Abstract: Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level & gt; 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin ( & lt;40 g/L) and low hemoglobin ( & lt;120 g/L) levels were significantly associated with worse PFS in the R2 arm (p=0.001, and p=0.023), but not in the R-chemo arm. Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: Salvage chemotherapy followed by high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) is the standard treatment of young patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). A complete remission before ASCT is the most important prognosis factor for a better outcome. Selinexor is a first-in-class, oral selective inhibitor of nuclear export compound, an exportin 1 [XPO1] inhibitor, which, through XPO1 blockade, causes nuclear accumulation and activation of tumor suppressor proteins, reduction in oncoproteins and cancer cell apoptosis. Selinexor has been approved by the US Food and Drug Administration for the treatment of R/R DLBCL, de novo or transformed from follicular lymphoma (FL) pts after ≥2 therapies. The phase Ib SELINDA (EUDRACT 2015-005612-15) study assessed safety and efficacy of selinexor, in combination with R-GDP for pts with R/R B-cell lymphoma. Patients & methods: Eligible pts & lt; 70 years with R/R B-cell lymphoma after first or second treatment failure received every 21 days (d) 3 cycles of rituximab 375 mg/m² on d1, dexamethasone 40 mg on d1 to 4, cisplatin 75 mg/m² d1 and gemcitabine 1 gr/m² on d1 and 8 (R-GDP) in combination with escalating doses of selinexor. The starting dose (dose level 1, DL1) 40 mg was given on days 1, 3, 8, 10 (Cohort A), and from December 2017 on days 1, 8 and 15 (Cohort B). The dose-variation scheme followed a traditional "3+3" design (DL1: 40 mg; DL2: 60 mg). The primary endpoint of SELINDA was the determination of the recommended phase 2 dose of selinexor in combination with R-GDP. Secondary and exploratory endpoints were safety, efficacy, and feasibility of ASCT after selinexor-R-GDP. Results: The R2PD for selinexor in combination with R-GDP was established as 40 mg on days 1, 8, and 15 (Maerevoet, IMCL 2021#176). Between January 2017 and January 2021, 32 pts received selinexor-R-GDP. We focused on the 18 pts who received the R2PD: 15 had DLBCL, 2 FL, 1 marginal zone lymphoma. In this cohort, median age was 61 years (range 44-69); 14 pts (78%) has stage III/IV. Thirteen pts received 1 previous line before inclusion, 5 pts received 2 previous lines. At inclusion, 6 pts had refractory disease and 12 relapsed. Four pts prematurely discontinued treatment: 2 for thrombocytopenia, 1 for COVID, 1 for progression. Major adverse events (AEs) in & gt;10% of pts were reversible neutropenia (50%), thrombocytopenia (39%), and nausea (22%). No AEs leading to death were observed. Seven pts (39%) achieved a complete metabolic response (CMR), 5 pts (28%) partial metabolic response (PMR). Overall response rate (CMR+PMR) assessed at the end of treatment according to Lugano classification was 67% (12 of 18). Nine of the 15 pts (60 %) with DLBCL had metabolic response (CMR:4, PMR:5). Per protocol, peripheral stem cell collection and ASCT were optional, 4 pts of this RP2D cohort proceeded to high dose therapy (BEAM) and ASCT. Conclusion: This study established the safety profile of weekly 40mg of Selinexor in combination with R-GDP for R/R B cell lymphoma with an ORR of 67%. Reversible AEs are expected for platinum-based regimen. An ongoing randomized phase 2 study comparing R-GDP and R-GDP plus selinexor in pts with R/R DLBCL will now establish the safety and efficacy of the combination. Disclosures Casasnovas: Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding; Amgen: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Genentech, Inc.: Consultancy; Chugai: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Feugier: Amgen: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria.

Abstract: Introduction: For patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL) who develop resistance to rituximab, treatment options are limited and the prognosis is poor. The open-label, randomized, Phase III GADOLIN (NCT01059630) study compared the efficacy and safety of obinutuzumab (GA101; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (B arm; standard of care) in rituximab-refractory iNHL. The primary analysis in 396 pts (data cutoff: September 1, 2014; median observation time, 21.0 months) showed that Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was significantly longer with G-B (median not reached [NR]) vs B (14.9 months), corresponding to a 45% reduction in risk of progression or death (hazard ratio [HR] , 0.55; 95% confidence interval [CI]: 0.40, 0.74; p=0.0001; Sehn et al. Lancet Oncol 2016). The safety profile of G-B was manageable. Here, we report the final analysis of efficacy and safety for GADOLIN (when safety follow-up for all pts had been completed [2 years' safety follow-up from last dose] ; data cutoff: November 30, 2018). Methods: Enrolled pts were aged ≥18 years with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg intravenously (i.v.) (Days [D] 1, 8, and 15 of Cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6) or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6) in 28-day cycles. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 months for 2 years or until disease progression). Final analysis endpoints included investigator (INV)-assessed PFS, overall survival (OS), time to new anti-lymphoma treatment (TTNT), and safety. The safety population included pts who received ≥1 dose of study treatment, excluding two pts crossing over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had follicular lymphoma (FL). Median (range) observation time was 57.5 (0.4-97.6) months for the G-B arm and 47.9 (0-100.9) months for the B arm (i.e. 27.6 and 35.6 months additional follow-up since the primary analysis). Median INV-assessed PFS was 25.8 months for the G-B arm vs 14.1 months for the B arm (HR, 0.57; 95% CI: 0.45, 0.73; p 〈 0.0001) in all iNHL pts (Figure 1A). Overall, fewer iNHL pts died in the G-B (84/204; 41.2%) than in the B (100/203; 49.3%) arm; median OS was 88.3 vs 65.6 months (HR, 0.77; 95% CI: 0.57, 1.03; p=0.0810; 23% risk reduction [Figure 1A]). Median TTNT was also longer with G-B vs B (38.2 vs 18.9 months, respectively [HR, 0.60; 95% CI: 0.47, 0.76] ). Results for FL pts were as follows: median PFS, 24.1 vs 13.7 months (HR, 0.51; 95% CI: 0.39, 0.67; p 〈 0.0001 [Figure 1B]); median OS, NR vs 60.3 months (HR, 0.71; 95% CI: 0.51, 0.98; p=0.0343); median TTNT, 33.6 vs 18.0 months (HR, 0.56; 95% CI: 0.43, 0.73). In the safety population (N=407; G-B, 204; B, 203), 149/204 (73.0%) of pts in the G-B arm and 134/203 (66.0%) in the B arm experienced grade ≥3 adverse events (AEs). Compared with B, grade ≥3 neutropenia (37.3% vs 30.0%) and grade ≥3 infusion-related reactions (11.3% vs 5.4%) were more frequent with G-B, and grade ≥3 thrombocytopenia (10.8% vs 15.8%) and anemia (7.4% vs 10.8%) were less frequent. The incidences of grade ≥3 infections (22.5% vs 19.2%) and grade ≥3 second malignancies (7.8% vs 5.9%) were similar between arms. The proportion of pts with serious AEs was 91/204 (44.6%) in the G-B arm and 76/203 (37.4%) in the B arm; fatal AEs were reported in 20/204 (9.8%) and 15/203 (7.4%) of pts, respectively. The most frequent AEs leading to death in the G-B vs B arms were infections (six vs seven pts, respectively) and second malignancies (eight vs four pts, respectively). Safety results in FL pts were comparable with all iNHL pts. Conclusions: Final analysis of the GADOLIN study showed that G-B was associated with a 43% reduction in the risk of progression or death compared with B in pts with rituximab-refractory iNHL and a 49% reduction in pts with FL, with a sustained and clinically relevant OS benefit in pts with FL. There were no new safety signals with longer follow-up. Acknowledgments: The GADOLIN study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Sehn: TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Trněný:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Bouabdallah:Roche: Consultancy, Honoraria, 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, Speakers Bureau. Dueck:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Roche: Research Funding. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Lugtenburg:Celgene: Honoraria; Janssen-Cilag: Honoraria; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Genmab: Honoraria. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Liu:Roche Pharma Development, Shanghai, China: Employment. Cheson:Seattle Genetics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.

Abstract: Introduction: Anti-PD-1 monoclonal antibodies (mAbs) are highly active in relapsed/refractory classical Hodgkin lymphoma (cHL), but most patients (pts) will still relapse. Given this, allogeneic stem cell transplantation (alloHSCT) remains an important option for pts after PD-1 blockade, as it offers the possibility of cure. Prior reports have suggested that alloHSCT after PD-1 mAbs may be associated with severe immune-related complications including acute graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytokine release/febrile non-infectious syndrome (CRS). Prior studies of alloHSCT after PD-1 blockade in cHL have been limited by the small number of pts and short follow-up, preventing an accurate assessment of long-term outcomes and complications, risk factors for early toxicity, and the impact of transplant strategies such as choice of GVHD prophylaxis. We therefore assembled a large retrospective international cohort of cHL pts who underwent alloHSCT after PD-(L)1 blockade to better answer these questions, including an assessment of the impact of post-transplant cyclophosphamide (PTCy) on efficacy and toxicity. Methods: Medical records and databases were reviewed at 26 European and United States transplant centers to identify pts with cHL who underwent an alloHSCT any time after receiving a PD-1 or PD-L1 mAb. Response assessment was performed by local investigators according to Lugano 2014 criteria. Overall survival (OS), progression-free survival (PFS), cumulative incidence (CumInc) of relapse (CIR), non-relapse mortality (NRM), acute (a) and chronic (c) GVHD were estimated, as was the association between baseline variables and these outcomes. Results: Between 2014 and 2019, 150 pts were identified who underwent alloHSCT after a median of 10 (range, 1-74) doses of nivolumab (n=118), pembrolizumab (n=31), or avelumab (n=1). The median age was 31 (range 17-68) and pts had received a median of 4 (range, 2-11) lines of therapy prior to PD-(L)1 blockade. 138 pts (92%) had failed BV and 111 (74%) autologous HSCT. The best overall response to PD-(L)1 mAbs was CR for 62 pts (41%), PR for 55 (37%), SD for 17 (11%), PD for 15 (10%) and unknown for 1 (1%). Median time from last dose of PD-(L)1 mAb to alloHSCT was 80 days (range, 17-756) with 70 pts (47%) receiving intervening systemic therapy. At alloHSCT, 90 pts were in CR (60%), 45 in PR (30%), 5 in SD (3%), and 10 in PD (7%). Donors were haploidentical (n=71, 47%), matched sibling (n=29, 19%), matched unrelated (n=39, 26%), mismatched unrelated (n=7, 5%), cord blood (n=2, 1%), or unknown (n=2, 1%). Stem cell source was bone marrow (n=38, 25%), peripheral blood (n=110, 73%), or cord blood (n=2, 1%). GVHD prophylaxis included PTCy in 88 pts (59%) (69/71 (97%) with haploidentical donors; 19/79 (24%) with other donors). With a median post-alloHSCT follow-up for survivors of 23.8 months (range, 1-67), the 2y OS and PFS were 79% (95CI 71-86%) and 65% (95CI 55-73%), respectively, while the 2y CumIncs of relapse and NRM were 21% (95CI 13-29%) and 14%, (95CI, 8-22%), respectively (Fig. 1A-B). 27 pts have died, 3 due to disease and 24 to NRM, including aGVHD (n=7) and VOD (n=2). Veno-occlusive disease (VOD) occurred in 5 pts (day 100 CumInc 4%) and 29 pts (19%) developed CRS (grade 1 n=16; grade 2 n=7; grade 3 n=4; grade 4 n=2). The 6-month CumIncs of grade 2-4, grade 3-4 and grade 4 aGVHD were 39%, 16% and 8%, respectively. Hyperacute GVHD (onset ≤ 14 days after alloHSCT) occurred in 4% of pts and was fatal in 2 pts. The 2y CumInc of cGVHD was 45%. Neither receipt of & gt; 10 doses (median) of anti-PD-(L)1 mAb nor undergoing alloHSCT ≤80 days (median) after last dose of PD-(L)1 mAb were associated with PFS or OS. However, pts with a shorter time to transplant (≤80 days) appeared to have a higher risk of severe (grade 3-4) aGVHD (6m CumInc 24% vs 9%, p=0.006). Recipients of PTCy in this cohort had lower 2y CumIncs of cGVHD (34% vs 58%, p=0.01) and relapse (12% vs 31%, p=0.02), superior 2y PFS (76% vs 54%, p=0.015), and similar rates of severe aGVHD (15% vs 18%, p=0.5), 2y NRM (12% vs 16%, p=0.5), and 2y OS (82% vs 78%, p=0.6). Conclusions: With extended follow-up of a large international cohort, our results argue that alloSCT performed after PD-(L)1 mAbs is a feasible strategy associated with an excellent PFS and a very low CIR for this disease. The use of PT-Cy appears to be associated with improved outcomes and may at present represent the optimal transplant strategy in this pt population. Figure Disclosures Corradini: kite: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Hamadani:Pharmacyclics: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Otsuka: Research Funding; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy. Ansell:LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Feldman:Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Takeda: Honoraria, Speakers Bureau. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Stamatoulas Bastard:Celgene: Honoraria; Takeda: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Manson:Bristol Myers Squibb: Honoraria. Orvain:Incyte: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Other: Travel & accommodations; Pfizer: Other: Travel & accommodations. Bouabdallah:Roche: Consultancy, Honoraria, 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, Speakers Bureau. Frigault:Novartis: Consultancy; Kite/Gilead: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Juno/Celgene: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy. Chen:Takeda: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Incyte: Consultancy. Lynch:T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Juno Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Smith:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Incyte Corporation: Research Funding; Ayala (spouse): Research Funding; Seattle Genetics: Research Funding. Byrne:Karyopharm: Research Funding. Cohen:Hutchison: Research Funding; Astra Zeneca: Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Genentech, Inc.: Consultancy, Research Funding; UNUM: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau. Armand:Sigma Tau: Research Funding; Otsuka: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Genentech: Research Funding. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Carlo-Stella:Servier: Consultancy, Honoraria, Other: Travel, accommodations; Genenta Science srl: Consultancy; Boehringer Ingelheim: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations.

Abstract: The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.

Abstract: Background: Duvelisib is an oral, dual inhibitor of PI3K-d,γ, in development for the treatment of hematologic malignancies, including follicular lymphoma (FL). Duvelisib disrupts PI3K-d,γ-mediated signaling within tumor cells and their interactions with the tumor microenvironment, hindering hematologic tumor cell survival. Data from a Phase 1 study of duvelisib indicate the potential for duvelisib to be an effective treatment for FL, with an acceptable safety profile. CONTEMPO (NCT02391545), is designed to evaluate the safety and clinical activity of duvelisib in combination with rituximab (DR) or obinutuzumab (DO) in patients (pts) with previously-untreated CD20+ FL. Methods: In CONTEMPO, duvelisib is administered at 25 mg BID continuously in 28-day treatment cycles, combined either with rituximab (375 mg/m2 for 4 weekly doses, then 1 dose every 2 cycles) or obinutuzumab (1000 mg for 4 weekly doses, then 1 dose every 2 cycles). Pts are assigned 1:1 into the two parallel treatment arms. Key inclusion criteria include: diagnosis of previously-untreated CD20+ FL, Stage II with bulky disease (≥ 7 cm lesion), or Stage III-IV disease, at least 1 measurable disease lesion 〉 1.5 cm, adequate liver and renal function, and no clinical evidence of transformation to a more aggressive subtype of lymphoma or Grade 3B FL. Prophylaxis for herpes (HSV/VZV) is recommended. For pts with a history of CMV infection requiring treatment, prophylaxis and monitoring of reactivation is recommended. The original protocol mandated PJP prophylaxis when CD4 counts were ≤ 200 cells/mm3, and was subsequently amended to include all pts. Disease response assessments (CT scans and physical exams) occur on Day 1 of Cycle 4 (C4), C8, C12, C16, C20, and C26. Results: As of 19 July 2016 (data cut-off), 28 pts received DR and 27 received DO. For DR pts, the median age was 58 years, most were male (64%), 21% had Gr 1 and 64% Gr 2 disease at baseline, and 54% had bone marrow involvement. Median time from diagnosis was 2.3 months. For DO pts, the median age was 58 years, most were female (59%), 48% had Gr 1 and 30% Gr 2 disease at baseline, and 59% had bone marrow involvement. Median time from diagnosis was 2.6 months. DR pts were on treatment for a median of 3.9 months, DO pts for 4.5 months. The overall response rate (ORR) per IWG criteria for DR was 87% and for DO was 91% (see table) The rate of AEs for DR pts was 93%, with 50% having a ≥ Gr 3 AE. 64% of DR pts had an AE leading to duvelisib dose modification (reduction or hold), while 14% discontinued duvelisib due to an AE. The most common ≥ Gr 3 AEs on DR ( 〉 2 pts) were ALT increased (21%) and rash (14%). The rate of ≥ Gr 3 infections was 11%, including PJP (n=2; no prophylaxis, pre-amendment), followed by lung infection and pneumococcal pneumonia (1 pt, each). One PJP case resolved and the pt continued on study. The second PJP case resolved, however the pt had a subsequent fatal event of acute respiratory distress, the only fatal AE on study. The rate of AEs for DO pts was 89%, with 70% of pts having a ≥ Gr 3 AE. 63% of DO pts had an AE leading to duvelisib dose modification (reduction or hold), while 7% discontinued duvelisib due to an AE. Most common ≥ Gr 3 AEs ( 〉 2pts) on DO were neutropenia (19%), ALT increased (15%), and AST increased (11%). The rate of ≥ Gr 3 infections was 15%, including conjunctivitis, RSV pneumonia, pyelonephritis, and septic shock (1 pt, each). No pts on DO died due to an AE. Conclusions: Preliminary clinical activity with DR (87% ORR, 22% CR) and DO (91% ORR, 18% CR) supports the potential role of duvelisib in combination with an anti-CD20 monoclonal antibody as initial treatment for pts with FL. The safety profile was manageable with appropriate risk mitigation measures, suggesting further investigation of these combinations may be warranted. Disclosures Casulo: Celgene: Research Funding; Infinity: Consultancy, Honoraria. Sancho:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gyan:Amgen: Honoraria; Sanofi: Honoraria; Pierre Fabre: Honoraria; Novartis: Research Funding; Celgene: Research Funding; Fresenius Kabi: Honoraria; Gilead: Consultancy, Speakers Bureau; Mundipharma: Consultancy; Roche: Research Funding. Steelman:Infinity: Employment. Pearlberg:Infinity: Employment. Goy:Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding.

Abstract: Background: Treatment options for patients (pts) with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) are limited. GADOLIN (NCT01059630) is an open-label, randomized, Phase 3 trial comparing the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (standard of care) in rituximab-refractory iNHL pts. In the primary analysis, which involved all pts enrolled as of September 1, 2014 (n=396; median observation time, 21.0 months [mo]), median Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was longer in the G-B arm (194 pts; median not reached) than in the B arm (202 pts; 14.9 mo), with a 45% reduction in risk of progression or death (HR 0.55; 95% CI 0.40, 0.74; p=0.0001). Investigator (INV)-assessed PFS was also significantly longer in the G-B arm, but overall survival (OS) data were immature. Safety profiles were comparable. The most common grade ≥3 adverse events (AEs) were neutropenia, thrombocytopenia, anemia, and infusion-related reactions (IRRs). Seventeen additional pts were enrolled after the data cut-off for the primary analysis. Here, we report updated time-to-event and safety results from a planned analysis of all pts (n=413) using a data cut-off of April 1, 2016. Methods: Enrolled pts were aged ≥18 years (yrs) with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg i.v. (days [D] 1, 8, and 15 of cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6), or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6); each cycle was 28 days. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 mo for 2 yrs or until disease progression, whichever occurred first). In the current analysis, assessments included INV-assessed PFS, OS, time to new anti-lymphoma treatment (TTNT), and safety. Efficacy assessment was performed on the intent-to-treat (ITT) population. Safety analysis included all pts who received any study treatment, excluding 2 pts who crossed over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had FL. Baseline characteristics of the ITT population were balanced between arms. Median number of prior regimens was 2 in both arms (pts with ≤2 prior regimens: G-B, 80.4%; B, 77.5%). Most pts were refractory to their last regimen (G-B, 92.2%; B, 92.3%). After 31.8 mo median follow-up, median INV-assessed PFS was 25.8 mo in the G-B arm and 14.1 mo in the B arm; HR was 0.57 (95% CI 0.44, 0.73; p 〈 0.0001), i.e. a 43% reduction in risk of progression or death for G-B relative to B. Fewer pts died in the G-B arm (25.5%) than the B arm (34.9%), with a HR for OS of 0.67 (95% CI 0.47, 0.96; p=0.0269; risk reduction, 33%; Figure 1A); median OS was not reached for either arm. Results for FL pts were consistent with those for ITT pts (median PFS: 25.3 vs. 14.0 mo [HR 0.52; 95% CI 0.39, 0.69; p 〈 0.0001]; median OS: not reached vs. 53.9 mo [HR 0.58; 95% CI 0.39, 0.86; p=0.0061; Figure 1B] ). Median TTNT was also longer in the G-B arm than in the B arm (ITT pts: 40.8 vs. 19.4 mo, respectively [HR 0.59; 95% CI 0.45, 0.77]; FL pts: 33.6 vs. 18.0 mo, respectively [HR 0.57; 95% CI 0.43, 0.75] ). The overall safety profile of G-B remained consistent with results of the primary analysis. In the ITT population, there were more grade ≥3 AEs with G-B than with B (72.5% vs. 65.5%, respectively), notably neutropenia (34.8% vs. 27.1%) and IRRs (9.3% vs. 3.5%); grade ≥3 thrombocytopenia (10.8% vs. 15.8%) and anemia (7.4% vs. 10.8%) were less frequent in the G-B arm, while grade ≥3 infections (22.5 % vs. 19.2%) and secondary malignancies (5.9% vs. 5.4%) were reported with a similar incidence. Serious AEs were more frequent in the G-B arm (43.6% vs. 36.9%), but the incidence of grade 5 (fatal) AEs was similar (7.8% vs. 6.4%). Safety results in FL pts were comparable with those in all iNHL pts. Conclusions: Updated analysis of the GADOLIN study with ~10 mo additional follow-up confirms the previously reported PFS benefit of G-B over B in pts with rituximab-refractory iNHL, and demonstrates a significant improvement in OS in the G-B arm. No new safety signals were detected. Figure 1. OS results: A) ITT population; B) FL pts Figure 1. OS results: A) ITT population; B) FL pts Disclosures Cheson: Roche-Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astra Zeneca: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Teva: Research Funding. Trněný:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Roche: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Research Funding; Lundbeck: Honoraria, Research Funding. Lugtenburg:Celgene: Consultancy; Mundipharma: Consultancy; Servier: Consultancy; Roche: Consultancy; Takeda: Consultancy. Salles:Mundipharma: Honoraria; Gilead: Honoraria, Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Wassner-Fritsch:elisabeth.wassner_fritsch@roche.com: Employment. Sehn:Roche/Genentech: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Lundbeck: Consultancy.

Abstract: Introduction: Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) that blocks XPO1, forcing the nuclear retention and re-activation of tumor suppressor proteins including p53, p73, FOXO, I□B and Rb. The phase 2b SADAL study included 134 patients with relapsed or refractory DLBCL with single agent oral selinexor twice weekly. The overall response rate (ORR) was 29.1%, median duration of response (DOR) was 9.3 months and the median overall survival (OS) was 9 months. Based on these data, selinexor was recently approved by the US FDA for the treatment of relapsed or refractory DLBCL, de novo or transformed from follicular lymphoma. Patients with DLBCL tend to be older (over the age of 65) and have a number of comorbidities, which limits the use of aggressive and multi-agent combination therapies. We performed post-hoc analyses of the SADAL study to determine the effects of age on the efficacy and safety of selinexor in this population. Methods: The SADAL study is multi-center, open-label Phase 2b study that enrolled patients with DLBCL previously treated with 2-5 lines of therapy. Patients may have progressed post-stem cell therapy (SCT) or were not candidates for SCT. In this study, 60 mg of selinexor was administered twice weekly until disease progression. The primary endpoint was ORR, and other endpoints included DOR, OS, and safety assessments. For the current analysis, outcomes were assessed in patients & lt;65 versus those ≥65 years old. Results: Of the 134 patients enrolled in the study, 52 (39%) were & lt;65 and 82 (61%) were ≥65 years old. In the & lt;65 group, 14% patients had baseline creatine clearance (CrCl) of 30- & lt;60 mL/min compared with 33% in ≥65 group. Patients with transformed DLBCL accounted for 17% and 27% of patients in the & lt;65 and ≥65 groups, respectively. Subtype analysis revealed 43% GCB and 55% non-GCB DLBCL in ≥65 year olds, and 54% GCB and 40% non-GCB in the & lt;65 group. The & lt;65 group had baseline ECOG performance status of 2 in 8% compared with 13% in the ≥65 group. Patients & lt; 65 received numerically higher median doses of selinexor (1360 and 770 mg [p=0.079] ) and a longer duration of treatment (13.5 vs. 8.0 weeks [p=0.049]). There was no statistical difference in ORR in patients & lt;65 vs. ≥65 years old: 36.5% vs. 24.4% (p=0.189). The complete response (CR) rates were 17.3% and 11% (p=0.431), respectively. Median DORs were similar at 9.7 months in the & lt;65 compared to 9.2 months in the ≥65 year olds. While the median progression-free survival (PFS) (3.6 and 2.3 months) was similar between groups, the OS was higher in the & lt;65 year olds: 13.7 vs. 7.8 months (p=0.037). The incidence of treatment-related AEs was comparable between both groups: The most common grade ≥3 AEs in & lt;65 versus ≥65 year olds were thrombocytopenia (42.3% vs. 39.0%), nausea (3.8% vs. 7.3%), and fatigue (5.8% vs. 13.4%). Treatment-related serious AEs occurred in 11.5% of patients & lt;65 (n=6) and 26.8% ≥65 (n=22), with general disorders and administration site conditions (n=12) and fatigue (n=6) as the largest contributors in the ≥65 group. Treatment discontinuations due to AEs occurred at a lower incidence in the & lt;65 group compared with & gt;65 (3.8% vs. 11.0%). Conclusions: Patients with relapsed/refractory DLBCL who were ≥65 years had a similar clinical benefit to those & lt;65 when treated with selinexor, with comparable ORR, CR, PFS, DOR, and safety profile. As expected, younger patients ( & lt;65 years old) had a longer overall survival than those ≥65 years old, most likely due to comorbid medical conditions in the patients ≥65 years. These results indicate that selinexor can induce durable responses in younger and older patients with heavily pretreated DLBCL with similar tolerability. Disclosures Schuster: Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Canales:Janssen: Honoraria; Roche: Speakers Bureau; Gilead: Honoraria; Sandoz: Honoraria; Janssen: Speakers Bureau; Sandoz: Speakers Bureau; Roche: Speakers Bureau; Novartis: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Takeda: Speakers Bureau; Novartis: Honoraria; Sandoz: Speakers Bureau; iQone: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau; Roche: Honoraria; Janssen: Speakers Bureau. Westin:Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Curis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Amgen: Consultancy; Janssen: Consultancy, Research Funding. Zijlstra:Roche: Research Funding. Follows:Karyopharm, Roche, Abbvie, Astrazeneca, Janssen, BMS: Membership on an entity's Board of Directors or advisory committees. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Verastem, Gilead, Celgene, Roche: Research Funding; Gilead, Janssen, Karyopharm: Honoraria. Goy:Constellation: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Infinity: Research Funding; Karyopharm: Research Funding; PracticeUpdate Oncology: Consultancy; MD Anderson: Research Funding; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; RCCA/OMI: Current Employment; Morphosys: Research Funding; Genentech/Roche: Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; CALBG: Research Funding. Casasnovas:Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Honoraria; Bayer: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Cavallo:Gilead: Other: Speaker Fee; Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees. Hill:Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Gurion:JC Health CARE: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Martin:Janssen: Consultancy; Regeneron: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding. Davies:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy. Collins:Amgen: Research Funding; Pfizer: Honoraria; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salles:Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Novartis: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Epizyme: Consultancy; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Autolus: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events. Ma:Karyopharm: Current Employment, Current equity holder in private company. Corona:Karyopharm: Current Employment. Saint-Martin:Karyopharm: Current Employment. Joshi:Karyopharm Therapeutics Inc: Consultancy. Chamoun:Karyopharm: Current Employment. Wang:Curis: Ended employment in the past 24 months; Karyopharm: Current Employment. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Shacham:Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman:Karyopharm Therapeutics Inc: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background. Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor, is currently under investigation in prospective trials in R/R MCL. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody approved in frontline and R/R follicular lymphoma which has shown efficacy in MCL (Chiron Blood 2016, Le Gouill ICML/EHA 2019). Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016) The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study that was designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. The study is divided into three steps (A, B,C, respectively) : step A enrolled nine R/R MCL who were treated with Ibrutinib plus Obinutuzumab and step B enrolled 24 R/R MCL patients who were treated with Ibrutinib/Venetoclax/Obinutuzumab (Venetoclax dose from 200 to 800mg ). The Ibrutinib/Venetoclax/Obinutuzumab combination demonstrated a good safety profile and high response rates in R/R MCL (step B). No DLT was reported in either step (Le Gouill et al, ASH 2018). Herein, we present the safety (primary objective), clinical and MRD results for Oasis step C where Ibrutinib/Venetoclax/Obinutuzumab was given to newly-diagnosed, untreated MCL patients. Methods: Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment. Results. Fifteen untreated MCL patients were enrolled from August 2018 to April 2019, in 6 participating centers (France and UK). Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass & gt;5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 13 patients (one was not informative and two are ongoing) of these one presented TP53 mutation. IGHV status (assessed in 13 patients, ongoing in 2) was mutated in two cases including the p53mutcase and not mutated in 8 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis - grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 7 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 8 patients (others are ongoing) were assessed at end of cycle 3 and all were MRD negative in BM (n=6) and/or in blood (n=8), including the p53mutpatient. Seven patients completed 6 cycles, all reached CR according to Lugano criteria (6 in CR/Cru according to Cheson criteria) and were MRD neg (in blood in all cases and in BM in 6 cases -one not done), including the P53mut patient. At date of last monitoring (Jul 2019), no disease progression is reported and all patients remain under the planned treatment. Conclusion. Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL. Disclosures Le Gouill: Janssen-cilag: Consultancy, Honoraria; Novartis: Consultancy; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; loxo: Consultancy, Honoraria; Takeda: Consultancy. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Napp: Consultancy; TG Therapeutics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. OffLabel Disclosure: Venetoclax, obinutuzumab in mantle cell lymphoma

Abstract: Myelodysplastic syndromes are an heterogenous group of malignancies with a poor outcome. In order to improve the response rates and to prolong survival, many trials have been conducted including new scoring systems and using combination of new drugs. We conducted a multicentric opened phase II trial with topotecan (1,5 mg/m² CI dy 1 to 5), cytarabine (1,0 mg/m² CI dy 1 to 5) and amifostine (200 mg/m² dy 1,3 & 5) in 31 consecutive patients (M=33, F =8) with high risk myelodysplastic syndrome according to the FAB classification and defined as refractory anemia with excess of blasts (RAEB [18 pts]), RAEB in transformation (RAEBt [6 pts] ), chronic myelomonocytic leukemia (CMML [6 pts]) and with an IPSS ≥1,5 (median = 2). The main characteristics of patients are summarized in table 1. table 1: patient characteristics at diagnosis The treatment plan consisted in two or three induction courses followed by two additional cycles at lower doses (half-dose) for those with partial response (PR), very good partial rsponse (VGPR) or hematological improvement (HI). Patients in CR or with progressive disease could receive consolidation therapy with either autologous or allognenic stem cell transplantation if eligible for intensive treatment. The main objective of the study was to evaluate the response rate after the induction courses. Three patients diden’t receive the treatment (2 for acute transformation, 1 death). The data study are analyzed by “intention to treat analysis” (ITT). The median follow-up is 14,5 months. The post-induction CR and CR+PR rates are respectively of 38,7% and 45,2%. During the study 48% of patients achieved a CR (RAEB 61%, RAEBt 67%, CMML 0%). The median time to achieve CR is 2,9 months (95% CI, 1,1–4,8) with a probability of 59,1% (± 19,6). The median duration of CR is 7 months (95% CI, 2,1–11,9). The median overall survival is 24 months (95% CI, 9,89-NR) [RAEB NR, RAEBt = 10,8, CMML = 5,3]. The probability of overall survival at 25 months is 47% (± 24,8) with the worst scores for patients with RAEB and RAEBt and those with IPSS ≥ 2,5 Twenty-four patients had an adverse event with grade & gt; 2, mainly from infectious cause. Twelve patients died (5 from relapse, 2 from secondary leukemia, 4 miscellaneous). One toxic death occured during the srudy. Nine patients were eligible forr intensification. Seven are alive of which 6 are in continuous CR with a median follow-up from transplant of 17 months. Two patients died respectively from aGVHD and relapse. This combination is a safe procedure in patients with high risk myelodysplastic syndrome. In patients eligible for intensive treatment it could be an interesting regimen prior to transplantation since, per protocol, 53,5% of patients achieve a CR during the study, especially those with RAEB and RAEBt n age (median) RAEB RAEBt CMML IPSS (median) Follow-up Cytogenetic 31 58 18 6 6 2 14,5 29