effective approach with manageable toxicity and excellent survival considering the median age and the high MIPI risk of the series. We plan to test this global approach in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.