FLIPI Score Research Articles

Mutational Profile and Copy Number Alterations of Follicular Lymphoma Patients with Different Clinical Behavior

Introduction Outcomes for follicular lymphoma (FL) patients are generally good. Clinical and biological variables have been studied to identify patients at higher risk of early relapse, which markedly impacts survival. However, the genetic landscape of FL according to its clinical behavior (need of treatment and timing of relapse) is not well characterized, which was the aim of the present study. Patients and Methods We included 67 samples from 55 grade 1-3A FL patients from a single institution [55 samples at diagnosis (D), and 12 at relapse (R)]. Five groups were defined according to their clinical behavior: never required treatment after >5 years (y) of follow-up [never treated (NT), n=7]; treated and did not relapse after >9 y of follow-up, [non-relapsed (NR), n=19]; treated and relapsed beyond 24 months of frontline therapy [late relapse (LR), n=14]; treated and relapsed within 24 months of frontline treatment [early relapse (ER), n=11]; and primary refractory (PR, n=4). Of the 48 treated patients, 96% received R-CHOP. Patients developing histologic transformation were not included. DNA was extracted from FFPE tissue biopsies. Copy number alterations (CNA) were assessed in 50 D and 11 R samples [OncoScan CNV Assay (Thermofisher)], and single nucleotide variants (SNV) and insertions/deletions (indels) in 51 D and 10 R samples using a B-cell malignancy NGS panel examining 121 genes (SureSelectXT, Agilent Technologies). Genes and genomic regions were considered altered if they harbored SNV/indels and/or CNA. For comparisons and plotting, only the 52 D samples with both NGS and CNA data were considered. Non-parametric statistical tests were used. Results Median age was 56 y (range, 26−79), and 30 patients (55%) were female. Forty-two patients (76%) had stage III-IV disease, without significant differences among groups. Thirteen patients (25%) had a high-risk FLIPI score, a percentage that was higher in the LR and PR groups (50 and 67%, respectively, P=0.02). With a median follow-up of 12.9 y, 10-y overall survival estimates were 71, 100, 74, 82, and 0% for NT, NR, LR, ER, and PR patients, respectively. We detected CNA in all samples, with a median number of 7 (range, 1−27) for D samples, and of 6 (2−19) for R samples. We also identified SNV/indels in all samples, with a median number of 10 (1−23) for D samples, and of 9 (3−18) for R samples. The most commonly altered genes at diagnosis were KMT2D (82%), CREBBP (73%), SPEN (38%), TNFRSF14 (38%), ARID1A (33%), and BCL2 (33%) (Figure). There were no significant differences in the number of altered genes/regions among the five groups. Genes or regions with significantly different alteration frequency among groups were: CARD11 (57, 12, 0, 9, and 0% for NT, NR, LR, ER, and PR, respectively, P=0.014), CD70 (12% for NR, 50% for PR, and 0 for the remaining groups P=0.026), HIST1H1B (29% for NT, and 0% for the remaining groups, P=0.020), HVCN1 (43, 6, 0, 18, and 0% for NT, NR, LR, ER, and PR, respectively, P=0.048), KLHL6 (12% for NR, 75% for PR, and 0 for the remaining groups, P=0.002), PRKCB (0, 6, 0, 18, 50%, P=0.037), and 13q14.2-q14.3 loss (DLEU1/DLEU2) (24% for NR, 50% for PR, and 0 for the remaining groups, P=0.015). Two genes had a significantly lower alteration rate comparing the cases with a favorable (NT, NR, LR) and more aggressive (ER, PR) clinical behavior: CIITA (22 vs. 53%, P=0.043), and PRKCB (3 vs. 27%, P=0.044). Of the 51 patients for which the m7-FLIPI was calculated, six (12%) had a high-risk score. Of note, none of the high-risk patients belonged to the NT or NR groups. No significant differences were found in the number of altered genes/regions between D and R, or in the alteration frequency of each gene/region. We identified the presence of an ancestral common precursor cell with a divergent evolution in all paired cases. The median percentage of shared alterations between D and R was 50% (range 28−63%). Conclusions In this comprehensive genetic analysis of 55 FL patients, categorized into five groups according to their clinical behavior, alterations in the chromatin modifying genes KMT2D and CREBBP were the most frequent, and CIITA and PRKCB were more frequently altered in cases with a shorter duration of response. These data warrant further study of the mechanisms underlying these mutations, mutual exclusivity/co-occurrence, and relationships with B-cell biology and the tumor microenvironment. Disclosures Nadeu: Janssen: Honoraria. Giné:Gilead: Research Funding; Janssen: Research Funding; Roche: Research Funding. Armando:Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Initial report of a phase II study with R-FND followed by ibritumomab tiuxetan radioimmunotherapy and rituximab maintenance in patients with untreated high-risk follicular lymphoma

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of 90yttrium ibritumomab tiuxetan (90YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by 90YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1–3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After 90YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.

IBCL-244: Hepatitis C Viral Infection Impact on the Clinicopathological Features and Clinical Outcome in Egyptian Follicular Lymphoma Patients

Context: Hepatitis C virus (HCV) is both hepatotropic and lymphotropic. Chronic HCV infection has been associated with extrahepatic manifestations, especially lymphoproliferative disorders. Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. Objective: To clarify the relationship between HCV and FL, we compared the prevalence of clinicopathologic characteristics between HCV-infected and HCV-non-infected FL patients. Design: A comparative retrospective study included 103 FL patients who presented at our institution during 2008-2018. Setting: It was carried out in the Hematology unit at Oncology Center, Mansoura University (OCMU). Patients: 103 patients with FL who were F/M (47.6/52.4%) with mean age 55.36 ± 11.82 years. The prevalence of HCV infection among FL patients was found to be 49.5%. Interventions: They were treated by rituximab ± anthracycline or alkylator-based regimens. Radiotherapy was the treatment of choice in selected low stage I/II. Main Outcome Measures: The impact of HCV infection on clinicopathological features of FL and its impact on clinical outcome. Results: In this study, HCV-positive FL patients commonly had B symptoms (P = 0.023), stage IV (P = 0.016), high FLIPI score (P =0.042) and absent BCL2 expression (P = 0.041). While no differences were detected regarding gender (P =0.28), grade (P = 0.78) and overall response rate (P = 0.2). PFS was significantly improved with low FLIPI score (P = 0.028), meanwhile, no differences were detected regarding HCV-status (P = 0.27) and grade (P = 0.17). Median OS was not reached. It was significantly improved in Grade 1, 2 (P Conclusion: The prevalence of HCV infection among our studied FL patients is ∼49.5%. HCV infection was significantly associated with more aggressive clinicopatholigical features and shortened OS. Thus, early detection and eradication of HCV infection in FL may improve the outcome.

Abstract 2682: Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients

Abstract Follicular lymphoma (FL) still remains an incurable disease, with most of the patients undergoing subsequent phases of remission and relapse. In the era of immunotherapy, understanding the immunobiology of FL patients who experience progression of disease within 24 months (POD24) and show chemotherapy resistance remains a priority and an unmet clinical need. Tumor-associated macrophages (TAM) are multifaceted cellular components of the tumor microenvironment (TME). In concert with lymphoid-lineage B and T cells at various developmental stages, TAM can mediate enhanced tumor progression, often leading to poor clinical prognosis and impact the clinical response to chemotherapy. Recently, Joshua and colleagues demonstrated that a subset of FL patients with low immune infiltration was enriched in POD24 events. In our work, we characterized the immune repertoire of lymph node biopsies collected retrospectively from 30 patients with histological diagnosis of FL according WHO criteria. Median follow up was 8 years. The expression levels of TAM (CD68, CD163, MS4a4a) and tumor-infiltrating T-lymphocytes (CD8, PD-1 positive subsets) were assessed by immunohistochemistry and summarized using descriptive statistics. Our data highlighted that the subset of patients with a high extrafollicular CD163/CD8 ratio was enriched in POD24 events (p = 0.01). In addition, patients who showed an higher number of intrafollicular CD68+ macrophages, showed a longer disease free survival (p= 0.04). Another difference was related to the number of CD68, CD163, MS4A4A-positive polarized macrophages that resulted higher in bcl-2 negative than bcl-2 positive cases (p< 0.05 for all markers). In the evaluation of T lymphocytes, most relevant associations were found between the content and distribution of PD1+ cells and the treatment response: the higher the number of intrafollicular PD1+ lymphocytes the lower chemotherapy response rates (p= 0.04). No association was found between the number of positive elements in extrafollicular areas, where instead the PD1/CD8 ratio seems to be related with therapy response: the higher the ratio the lower response rate (p= 0.01). This finding could be explained assuming that there may be different types of cellular interactions inside and outside the neoplastic follicles. No other statistically significant difference in terms of expression of these markers was observed in relation to clinical pathological features such as staging, grade and FLIPI score. In conclusion, extrafollicular high CD163/CD8 ratio is associated with POD24 in FL patients, this finding underlines the pathological significance of CD163-expresing macrophages in TME, suggesting this biomarker as a potential therapeutic target in this disease. Citation Format: Clara Bertuzzi, Maria Maddalena Tumedei, Sara Ravaioli, Claudio Agostinelli, Maurizio Puccetti, Sara Bravaccini, Simona Righi, Beatrice Casadei, Andrea Pession, Giovanni Martinelli, Giorgia Simonetti, Elena Sabattini, Serena De Matteis. Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2682.

A closer look at Hispanics with follicular lymphoma in a majority-minority community.

e20047 Background: Follicular Lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. It is most commonly diagnosed in non-Hispanics (NH) and is well characterized in this population. Hispanics (HI) on the other hand have been historically underrepresented in clinical trials and observational studies. Some studies suggest that there are differences in age, clinical presentation, treatment patterns and outcomes in HI. The aim of our study was to determine demographics and clinical characteristics of FL patients and compare outcomes between HI and NH. To our knowledge, this is the largest cohort of FL patients from a single academic institution that serves predominantly HI. Methods: We retrospectively analyzed 123 patients with FL; all received care between 2008-2018. Key variables included age, gender, race/ ethnicity, comorbidities, insurance status, stage, treatment received, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with mean/standard deviation and categorical outcomes with frequencies/percentages. Significance of associations between categorical outcomes was assessed with Pearson’s Chi Square or Fisher’s Exact test. All statistical testing was two-sided with a significance level of 5%. Results: We identified 123 patients with diagnosis of FL, 71 HI (58%), 49 NH (40%), 3 unspecified (2%); 88% Caucasian, 5% African American, 4% Asian, 3% other; 56% females and 44% males. Median age at diagnosis was 56.31 (SD 11.97). Funding source was commercial insurance N = 55 (45%), Medicare N = 40(33%), hospital payment plan N = 20 (16%), unfunded N = 5 (4%) and Medicaid N = 3 (2%). Most prevalent co-morbidities were HTN 40% and diabetes mellitus 20%; 40% had no co-morbidities. At diagnosis ECOG of 0-1 was seen in 116 (94%); 21 were Stage I (17%), 19 Stage II (15%), 40 Stage III (33%), and 43 Stage IV (35%). FLIPI score was 0-1 in 43 patients (35%), 2 in 32 (26%), 3 in 23 (19%), not documented in 25 (20%). Median PFS was 1287.10 days (SD 879.18). At 3 year follow up there was: complete/ partial response in 76% HI vs 84% NH; disease progression in 18% vs 3%; death in 6% vs 3%, respectively (p-value = 0.739). At 5 year follow up: complete/partial response in 76% HI vs 86% NH; disease progression in 14% vs 10%; death 10% vs 3%, respectively (p-value = 0.62). At the end of 2018, 88% HI were alive compared to 95% NH, [p-value = 0.457]. Conclusions: Contrary to existing data, our study found that HI with FL have no difference in outcome when compared to NH. This could be explained by our prevalently HI population, but further studies are needed.

Prognostic relevance of CD4+ T-cells in the microenvironment of newly diagnosed follicular lymphoma (FL) patients is independent of the tumor gene expression profile.

8052 Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p < 0.001) predicted early failure, and the association remained (OR = 2.14, p < 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.

Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.

Predictive Factors of Response and Survival of Lenalidomide and Rituximab As Initial Treatment of Follicular Lymphoma

Introduction. The combination of rituximab and lenalidomide (R2) is active in patients with untreated indolent lymphoma. Recent randomized trials (RELEVANCE) have demonstrated similar efficacy when compared to standard chemo-immunotherapy backbones. Long term follow up of patients receiving R2 as well as predictors of long term remission and survival have yet to be published. Methods. We prospectively evaluated patients with low grade advanced stage FL who received R2 as initial treatment at our institution between 07/2008 and 10/2014. Lenalidomide was given at 20 mg (day 1-21, in a 28 day cycle) for 6 cycles with rituximab monthly. Lenalidomide starting dose was 10 mg if baseline creatinine clearance was < 60 mL/min. Patients with an objective response continued with 10-20 mg of lenalidomide with rituximab for up to 12 more cycles. Response was evaluated according to 2014 Lugano criteria. Results. One-hundred and one patients were included in the analysis, baseline characteristics are shown in the Table. Median number of provided cycles was 7 (range, 1-20). Median dose of lenalidomide was 20 mg (range, 5-20 mg), and 29 (29%) patients required a dose reduction. Fifty-six (55%) patients experienced grade 3-4 treatment-related toxicities, the most common (> 5%) being neutropenia (39%), skin rash (20%), myalgia (16%) and fatigue (16%). Seven (7%) patients discontinued treatment before completion, after a median time of 4 months (range, 1-10 months): 4 because of toxicity (arterial thrombosis in 2, respiratory failure in 1, and skin rash in 1), and 3 because of progression. Ninety-eight patients were evaluable for response, while 3 patients discontinued treatment because of toxicity before first response assessment. Overall response rate was 98%, CR rate 90% (both achieved after a median of 6 months [range, 3-22 months]), and CR rate at 30 months (CR30) was 80%. Only female sex associated with a higher CR rate (96% vs 83%, p=0.05), while no baseline characteristic associated with CR30 rate. After a median follow-up of 88 months (95% confidence interval, 84-92 months), 31 (31%) patients progressed and/or died, 7-year progression-free survival (PFS) was 63%, and 13% of patients had a PFS < 24 months (PFS24). Failure to achieve CR was the only factor associated with significantly decreased PFS (10 months vs not reached, p<0.001) and higher likelihood of PFS24 (46% vs 5%, p<0.001). No association was observed with baseline characteristics, including FLIPI and FLIPI-2 score. At most recent follow-up, transformation was reported in 3 (3%) patients, after 30, 32 and 42 months, respectively. Two (2%) patients have died, 1 of unrelated comorbid health conditions, 1 of progressive disease, and 7-year overall survival was 98%. Second cancers (excluding transformation) were diagnosed in 8 (8%) patients, after a median of 55 months (range, 3-105 months). These included: breast adenocarcinoma (2), melanoma (2), pancreatic adenocarcinoma (1), esophageal adenocarcinoma (1), and therapy-related acute myeloid leukemia. Discussion. Long-term follow-up show very favorable outcomes for patients with advanced stage FL receiving R2 as initial treatment, independent of traditional prognostic factors relevant to patients treated with chemoimmunotherapy, including FLIPI and FLIPI-2 score. Combination strategies, aimed at increasing depth of response to R2, may further improve outcomes observed with this regimen. Table. Disclosures Nastoupil: Bayer: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Westin:Janssen: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Wang:AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; BioInvent: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno Therapeutics: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Research Funding; Aviara: Research Funding; Kite Pharma: Consultancy, Research Funding; Guidepoint Global: Consultancy; VelosBio: Research Funding; Loxo Oncology: Research Funding. Neelapu:Pfizer: Consultancy; Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Allogene: Consultancy; Novartis: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Cellectis: Research Funding; Acerta: Research Funding; Karus: Research Funding; Poseida: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: lenalidomide and rituximab are not yet FDA-approved as frontline treatment for patients with FL

EARLY STAGE Follicular Lymphoma: First Results of the FIL “Miro” Study, a Multicenter Phase II Trial Combining Local Radiotherapy and MRD-Driven Immunotherapy

EARLY STAGE Follicular Lymphoma: First Results of the FIL “Miro” Study, a Multicenter Phase II Trial Combining Local Radiotherapy and MRD-Driven Immunotherapy

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Implication of Inherited Genetic Variants Associated with Follicular Lymphoma Susceptibility in the Prognosis of Patients Treated By Immunochemotherapy in PRIMA Study

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.

Clinical Significance of Uptake Value on F18-FDG PET/CT and Histological Grade in 164 Patients with Follicular Lymphoma Including Transformation - a Single Center Retrospective Study

Introduction: Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, but has heterogeneous clinical behavior. PET-CT scan has the central role of determining of clinical staging and its five-point Deauville scale to grade response has been widely accepted in the management of follicular lymphoma. PET-CT scan also plays a significant role of predicting transformation of follicular lymphoma by considering high uptake of standardized uptake value (SUV). Recently, the total metabolic tumor volume (TMTV) measured by PET-CT scan and histological grades are prognostic factors of FL. But TMTV is not easily measured as everyday medical care, more simplified marker such as SUV value is desired. Methods: We retrospectively analyzed 275 patients who were diagnosed as follicular lymphoma including transformed form in our hospital between January 2008 and November 2018. One patient had also been diagnosed as rectal cancer as well as follicular lymphoma, aso we excluded this patient from our study. Results: We first investigated the relationship between histological grade and SUV value on FDG PET/CT. One hundred and ninety-eight biopsies were conducted at the same time of PET-CT. The median SUVmax value was 6.6 (range, 0-34.1) in FL grade 1 patients (n=89), 7.4 (0-23.9) in FL grade 2 patients (n=59), 12.1 (4.6-26.5) in FL grade 3a patients (n=33), and 14.8 (6.5-34.4) in FL grade 3b (n=17) (p<0.01). We then analyzed clinical impact of SUVmax value on follicular lymphoma grade 1-3a. Patients with follicular lymphoma grade 3b, or lack of information were excluded, so we finally analyzed 164 patients. Median follow-up of survivors was 47.5 (0.4-10989) months. The median age at diagnosis was 62 (31-90) years. Ninety patients were male. Thirty-two patients were diagnosed as duodenum follicular lymphoma. Ninety-four patients were advanced clinical stage (III/IV). Using FLIPI2 score, 32 patients (20%) were in the low risk group, 105 (64%) in the intermediate group, and 27 (16%) in the high risk group. Thirty-six patients had high tumor burdens defined by GELF criteria. The median SUVmax value was 7.5 (range, 0-34.1). As first line treatment strategy, 83 patients (51%) received watch and wait strategy, 38 (23%) received R-CHOP, 3 patients (2%) received R-CVP, 14 (9%) received R-Benda, 20 (12%) received RIT, and 6 (4%) received others. High uptake value (SUV max ≧ 10 vs. SUV max < 10) correlated with high tumor burden and sIL2-R (p<0.01), but did not affect OS and time to next treatment (TNT) (97.3% vs. 98.9% in 5-year OS (p=0.82), 54.6% vs. 72.3% in 5-year TNT (p=0.09)), regarless of first line treatment. Conclusion: Uptake value of SUVmax correlated with histological grade of FL and high tumor burden, but did not affect OS and TNT. Disclosures No relevant conflicts of interest to declare.

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Follicular Lymphoma Frontline Immuno-Chemotherapy: Survival Outcomes and Infection-Related Morbidity

Background Follicular lymphoma (FL) patients (pts) receiving immunochemotherapy now have a median overall survival (OS) of 15-20 years (y). ~80% of pts demonstrate an age/sex-matched OS compared to the population (Casulo et al, 2015). As such, optimizing therapy and minimizing toxicities are key outcome measures. The GALLIUM trial (Marcus et al, 2017) reported excess toxicity with front line (1L) obinutuzumab (O) compared to rituximab (R) (neutropenic fever, infection) and with bendamustine (B) (treated-related mortality ~4-5%). Methods We performed a single institution retrospective analysis of 132 consecutively 1L FL pts (2009-19) to assess factors associated with progression-free survival (PFS), OS, and morbidity following chemotherapy (R or O with CVP, CHOP, or B) +/- anti-CD20 antibody (ab) maintenance. Transformed FL was excluded. We collected data on all-cause infection over a 3y period, including infective-related admissions and grade (G) 1-2 infections regardless if they received maintenance. Univariable (UVA) and multivariable analyses (MVA) assessed factors for infective complications. Potential factors included were: age, baseline Hb (<12), CIRS-G, CIRS-G severity (CIRS-G/number of comorbidities), FLIPI, smoking history, COPD, immunochemotherapy, and maintenance. Results Across all pts, the median age was 63 y (range 28-90). Time from diagnosis to 1L was 1.6 months (range 0.03-110). Regimens included R-CHOP (n=34), R-CVP (n=53), R-B (n=32), O-B (n=9). B-treated pts were younger (median 57 y) than R-CHOP (median 62 y) and R-CVP (median 71 y). The mean CIRS-G (R-CHOP 1.38 vs R-CVP 2.76 vs B-R 1.1) and CIRS-G severity score (R-CHOP 0.81 vs R-CVP 1.38 vs R-B 0.81) were both higher in R-CVP pts. R-CVP pts had lower FLIPI scores (FLIPI 3-5: B-R/O 71%, R-CHOP 68%, R-CVP 55%). 68% R-CHOP, 51% R-CVP and 76% B-R/O of pts started anti-CD20 ab maintenance. The 3y PFS was 70% (95% confidence interval (CI) 61-78%) (Fig A) and 3y OS 89% (95% CI 82-93%) (Fig B) across all pts. Pts receiving R-CVP had an inferior PFS (Fig C) than RCHOP or B-R/O (3y PFS 52% (95% CI 37-66%) vs R-CHOP 3y PFS: 82% (95% CI 63-92%) vs BR 88% (95% 70-95%) vs B-O 63% (CI 24-87%) p=0.004). This translated to R-CVP pts having an inferior OS (Fig D) compared to RCHOP or B-R/O (3y OS 82% (95% CI 68-90%) vs R-CHOP 100% vs BR 91% (95% 74-97%) vs B-O 88% (95% CI 39-98%) p=0.006); reflecting both pt characteristics and treatment efficacy. Across all pts, the 3y PFS was 81% (95% CI 70-89%) with anti-CD20 ab maintenance versus 53% (95% CI 37-66%) without maintenance (p=0.001) (Fig E). There was an OS difference in favour of maintenance (3y OS 75% vs 97%) (p=0.012) (Fig F). There were 74 documented infective episodes (G1+) across all pts over 3y follow up. There were 43 infective-related admissions (G3+) during induction (n=132) and 16 during maintenance (n=83). The highest numerical risk of any infective episode(s) within 3 y follow up was BR (69% 22/32) and lowest R-CVP (50% 25/50) (p=0.09). G3+ infection during induction was significantly higher with R-CHOP (52% 17/33) compared to BR 6/32 (19% 6/32) (p=0.006). Conversely during maintenance, infective-related admissions were numerically higher in B-treated (R+O) (23% 7/31) compared to RCVP/RCHOP pts (16% 8/50) (p=0.46). Factors associated with an increased risk for all grade infections by UVA included: maintenance (odds ratio (OR): 2.1 (95% CI 1-4.4), p=0.05), CIRS-G* (OR: 1.2 (95% CI 1-4.4), p=0.07), CIRS-G severity* (OR: 1.5 (1.0-2.2) p=0.04). On MVA, the only risk factor for all grade infective episodes (ref: R-CVP) was BR (OR 3.8 (95% CI 1.2-11.6); p=0.02). Factors associated with an increased infective-related admission by UVA included high CIRS-G* (OR:1.15 (95% CI 1-4.4), p=0.09). On MVA, the factors of significance for an increased infective admissions were CIRS-G* (OR 1.34 (95% CI 1.0-1.8) and R-CHOP (ref: R-CVP OR:1.0) OR 3.2 (95% CI 1.1-9.1); p=0.03). Conclusions OS and PFS were superior in pts receiving R-CHOP or B-based treatment compared to R-CVP. Similarly, superior OS and PFS were seen in pts receiving anti-CD20 maintenance. Consistent with GALLIUM, we show the risk of infective-related episodes across 3 y following bendamustine when accounting for other factors. Careful anti-infective measures (anti-viral, anti-PCP) are required following B-based therapy, including on maintenance. Infective-related admissions (G3+) were independently associated with R-CHOP. *continuous variable Disclosures Djebbari: Takeda: Honoraria, Other: support with conference attendance; Novartis: Honoraria; Celgene: Honoraria, Other: support with conference attendance, Research Funding; Amgen: Honoraria. Collins:Gilead: Consultancy, Honoraria. Eyre:Roche: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Janssen: Honoraria; Abbvie: Honoraria.

Validation of the PRIMA-Prognostic Index for Patients Treated with Rituximab Plus Chemotherapy and Refinement of Prognostic Parameters for Patients on Rituximab Plus Lenalidomide in the Phase III Relevance Trial

Validation of the PRIMA-Prognostic Index for Patients Treated with Rituximab Plus Chemotherapy and Refinement of Prognostic Parameters for Patients on Rituximab Plus Lenalidomide in the Phase III Relevance Trial

Progression of Follicular Lymphoma within 24 Months of First Treatment (POD -24) As a Predictor of Overall Survival - a Single Center Retrospective Analysis

Background: Follicular lymphoma (FL) is the most common indolent lymphoma in the western world with a median survival approaching 20 years. However, the course of the disease is extremely heterogeneous and therefore, at diagnosis it is difficult to predict survival. Roughly 20% of patients experience rapid progression of disease post first line treatment. Progression of disease within 24 months of first treatment (POD24) was previously identified a robust predictor of reduced overall survival (OS) (Casulo et al., JCO, 2015). Aims: We aimed to validate POD24 as a predictor of poor OS in a real-world cohort of patients, which was not uniformly treated, including patients that were initially treated with radiation or observed at least 6 months prior to first line therapy. Methods: We thoroughly reviewed 635 patient's records that were diagnosed between 1987 and 2018. Patients with FL grade 3B or de-novo transformation, as well as those that were never treated, treated prior to the rituximab era or had missing relevant clinical data were excluded. POD24 was defined as time from first therapy (systemic or radiation therapy) to first documented progression (either clinical or by imaging). Overall Survival was defined as time from diagnosis to either last follow-up or death. Progression Free Survival (PFS) was defined as the time from first treatment to first documented progression, death or last follow-up. Survival was analyzed with Kaplan-Meier method and comparison of survivals was done with Log-Rank test. Multivariate analysis was conducted with Cox regression. Results: A total of 317 patients met the study inclusion criteria and were included in our analysis. Median age was 57 (23-87), 162 (51%) were male and 155(49%) female .Median follow-up was 7.5 years (0.24-24.4). FLIPI (available in n=149) was high in 41 (27%) patients, intermediate in 37 (25%) and low in 71 (48%). Eighty seven patients (27.4%) received radiation as their first treatment and 86 (27%) were initially observed. Systemic therapy regimens included alkylator based regimens (n=152, RCHOP-88), bendamustine based (45), fludarabine Based (32), and Rituximab alone (2). Maintenance therapy administration was documented in 119 patients. Progression was documented in 133 (42%) patients, and transformation in 34 (11%). Thirty four patients (11%) deceased. Median OS was not reached in our study cohort, and median PFS was 109 months (CI:68-150). Early progression (POD24) was captured in 68 (21.5%) patients. The OS of those patients was significantly lower than those whom did not progress within 24 months of first therapy (figure 1A, p<0.0001). High FLIPI score also predicted lower OS (p=0.001). In multivariate analysis both factors remained significant (POD24 p=0.013, FLIPI p=0.023). In the group of patients that were initially observed (86), 18 had early progression after first treatment. In this group, OS did not differ between the patients that had POD24 vs those who did not (p=0.095). The same was true for patients that had radiation as their first line therapy (p=0.36). The impact of POD24 on OS was observed in patients that were treated with alkylator based regimens (p=0.02) as well as with bendamustine based regimens (p=0.028). In the Fludarabine treated patients no significant difference in OS was observed in the different POD24 groups, probably due to small sample size. Interestingly, POD24 did not predict inferior OS in 69 patients in whom progression was diagnosed by routine imaging (PET/CT or CT) (Figure 1B). However, it was borderline predictive (p=0.1) when progression was clinically diagnosed (n=38). Conclusions: Our real-world analysis validated the importance of POD24 as predictor of OS in patients who were treated at diagnosis with alkylator or bendamustine based regimens. POD24 did not predict survival in patients treated with radiation or in those initially observed, a result that may reflect their superior outcome. Notably, POD24 did not predict OS in patients that were diagnosed with progression by routine imaging. As we, and others use imaging studies frequently in the follow-up of FL patients, especially in first two years after therapy, the scenario of positive findings in imaging is relatively frequent. Our data suggest that random findings in imaging that do not have clinical expression may not predict inferior outcome which is of major clinical implications. Disclosures No relevant conflicts of interest to declare.

284P - Differences in disease characteristics and survival outcomes of follicular lymphoma in young adults and older population: An institutional analysis

BackgroundFollicular Lymphoma (FL) is known to be a disease of the elderly and younger patients are postulated to have distinct tumor biology and treatment outcomes. Various lymphoma groups across the world have studied this to understand if young adults (YA) need a different treatment approach. Our study fills the void in paucity of data from an Asian country on YA versus older population of Follicular Lymphoma. MethodsThe records of patients presented at our center between 2012 and 2018 were retrospectively reviewed. They were stratified by age into ≤40 (YA) and > 40 years and their demographics, clinicopathological features and outcomes were analyzed. ResultsA total of 167 patients of follicular lymphoma were identified with 24 (14.3%) patients belonging to YA group. A final analysis of 154 patients is presented after excluding patients with upfront Grade 3b disease. Median age in YA and older patients was 37 and 55 years respectively. YA group had a higher incidence of extranodal involvement, bone marrow involvement, and advanced disease at presentation, whereas high LDH and low hemoglobin levels were more common in older patients. As per FLIPI risk scoring, 43% of our patients in both groups had high-risk disease. All YA received treatment upfront, while 7.7% of older population underwent observation. Most commonly used chemotherapy regimen was CVP and 46% of our patients received Rituximab. The ORR was significantly more in YA population (91.3% vs 83.2%) At a median follow-up of 3.5 and 3.2 years (YA and >40 years respectively), YA had a better median PFS (3.5 yrs) and OS (5.9 yrs) compared to those older than 40 (PFS 3.1 yrs, OS 5.2 yrs). On multivariate analysis, normal LDH, lower FLIPI score and use of Rituximab were associated with a significantly longer PFS in older patients, however, it showed a trend towards improved PFS in young adult population that did not reach statistical significance. No parameter showed a significant association with OS. ConclusionsYA more frequently present with advanced stage requiring upfront treatment, however they exhibit higher ORR and better PFS and OS compared to older counterparts. The survival rates seen are comparable to another Indian study but lower than the Western data. Legal entity responsible for the studyDepartment of Medical Oncology, Kidwai Cancer Institute, Bengaluru. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

M7FLIPI and targeted sequencing in high-risk follicular lymphoma.

Patients with follicular lymphoma (FL) refractory to front-line immunochemotherapy (ICT) have a poor overall survival (OS). Gene mutation analysis may be more accurate than classical risk factors to pick out these patients before treatment. This study aimed to describe the prevalence of selected genetic mutations in a cohort of patients with high-risk FL. Twenty-five patients with FL refractory to front-line ICT and 10 non-refractory patients matched for age, sex, and FLIPI score were included. We sequenced 18 genes (custom targeted sequencing panel) previously reported to potentially have prognostic impact, including the seven genes necessary to determine m7FLIPI risk. The 35 patients had a median age of 62. The FLIPI and FLIPI2 were high in 27 (84%) and 14 (48%), respectively. Three-year progression-free survival (PFS) and OS probabilities were 25% (95% CI, 13%-41%) and 53% (34%-69%), respectively. There were 73 variants in the 18 genes among the 35 patients. The median number of mutations per patient was 1 (interquartile range, 0-3). The most commonly mutated genes were CREBBP (11 of 35, 31%) and EP300 (10 of 35, 29%). EP300 mutations were associated with refractoriness to treatment (10 of 25 among refractory and 0 of 10 among non-refractory). In conclusion, in this study, patients with high-risk follicular lymphoma were genetically heterogeneous.

M7-FLIPI is not prognostic in follicular lymphoma patients with first-line rituximab chemo-free therapy.

The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into "low-risk" and "high-risk" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P=0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P=0·04) and in EP300 mutations were associated with shorter TTF (log-rank P=0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen.

PS1323 HIGH SERUM LEVELS OF IL‐2R, IL‐6 AND TNF ARE ASSOCIATED WITH HIGHER TUMOR BURDEN AND POORER OUTCOME IN PATIENTS WITH NEWLY DIAGNOSED FOLLICULAR LYMPHOMA

Background:Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL‐2R), interleukin 6 (IL‐6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL‐2R has been associated with shorter progression‐free survival (PFS) in FL, but the impact of the levels of IL‐6 and TNF is not known in this disease specifically.Aims:To determine the prognostic significance of the serum levels of sIL‐2R, IL‐6 and TNF in patients with newly diagnosed FL.Methods:We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL‐2R, IL‐6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines.Results:Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL‐6 or TNF levels were older and those with elevated IL‐6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL‐2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2‐microglobulin (β2m) levels or a high‐risk FLIPI score. A Ki67 index >30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R‐CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single‐agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL‐2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10‐year PFS was significantly lower for patients with high levels of either sIL‐2R, IL‐6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10‐year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion:FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.image