Abstract: Background Ibrutinib, inhibitor of Bruton's tyrosyne kinase (BTK), demonstrated exceptional activity both in untreated and relapsed/refractory CLL patients, obtaining overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) far superior to chemoimmunotherapy (Byrd, 2014). Interestingly, NOTCH1 mutations (M) were significantly correlated with CD49d overexpression which identified cases with reduced lymphocytosis and inferior nodal response (Tissino, 2018). Moreover, NOTCH1 M were characterized by remarkable expression of the NF-kB pathway genes (Benedetti, 2017) and thus may confer poor response to ibrutinib. Aims On this background, the primary aims of our research were: i) to correlate NOTCH1 M with biological and clinical prognosticators in ibrutinib-treated patients; ii) to verify the impact of NOTCH1M both on the peripheral lymphocytes redistribution and on the nodal response calculated as percentual reduction from baseline (SPD); iii) to evaluate the impact of NOTCH1 M on ORR, PFS and OS; iiii) finally, to assess NOTCH1 M as an independent prognostic factor. Patients and Methods Therefore, we evaluated the efficacy of ibrutinib as single agent, in a real-life contest, on 166 patients recruited from three independent cohorts from Italy, median age 61 years (27-85), median number of previous regimens 2 (0-4; 15% previously untreated). Noteworthy, 23/60 (38%) TP53M patients were treated in first line with ibrutinib (p 〈 0.0001). Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Median follow up on ibrutinib was 16 months. NOTCH1 M were investigated with ARMS PCR for c.75447545delCT or by Sanger sequencing of NOTCH1 exon 34 and all cases were confirmed with next generation sequencing (NGS) method. Results Sixty-one patients were NOTCH1 M (36.75%). NOTCH1 M were significantly correlated with trisomy 12 (p=0.00045) and with CD49d 〉 30% (p=0.001). Absolute lymphocyte counts (ALCs) were collected before treatment and at days ranging from 30 to 90 on ibrutinib. NOTCH1 M were significantly correlated with lower median ALCs measured both before (28.9 x 106/ml vs 57.0 x 106/ml; p=0.0006) and during (28.0 x 106/ml vs 54.6 x 106/ml; p=0.0005) ibrutinib therapy. Also the median SPD, calculated at 3-6 months on ibrutinib, was significantly lower in NOTCH1 M patients (51.8% vs 75.7%; p 〈 0.0001, Figure A). ORR was 89% (complete response (CR): 21%, partial response (PR): 31%, PR with lymphocytosis (PR-L): 37%). The estimate 1-year PFS and OS were 81% and 86%, respectively. Fifty-one patients (30.7%) discontinued ibrutinib therapy due to progression (n= 25), and adverse events (n=26). Fourteen patients in progression were treated subsequently with venetoclax. With regard to clinical outcome, PR was significantly correlated with NOTCH1 M (31/61; p=0.00002). Significant shorter PFS and OS were observed in NOTCH1 M patients (39% vs 71% and 71% vs 81% at 24 months, respectively; p=0.03 and p=0.02; Figures B and C). In multivariate analysis of PFS and OS including TP53 M, IGHV mutational status and age 〉 or 〈 60 years, only NOTCH1 M were confirmed as an independent prognostic factor (p=0.01 and p=0.04, respectively). Conclusions NOTCH1 M patients were characterized by a reduced redistribution lymphocytosis and by a lower and/or slower nodal response under ibrutinib treatment. The clinical consequences were a significant higher number both of PR without lymphocytosis and relapses. Therefore, evaluation of NOTCH1 M in patients initiating ibrutinib may identify those cases that would benefit from combination therapy approaches, which are already underway in experimental protocols, using new molecules working through different pathways, such as venetoclax or obinutuzumab. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract: Novel therapies targeting BTK (ibrutinib), PI3Kδ (idelalisib) and BCL2 (venetoclax) are active in poor-risk chronic lymphocytic leukemia (CLL) and are widely administered to patients with relapsed/refractory (R/R)-CLL. Given the activity of ibrutinib in high-risk CLL patients, including those with del17p/TP53 mutation or germline IGHV genes, we assumed that this drug could diminish the prognostic utility of the CLL-IPI, because the outcome of patients with high- and very high-risk CLL-IPI scores may improve. Recently, Soumerai et al (Lancet Hematology, 2019) proposed a new risk score for overall survival (OS) based on four accessible markers, called BALL (β2-microglobulin, anemia, LDH, last therapy), in the setting of R/R-CLL patients receiving chemo-immunotherapy or targeted therapies in clinical trials. This model segregates CLL patients into three groups with significantly different OS. This multicenter, observational retrospective study aimed at validating the proposed BALL score for R/R-CLL real-world patients treated with ibrutinib. The primary objectives were to determine whether: i) the BALL score is of prognostic value for ibrutinib R/R-CLL patients, ii) the BALL score is predictive of progression-free survival (PFS); and iii) the CLL-IPI retains its prognostic power also in R/R patients treated with ibrutinib. This study, from an institutional Italian multicenter working group on CLL ('Campus CLL'), included CLL patients collected from 18 Italian centers and 1 Israeli center, who received ibrutinib 420 mg/day outside of clinical trials as salvage therapy with available data for the calculation of the BALL and CLL-IPI scores at the time of the start of treatment. OS was estimated for all subgroups according to both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by the Harrell's C-index. Overall, 541 CLL patients were included in this analysis. The majority of patients were Binet stages B and C (87.2%). The median age was 70.4 years (range 37 - 88) and 353 cases (65.2%) were male. The median number of previous therapies was 2 (range 1-9). The baseline patients' features are listed in Table 1. After a median follow-up of 1.8 years (range 1 month to 5.8 years), 101 patients had died and 206 experienced an event (death or progression). According to the BALL score, 372 patients (68.8%) were classified as low-risk, 132 (24.4%) as intermediate-risk and 37 (6.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 89.2% (HR=1), intermediate-risk of 79.9% (HR=2.8, 95%CI 1.8-4.4, P 〈 0.0001) and high-risk of 48.2% (HR=6.6, 95%CI 3.9-11, P 〈 0.0001) (Figure 1). The C-statistic was 0.66 (P 〈 0.001) for OS prediction. The CLL-IPI score indicated that 32 patients (5.9%) were classified as low-risk, 123 (22.7%) as intermediate-risk, 252 (46.6%) as high-risk and 134 (24.8%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow to predict significant differences in OS. Indeed, low-risk patients had a 2-year OS probability of 92.7% (HR=1), intermediate-risk patients of 88.4% (HR=2.3, 95%CI 0.5-9.9, P=0.26), high-risk of 84% (HR=3.3, 95%CI 0.8-13.7, P=0.1) and very high-risk of 76.4% (HR=4.3, 95%CI 1.038-17, P=0.046). Both the BALL and CLL-IPI scores failed to stratify patients significantly in terms of PFS. Our multicenter retrospective study confirms the prognostic power of the BALL score in this real-world series of R/R-CLL patients treated with ibrutinib, as previously reported in the setting of clinical trials (Soumerai et al, Lancet Hematology 2019). Furthermore, the CLL-IPI did not retain a discriminative power in the current retrospective study of ibrutinib-treated patients, possibly due to i) the well-known activity of ibrutinib in high-risk CLL patients, i.e. those with TP53 disruption and/or germline IGHV genes, which represent the most heavily weighted adverse risk factors contributing to the CLL-IPI, and to ii) the fact that the CLL-IPI was designed for patients receiving front-line chemo-immunotherapy. Conversely, the BALL score may identify higher risk R/R-CLL patients potentially requiring alternative and more effective therapeutic strategies. Disclosures Mauro: Jannsen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: 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. Herishanu:Roche: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Gilead: Other: travel expenses; Janssen: Consultancy. Rigolin:AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Gilead: Research Funding. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria. Cuneo:Amgen: Honoraria; Abbvie: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Foà:Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 777 Introduction. Fludarabine containing regimens are effective in FL; the role of Rituximab (R) maintenance has been established recently. Aim of the study was to investigate efficacy and safety of R-maintenance vs. observation in elderly FL patients who respond to a brief chemo-immunotherapy with four courses of R-FND + four doses of Rituximab as consolidation. Methods. From January 2004 to December 2007, elderly patients (age 60–75) with untreated advanced stage FL who required treatment, were enrolled by 33 FIL centers. Treatment plan was: four courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by four weekly Rituximab infusions as consolidation; responding (Complete Response, CR + CRu + Partial Response, PR) patients were randomized between a short Rituximab maintenance with a single dose every two months for a total of four doses (Arm A) or observation (Arm B). Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results. 242 patients were enrolled at diagnosis in the study and 234 were eligible for treatment: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. According to FLIPI risk patients were: Low 11%, Intermediate 34%, High 55%. According to Comprehensive Geriatric Assessment (CGA), concomitant illness were: one in 38% and greater than or equal to two in 23% of patients. Qualitative PCR analysis for IgH/Bcl-2, performed in 223 patients at diagnosis, was positive in 49%. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of stable/progressive disease (15), adverse events (nine) or other causes (eight). At the end of chemoimmunoterapy and consolidation overall response rate was 86% with 68% CR and 18% PR. After four courses of chemo-immunotherapy, 90 patients were in PR of whom 37 (41%) were converted to CR with the addition of Rituximab consolidation. As regard to Bcl2 analysis, PCR negativity was detected in 61% after R-FND and increased to 73% after R consolidation. With a median follow-up of 33 months, two-years Overall Survival and Progression Free Survival (PFS) were 93% (95% CI 92%–97%) and 77% (95% CI 71%–93%), respectively. Two-years PFS according to maintenance/observation phase was: 80% vs 68% (p.225), Figure 1. Two-years PFS rates according to FLIPI score were 87% for low/intermediate risk and 70% for high risk (p 〈 0.0001). A total of 1119 courses were delivered; the most frequent CTC grade 3–4 toxicity was neutropenia in 25% of the courses, with only 13 events of serious infections. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. In the maintenance/observation phase the following severe (WHO grade 3–4) toxicities were recorded: 15 patients experienced neutropenia, 8 cardiac events, 4 infections; no other relevant toxicities were recorded. Second malignancy were recorded in 11 patients. Conclusions. a short term chemo-immunotherapy R-FND + Rituximab consolidation is able to achieve high CR rate and a good two-years PFS in elderly FL patients. Good results were also observed in higk-risk FLIPI score. Two-years PFS of 80% in patients randomized to R maintenance was promising although there was no statistical difference compared to observation. This finding may be attributed to the relatively short follow-up or to the choice of a short course of Rituximab maintenance (only four doses) or both.Figure 1Figure 1. Disclosures: Vitolo: Jannsen-Cilag: Speakers Bureau; Celgene: Speakers Bureau; Roche Italy: Speakers Bureau. Off Label Use: The study includes use of Rituximab as maintenance in responding patients after first line chemoimmunotherapy. Gamba:Roche Italia: Employment. Supekar:Roche Italia: Employment.

Abstract: Recently, in an attempt to improve the discrimination power of the international prognostic index ( IPI ), patients with diffuse large B‐cell lymphoma were evaluated to determine the prognostic roles of peripheral blood absolute monocyte count ( AMC ) and absolute lymphocyte count ( ALC ). Here, we analysed data of 428 patients with follicular lymphoma ( FL ) enrolled in a prospective, randomized trial ( FOLL 05 study) conducted by Fondazione Italiana Linfomi, to assess the impact of AMC and ALC on progression‐free survival ( PFS ). All patients had been treated with one of three treatment combinations: (i) rituximab (R) plus cyclophosphamide, vincristine and prednisone; (ii) R plus cyclophosphamide, doxorubicin, vincristine and prednisone or (iii) R plus mitoxantrone and fludarabine. We showed that only AMC was a powerful predictor of PFS , and possibly overall survival, in patients with FL treated with combination chemotherapy regimens that contained R. The AMC can be used alone as a novel, simple factor that can predict survival outcome in patients with FL , independent of the immunochemotherapy regimen. It may therefore be widely used by clinicians, due to its simplicity and broad applicability. Additionally, it can be combined with other factors that determine the IPI or FLIPI , to increase the discriminating ability of these indices.

Abstract: The introduction of agents inhibiting the BCR-associated kinases such as ibrutinib has dramatically changed treatments algorithms of chronic lymphocytic leukaemia (CLL) as well as the role of different adverse prognosticators. We evaluated the efficacy of ibrutinib as single agent, in a real-life context, on 180 patients with CLL mostly pre-treated, recruited from three independent cohorts from Italy. Patients received 420 mg oral ibrutinib once daily until progression or occurrence of unacceptable side effects. Seventy-three patients discontinued ibrutinib for progression or for adverse events. NOTCH1 mutations (M) were correlated with a reduced redistribution lymphocytosis, calculated at 3 months on ibrutinib (p=0.022). Moreover, NOTCH1 mutated patients showed inferior nodal response at 6 months on ibrutinib compared to NOTCH1 wild type patients (p 〈 0.0001). Significant shorter progression free survival (PFS) and overall survival (OS) were observed in NOTCH1 mutated patients (p=0.00002 and p=0.001). Interestingly, NOTCH1 M plus lower bax/bcl-2 ratio identified a CLL subset showing the worst PFS and OS (p=0.0002 and p=0.005). In multivariate analysis of PFS and OS, NOTCH1 M were confirmed an independent prognosticator (p=0.00006 and p=0.0039). In conclusion, NOTCH1 M are strongly associated with lower bax/bcl-2 ratio, consistent with a defective apoptosis, lower redistribution lymphocytosis and lower nodal shrinkage under ibrutinib treatment, this last responsible for partial responses, subsequent relapses, shorter PFS and OS. The therapeutic options for NOTCH1 mutated patients could be represented by either new small molecules combination approaches or from antibodies targeting NOTCH1.

Abstract: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Experimental Design: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. Results: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P & lt; 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. Conclusions: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.

Abstract: Abstract 1706 Poster Board I-732 Introduction in order to maintain efficacy and reduce toxicity of the treatment in elderly follicular lymphoma (FL) patients, we designed a study with a short chemo-immunotherapy R-FND with Rituximab consolidation followed by randomization between R maintenance or observation. Material and methods: From January 2004 to December 2007, 242 patients (age 60-75) with untreated advanced stage FL were enrolled by 33 IIL centres. Treatment plan was: 4 courses of R-FND (standard doses of Rituximab, Fludarabine, Mitoxantrone, Dexamethasone) every 28 days followed by 4 weekly Rituximab infusions as consolidation; responding (CR+CRu+PR) patients were randomized between Rituximab maintenance, one dose every 2 months for a total of 4 doses or observation. Qualitative and quantitative PCR monitoring for IgH/Bcl-2 rearrangement on bone marrow (BM) was performed at diagnosis, after R-FND and R consolidation and during maintenance/observation. Results 234 patients were eligible for the study: median age was 66 yrs; advanced stage II 14%, stage III 21% and stage IV 65%; BM involvement and B symptoms were documented in 55% and 18% respectively. FLIPI score was: Low 11%, Intermediate 34%, High 55%. One and 2 or more comorbidities were present in 36% and 23% of the patients respectively. Qualitative PCR analysis for IgH/Bcl-2 was performed in 223 patients at diagnosis and 51% were positive. Two hundred and two (86%) patients completed the induction treatment and were randomized between maintenance or observation; 32 were not because of: stable/progressive disease (16), adverse events (10) or other causes (6). Overall response at the end of treatment was 86% with 69% CR and 18% PR; PCR negativity at the end of treatment was 75%. Rituximab consolidation was able to induce CR in 37/90 (41%) partial responders and to increase PCR negativity from 61% to 75%. With a median follow-up of 22 months, two-years OS and PFS were 92% (95% CI 87%-95%) and 75% (95% CI 68%-81%), respectively (see Figure). Two-years PFS rates according to FLIPI score were 85% for low/intermediate risk and 65% for high risk (p 〈 0.001); 2-years PFS rates were 57% and 79% respectively in patients with and without B symptoms (p 〈 0.001). The patients in more advanced decade ( 〉 70 years) or those with 2 or more comorbidities did as well as younger ones or those with one or no comorbidities: 2-yr PFS rates for patients more or less seventy were 73% vs 76% (p = 0.39); for patients with ≥2 comorbidities or one or none were 84% vs 67% vs 76%, respectively (p = 0.82). A total of 1119 courses were delivered; the most frequent CTC grade 3-4 toxicity was neutropenia in 25% of the courses, with only 13 serious infections. One patients developed acute myelogenous leukaemia during treatment and died. Two toxic deaths during treatment (0.8%) occurred: 1 HBV reactivation and 1 Steven Johnson syndrome. So far 212 patients are alive; besides the above mentioned deaths, 15 patients died of lymphoma, 2 died of cardiac failure, 1 died of stroke and 1 died of drowning. So far too few events occurred to proper analyse the efficacy of the Rituximab maintenance. In the maintenance/observation phase the following severe (WHO grade 3-4) toxicities were recorded: 15 patients experienced neutropenia, seven cardiac events, four infections; no other relevant toxicities were recorded. The cumulative incidences of toxic events accounting for competing events at 18 months for maintenance arm (Arm A) versus observation arm (Arm B) were as follows: neutropenia 17% vs 1% (p 〈 0.001); infections 2% vs 2% (p = 0.586); cardiac events 4% vs 4% (p= 0.627). Conclusions a short term chemo-immunotherapy R-FND + Rituximab consolidation is safe and effective with a good 2-yr PFS rate also in patients with high risk FLIPI score or in patients in more advanced decade or with comorbidities. Rituximab maintenance is safe with a more frequent neutropenia that was not associated with an increased risk of infections. Final results of the study will provide insights on the role of Rituximab maintenance after R-chemotherapy. Disclosures Vitolo: Roche: Lecture fees; Mundipharma: Lecture fees. Off Label Use: Study was supported by Roche: Rituximab maintenance in first line treatment is off-label. Boccomini:Roche: Lecture fees. Ladetto:Roche Italy: Research Funding; Amgen: Honoraria, Research Funding.

Abstract: Introduction. The administration of immuno-chemotherapy (ICT) followed by rituximab maintenance (RM) is the recommended approach for the front-line therapy of high tumor burden follicular lymphoma (HTB-FL) patients. Among available ICT regimens, RB (Rituximab-bendamustine) and R-CHOP regimen, are preferred options with high, similar efficacy. Regarding RM, its use is strongly supported after R-CHOP by the results of the PRIMA randomized trial; conversely, no prospective data are available to confirm the efficacy of RM in patients initially treated with RB. The FOLL12 trial was conducted to try to demonstrate that a response adapted post induction management of patients with HTB-FL could be as effective as standard RM in terms of Progression Free Survival (PFS). The trial actually showed the better efficacy of standard RM compared to the experimental approach thus providing indirect confirmation of the efficacy of RM after ICT, 10 years after the PRIMA trial. We here analyse the impact of initial ICT in the FOLL12 study that left treatment choice between RB and R-CHOP at physician discretion and on an individual patient basis. Methods. FOLL12 is a multicenter, randomized, phase III trial that compared standard RM vs. a response adapted post induction management in treatment naïve adult patients with grade 1-3a, stage II-IV and a HTB-FL. All patients received induction immunochemotherapy with 6 cycles of either R-CHOP or R-Bendamustine both followed by two additional doses of rituximab. Choice of ICT was at the physicians' discretion. After ICT, patients in the standard arm received bimonthly rituximab for up to two years. Patients in the experimental arm were managed according to centrally reviewed metabolic and molecular response. Patients achieving complete metabolic (CMR) and molecular response were managed with observation only, those in CMR with molecular persistence received 4 weekly rituximab doses. Patients not achieving CMR were treated with radioimmunotherapy with ibritumomab tiuxetan followed by standard RM. Primary study endpoint was 3 years progression free survival (PFS). Results. A total of 786 eligible patients were enrolled and 1:1 randomized either to standard or experimental arm. By backbone therapy, 341 patients received RB and 445 received RCHOP induction immunochemotherapy. RB was more frequently prescribed in older and female patients (OR 1.6, p=0.001) whereas RCHOP was preferred in patients with bulky disease ( & gt;6cm) and grade 3a histology (OR 0.65, p=0.013). The median follow-up of the analysis was 56 months (range 1-71). In the non-randomized comparison between RB and RCHOP, no difference in terms of PFS was observed between the two regimens (HR for RB 1.07, 95%CI 0.83-1.38, p=0.597, Figure 1). Standard maintenance arm was more effective than experimental arm both in patients initially treated with RCHOP and in those treated with RB (HR RCHOP 1.61, 95% CI 1.16-2.25; HR RB 1.89, 95% CI 1.27-2.82). An unequal interaction between RB and RCHOP and post-induction therapy was observed for sex and for bone marrow involvement. Considering grade 3 to 5 adverse events (AEs), neutropenia was less frequently observed in RB (35.7%) compared to RCHOP (46.2%). Among extra-hematological AEs, higher frequency of grade 3-4 infections and of cutaneous toxicity were observed in RB treated patients (3.8% vs. 1.2% and 2.4% vs. 0.2%). Overall, 54 second malignancies (SM) have been observed including 23 hematologic malignancies and 31 solid cancers. Cumulative incidence of secondary cancer (excluding non melanoma skin cancers) at 3 and 5 years was 3.7% (95%CI 2.4-5.3%) and 8.1% (95%CI 5.8-10.9%). Conclusion. The current update of the FOLL12 trial demonstrated superiority of standard RM compared to the response adapted post induction management irrespective of prescribed regimen thus proving a first prospective non-randomized evidence of RM efficacy in patients with high tumor burden follicular lymphoma patients treated with RB. Both R-CHOP and RB were associated with a similar efficacy profile. Figure 1. Progression free survival for the standard maintenance arm (A) versus response oriented experimental arm (B) of the FOLL12 trial in patients treated with R-CHOP or R-Bendamustine (RB). Figure 1 Figure 1. Disclosures Luminari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Other: Travel, Accomodations, Expenses; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; GENELAB SRL: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ferrero: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda, Pfizer, Sandoz, Merk: Consultancy; Gilead, Bristol: Speakers Bureau. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy.