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BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P 1 and S1P 5 , demonstrated superior efficacy and safety vs placebo for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in a phase 3 study (True North). In this post-hoc analysis, we evaluated the impact of prior biologic exposure on response to ozanimod. METHODS: True North consisted of two cohorts. In cohort 1, patients with UC received double-blind treatment with once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo. In cohort 2, patients received open-label once daily ozanimod 0.92 mg. Ozanimod responders after a 10-week induction were re-randomized to double-blind maintenance with ozanimod 0.92 mg or placebo through week 52. Outcomes based on prior biologic exposure (biologic-naïve, 1 biologic, and 2+ biologics) and prior biologic type (anti-tumor necrosis factor [TNF] agents, vedolizumab, or both) were analyzed for clinical remission, clinical response, endoscopic improvement, and mucosal healing. Patients exposed to only a JAK inhibitor were excluded from the analysis. RESULTS: A total of 992 patients (n = 213 placebo and n = 426 ozanimod in cohort 1, n = 353 ozanimod in cohort 2) were included in the analysis for induction; 616 were biologic-naïve, 162 had exposure to 1 biologic, and 214 were exposed to 2 or more biologics. At baseline, biologic-exposed patients had more prior corticosteroid use, longer disease duration, and more extensive disease than biologic-naïve patients. During induction, greater therapeutic effects of ozanimod were generally seen in biologic-naïve vs biologic-exposed patients, and ozanimod-treated patients had greater responses on nearly all reported endpoints at week 10 (cohort 1). Clinical remission was achieved in 23% vs 6.6% of patients on ozanimod vs placebo who were biologic naïve, 17.2% vs 8.3% on 1 prior biologic, and 3.7% vs 2.5% on 2 or more biologics. Clinical response was reached in 53% vs 28% of patients on ozanimod vs placebo who were biologic naïve, 50% vs 33% on 1 biologic, and 27% vs 15% on 2 or more biologics. During maintenance, ozanimod-treated patients had greater responses on all endpoints versus placebo, with similar proportions of patients achieving clinical response to ozanimod regardless of prior biologic exposure (61% for biologic naïve, 60% for 1 biologic, and 55% for 2 or more biologics). At week 52, the proportion of patients on ozanimod with clinical remission was similar in the 1-biologic and 2+-biologic exposure groups (28% and 26%, respectively), and proportions of patients on ozanimod with endoscopic improvement and mucosal healing were similar for the 1-biologic and biologic-naïve groups (47% and 50%, 30%, and 33%, respectively). Among patients with inadequate response to prior anti-TNF agents, vedolizumab, or both at baseline, treatment effects favored ozanimod vs placebo on these endpoints in all three groups during both induction and maintenance. CONCLUSION: Ozanimod improved clinical, endoscopic, and histologic outcomes in both biologic-exposed and -naïve patients. Patients with prior biologic use may require additional time to respond to treatment. Outcomes were improved with ozanimod regardless of prior use of anti-TNF agents and vedolizumab.

Abstract Introduction: Treatment resistance remains a challenge that most patients (pts) with MM will encounter in their disease course. With each subsequent line of therapy (LOT), pt outcomes and health-related quality of life (HRQoL) worsen. Pts with MM who are refractory to immunomodulatory drugs, proteasome inhibitors (PIs), and anti-CD38 antibodies (triple-class refractory; TCR) have a poor prognosis and the holistic burden is not well understood. To capture these features, the ongoing prospective Connect ® MM Disease Registry was used to report treatment patterns and outcomes in pts with TCR MM. Methods: Data from September 28, 2009 to February 4, 2021 were used. Eligible pts were ≥18 years of age at first documented diagnosis of MM, which became TCR during their disease course. MM was defined as refractory to therapies based on the International Myeloma Working Group Criteria. Index date was defined as first record of TCR during the disease course. Data analyzed included pt characteristics, treatment patterns pre- and post-index, overall survival (OS), healthcare resource utilization (HCRU), and HRQoL. General HRQoL was captured by EQ-5D-3L utility index (range −0.11-1, higher score indicated better HRQoL), EQ-5D visual analog scale (VAS) score (range 0-100, "worst imaginable" to "best imaginable" health status), and FACT-G total score (range 0-108). Disease-specific HRQoL was measured by FACT-MM total score (range 0-164), FACT-MM Trial Outcome Index (TOI) (range 0-112), and the Brief Pain Inventory (BPI) average pain item (range 0-10, "no pain" to "worst pain you can imagine"). Higher scores indicated better HRQoL for all FACT-related index scores. Cohort-level clinically meaningful change in HRQoL during post-index year 1 was defined as 0.08 for the EQ-5D utility index, 7 for the EQ-5D VAS, and 6-8 points for the FACT-G total score. Validated thresholds were unavailable for other index scores. All statistical analyses were descriptive. Results: This analysis included 240 pts identified from the Registry. Mean age at index date was 68.1 (standard deviation [SD] 10.4) years. Mean time from initial MM diagnosis was 64.1 (SD 26.9) months. 63.3% of pts had prior stem cell transplantation. Mean number of prior LOTs was 4 (SD 1.7). 64.6% of pts had received a subsequent MM LOT since index date. Median follow-up time post-index date was 4.6 months. Treatment pattern analysis of post-index treated pts (Table A) revealed that retreatment with an immunomodulatory drug, PI, or anti-CD38 agent post-index date was common, led by carfilzomib (47.1%) and pomalidomide (40.0%). However, no therapeutic combination was preferred in this pt population. Regarding their index therapy (first post-index LOT), 70.3% and 22.6% were on triplet and quadruplet combination therapy; 3.2% initiated belantamab mafodotin, selinexor, melflufen, and/or idecabtagene vicleucel; mean duration of treatment was 5.6 (SD 6.1) months. For all pts, median OS was 8.9 months; median OS for those who received < 4 prior LOTs (43.8%) versus those who received 4 or more prior LOTs (56.2%) was 10.0 and 8.0 months, respectively. Regarding HCRU during the post-index follow-up, all-cause and MM-related hospitalizations were observed in 49.6% and 23.8% of all eligible pts, respectively. Among these pts, annualized mean number of all-cause/MM-related hospitalization and length of hospital stay were estimated as 8.5 (SD 18.2)/11.0 (SD 25.2) and 64.0 days (SD 80.0)/ 69.2 days (SD 83.7), respectively. Analysis of HRQoL showed a numerical decline in HRQoL relative to index during the 1-year post-index period across all studied HRQoL instruments. There was a clinically meaningful decline in HRQoL from baseline following the index date based on the EQ-5D utility index, EQ-5D VAS, and FACT-G total score (Table B). Conclusion: Pts with TCR MM experienced poor survival, substantial hospitalizations, and a clinically meaningful decline in HRQoL. 35.4% of pts did not receive any new LOTs since the disease became TCR. Among those who did receive subsequent LOTs, re-treatment with an immunomodulatory drug, PI, or anti-CD38 antibody therapy occurred, showing a lack of novel treatment options. This study suggests novel tolerable and efficacious therapeutic agents are needed to address the burden of illness in pts with MM. Figure 1 Figure 1. Disclosures Tang: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ramasamy: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel: Celgene: Consultancy, Honoraria, 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Joshi: Bristol Myers Squibb: Current Employment. Liu: Bristol Myers Squibb: Current Employment. Che: Bristol Myers Squibb: Current Employment. Hernandez: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abonour: Jensen: Honoraria, Research Funding; Celgene-BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Hardin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Rifkin: Sanofi: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Coherus: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Ailawadhi: BeiGene, Ltd.: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Medimmune: Research Funding; Cellectar: Research Funding; Xencor: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy; Genentech: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Lee: Legend Biotech: Consultancy; Sanofi: Consultancy; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Consultancy; Regeneron: Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding. Terebelo: Pharmacylics: Speakers Bureau; Celgene-BMS: Consultancy; Takeda: Speakers Bureau; Janssen: Speakers Bureau. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Narang: Bristol Myers Squibb: Consultancy; TG Pharma: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Gasparetto: Oncopeptide: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Gsk: Consultancy, Honoraria, Speakers Bureau. Wagner: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy; Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;. Jagannath: Janssen Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy.

Abstract Background: Clonal cytopenia of undetermined significance (CCUS) is defined as persistent unexplained cytopenia with evidence of clonality [myeloid-associated somatic mutations (MTs) or cytogenetic [CG] abnormalities] but without definitive evidence of myeloid neoplasms (MN). The outcomes in CCUS patients (pts) are not well understood. Methods: The CCUS International Study database includes pts from 17 institutions who meet the criteria of CCUS and do not have other causes of cytopenia. Pts with MDS defining CG abnormalities were excluded. We collected baseline clinical data, laboratory parameters, CGs, molecular genetics, treatment, and disease course. Diverse gene panels from different institutions were collated to include a total of 70 myeloid-related somatic genes (30 genes in common). 2018 IWG MDS response criteria were used to determine response rate (RR). Disease progression (DP) is defined by progression to MN. The relationship between independent variables and DP and death was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. All statistical analysis was performed using SAS. Results: A total of 258 pts were captured by July 2021. The median age was 71 (IQR 63-77) years, and 66% were male. Among 73 (28%) pts with known malignancy history, 27 (37%) pts received previous chemo- or radiation therapy. 27 (10%) pts had non-malignant hematology comorbidities. 91 (35%) had cardiovascular disease, and 33 (13%) had inflammatory disease. (Table 1) The red blood cell and platelet transfusion-dependent rates were 7.3% and 2.3%, respectively. The median number of MTs was 2 (IQR 1-3), with 221 (86%) pts had ≥1 MT, of which 116 (53%) had ≥ 2 MTs. The most common 5 MTs were TET2 (n=78, 30%), SRSF2 (n=50, 19%), DNMT3A (n=47, 18%), ASXL1 (n=40, 16%), and U2AF1 (n=22, 9%) (Figure 1). The median VAF (mVAF) was 28% (IQR: 9.2%, 43%) with VAF < 10% in 47 (18%) and VAF ≥40% in 78 (30.2%) of the MTs. mVAF of the all genes are shown in Figure 2. Among pts with CG abnormalities (n=62, 24%), trisomy 8 and -Y are the most common karyotypes (n=15 for each, 24%) (Table 2). Eighty one (31%) patients received various treatments for CCUS with modest RR, including growth factors (n=47, 18.2%, RR: 25.5%), supportive care (n=23, 9%, RR: 26%), immunoglobulin/immunosuppressive therapy (n=15, 6%, RR: 40%), and DNMTi (n=8, 3%, RR=13%). The median length of follow-up was 15.6 (IQR 6.9-30.6) months. 24 pts progressed to MN, 14 (58.3%) of which were MDS, 8 (33.3%) CMML, and 2 (8.3%) AML. The 2-year PFS was 86.1% (95% CI: 80-93%) with a median PFS of 16.3 (IQR: 3.7, 21) months. In the multivariable model, positive MT of KRAS (HR: 8.4, 95% CI: 1.9-36.9, p=0.005) and CBL (HR: 16.5, 95% CI: 3.7-73.8, p=0.003) were significantly associated with DP. In the functional pathway analysis, having at least 1 splicing factor MT was significantly associated with DP (HR: 2.6, 95% CI:1.2-5.9, p=0.02). TP53 was not significantly associated with DP (HR: 1.2, 95% CI: 0.2-8.7, p=0.88). Having >1 MT (HR: 3.57, 95% CI: 1.19-10.7, p=0.02) compared to a single MT was significantly associated with DP (Figure 3). Over the follow-up period, 35 pts died. The 2-year OS was 81% (95% CI: 74.9-87.9%). In the multivariable model, MT of KRAS (HR: 6.1, 95% CI: 1.8-20, p=0.003), CBL (HR: 7.3, 95% CI: 1.7-31, p=0.007), and FLT3 (HR: 19.9, 95% CI: 2.5-155, p=0.004) were significantly associated with inferior survival. In the functional pathway analysis, MTs in activated signaling pathway were significantly associated with death (HR: 4.1, 95% CI: 1.8-9, p<0.001). None of the pts with TP53 MT died. Having >1 MT was not statistically significantly associated with higher risk of death (HR: 1.5, 95% CI: 0.7-3.0, p=0.28) (Figure 4). After adjustment for co-MT status and comorbidities, baseline Hb<10 g/dL (HR: 3.7, 95% CI: 1.8-7.9, p<0.001) was significantly associated with greater mortality. Conclusion: This large retrospective study summarizes the CCUS pts' characteristics, with different MT patterns and VAF. We confirmed the impact of having >1 MT on DP, but not OS. Genes involved in activated signaling had a significant impact on both DP and OS. TP53 MT was not associated with worse outcome. Findings may be due to limited cases in the particular genes and different gene panels from multiple institutions. A longer follow-up is planned to further describe the predictors for outcome in this ongoing study. Figure 1 Figure 1. Disclosures Komrokji: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy. Zeidan: BioCryst: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Janssen: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; AstraZeneca: Consultancy; Agios: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Astex: Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; Astellas: Consultancy; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foran: trillium: Research Funding; actinium: Research Funding; kura: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; abbvie: Research Funding; aptose: Research Funding; pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; OncLive: Honoraria; gamida: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Desai: Astex: Research Funding; Janssen R&D: Research Funding; Kura Oncology: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy. Ades: ABBVIE: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Brunner: Novartis, Celgene, Takeda, AstraZeneca: Research Funding; Celgene, Forty Seven Inc, Jazz: Other: Advisory Board. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Abstract Background: Splenomegaly is a marker of disease progression in MF; larger spleen size (SS) is correlated with poorer survival and debilitating MF symptoms. In a retrospective real-world study of 408 patients (pts) with MF treated with ruxolitinib (RUX), pts with SS ≥ 10 cm below the left costal margin (LCM) were significantly less likely to attain a spleen response than pts with SS < 10 cm (Palandri 2017); this finding has not been reported in clinical trials of RUX. FEDR is a JAK2-selective inhibitor approved in the US, EU, Canada, and elsewhere as first-line (1L) MF treatment (Tx) and in pts previously treated with RUX. FEDR was evaluated as 1L MF Tx in the phase 3, placebo (PBO)-controlled JAKARTA trial, and in the phase 2, single-arm JAKARTA2 trial in pts previously treated with RUX. Pts allocated to FEDR 400 mg/day (d) in these trials reported substantial reductions from baseline (BL) in spleen volume and MF symptom severity after 6 FEDR Tx cycles. It is important to determine whether spleen volume and symptom improvements during FEDR Tx are influenced by degree of pre-Tx splenomegaly. Objective: Investigate the clinical efficacy of FEDR 400 mg/d in pts in JAKARTA & JAKARTA2 with large spleens at BL. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK-inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS > 5 cm from LCM by palpation, platelets ≥ 50 ×10 9/L, and ECOG PS ≤ 2. These analyses include pts in each trial allocated to receive FEDR 400 mg/d in continuous 28d Tx cycles. Too few pts had BL SS < 10 cm by palpation in JAKARTA (n = 21) and JAKARTA2 (n = 12) for meaningful comparison vs SS ≥ 10 cm. Thus, in these post hoc analyses we divided pts according to the median SS (mSS) at BL in each study , and assessed changes from BL in spleen volume and MFSAF total symptom score (TSS) at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Pts must have had spleen volume and/or TSS data at BL and EOC6. R esults: In JAKARTA, 96 pts were randomized to FEDR 400 mg/d; mSS at BL for all pts was 16 cm (range 5-40). Median (range) BL spleen volume was 1771 (316-3396) mL in the < mSS cohort and 3329 (983-6430) mL in the ≥ mSS cohort; median TSS was 13.0 and 17.6, respectively. Spleen volume data were available at BL and EOC6 for 37 (82%) and 38 (75%) pts in the < mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the < mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the < mSS (n = 37) and ≥ mSS (n = 34) cohorts, with median TSS reductions of -49% and -51%, respectively. For individual symptoms, median reductions in abdominal discomfort, bone/muscle pain, and early satiety were similar between BL SS cohorts, whereas changes were greater in the < mSS group for pruritus and pain under ribs-left side, and greater in the ≥ mSS group for night sweats. In JAKARTA2, 97 pts received FEDR 400 mg/d (starting dose); BL mSS for all pts was 18 cm (range 5-36). Median (range) BL spleen volumes were 1937 (737-4305) and 4002 (1821-7815) mL for pts with < mSS and ≥ mSS, respectively; and BL TSS was 17.2 (0.7-48.0) and 23.6 (1.0-44.0). Spleen volume and MFSAF TSS data were available at BL and EOC6 for 41 and 29 pts, respectively, in the < mSS cohort, and for 41 and 22 pts in the ≥ mSS group. At EOC6, median SVR from BL was -35% [95%CI -40%, -29%] for pts with < mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the < mSS and ≥ mSS cohorts, respectively; pts with ≥ mSS at BL had similar or greater reductions from BL in 5/6 MFSAF symptoms (all except pruritus) vs those with < mSS. Conclusions: These analyses demonstrate that extent of splenomegaly at BL in JAKARTA and JAKARTA2 did not influence the likelihood of achieving improvements in spleen volume or MF symptom severity for pts receiving FEDR 400 mg/d as 1L MF Tx or as post-RUX salvage Tx. For pts who completed 6 FEDR Tx cycles, reductions in spleen volume and TSS at EOC6 in the ≥ mSS cohorts in both studies were similar to those in the < mSS cohorts, even though BL spleen volumes and TSS were higher in the ≥ mSS groups. Figure 1 Figure 1. Disclosures Kiladjian: Incyte Corporation: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Passamonti: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees. Talpaz: Imago: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support . Cervantes: Bristol Myers Squibb: Consultancy, Honoraria. Harrison: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa: AOP: Consultancy; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Samus: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; CTI: Research Funding; Pharma: Consultancy; Promedior: Research Funding. Mascarenhas: Geron: Consultancy; Merus: Research Funding; Geron: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek: Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb - Celegene: Consultancy; Novartis: Consultancy. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhang: Bristol Myers Squibb: Current Employment. Sy: Bristol Myers Squibb: Current Employment.

Abstract Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell maturation antigen (BCMA) directed CAR T cell therapy which uses the same CAR molecule as ide-cel, with the addition of a PI3K inhibitor (bb007) during ex vivo culture to enrich the drug product (DP) for memory-like T cells and decrease the proportion of highly differentiated or senescent T cells. We hypothesize that DPs enriched for memory like CAR T cells will persist and function longer than non-enriched DPs and this increased persistence will positively influence duration of response (DOR). We previously demonstrated patients with sustained response are more likely to have drug product enriched for naïve gene signatures and depleted of effector gene signatures compared to patients without a sustained response. Methods: CRB-402 (NCT03274219) is a multi-center phase 1 trial of bb21217 in RRMM patients who received ≥3 prior lines of antimyeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory to both classes. In expansion, patients were required to have prior exposure to an anti-CD38 antibody and were required to be refractory to their last line of therapy. Patients underwent lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days, then received a single infusion of bb21217 at 150, 300 or 450 x 10 6 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. Exploratory analyses include correlation of outcome with the molecular characteristics of materials collected temporally through the treatment course, including PBMCs at apheresis, CAR+ T cells from drug product and CAR+ T cells collected from patients around the time of peak expansion. Results: Asof Feb 16, 2021, 72 patients received bb21217, 12 at 150, 14 at 300 and 46 at 450 x 10 6 CAR+ T cells; median follow up for all patients is 9.0 (<1-36) months (M). Patients had a median of 6 (3-17) prior lines of therapy with 49/72 (68%) triple refractory. Cytokine release syndrome (CRS) developed in 54/72 (75%) patients and was predominately G1/2 (51 pts), with 1 G3 event and 2 deaths (previously reported). Median time to first onset of CRS was 2 days (1-20); tocilizumab (38 pts) + corticosteroids (12 pts) was used to manage CRS. Eleven (15%) patients developed neurotoxicity [8 G1/G2, 2 G3, 1 G4] with median time to first onset of 7 (2-24) days. Response was assessed per investigator for 72 patients treated with bb21217 (Table). CAR+ T cells remained detectable in 30/37 (81%) patients and 9/15 (60%) patients at 6 and 12 M respectively, post bb21217 infusion. Of the 15 patients evaluable for MRD with ≥CR, 14 (93%) were MRD negative at 10 -5 by NGS. Analysis of peripheral blood samples collected 15 days post bb21217 infusion demonstrated patients with higher than the median number of CD8+ CAR+ T cells expressing CD27 and CD28 had significantly longer DOR (p=0.0024), compared to patients with lower than the median values. This suggests less differentiated, more proliferative CAR+ T cells at peak expansion are associated with prolonged disease response (median DOR in high vs low: 27.2M (95% CI; 16.8, NE) vs 9.4M (95% CI; 5.1, NE). Conclusions: Adverse events are consistent with known toxicities of CAR T cell therapies. Efficacy results are encouraging with a median DOR estimate of 17M, CR rate continues to mature. Patients with higher levels of proliferative, less differentiated memory like CAR+ T cells at peak expansion are more likely to experience prolonged DOR, continuing to support the hypothesis that the memory like T cell phenotype associated with bb21217 results in prolonged DOR. Figure 1 Figure 1. Disclosures Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Shah: Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Kite: Consultancy; Nektar: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CSL Behring: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; Teneobio: Research Funding. Kaufman: BMS: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Siegel: Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria, Speakers Bureau. Munshi: Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Legend: Consultancy; Adaptive Biotechnology: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Karyopharm: Consultancy; Pfizer: Consultancy. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Lin: Sorrento: Consultancy; Takeda: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Timm: bluebird bio: Current Employment. Yeri: bluebird bio: Current Employment. Martin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Finney: bluebird bio: Current Employment, Current equity holder in publicly-traded company. Truppel-Hartmann: bluebird bio: Current Employment. Petrocca: blue bird bio: Ended employment in the past 24 months. Berdeja: Abbvie, Acetylon, Amgen: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding.

Abstract Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population. Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue. Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients. Figure 1 Figure 1. Disclosures Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: immunomedics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.

Abstract Introduction: Non-Hodgkin lymphoma (NHL) constitutes ~40% of hematologic malignancies and, in 2020, resulted in 19,940 deaths in the USA. The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL), including primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL). Although a majority of patients respond to standard-of-care therapy, many patients with NHL eventually relapse, highlighting the need for additional treatments. Real-world data regarding the safety and efficacy of emerging therapies in the relapsed/refractory (R/R) population, and the association between treatment patterns and patient outcomes, are limited. These data could provide unique insights to clinical and health-related quality of life (HRQoL) outcomes in patients with DLBCL, FL, or PMBCL treated with emerging therapies, especially novel options such as chimeric antigen receptor (CAR) T cell therapies. Methods: The Connect ® Lymphoma Disease Registry (NCT04982471) is a US-based, multicenter, prospective observational cohort study of patients with R/R NHL (DLBCL, FL, and PMBCL). Approximately 2100 patients ≥ 18 years of age from ~200 community oncology (~80%) or academic (~20%) sites will be enrolled over a ~3-year period. Patients with histologically confirmed NHL subtypes will be enrolled into 1 of 4 cohorts: first R/R DLBCL, second R/R DLBCL, first R/R FL, or first R/R PMBCL (Figure). Patients will be required to have begun second- (first R/R) or third- (second R/R) line systemic treatment within 60 days prior to enrollment. Patients receiving treatment for any active malignancy other than DLBCL, FL, or PMBCL at the time of enrollment, or who are diagnosed with any other malignancy in the 6 months prior to enrollment, will be excluded. All treatment and management decisions will be determined by the practicing clinicians. Patients may undergo hematopoietic stem cell transplantation, CAR T cell therapy, or other treatments at other sites while participating in this study. Patients will be followed from enrollment for up to 5 years or until death, withdrawal of consent, loss to follow-up, or study termination, whichever occurs first. Data collection will occur at enrollment (baseline) and then every ~3 months. The main objectives of the Connect ® Registry are to describe patient characteristics, practice patterns, and factors associated with treatment choice, sequencing, and effectiveness in NHL subtypes. Secondary objectives include describing treatment regimen safety, patient-reported outcomes (PROs) including HRQoL, and healthcare resource utilization outcomes. Exploratory objectives include tumor and blood biomarker evaluation and understanding the availability of social support and its impact on long-term treatment decision-making. Case report forms will be used to collect clinical and treatment data, including baseline demographics, clinical characteristics, treatment details and response, and socioeconomic factors. Outcome measures for efficacy will be progression-free survival, event-free survival, objective response rate, time to next treatment, and overall survival. The availability of social support will be assessed via a specific questionnaire administered at baseline. General (EQ-5D-5L) and disease-specific (FACT-Lym) questionnaires will also be administered. Patients may also optionally agree to release tumor biopsies and blood samples for biomarker analysis. Clinicians will be required to report serious adverse events (AEs), secondary primary malignancies, and confirmed COVID-19 infections within 24 hours. Non-serious AEs of interest include grade 1-3 cytokine release syndrome, grade 1-3 neurotoxicity, grade 3 colitis, grade 3 arrhythmia, grade 3 hemorrhage. Other AEs of interest to be collected include grade 3 hypogammaglobulinemia, prolonged grade 3 cytopenia, and grade 3 infections. Data collected in the Connect ® Registry will increase understanding of the association between emerging therapies and patient outcomes for R/R DLBCL, FL, and PMBCL. Study support: Bristol Myers Squibb Figure 1 Figure 1. Disclosures Flowers: Amgen: Research Funding; Janssen: Research Funding; Biopharma: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Iovance: Research Funding; Allogene: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; BeiGene: Consultancy; Kite: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Novartis: Research Funding; Epizyme, Inc.: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; 4D: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Guardant: Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; SeaGen: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding. Andorsky: Celgene/Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AstraZeneca: Other: served on steering committees; Epizyme: Research Funding; AbbVie: Research Funding. Burke: SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; Beigene: Consultancy, Speakers Bureau; Kymera: Consultancy. Cerhan: Genentech: Research Funding; NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration. Grinblatt: Astellas Pharma, Inc.: Consultancy; Bristol Myers Squibb: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Zelenetz: Gilead: Honoraria, Research Funding; Verastem: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; SecuraBio: Honoraria; Abbvie: Honoraria, Research Funding; MorphoSys: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; LFR: Other; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; MethylGene: Research Funding; Beigene: Honoraria, Other, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Sullivan: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Flick: Bristol Myers Squibb: Current Employment. Kiselev: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kaplan: Bristol Myers Squibb: Current Employment. Ahn: Bristol Myers Squibb: Current Employment.

Abstract Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM. Methods: Adults (age ≤ 75 yrs) with R/R LBCL (≤ 12 mo after 1L therapy), who were eligible for autologous stem cell transplantation (ASCT), were randomized to receive either SOC (3 cycles of salvage chemotherapy [CT] and BEAM + ASCT for responding pts) or liso-cel after lymphodepletion. Crossover to receive liso-cel was allowed in the SOC arm for pts who failed treatment. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) were administered at randomization (baseline) and on Days 29 (infusion of liso-cel or 2 cycles of salvage CT), 64 (1 mo post liso-cel or completion of CT), 126 (3 mos post liso-cel or 2 mos post ASCT), and Mo 6 and other prespecified timepoints up to Mo 36 or end of study. No PRO data were collected after crossover. The analysis was based on the PRO-evaluable population (pts with a baseline and ≥ 1 post-baseline assessment). Predefined thresholds determined clinically meaningful changes. Global health/QOL (GH/QOL), physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS were the primary domains of interest based on their relevance to the study population and treatment. A linear mixed model for repeated measures (MMRM) analysis was performed to assess the between-treatment difference in overall least squares (LS) mean change from baseline for each primary domain, using data collected up to Day 126 for visits with a sample size per arm ≥ 10. Proportions of pts with meaningful change from baseline were assessed for each primary domain up to Mo 6. All analyses were descriptive only. Results: Of 184 randomized pts, 90 (49%) and 85 (46%), respectively, were included in the PRO-evaluable population for the EORTC QLQ-C30 (SOC vs liso-cel n=43 vs 47) and FACT-LymS (n=40 vs 45, respectively). The PRO assessment completion rate from baseline up to Mo 6 was ≥ 45%, which was lower than expected primarily due to operational challenges during the COVID-19 pandemic but was comparable for both arms. In the MMRM analysis, the liso-cel arm had more favorable overall LS mean changes from baseline to Day 126 than the SOC arm in most of the EORTC QLQ-C30 domains and FACT-LymS. In particular, the between-treatment differences for cognitive functioning (−2.09 vs 2.21) and fatigue (3.75 vs −1.95) for SOC versus liso-cel, respectively, exceeded the prespecified minimal important difference threshold (Table); in those domains, the SOC arm deteriorated while the liso-cel arm improved. In individual-level analyses, the proportion of pts with meaningful improvement for fatigue and GH/QOL was higher, while deterioration was lower, in the liso-cel arm versus SOC arm from baseline up to Mo 6 (Figure). At Mo 6, a higher proportion of pts experienced worsened fatigue (71% vs 18%) and a lower proportion experienced improved fatigue (29% vs 47%) in the SOC arm compared with the liso-cel arm; for GH/QOL, a higher proportion of pts worsened (57% vs 18%) and lower proportion improved (14% vs 53%), respectively. For the other primary domains, the proportions of pts with improvement or deterioration favored liso-cel or were similar between arms. Conclusions: Compared with SOC, liso-cel showed favorable improvement in most primary PRO domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more pts showed PRO improvements and fewer showed deterioration by Mo 6 with liso-cel. The results were achieved despite only responders remaining in the SOC arm after salvage CT. HRQOL was either improved or maintained after liso-cel treatment in pts with R/R LBCL after failure of 1L therapy. Figure 1 Figure 1. Disclosures Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Kite Pharma: Consultancy; Kymera: Consultancy; Incyte Corporation: Consultancy; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; BeiGene: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman: BMS: Current Employment, Current equity holder in publicly-traded company. Guo: Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bristol Myers Squibb: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Kamdar: ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; Genetech: Other; Celgene (BMS): Consultancy.