ALBERT

Description: The development of the NCCN International Prognostic Index (NCCN-IPI) for patients with DLBCL treated in the rituximab era improves discrimination when compared to the original IPI model. The aim of the present study is to validate the results of the NCCN-IPI in a large independent series of patients in a different geographical area. Materials & Methods. This nation-wide retrospective study includes 2156 patients with de novo DLBCL diagnosed in 20 (mostly) large academic Spanish centers within the Grupo Español de Linfomas y Transplante de Médula Osea (GELTAMO) network between 1998 to July 2014. Patients had to be ≥ 18 years-old, treated with rituximab plus chemotherapy (R-CHOP or variants and also more intense treatments) and a minimum of 1 year of follow-up; all histological subtypes of DLBCL and primary extranodal cases were acceptable, with the only exclusion of primary testicular or CNS sites. In the whole series the scoring of the IPI and NCCN-IPI indexes were used and 5-year Overall Survival (5y-OS) estimated with the Kaplan-Meier method and compared with the log-rank test. Results. Debugging the database resulted in a final working series that included 1885 patients. The demographics of the series were comparable to the NCCN series: NCCN/GELTAMO male gender(%) 54 vs 50.4, Age(y) 57 vs 60, LDH〉1(%) 50 vs 54.7, Ann Arbor stage III-IV (%) 59 vs 62.5, ECOG PS≥2(%) 11 vs 30, extranodal disease(%) 36 vs 40.7. The IPI scoring (1760 patients) significantly separated the four risk groups, low (LR, 33.6% of the patients), low/intermediate (LI, 22.7%), intermediate/high (HI, 25.1%) and high (HR, 18.6%) with significantly different (p

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most common malignant neoplasms in elderly patients, potentially curable when optimum treatment is administered. The combination of rituximab with CHOP chemotherapy (R-CHOP) is considered standard for these patients, but randomized studies published to date are limited to the range of age from 60 to 80 years, so that in patients over this age treatment election is not so clear, usually opting for palliative treatment or a "full" treatment at a reduced dose. This retrospective study is primarily aimed to analyze the influence of the type of treatment and comorbidity scales in overall survival (OS) of a large series of patients 〉80 years with aggressive B-cell lymphoma. Methods: Eligible patients were aged ≥ 80 years, diagnosed of DLBCL, follicular lymphoma grade 3B or transformed lymphoma. The main patient characteristics were obtained retrospectively from the medical records, including a complete geriatric assessment (CGA, "comprehensive geriatric assessment") and the Charlson comorbidity index. The Ethics Committee of the University Hospital of Salamanca approved the study. Results: 288 patients from 19 GELTAMO hospitals were registered in the study, of which 234 (60% women) were evaluable and have been included in this preliminary analysis. The median age was 84 years (80-94) and the vast majority (94%) were DLBCL. According to the Charlson index, 65% of patients were low-intermediate risk, and according to CGA, 63% of patients were considered "fit". A higher proportion (60% v 44%, p = 0.03) of patients with low or intermediate comorbidity index were treated with a curative intent (CHOP +/- rituximab), as compared with patients with high or very high index. With a median follow up of 41 (range 9-142) months, the median OS was 11.5 months (33% estimated at 3 years). The median OS for patients treated with R-CHOP-like (N=96) was 35.3 months, significantly better (p

Description: Background: Survival of DLBCL patients with high IPI treated with RCHOP immunochemotherapy is poor. In this population, the combination of RCHOP with new drugs is an attractive approach, along with performing an evaluation with PET/CT after 2 to 4 cycles to change the therapy if an early complete response is not achieved. Methods : We performed a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib 1.3 mg/m2 sc days 1, 8, and 15 of a 21-day cycle. Pre-phase therapy was permitted for patients who could not wait the results of the screening procedures to start therapy due to the aggressiveness of the disease. (ClinicalTrials.gov Identifier: NCT01848132). Patients younger than 71 yrs diagnosed with DLBCL and an age-adjusted IPI (aaIPI) 2-3 or aaIPI 1 with increased beta2microglobulin were eligible. The primary endpoint was the proportion of patients who survives free of event at 2 years. Centralized anatomopathology review was performed in all cases; samples were classified as germinal center B-cell-like (GCB) vs non-GCB subtypes by immunohistochemistry according to the Hans algorithm. PET/CTs were performed baseline, after 2, 4 and 6 cycles (PET2, PET4, and PET6), and were reviewed at real time by at least 3 experts of a central panel. Response at the end of therapy was analyzed following the visual method with the Deauville scale, and response after PET2 and PET4 was evaluated using the semiquantitative method. Persistent disease at PET4 was considered as failure of therapy and these patients were removed from trial treatment. EFS was calculated from diagnosis until event defined as death from any cause, relapse, progression or need of salvage therapy (defined as PET4 or PET6 positive). Overall survival (OS) was calculated from diagnosis until death for any cause. We present here a preliminary analysis of results. Results: One hundred and twenty-one patients were included; data on 113 are presented (diagnosis not confirmed in 6, data missing in 2). Median age was 57.1 yrs (range 23-70), 57 (50.4%) were males. Characteristics at diagnosis were: non-GCB subtype 32/87 (36.8%), immunohistochemical co-expression of myc/bcl2 56/82 (77.8%), stage III-IV 107 (94.7%), ≥2 extranodal locations 55/76 (72.5%), ECOG 2-3 36 (32.1%), increased LDH 88 (77.9%), increased beta 2 microglobulin 73 (64.6%), aaIPI 3: 32 (28.3%). No differences were found between treatment arms. Fifty-five patients were treated in the experimental arm (EA) and 58 in the control arm (CA). Twenty-eight (28.3%) out of 99 patients required of pre-phase treatment. The mean relative dose intensity for bortezomib was 88.3%. Data about the most frequent toxicity are shown in table 1. Twenty-nine (30.2%) out of 96 patients who have finished 4 cycles had a positive PET4 according to central review and were withdrawn to receive salvage therapy. Complete remission (CR) at the end of therapy (PET4-/PET6-) was observed in 44 (45.8%) patients. After a median follow-up of 9 months, estimated 12-mo EFS was 36.6%, and 12-mo OS was 82.9% in the whole series. Data of the subgroup analysis according the immunohistochemistry subtypes by Hans algorithm are show in table 2. Conclusions: In the present preliminary analysis, no significant differences were found between RCHOP and BRCAP in terms of CR and EFS in this very high-risk population of young DLBCL patients. However, in the subgroup analysis of patients with non-GCB disease, we found a significantly better CR rate in patients treated with BRCAP. A longer follow-up is needed to evaluate the real impact of this therapy on survival. Disclosures González-Barca: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Martín:Sevier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. López-Jiménez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Velgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: 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; MundiPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. López-Guillermo:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MundiPharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramírez:Bristol-Myers-Squibb: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Conde:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees.

Description: INTRODUCTION Cell free tumor DNA (cftDNA) based targeted next generation sequencing (NGS) is a novel tool that enables accurate and minimally invasive tumor genotyping. MATERIAL AND METHODS Here we have performed cftDNA targeted NGS for the molecular diagnosis of a series of 92 peripheral blood samples obtained at diagnosis in patients included in a phase II randomized clinical trial comparing standard RCHOP versus BRCAP as first line treatment in patients with poor IPI (aaIPI2-3 or aaIPI1 with high b2m, age 18-71, NCT01848132). Centralized histopathological review of diagnostic tissue samples confirmed the diagnosis: 83 DLBCL (68%, 55/81 GCB, 32%, 26/81 non-GCB, according to Hans immunohistochemical algorithm), 4 TCHRBCL, 3 PMBCL, 1 concurrent DLBCL and FL3A, 1 FL 3B. 7 out of 83 cases had DLBCL morphology and DH by FISH (6 MYC/BCL2 and 1 MYC/BCL6, all GCB-type by IHC). A targeted NGS approach using amplicon-based chemistry (Truseq, Illumina) that interrogates exonic regions of 35 relevant genes in DLBCL (1458 amplicons analyzed) was used for library generation from plasma derived DNA. Germline DNA from peripheral blood granulocytes from 89 out of 92 patients was sequenced in parallel and used as control DNA for variant calling. Only somatic variants with a read depth above 100 and Variant Allele Frequency 〉 5% were considered. RESULTS cftDNA concentration (hGE/mL) was associated with LDH levels (U/mL) at diagnosis. Mean cftDNA concentration was lower in patients with low LDH (U Mann whitney p= 0.005). Somatic mutations were identified in 74% (68 out of 92) patient plasma samples. 242 somatic mutations were considered after filtering. Mean of 3.6 mutations per patient. 10 genes were mutated in 〉10% of the patients, including: FAT2 (19.6%), ARID1A (18%), NOTCH1 (17.4%), NOTCH2 (15.2%), KMT2D (14.13%), SMARCA4 (14%), ATM (13%), EP300 (13%), EZH2 (13%), PLCG2 (13%). Recurrent mutations were found in EZH2 (2 patients). Mutations in BCR/TLR pathway genes were found in less than 10% of the cases (CARD11, 7.6%; MYD88, 4.4%; CD79A, 5.4%; CD79B, 1%; BTK, 4.4%). NOTCH1 mutations were found preferentially in GCB type DLBCL (12/55 GCB vs 1/26 nonGCB, Chi square p value

Description: Background and objective. Idelalisib is an oral inhibitor of the p110δ isoform of PI3K (phosphoinositide 3-kinase) approved in Europe and USA as monotherapy in relapsed/refractory follicular lymphoma (FL) after 2 previous lines of therapy based on a phase 2 study (Gopal et al, N Eng J Med 2014). However, there are scarce data on the use of idelalisib in clinical practice (Eyre et al, Br J Haematol 2017). The objective of this study was to analyze the efficacy and toxicity of idelalisib in relapsed/refractory FL patients in clinical practice in Spanish hospitals of GELTAMO group (GELT-IDE-2018-02 Study). Patients and Methods. Retrospective study of relapsed/refractory FL patients treated with idelalisib as salvage therapy in clinical practice. Demographic and clinical and biological variables were analyzed at FL diagnosis and at the time of idelalisib therapy, as well as its efficacy and toxicity. Results. A total of 43 patients from 20 hospitals were included. At time of idelalisib therapy, median age was 63 years (range 44-83), number of previous lines of therapy was 3 (2-7), 42% (n=18) were refractory to last previous treatment and 42% (n=18) had received an autologous stem cell transplantation (SCT); 56% (n=24) had progressed in the first 24 months after FL diagnosis (POD24). Median duration of treatment with idelalisib at time of analysis was 8.1 months (1.1-37.4) and 28/43 patients (65%) discontinued therapy, 13 due to progression, 12 due to adverse events (AE) and 3 due to physician's decision. Overall response rate (ORR) was 73% (32% CR) and median PFS 14.6 months (95% CI 0-32.2), with a trend to be higher in non-POD24 group (median PFS of 9.4 months [95% CI 1.7-16.9] in POD24 vs. 27 months [95% CI NA] in non-PO24 patients, p=0.082); median duration of response to idelalisib was 25.1 months (95% CI 13.1-37.6). Median overall survival (OS) was not reached at the time of analysis, with a 2-year OS of 74% (95% CI 58%-90%) (Figure). In 4 patients, an allogeneic SCT was performed after idelalisib. A total of 86% (n=37) of patients showed any AE, being in 56% (n=24) of grade ≥3 AE. Toxicities of grade ≥3 more frequent were: neutropenia (23% of patients), diarrhea (23%), infections (23%: pneumonia in 4 patients, CMV infection in 2, febrile neutropenia in 1 and other infections in 3 [1 of them died due to Aspergillus infection]), and increased transaminases (9%). Conclusions. In this series of patients with relapsed/refractory FL, several previous lines of therapies and factors associated with poor prognosis, the treatment with idelalisib was associated with efficacy and toxicity similar to published studies. These results support the use of idelalisib as an option for FL patients with multiple or poor risk relapses. Financial support: Gilead Figure. Progression-free survival (PFS) and overall survival (OS) for patients with follicular lymphoma treated with idelalisib. Figure Disclosures Sancho: SERVIER: Honoraria; SANOFI: Honoraria; Novartis: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Martín:Kiowa Kirin: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; iQone: Consultancy; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses. Armando:Roche: Consultancy, Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Description: Abstract 4478 Background: The optimal therapy after transformation of follicular lymphoma into diffuse large B-cell lymphoma (DLBCL) is unknown. Most of retrospective registry data and phase II studies suggest a potential benefit of high-dose therapy and autologous transplantation (HDT-ASCT) for patients with transformed lymphoma (TL). Addition of rituximab to CHOP chemotherapy could improve survival in TL. However, the effect of prior rituximab-based therapy upon the efficacy of subsequent autologous stell cell transplantation (ASCT) in TL is still unknown. Patients and methods: We have identified the patients with follicular lymphoma who developed confirmed histological transformation to DLBCL treated with HDT-ASCT included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry between October 1994 and March 2011. Patients were divided into two groups, according to whether rituximab-based regimens were given (n = 28, ‘R+’ group) or not (n = 22, ‘R-’ group) at the time of transformation. Kaplan-Meier survival curves were estimated, and differences in survival curves between groups were assessed using the log-rank test. Results: Fifty patients (23 women) with a histological diagnosis of TL who underwent HDT-ASCT were included. Median age at transplantation was 55 years (range 32–70). Patients had received a median of 2 (range 1–5) chemotherapy regimens prior to ASCT. Median time from diagnosis of follicular lymphoma to transformation was 49 months (range 8–135). Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 11 patients (22%). Disease status prior to ASCT was first complete remission in 4 patients (8%), second CR in 56% and active diseasein 14%: sensitive disease in 11 (22%) and refractory disease in 3 (6%) patients. Conditioning regimen consisted of BEAM in 92% of patients, BEAC in 4%, and cyclophosphamide /TBI in 4%. With a median follow-up of 61 months, estimated overall survival (OS) and progression-free survival (PFS) at 5 years after ASCT were 56.5% and 51.3%, respectively. No patients died of transplant-related mortality. Thirteen patients experienced relapse or progression after HD-ASCT; nine of these patients have died because of disease progression. By multivariate analysis three variables significantly influenced both OS and PFS: number of regimens prior to ASCT, disease status at transplant and achievement of response after HD-ASCT. Age-adjusted IPI at transformation had significant influence only on OS. Patients who did not receive rituximab-based regimens had similar characteristics to patients who received rituximab at transformation. Patients in the R+ group had similar 5-year PFS (48.2% vs 48.4%, P = 0.359) and 5-year overall survival (OS) (66.4% vs 67.2%, P = 0.607) compared to patients in the R- group (Figures 1 and 2). Eight out of 28 “R+” patients had not received rituximab prior to transformation; these patients had better PFS (69% vs 38%, p = 0.912) and OS at 5 years (74.1% vs 54.5%) compared to the 20 patients who were treated with rituximab prior to transformation, but the difference did not reach statistical significance (p 〉0.1). Patients treated with rituximab-based regimens at any time prior HDT-ASCT had similar OS (70% versus 63.8% at 5 years, P = 0.697) and PFS (50% versus 44% at 5 years, P = 0.445) than patients who received chemotherapy alone before ASCT. Conclusion: Our results show that HDT-ASCT remains a valuable therapeutic choice for patients with histological confirmed TL since it allows a long-term disease control in a significant proportion of patients. The addition of rituximab to conventional chemotherapy after transformation does not appear to improve the outcomes of subsequent ASCT, although larger prospective studies are required. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: We have evaluated the clinical outcome and the prognostic variables in patients with large B-cell non-Hodgkin’s lymphoma (DLBCL) who relapse after autologous stem cell transplantation (ASCT). Methods. One hundred and two patients autografted for DLBCL [58 males (60%) and 44 (40%) females, median age of 49 (18–70) years] reported to the GEL/TAMO Cooperative Group between July 1993 and July 2007 who relapsed at a median time of 9 (range, 2–90) months after ASCT were included in this retrospective multicenter study. Inclusion criteria were to achieve at least a partial response (PR) after transplant and to receive treatment after relapse. After transplant 81 patients (79.4%) had achieved complete remission (CR), 11 (10.8%) uncertain CR, and 10 (9.8%) were partial responders. At relapse or progression, 65 patients (67%) had advanced clinical stage, 28.4% presented with B symptoms, 20 patients (15%) had age older than 60 and 13.8% with a bulky disease. Forty-seven percent of the patients had an age-adjusted IPI 2 or 3 and 52 (53.6%) and 25 (41%) had an elevated LDH or a high beta 2 microglobulin respectively. Regarding treatment at relapse or progression, forty-seven patients (46%) received rituximab, either alone (n=7) or in combination with chemotherapy (n=40), 44 received chemotherapy, 6 involved-field radiotherapy and the remaining 5 patients received a palliative treatment. Finally, 20 patients received a consolidation therapy with a second stem cell transplantation, (9 a second ASCT, and 11 an allogeneic transplant). Results. Overall response (OR) rate was 54% (38.2% CR). Among the 47 patients who received rituximab-based protocols, the OR rate was 70.2% (48.9% CR). With a median follow-up after relapse/progression of 39.3 months (2.6 to 121.8) for surviving patients, the median overall survival (OS) from ASCT failure was 288 days with a median time to progression of 120 days. The actuarial 5-year OS and event-free survival (EFS) for the entire population of relapsed patients were 30.7% and 0%, respectively. Adverse prognostic factors significantly influencing OS and EFS in multivariate analyses were: haemoglobin level

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.