ALBERT

Description: Introduction: The risk of developing a follicular lymphoma (FL) begins to be better understood with the identification in large epidemiological studies of familial predisposition, some occupational exposures and genetic factors. Genome wide-association studies (GWAS) identified constitutional single nucleotide polymorphisms (SNPs) at risk of FL in HLA region (rs12195582), in 11q23.3 (near CXCR5), in 11q24.3 (near ETS1), in 3q28 (near LPP), in 18q21.33 (near BCL2), and 8q24 (near PVT1); three suggestive loci are localized at 17q25.3 (near CYBC1), 3q13.33 (CD86), 18q12.3 (SLC14A2) (Skibola, Am J Hum Genet. 2014). High t(14;18) frequency in blood years before diagnosis from healthy individuals was also defined as a predictive biomarker for FL (Roulland, J Clin Oncol 2014). It is currently unknown whether any relationship exists between inherited genetic variants associated with FL susceptibility and t(14;18) frequency and if the combination of the two biomarkers could be useful for a better stratification of risk of FL development in healthy individuals. Methods: We used quantitative PCR assays to estimate t(14;18) frequency in prediagnostic blood samples from 105 individuals that were obtained on average 6.4 years before FL diagnosis (pre-FL group) together with 236 age and gender-matched individuals (control group) that were issued from the participants in the EPIC cohort ( European Prospective Investigation Into Cancer and Nutrition). Constitutional DNA was analyzed for the genotyping of the nine SNPs associated with FL risk (HLA, rs12195582; CXCR5, rs4938573; ETS1, rs4937362; LPP, rs6444305; BCL2, rs17749561; PVT1, rs13254990; CYBC1, rs3751913; CD86, rs2681416; SLC14A2, rs11082438). Genotyping were performed in duplicate using TaqMan® assays on Fluidigm platform. The nine SNPs were analyzed individually and combined in a polygenic risk score (PRS). PRS is a weighted average of the number of risk alleles with the weights being the log of the odds-ratio (OR) reported in the FL GWAS (Skibola, Am J Hum Genet. 2014). A model for FL risk was developed using multivariable logistic regression. Predictive ability was assessed by area under Receiver Operating Characteristic (ROC) curve, with 10-fold cross-validation. This work is supported by the French NCI (INCA, PRT-K16-167). Results: t(14;18) frequency as a log-transformed continuous variable is predictive of FL risk (OR: 1.50; 95%CI: 1.29-1.78, P

Description: Introduction: Genome wide-association studies (GWAS) identified specific constitutional single nucleotide polymorphisms (SNPs) at risk for follicular lymphoma (FL). Top SNP is localized in HLA region (rs12195582). Five genome wide significant loci have been identified outside of HLA region, including 11q23.3 (near CXCR5), 11q24.3 (near ETS1), 3q28 (near LPP), 18q21.33 (near BCL2), and 8q24 (near PVT1) in addition with three suggestive loci at 17q25.3 (near CYBC1), 3q13.33 (CD86), 18q12.3 (SLC14A2) (Skibola, Am J Hum Genet. 2014). We investigated if these nine known FL loci could affect response to immunochemotherapy, histological transformation and outcome of a subgroup of patients treated uniformly in the prospective PRIMA phase III study. Methods: Among the 1.193 patients included in the PRIMA study, 390 patients had genotyping of the nine SNPs associated with FL risk (HLA, rs12195582; CXCR5, rs4938573; ETS1, rs4937362; LPP, rs6444305; BCL2, rs17749561; PVT1, rs13254990; CYBC1, rs3751913; CD86, rs2681416; SLC14A2, rs11082438). DNA was extracted from peripheral blood mononuclear leukocytes before any treatment. The genotyping was performed using custom TaqMan genotyping assays as part of the FL GWAS (Skibola, Am J Hum Genet. 2014). Correlations between response to induction treatment, biopsy-proven histological transformation (HT) and progression free survival (PFS) were performed for the each nine SNP individually. We also computed a combined polygenic risk score (PRS) and the number of allele at risk (nbRA) using the 9 SNPs for each individual. The PRS is a weighted average of the number of risk alleles with the weights being the log of the odds-ratio (OR) reported in the FL GWAS (Skibola, Am J Hum Genet. 2014). Survival analyses were stratified on FLIPI score and randomized arm (rituximab maintenance or observation). Piecewise cox models with pre-specified cutoffs at 2 years and 5 years were used to study early and late relapses. This work is supported by the French NCI (INCA, PRT-K16-167). Results: Among the 390 patients who received immunochemotherapy in the PRIMA study, 173 were randomized in rituximab maintenance arm, 166 were observed and 51 were not randomized. Complete response (CR) and unconfirmed CR were achieved in 251 patients (68%) at the end of induction phase. HT was documented in 16 patients (18%) among the 91 patients who had a biopsy with histological documentation at relapse. With a median follow-up of 9.8 years, the 5-year PFS since registration date for the whole cohort was 57% (95%CI, 52-62), 71% (95%CI, 64-78) in the rituximab maintenance arm, 47% (95%CI, 40-56) in the observation arm, and 39% (95%CI, 27-56) for the patients not randomized, thereby confirming the results of the PRIMA study. SNP rs17749561 C〉T (CC, n=326; CT+TT, n=61) at 18q21.33 near BCL2 (HRCT/TT: 2.13; 95%CI, 1.20-3.70, P=0.009) and SNP rs3751913 A〉G (AA, n=292; AG+GG, n=90) at 17q25.3 near CYBC1 (HRAG/GG: 1.83; 95%CI, 1.12-2.99, P=0.016) influenced the quality of response after induction therapy (CR/CRu versus partial response, stable and progressive disease) after FLIPI stratification but not PRS and nbRA. HT was not influenced by the allele status of the 9 individual SNPs, nor PRS and nbRA with the limitation of the low numbers of events. rs3751913 A〉G near CYBC1 influenced PFS with 5-year PFS rates of 55%, 63% and 30% for patients with AA (n=293), AG (n=80) and GG (n=10) (P=0.036), respectively, with the limitation of the low number of patients with GG genotype. No association with PFS was observed for the remaining SNPs and when the 9 alleles were combined in a PRS or nbRA analyzed as continuous variables or per quantiles. We then investigated the susceptibility SNPs could influence early or late relapse. Using Piecewise cox models, we globally did not observe any influence on the risk of relapse in the 2 years after registration, between 2 and 5 years and after 5 years of SNPs analyzed individually by PRS or nbRA. Conclusions: Two susceptibility SNPs for FL identify by GWAS near BCL2 and CYBC1 genes influenced the quality of the response after induction therapy by immunochemotherapy. CYBC1 gene codes for cytochrome b-245 chaperone 1, a member of multi-subunit phagocyte NADPH oxidase. These results require replication in an independent cohort. Overall, susceptibility SNPs for FL are not associated with HT and PFS in this cohort of patients. Disclosures Cartron: Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Brice:Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria; BMS: Honoraria. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria.

Description: This study was aimed at analyzing long-term data on survival, relapse, and treatment-related neurotoxicity in all patients with newly diagnosed primary CNS lymphoma (PCNSL) and patients specifically treated with the C5R protocol (Blay et al, Blood86:2922,1995). We also identified prognostic factors of survival in order to propose a predictive model.132 patients with PCNSL seen at Leon Berard cancer centre between 1984 and 2006 were analyzed. Median age was 59 years (range: 26–81); 49% of the patients had a performance status (PS) of 2 to 4; 8% had leptomeningeal and ocular involvement. Initial treatment was chemotherapy and radiotherapy in 122 patients and chemotherapy alone in 10. Fifteen patients did not receive high-dose methotrexate as part of initial chemotherapy. The median overall (OS) and progression-free survival (PFS) for the whole series were 21.6 and 13.3 months for a median follow-up of 84.2 months. Twenty-five (19%) patients experienced toxic death, 24 (18%) progressed during treatment and 39 (30%) relapsed. Neurotoxicity was observed in 16% of the patients. Of the 49 patients receiving the intensive C5R protocol, 6 (12%) experienced toxic death, 3 (6%) progressed during treatment, 17 (35%) relapsed and 14% developed leukoencephalopathy. Median OS and PFS for patients treated with the C5R protocol were 73.8 and 44.4 months, respectively. Univariate analysis of the whole series showed that age over 60 years, elevated serum LDH, PS greater than 1 and the International Extranodal Lymphoma Study Group score were prognostic factors for OS and PFS, but not the presence of deep or multiple lesions or a high CSF protein level. The backward regression model integrating age, serum LDH, number and location of lesions, and CSF protein level showed that age, serum LDH and a tumor location within deep regions were predictive of OS and PFS. Four prognostic groups presenting 0, 1, 2 or 3 factors could be significantly distinguished regarding OS and PFS. Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis 〉 60 and deep lesion Overall Survival probability as a function of the number of risk factors among abnormal LDH, Age at diagnosis 〉 60 and deep lesion This study allowed to identify a new prognostic model using 3 factors. This model has the interest to withdraw the PS which could be a subjective data and CSF protein level for which the accurate cutoff is not well known. This study also showed that, with a long follow-up, patients treated with the C5R protocol have excellent OS and PFS.

Description: Introduction Primary cerebral lymphoma (PCNSL) is an uncommon subtype of diffused large B-cell lymphoma (DLBCL) with a particular poor outcome as compared to systemic DLBCL, especially in elderly. For patients older than 60 years, standard treatment consists of high-dose methotrexate (HD-MTX) chemotherapy without consolidation brain radiotherapy to reduce the risk of leukoencephalopathy. Rituximab in combination with HD-MTX, procarbazine, vincristine followed by HD-cytarabine consolidation is one of standard of treatments for PCNSL patients with a 2-year PFS rate of 47% for patients aged of 60 or older in prospective trial (Morris JCO 2013). Etoposide and Ifosfamide are two drugs that can diffuse across blood-brain barrier and commonly used for relapsed/refractory PCNSL. To improve efficacy of R-MPVA protocol, we developed a new regimen which consisted in adding etoposide and ifosfamide for patients with a newly diagnosed PCNSL aged between 60 and 75 years old. Patients & Methods The protocol consisted of 3 cycles every 28 days of rituximab (375mg/m2, J1 and J15), MTX (3.5 g/m2, J1 and J15), vincristine (1.4 mg/m2, J1 and J15), vepeside (100mg/m2, J2) and procarbazine (100mg/m2, J1-7). Consolidation therapy consisted of 2 cycles every 21 days rituximab (375mg/m2, J1) in combination with cytarabine (3g/m2, J1-2) with ifosfamide (1.5 g/m2, J1-3). Response evaluations were planned after the 3 cycles of induction (R-MPV-VP16) and after consolidation (R-AraC-Ifo). We retrospectively reviewed treatment modalities, toxicities, response and outcome with this protocol and compared results with a matched group of patients with the same range age (60 - 75 years) treated with R-MPVA. Results Between 2013 and 2018, 28 PCNSL patients were treated with this protocol. The median age was 67.5 years old (range, 61-74). Poor performance status (PS 3-4) was presented in 9 patients (32%). As compared to 31 patients treated between 2007 and 2018 with R-MPVA, patients treated with intensive protocol were younger (66 vs. 69 years, P=0.01) and had less frequently a poor PS 3-4 (32% vs. 61%, P=0.04). In intent-to-treat analysis, 27 patients received 3 cycles of R-MPV-VP16 but one received only 2. Among them, five patients achieved PR and then received 1 to 2 additional cycles of R-MPV-VP16. Following this induction, 25 patients underwent 2 cycles R-AraC-ifo consolidation, 3 of them did not received ifosfamide for the second cycle because of hematological toxicity and poor PS. One patient in complete response (CR) after whole treatment received high-dose therapy followed by autologous stem cell transplantation. After R-MPV-VP16, 10 patients (36%) achieved CR and 14 partial responses (50%) (PR) as compared to 12 CR (39%) and 12 PR (39%) for patients treated with R-MPVA. After consolidation phase, 23 patients (82%) achieved CR after R-AraC-Ifo as compared to 21 CR (68%) after R-AraC in the historical arm. Differences were not statistically significant. R-MPV-VP16 regimen was associated with favorable toxicity profile with 13 (46%) grade 4 hematological toxicity, 8 (28%) grade 3 and one grade 4 (3%) renal toxicity, 3 (10%) grade 3 and one grade 4 (3%) hepatic toxicity, 6 (21%) grade 3 and 4 grade 4 (14%) and infectious toxicity. With a median follow-up of 46.5 months, patients treated with R-MPV-VP16 followed by R-AraC-ifo had a median event-free survival (EFS) of 33.2 months (95%CI, 17.6 - not reached [NR]) with a 2-year EFS rate of 52%; the median overall survival (OS) was not reached (95%CI, 58.6-NR) with a 2-year OS rate of 70%. With a median follow-up of 94.2 months, patients treated with R-MPVA had a median EFS of 18.3 months with a 2-year EFS rate of 39% (P=0.14, Fig 1); the median OS was 65.9 months with 2-year OS rate of 64% (P=0.33, Fig 1). Conclusions In this retrospective analysis of two HD-MTX and HD-AraC based regimens for PCNSL patients aged between 60 and 75 years performed in real-life setting, R-MPVA was more frequently proposed for older patients with a poorer PS. Combination of vepeside to R-MPV and ifosfamide to R-AraC was feasible with a favorable toxicity profile. Despite not statistically different, we observed a trend for an improvement of response rate at the end of treatment (82% vs. 68% of CR) and reduced rate of relapses (2-year EFS rates: 52% vs. 39%) with the intensified protocol. These first results deserve a confirmative larger prospective study of R-MPV-VP16 followed by R-AraC-ifosfamide for elderly PCNSL patients. Disclosures Ferrant: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; GlaxoSmithKline: 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, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Amgen: Research Funding; Roche, Gilead: Consultancy.

Description: Background: Diagnostic-to-treatment interval (DTI) was recently described as a strong prognostic factor for newly diagnosed systemic diffuse large B-cell lymphoma patients (DLBCL) with an improvement of event-free survival (EFS) for patients with a longer DTI. These results have some implications for patient selection and result interpretations in clinical trials. This association has not been previously evaluated in DLBCL Primary CNS Lymphoma (PCNSL) patients who also present a clinically aggressive disease. Patients and Methods: The cohort constited of all consecutive DLBCL PCNSL patients treated in two Hematology Departments of the University of Lyon between 1984 and 2018 (N=244). All patients had DLBCL histology at diagnosis, obtained by brain biopsy (N=235, 96%), vitrectomy (N=4, 2%) or CSF evaluation (N=5, 2%). As first line treatments, all patients but 5 (2%) received high-dose (HD) methotrexate-based chemotherapy, associated with intra-venous rituximab for 154 patients (63%) and HD cytarabine for 182 patients (75%). Consolidation treatment by whole-brain radiotherapy was performed in seventy-six patients (31%). DTI was defined as the number of days between the date of diagnosis (i.e. biopsy) and the date of treatment initiation. Association between DTI and patient characteristics was assessed by chi-square tests or Student t-tests. EFS was defined from the start of therapy to progression, relapse, or death from any cause. As we previously described, prognostic factors such as age and performance status (PS) demonstrate a time-dependent effect on overall survival (OS) in PCNSL limiting the validity of traditional Cox proportional hazard models. We thus used a piecewise Cox model to allow assessment of prognostic effect over different time periods. All survival analyses were done in univariate and multivariate settings and stratified on rituximab use during first-line therapy. Results: With a median follow-up of 73.5 months, the 5-year EFS and OS rates were 31.6% and 48.4% for whole cohort, respectively. Median DTI was 16 days (range, 1 to 67 days). Short DTI (≤16 days) was associated with a poor PS (ECOG PS 2-4, 53.3% versus 38.5%), altered Karnofsky score ( 16 days, respectively (Figure 1). Using a standard cox model, in univariate analyses, PS (2-4 vs. 0-1) (HR: 1.40, 95%CI, 1.00 - 1.94, P=0.045) and age (per 10-year increase) (HR: 1.19, 95%CI, 1.05-1.36, P=0.006) were associated with EFS but not DTI (≤ or 〉 16 days) (HR: 0.80, P=0.19), deep involvement (HR: 0.97, P=0.85) and LDH level (HR=1.02, P=0.91). In multivariate analysis, only age was associated with EFS (HR: 1.27, 95%CI, 1.11-1.46, P=0.001). Using a piecewise Cox model over two periods of time (before and after 12 months), we confirmed in multivariate analyses, the time varying effect of PS and age on EFS with a high-risk period before 12 months and no prognostic effect after 12 months (Table 1). We also observed a time-dependent effect for DTI as shown by a significant interaction with time (P=0.02) (Table 1). Indeed, longer DTI was not associated with EFS before 12 months (HR: 1.14, 95%CI, 0.74-1.76, P=0.56) however, it had a strong protective effect after 12 months (HR: 0.44, 95%CI, 0.24-0.86, P=0.02). Conclusions: In this large cohort of DLBCL PCNSL, a short DTI was mainly associated with poor PS at diagnosis. We confirmed that prognostic factors for PCNSL outcome such as age and PS had time-varying effects with a good predictability of EFS only before 12 months. However, DTI allows prediction of long-term EFS (〉12 months) after first line treatment. These results could be related to different biological patterns of tumor aggressiveness. If confirmed in independent PCNSL cohorts, DTI should also be taken in consideration for patient selection and the interpretation of clinical trial results especially for long-term outcome. Disclosures Karlin: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Bachy:Amgen: Research Funding; Roche, Gilead: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria.