Citations

Abstract Aims Conotruncal anomalies share common embryogenic defects of the outflow tracts and great arteries, which result in a predisposition to aortic aneurysms. The purpose of this study was to describe the prevalence and risk of progressive aortic aneurysms in adults with conotruncal anomalies. Methods and results Retrospective study of adults with conotruncal anomalies that underwent cross-sectional imaging 2003–20. Aneurysm was defined as aortic root/mid-ascending aorta >2.1 mm/m2/>1.9 mm/m2, progressive aneurysm as increase by >2 mm, and severe aneurysm as dimension >50 mm. Of 2261 patients (38 ± 12 years; male 58%), 1167 (52%) had an aortic aneurysm, and 205 (14%) had a severe aortic aneurysm. Mean annual increase in aortic root/mid-ascending aorta was 0.3 ± 0.1 mm/0.2 ± 0.1 mm. The 3-, 5-, and 7-year cumulative incidence of the progressive aortic aneurysm was 4%, 7%, and 9%, respectively. The rate of aneurysm growth decreased with age, with no significant growth after age 40 years. There was an excellent correlation between aortic indices from cross-sectional imaging and echocardiography. Of 950 females, 184 had ≥1 pregnancy, and 81 (44%) of the 184 patients had aortic aneurysm prior to pregnancy. There was no aortic dissection or progression of the aortic aneurysm during pregnancy. Overall, there was no aortic dissection during 7984 patient-years of follow-up. Conclusions Aortic aneurysm was common in patients with conotruncal anomalies. However, the risk of progressive aneurysm or dissection was low. Collectively, these data suggest a benign natural history and perhaps a less frequent need for cross-sectional imaging. Further studies are required to determine the optimal timing for surgical intervention in this population.

Background: Chronic elevation of left heart filling pressure causes pulmonary vascular remodeling, pulmonary hypertension, and right heart dysfunction. Although diastolic dysfunction is relatively common in patients with coarctation of aorta, there are limited data about the prevalence and prognostic implications of pulmonary hypertension and right heart dysfunction in this population. The purpose of the study was to assess right heart function and hemodynamics in patients with coarctation of aorta and to determine the relationship between right heart indices and cardiovascular events defined as heart failure hospitalization, heart transplant, or cardiovascular death. Methods: Right heart structure, function, and hemodynamics were assessed with these indices: right atrial volume, right atrial pressure, right atrial reservoir strain, right ventricular global longitudinal strain, right ventricular end-diastolic area, right ventricular systolic pressure, and tricuspid regurgitation severity. Right heart hemodynamic score, range 0 to 5, was generated based on the correlation between the right heart indices and cardiovascular events, using half of the cohort (derivation cohort, n=411), and then tested on the validation cohort (n=410). The goodness of fit and discrimination power was compared using C statistics and risk score. Results: The median follow-up in the derivation cohort was 8.2 (4.0–11.1) years, and 59 (14%) patients had cardiovascular events during this period. Right heart hemodynamic score was independently associated with cardiovascular events (hazard ratio, 1.64 [95% CI, 1.38–2.17]) for every unit increase in right heart hemodynamic score after adjustment for clinical and echocardiographic indices (C statistic, 0.718 [95% CI, 0.682–0.746]). The right heart hemodynamic score was also independently associated with cardiovascular events in the validation cohort (C statistic, 0.711 [95% CI, 0.679–0.741]). The C statistic difference (0.007 [95% CI, 0.014–0.022]) and risk score (0.86 [95% CI, 0.54–1.17]) suggest a good model fit. Conclusions: The current study underscores the prognostic importance of right heart dysfunction in patients with coarctation of aorta and suggests that right heart indices should be used for risks stratification in this population.

Abstract Introduction: Brexucabtagene autoleucel (brexu-cel) was approved by US FDA for relapsed/refractory (R/R) mantle cell lymphoma (MCL) on July 24, 2020 based on results from the pivotal ZUMA-2 (NCT02601313) study, in which an objective response rate (ORR) of 93% and a complete response (CR) rate of 67% were achieved among the 60 treated patients with at least 7 months of follow-up. The study had stringent eligibility criteria, including prior treatment with a BTK inhibitor (BTKi), and only allowed BTKi and/or corticosteroid for bridging therapy. We report here the safety and efficacy of brexu-cel in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: Fourteen centers participated in this retrospective study. Patients who underwent leukapheresis by 6/15/2021 with an intent to manufacture brexu-cel were included. Baseline clinical characteristics, bridging therapy, adverse events after brexu-cel infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined based on characteristics at the time of leukapheresis. Duration of response (time from initial response to disease progression or death from any cause), progression-free survival (PFS; time from infusion to disease progression or death from any cause) and overall survival (OS; time from infusion to death from any cause) were analyzed using the Kaplan-Meier method. Results: At the data cut-off date of 7/9/2021, 107 patients underwent leukapheresis, among whom 93 (87%) completed brexu-cel infusion, 2 (2%) were waiting for infusion, and 12 (11%) did not receive infusion (manufacture failure n=6, organ dysfunction n=1, death n=5). Baseline clinical characteristics of the 93 infused patients are shown in Table 1. The median age was 67 years and 81% were male. 32% had high risk simplified MIPI, 77% had Ki-67≥30%, 45% had blastoid or pleomorphic variant, 46% had TP53 alteration, 29% had complex karyotype, and 7% had CNS involvement. The median number of prior lines of therapy was 3. Eighty-two percent had prior BTKi treatment, and 44% had refractory disease to the last line of therapy. Sixty-eight (73%) patients would not have met ZUMA-2 eligibility criteria. Reasons for ineligibility included ECOG PS ≥2 (n=8), CNS involvement by lymphoma (n=6), prior therapies (n=33), cytopenia (n=11), renal or hepatic dysfunction (n=13), other medical conditions (n=18), and active infection (n=2). Sixty (65%) of the 93 patients received bridging therapy, which included BTKi (n=27), venetoclax (n=14), chemotherapy (n=19), CD20 antibody (n=26), lenalidomide (n=3), corticosteroid (n=9), and radiotherapy (n=13). Only 13 (14%) patients received BTKi or corticosteroid alone as in ZUMA-2. Among 93 infused patients, cytokine release syndrome (CRS) rate was 88% (8% grade ≥3), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 58% (33% grade ≥3). No grade 5 CRS or ICANS occurred. Medications used to manage CRS and ICANS were 71 (76%) for tocilizumab, 64 (69%) for steroid, and 16 (17%) for anakinra. Twenty-four (26%) patients required ICU admission, 9 patients required vasopressors, and 4 patients required mechanical ventilation. With a median follow-up of 3.0 months (range 0.1-9.6), day 30 response was evaluable in 81 patients, and the ORR was 86%, with 64% CR (Table 2). The ORR/CR rates were 94%/70% for blastoid or pleomorphic variants, 82%/50% for TP53 altered, 84%/61% for BTKi-exposed, 94%/76% for BTKi-naïve, and 88%/67% for those not meeting ZUMA-2 eligibility criteria. The ORR/CR rates were 87%/69% for patients who received bridging therapy and 85%/56% for those who did not. For patients who achieved a response at day 30, the rate of continued response at 3-month was 83.7% (95% CI 68.3%-92.0%). The 3-month PFS rate was 80.6% (95% CI 68.6%-88.4%), and the 6-month OS rate was 82.1% (95% CI 67.7%-90.5%). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of brexu-cel in R/R MCL in the real world practice. The CRS and ICANS incidences were comparable to those reported in ZUMA-2, but use of tocilizumab and steroid was more frequent than in ZUMA-2. Although 73% of the patients would have been ineligible for ZUMA-2, the ORR and CR rate were comparable to those reported in ZUMA-2. Longer follow-up is necessary to confirm long term safety and efficacy. YW, PJ and FLL are co-first authors, and YL, MW and MDJ are co-senior authors. Figure 1 Figure 1. Disclosures Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Jain: Kite: Consultancy; Lilly: Membership on an entity's Board of Directors or advisory committees. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Umoja: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Munoz: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Beitinjaneh: Kite/Gilead: Other: Ad Board Event Attendee. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Dahiya: Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Jazz Pharmaceuticals: Research Funding; Atara Biotherapeutics: Consultancy; BMS: Consultancy. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; EcoR1 Capital: Consultancy. Goy: Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Phamacyclics: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Incyte: Honoraria; Hoffman la Roche: Consultancy; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Xcenda: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Shah: Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Paludo: Karyopharm: Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding. Lin: Legend: Consultancy; Novartis: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Wang: Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; InnoCare: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Genentech: Consultancy; OMI: Honoraria; Physicians Education Resources (PER): Honoraria; Clinical Care Options: Honoraria; CAHON: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; CStone: Consultancy; Loxo Oncology: Consultancy, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; BGICS: Honoraria; Bayer Healthcare: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Molecular Templates: Research Funding; Imedex: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Lilly: Research Funding; Celgene: Research Funding; Anticancer Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy.

Abstract Introduction: The management of CLL patients historically utilized FD chemoimmunotherapy (CIT), including fludarabine, cyclophosphamide and rituximab (FCR), or bendamustine and rituximab (BR). That changed with the introduction of Bruton Tyrosine Kinase inhibitors (BTKi) as an option for oral targeted monotherapy delivered continuously until disease progression or intolerance. Recently, novel combinations that include a B-cell lymphoma 2 inhibitor (BCL2i), such as venetoclax, have been developed as FD therapy. In addition, though not FDA approved, MRD assessment is emerging as a potential tool to guide FD therapy. Understanding the patient and their caregiver perspectives on FD and MRD is critical to providing the best care. Methods: CLL Society developed a web-based survey instrument of multiple-choice questions to assess patient and caregiver awareness, understanding, and preferences with MRD and FD therapies, where FD referred to both time and MRD guided limited duration therapies. Patients and caregivers were invited to participate via message boards, CLL Society's website, email, and online communities. Results: A total of 607 (96%) self-identified US patients and 36 (5%) caregivers, who answered on behalf of patients in their care, completed the survey between 31/AUG/2020 and 31/JAN/2021. The mean patient age was 64 (range, 30-90) years, 54% were female, 169 patients (27%) treatment-naïve, 239 (38%) with one line of prior therapy, and 214 (34%) with two or more. Targeted agents (e.g., venetoclax, ibrutinib, acalabrutinib, idelalisib, and duvelisib) had been used by 401 (64%). FD use with some novel therapies was known of by 565 (90%) patients, while 588 (93%) knew some were used as continuous daily treatment until disease progression or intolerance. If effectiveness and side effects were assumed similar, 485 (77%) preferred FD, and 398 (63%) wanted that finite treatment to be guided by MRD status. Only 42 (7%) preferred continuous therapy until disease progression or intolerance. The chance for continued remission while off treatment was ranked as a very important potential benefit after stopping a FD therapy by 581 (92%) patients. When considering therapy, 589 (93%), 575 (91%), 447 (71%), 415 (66%), 302 (48%), and 288 (46%) rated having overall survival, having future therapeutic options, avoiding chemotherapy, the ability to reach undetectable (u)MRD, minimal lab and office visits, and FD therapy as very important, respectively (Fig. 1). Being tested for MRD at least once was reported by 215 (34%), while 327 (52%) had not been tested, and 88 (14%) were unsure. There were 562 (89%) who were somewhat or very familiar with the term MRD, while 450 (71%) were confident of understanding what MRD testing measures, and 446 (70%) understood its role in CLL. Only 225 (36%) stated they understood different testing methods. While self-rated understanding of the indications for MRD testing was relatively high, some wanted testing done when not clinically indicated, such as when there was persistent CLL by routine laboratory findings, or at the time of diagnosis (Fig. 2). Respondents were mixed in their stated understanding as to which therapies could result in uMRD, with 241 (38%), 197 (32%), and 195 (32%) not knowing if CIT, BCL2i, and BTKi, could lead to uMRD, respectively. Two hundred and sixty-five (42%), 84 (13%), and 57 (9%) believed it was possible for most on a BCL2i, BTKi, or CIT to achieve uMRD, respectively (Fig. 3). If patients had evidence of MRD at the end of treatment, 365 (58%) would request frequent monitoring but would make no immediate treatment decisions based on MRD status, 279 (44%) were unsure, and only 88 (14%) would want further treatment immediately. Conclusions: The results from this patient-based study reveal a high awareness of FD therapies and MRD testing, as well as a clear preference for FD among internet-active patients and caregivers. However, there are gaps in the knowledge base, thus significant educational opportunities. Limitations included the opt-in sample where the survey results may not be projectable to the total CLL population. Moreover, the survey was not designed to assess preferences if either FD or continuous therapy offered improved outcomes. Nonetheless, as the potential role of MRD and FD therapy grows in CLL it will be incumbent on clinicians to ensure patients are well informed and engaged to help them better share therapeutic decisions. Figure 1 Figure 1. Disclosures Koffman: AbbVie: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Honoraria; Beigene: Current equity holder in publicly-traded company; Bristol Myer Squibb: Current equity holder in publicly-traded company, Honoraria; Gilead: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company, Honoraria; Sunesis Pharmaceuticals: Current equity holder in publicly-traded company; TG Therapeutics: Current equity holder in publicly-traded company; Regeneron: Current equity holder in publicly-traded company; Miragen Therapeutics: Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Portola Pharma: Current equity holder in publicly-traded company; MEI Pharma: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Stewart: Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company; Dr. Reddy's Laboratories Limited: Current equity holder in publicly-traded company; Adaptive Biotechnologies: Current equity holder in publicly-traded company; Pacific Biosciences: Current equity holder in publicly-traded company. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; Rigel Pharm: Honoraria; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding. Davids: BeiGene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Furman: Beigene: Consultancy; Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; X4 Pharmaceuticals: Consultancy; Oncotracker: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria. Jain: Bristol Myers Squibb: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Pharmacyclics: Research Funding. Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna: Juno Therapeutics, Inc.: Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; MingSight Pharmaceuticals, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy; TG Therapeutics, Inc: Research Funding; Verastem Oncology: Research Funding; Celgene Corporation: Consultancy; Oncternal Therapeutics: Research Funding; Pharmacyclics: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy. Mato: MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ujjani: Adaptive Biotechnologies: Research Funding; Atara Bio: Consultancy; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria; Gilead: Honoraria; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Loxo: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Pagel: Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy.

Abstract Introduction: Allogeneic stem cell transplantation (allo-SCT) can be curative for patients with hematologic malignancies. Despite optimization of supportive measures, the risk of non-relapse mortality is a particularly important consideration in older individuals. Sarcopenia, defined as low skeletal muscle mass, has been shown to be associated with decreased overall survival in cancer patients and may identify individuals at higher risk of treatment-related complications. Methods: Using Mayo Clinic Arizona's hematopoietic stem cell transplantation database, patients aged 60 years or older who underwent allo-SCT between 2008 and 2018 were identified. Patients who underwent abdominal computed tomography (CT) at our institution within 90 days prior to their transplant date were included in the study. The skeletal muscle area (SMA) was obtained using a fully automated algorithm for segmenting abdominal CT images to quantify body composition based on a deep learning approach (Weston et al., Radiology, 2019). The skeletal muscle index (SMI) was then calculated using the SMA and the subject's height at the time the CT was obtained. Sarcopenia was defined based on previously described consensus (Cruz-Jentoft et al., Age Ageing, 2010; Magudia et al., Radiology, 2021). T-tests and Fisher's exact tests compared patient characteristics between groups, where appropriate. Kaplan-Meier methods were used to construct survival times. Log-rank tests compared survival distributions and Cox proportional hazards models estimated hazard ratios. Results: A total of 79 patients met inclusion criteria (Table 1). Of these, 50 (63%, n=50/79) had sarcopenia, and 29 (37%, n=29/79) had normal skeletal muscle mass. Among the sarcopenia group, 43 (86%, n=43/50) had SMI measurements. No differences were seen between groups in age at transplant, sex, Karnofsky performance scale, disease risk index, or conditioning regimen intent. There was no statistically significant difference in overall survival between those with sarcopenia and those with normal skeletal muscle mass (log-rank p=0.18). Median survival was 3.3 years (95% CI: 0.8, not estimable (NE)) for those with sarcopenia and 3.6 years (95% CI: 1.3, NE) for those with normal skeletal muscle mass. Given the infrequency of events, the upper bounds of the median survival confidence intervals were not estimable. The unadjusted hazard ratio (HR) for sarcopenia versus normal skeletal muscle mass was 1.65 (95% CI: 0.79, 3.47; p=0.18). Males had a higher mean SMI than females, as expected (50.4 versus 37.5, p<0.001; mean difference 13.0, 95% CI: 8.9, 17.1). Without considering sex, higher or lower SMI was not associated with survival time in a Cox model in those with sarcopenia (HR: 0.97, 95% CI: 0.92, 1.03; p=0.32). Sex alone was also not associated with any survival benefit among these 43 patients. After adjusting for the difference seen in SMI between sexes, on average, those with higher SMI were associated with a survival benefit (HR: 0.92, 95% CI: 0.84, 0.99; p=0.039). This amounts to roughly an 8% reduction in hazard rate as SMI increased. Conclusions: The presence of sarcopenia alone was not associated with overall survival in patients 60 years and older undergoing allo-SCT for hematologic malignancy. Rating sarcopenia severity using SMI may assist in identifying high risk individuals with sarcopenia as lower sarcopenia severity was associated with improved overall survival. Further studies are warranted to explore the possible impacts of interventions directed at improving skeletal muscle mass on transplant-related outcomes. Figure 1 Figure 1. Disclosures Gaulin: DeciBio: Honoraria; Olson Research Group: Honoraria. Jain: CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B); 1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1)); other malignancies included squamous cell carcinoma of skin (n=3); sarcoma (n=1); endometrial (n=1); lung (n=1); mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. J.Y.S and M.D.J contributed equally; S.D and M.L contributed equally. Figure 1 Figure 1. Disclosures Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy. Nastoupil: Pfizer: Honoraria, Research Funding; MorphoSys: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Bayer: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Lin: Gamida Cell: Consultancy; Juno: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Oluwole: Curio Science: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. McGuirk: EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astelllas Pharma: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Goy: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; Xcenda: Consultancy; Acerta: Consultancy, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Genentech/Hoffman la Roche: Research Funding; MorphoSys: Honoraria, Other; Karyopharm: Research Funding; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Incyte: Honoraria; Medscape: Consultancy; Novartis: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Infinity/Verastem: Research Funding; Rosewell Park: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive Peer Exchange: Honoraria; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Hill: Pfizer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding. Muñoz: Seagen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Speakers Bureau; Juno/Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Alexion: Consultancy; BeiGene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Debiopharma: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Acrotech: Speakers Bureau; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene/Bristol Myers Squibb: Speakers Bureau; Genentech: Speakers Bureau; Aurobindo: Speakers Bureau; Physicians' Education Resource: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; OncView: Honoraria; Targeted Oncology: Honoraria. Westin: AstraZeneca: Consultancy, Research Funding; 47 Inc: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Morphosys: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Genentech: Consultancy, Research Funding. Chavez: Bristol Myers Squibb: Speakers Bureau; Karyopharm Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Kite/Gilead: Consultancy; Abbvie: Consultancy; MorphoSys: Speakers Bureau; BeiGene: Speakers Bureau; Novartis: Consultancy; Adaptive: Research Funding; Epizyme: Speakers Bureau; AstraZeneca: Research Funding. Bennani: Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Locke: GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Umoja: Consultancy, Other; Cowen: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Legend Biotech: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role. Dahiya: Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; Miltenyi Biotech: Research Funding; Jazz Pharmaceuticals: Research Funding; BMS: Consultancy. Lunning: Spectrum: Consultancy; AstraZeneca: Consultancy; Acrotech: Consultancy; Legend: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Myeloid Therapeutics: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Daiichi-Sankyo: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy.

Abstract The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.