Abstract: Background: MCL is a heterogeneous disease and the existence of indolent clinical forms is increasingly recognized although their biological ground is not fully elucidated. The aim of this study was to propose a frontline tailored treatment for indolent clinical forms with a chemo-free regimen, ibrutinib in combination with rituximab. In addition, an extensive genomic study was associated to gain biological insight into these clinical forms. Methods: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 14 Spanish GELTAMO sites (NCT02682641). Centralized histology, PET-CT review as well as minimal residual disease (MRD) studies (qPCR and NGS in peripheral blood [PB] and bone marrow [BM] ) and biological studies are conducted. A total of 50 previously untreated MCL patients with indolent clinical forms are planned to be recruited, defined by the following criteria: no symptoms attributable to MCL, ECOG 0-1, stable disease without therapy need at least for 3 months, non-blastoid variants, Ki-67 & lt;30% and largest tumor diameter ≤3 cm. Both leukemic non-nodal and nodal forms were acceptable. Patients received ibrutinib 560 mg daily and a total of 8 doses of Rituximab 375 mg/m2 (4 weekly doses during first 28-day cycle, followed by day 1 of cycles 3, 5, 7 and 9). Ibrutinib could be discontinued after 2 years of treatment in case of negative MRD for at least 6 months. The primary endpoint was the rate of complete remission (CR) achieved after 12 cycles according to the Lugano criteria (Cheson, 2014). Results: Forty patients (Gender M 29/ F 11; median age 65.7 years; low-risk MIPI 22% and intermediate/high MIPI 78%) were enrolled in the study up to data cut-off on 15 MAY 2019 (Consort diagram). The median observation time for the patients before treatment was of 7.6 months (range:3-107) and median follow-up was of 19 months. Efficacy data of the first 33 patients evaluable after 12 cycles of treatment are reported here, including two patients who were discontinued before cycle 12 due to related toxicity. A total of 27 patients achieved a response with an 82% overall response rate (ORR) and 75% CR. Among CR patients with evaluable MRD (N=23), the rate of undetectable MRD achieved after 12 cycles was 87%. Only 1 patient eventually became MRD positive at cycle 24, whereas 12 remained MRD negative and accordingly, nine of them discontinued ibrutinib as per protocol whereas 3 had interrupted treatment earlier because of intolerance. At data cut-off, all responding patients maintained the response with a median follow-up of 25 months (12-35). Only one patient progressed at one year of therapy. This particular case had shown intolerance to full-dose ibrutinib, received different salvage therapies and died of progressive disease. The estimated 15 month progression-free survival was 96% (CI95%: 89-100). Four patients withdrew the study because of serious adverse events, including cutaneous rash, severe aplastic anemia, pancreatic adenocarcinoma and lumbar fractures. Twenty-one additional G3 and G4 AEs related to Ibrutinib have been recorded including hematological toxicity in 7 patients, gastro-intestinal intolerance in 4 patients, arthralgias, atrial fibrillation and asthenia in one patient each. Conclusion: In indolent clinical forms of MCL frontline ibrutinib in combination with rituximab has a high efficacy, including undetectable MRD in the majority of cases, with a predictable toxicity profile. Figure Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Martín:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Teva: Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses; iQone: Consultancy; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Kiowa Kirin: Consultancy. Terol:Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy; Roche: Consultancy; Gilead: Research Funding; Abbvie: Consultancy. González-Barca:AbbVie: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Roche: Consultancy, Honoraria; Celtrion: Consultancy; Takeda: Honoraria. Lopez-Guillermo:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract: Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a ligand for CXCR4 that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. We have previously shown that FT inhibition by tipifarnib downregulates CXCL12 secretion. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age & gt;/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (wt CXCL12 3'UTR cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Tumor Whole Exon Sequencing (WES) was generated by NGS and gene expression data generated by RNA Seq. Ancillary studies also investigated the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results As of 24 May 2019, 50 PTCL pts (23 AITL, 25 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 31 pts in the ongoing AITL histology and wt CXCL12 3'UTR cohorts. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts (n=48 with available safety data) had at least one treatment-emergent adverse event (TEAE); 42 (88%) had at least 1 study drug-related TEAE and 13 (27%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade & gt;3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (40%), thrombocytopenia (33%), leukopenia (25%), anemia and febrile neutropenia (19% each). There have been 14 deaths on study; one related to study drug (lung infection). Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 5 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable of 16 pts enrolled), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the wt CXCL12 3'UTR cohort (n=12 evaluable pts), a 42% ORR was observed (3 CR, 2 PR), with 2 of the 3 CRs observed in patients of AITL histology (n=4). A total of 23 AITL subjects were enrolled in the overall study of whom 16 had WES data. A strong association with the activity of tipifarnib was observed in 8 of the 16 (50%) carrying KIR3DL2 gene variants C336R/Q386E: 50% CR rate, 75% ORR, 100% clinical benefit rate. These tumors expressed also very low levels of CXCL5, a ligand for CXCR2, that may mediate resistance to tipifarnib. High Allele Frequency of KIR3DL2 variants predicted CR to tipifarnib treatment (ROC AUC=0.94, p & lt;0.0001) and AITL patients carrying KIR3DL2 gene variants experienced a better outcome with tipifarnib treatment than with prior SOC treatment. While AITL tumors expressed high levels of CXCL12 and responded to tipifarnib, a trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR=1.8, p=0.09) was observed in a series of 50 PTCL subjects treated with SOC therapy. Fifty percent of AITL and 35% of non-AITL samples overexpressed CXCL12. Conclusion The AITL and wt CXCL12 3'UTR cohorts met pre-specified statistical hypotheses supporting proof-of-concept for tipifarnib in PTCL. AITL histology, KIR3DL2 and CXCL12 genotype provided robust tools for the selection/stratification of PTCL subjects treated with tipifarnib. Extended enrollment of AITL patients continues and an update on enrollment and outcomes will be provided at the time of the presentation. Disclosures Sokol: EUSA: Consultancy. Foss:Mallinckrodt: Consultancy; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy. Kim:Donga: Research Funding; Celltrion: Research Funding; J & J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding. Jacobsen:Kura Oncology: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Research Funding; Millennium: Research Funding. Roncero:Kura Oncology: Research Funding. Terol:Janssen: Consultancy, Research Funding; Roche: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy; Abbvie: Consultancy. Domingo-Domenech:Bristol-Myers Squibb: Other: Travel expenses; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Rodriguez:Kura Oncology: Research Funding. Bolognese:Kura Oncology: Consultancy. Kessler:Kura Oncology: Employment. Mishra:Kura Oncology: Employment. Curry:Kura Oncology: Employment. Kurman:Kura Oncology: Employment. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Gualberto:Kura Oncology: Employment, Equity Ownership, Patents & Royalties.

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, IkB 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 have a number of comorbidities, including poor renal function, which can require a reduction in the dose of intensive chemotherapy as well as lenalidomide, leading to inferior outcomes. Selinexor is not metabolized nor cleared by the kidneys and has been demonstrated to be safe and active in patients with myeloma and renal dysfunction. We performed post-hoc analyses of the SADAL study to determine the efficacy and safety among patients stratified by renal function at baseline. 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 according to baseline renal function as estimated by the Cockroft-Gault formula for creatinine clearance (CrCl). Groups included those with reduced (CrCl ≤60 mL/min) and normal (CrCl & gt;60 mL/min) renal function. Results: Of 134 patients, 37 (28%) had a reduced baseline CrCl (≤60 mL/min) while 97 (72%) had CrCl & gt;60 mL/min. The median age of patients with reduced CrCl was 74 years with 70% ≥70 years, while the median for those with normal CrCl was 65 years, with 35% ≥70 years. De novo and transformed DLBCL showed similar renal function levels: 78% and 22% with reduced CrCl and 76% and 24% with normal CrCl. Of patients with reduced CrCl, the DLBCL subtype was 41% GCB and 57% non-GCB compared to 50% and 46% in patients with normal CrCl. The group of patients with reduced CrCl had baseline ECOG performance status of 2 in 16% vs 11% in those with normal CrCl. Treatment with selinexor demonstrated a similar ORR in patients with a baseline reduced CrCl (29.7%) versus normal CrCl (28.9%). A complete response (CR) was observed in 8 (21.6%) patients with reduced and 10 (10.3%) patients with normal CrCl. The median duration of response (DOR) in patients who had reduced CrCl was 23.0 months compared to 9.2 months in patients with normal CrCl. The median progression-free survival (PFS) was 3.5 months (95% CI 1.7, 24.8) and 2.3 months (95% CI 1.9, 3.7) and overall survival was 7.8 months and 9.1 months in patients with reduced CrCl and those with normal CrCl. The most common grade ≥3 treatment-related AEs for patients with reduced versus normal CrCl were thrombocytopenia (45.9% vs. 38.1%), nausea (5.4% vs. 6.2%), and fatigue (8.1% vs. 11.3%). There was no clinically significant increase in treatment-related serious adverse events (21.6% vs. 20.6%) and adverse events leading to discontinuation (10.8% vs. 7.2%) in patients with reduced or normal CrCl, respectively. Conclusions: Selinexor showed similar anti-DLBCL activity and tolerability in patients with relapsed/refractory DLBCL with a reduced renal function (CrCl & lt;60 mL/min) compared to those with normal (CrCl ≥60 mL/min) renal function. No dose adjustments are required in patients with renal dysfunction and DLBCL who are treated with selinexor. 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:Novartis: Honoraria; Janssen: Honoraria; Novartis: Honoraria; iQone: Honoraria; Sandoz: Speakers Bureau; Karyopharm: Honoraria; Janssen: Speakers Bureau; Janssen: Honoraria; Roche: Speakers Bureau; Takeda: Speakers Bureau; Janssen: Speakers Bureau; Roche: Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria; Roche: Honoraria; Sandoz: Honoraria; Sandoz: Honoraria; Gilead: Honoraria; Roche: Honoraria; Karyopharm: Honoraria. Westin:Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Amgen: Consultancy; 47: 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; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Kalakonda:Gilead, Janssen, Karyopharm: Honoraria; Verastem, Gilead, Celgene, Roche: Research Funding. Goy:AbbVie: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; MD Anderson: Research Funding; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Morphosys: Research Funding; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; CALBG: Research Funding; Infinity Verastem: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding. Casasnovas:Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding. Cavallo:Takeda, Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Speaker Fee. Hill:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Tilly:BMS: Honoraria. Jaeger:Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; AbbVie: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Miltenyi: Consultancy, Honoraria; CDR Life AG: Consultancy, Research Funding. Gurion:JC Health CARE: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda Pharmaceuticals: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Medison: 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:Kite: Consultancy; Morphosys: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Cellectar: Consultancy; Beigene: Consultancy. Davies:Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celegene, Roche, Kite Pharma, Celegene: Honoraria. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Collins:BeiGene: Consultancy; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Amgen: Research Funding. Salles:Epizyme: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Genmab: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Autolus: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Takeda: Consultancy, Honoraria, Other. 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: Introduction: Patients (pts) with relapsed/refractory (R/R) DLBCL after two or more lines of therapy and who are not candidates for stem cell transplantation have limited effective treatment options and a poor prognosis. Selinexor, an oral XPO1 inhibitor, causes nuclear accumulation and activation of tumor suppressor proteins including p53, p21, and IκBα, along with reductions in c-Myc and Bcl-2 oncogenes. In a phase 1 clinical study (NCT01607892), pts with R/R DLBCL treated with selinexor had an overall response rate (ORR) of 32%, with 4 complete responses (CRs, 6%). Based on these findings, a phase 2b open-label study (SADAL) of selinexor in pts with R/R DLBCL not candidates for transplantation was initiated. Methods: Pts with R/R DLBCL were stratified by subtype (GCB or non-GCB). Pts achieving a best response of PR/CR on prior therapy required a 8 week washout before enrolling on trial. The primary objectives included efficacy (ORR and associated DOR) and safety.Pts were initially randomized to 60 or 100 mg of selinexor twice weekly (8 doses) per 28-day cycle. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014). Results: Preliminary results from the planned interim analysis showed similar ORRs on the 60 and 100 mg doses, but reduced DOR and tolerability at the higher dose; the 100 mg arm was therefore discontinued. 110 pts were enrolled on the 60 mg arm (66 M/ 44 F, median age 67 yrs) with a median of 3 (range 2-5) prior treatment regimens. The most frequently reported treatment related adverse events (AEs) included(all grades, grades 3, 4): nausea (51%, 6%, 0%), fatigue (50%, 10%, 0%), thrombocytopenia (47%, 22%, 15%), anorexia (35%, 2%, 0%), neutropenia (27%, 20%, 0%), and anemia (27%, 12%, 1%). These AEs were managed with dose modifications and/or standard supportive care. At the planned interim analysis (N=32, 60 mg) the ICRR determined ORR was 34.4% (5 CRs and 6 partial responses (PRs)). The median duration of response (DOR) was 8.4 months. ORR was 33.3% in GCB and 35.3% in non-GCB subtypes. The median overall survival (OS) was 9.0 months. Median OS (Figure 1) in pts ≥PR was not reached and was significantly longer vs median OS for pts ≤ stable disease (SD) of 4.1 months (p= 〈 0.001). Conclusion: Single agent oral selinexor is active in pts with R/R DLBCL across both GCB and non-GCB subtypes. Responses were deep with CRs noted on therapy and durable, with some responses 〉 24 months, consistent with significant clinical benefit. Importantly, response to therapy (≥PR) was associated with significant improvement in OS of 9.0 months vs 4.1 months for those with ≤SD. Enrollment completion is expected by September 2018. Full study results (N=130) will be presented, including longer follow up (DOR and OS) of pts from the original interim analysis. Pts enrolled in SADAL represent an unmet medical need population, and selinexor may help address this need. Disclosures Casasnovas: Roche: Consultancy, Research Funding; Merck: Consultancy; Bristol-Meyers Squibb: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Gilead: Consultancy, Research Funding. Goy:Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics/J & J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hackensack University Medical Center: Employment; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Seattle Genetics: Research Funding; COTA: Membership on an entity's Board of Directors or advisory committees. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows:Gilead, Janssen, Roche, Abbvie, Takeda, BMS: Membership on an entity's Board of Directors or advisory committees. Jaeger:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: 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, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding. Kuruvilla:Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Princess Margaret Cancer Foundation: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Lundbeck: Honoraria; Leukemia and Lymphoma Society Canada: Research Funding. Caimi:Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Matczak:Karyopharm Therpeutics: Employment. Ma:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Shah:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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: In 2020, the COVID-19 pandemic followed a two-wave pattern in most countries. Hospital admission for COVID-19 in one wave or another could have affected mortality, especially among the older persons. The objective of this study was to evaluate whether the admission of older patients during the different waves, before SARS-CoV-2 vaccination was available, was associated with a different mortality. We compared the mortality rates of patients hospitalized during 2020 before (first wave) and after (second wave) July 7, 2020, included in the SEMI-COVID-19 Registry, a large, multicenter, retrospective cohort of patients admitted to 126 Spanish hospitals for COVID-19. A multivariate logistic regression analysis was performed to control for changes in either the patient or disease profile. As of December 26, 2022, 22,494 patients had been included (17,784 from the first wave and 4710 from the second one). Overall mortality was 20.4% in the first wave and 17.2% in the second wave (risk difference (RD) − 3.2%; 95% confidence interval (95% CI) − 4.4 to − 2.0). Only patients aged 70 and older (10,973 patients: 8571 in the first wave and 2386 in the second wave) had a significant reduction in mortality (RD − 7.6%; 95% CI − 9.7 to − 5.5) (unadjusted relative risk reduction: 21.6%). After adjusting for age, comorbidities, variables related to the severity of the disease, and treatment received, admission during the second wave remained a protective factor. In Spain, patients aged 70 years and older admitted during the second wave of the COVID-19 pandemic had a significantly lower risk of mortality, except in severely dependent persons in need of corticosteroid treatment. This effect is independent of patient characteristics, disease severity, or treatment received. This suggests a protective effect of a better standard of care, greater clinical expertise, or a lesser degree of healthcare system overload.