Oral ixazomib in untreated follicular lymphoma permits COVID-19 vaccine response and its efficacy is associated with clinical factors and gene expression signatures

Background: Standard chemoimmunotherapy for first-line treatment of follicular lymphoma (FL) achieves high rates of disease control but is not curative and carries significant toxicities including prolonged immunosuppression that may attenuate response to vaccinations (Marcus et al., NEJM 2017). While proteasome inhibitors have shown modest activity in R/R FL (Goy et al., JCO 2005), limited data address their use frontline. The comparatively favorable toxicity profile and convenient oral dosing of ixazomib support its investigation in this space. Methods: We evaluated ixazomib and its combination with short-course rituximab (R) for FL as part of an open-label, phase II investigator-initiated trial at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance (NCT 02339922). Eligibility included an indication for treatment per NCCN guidelines and no prior standard systemic FL therapy. Ixazomib was administered at 4 mg orally once a week until disease progression or unmanageable toxicity. One course of R at 4 weekly doses of 375 mg/m2 was added during the 7th 28-day cycle, after an initial 6-cycle “window” on ixazomib alone. Available pretreatment formalin-fixed, paraffin-embedded tissue biopsies were subjected to RNA extraction by standard methods and gene expression profiling (GEP) using the NanoString™ PanCancer IO 360 panel to query pathways in proteasomal degradation and lymphomagenesis. Standard GEP quality control and data processing were performed with the ROSALIND® platform. Patients vaccinated per standard of care for COVID-19 while actively receiving ixazomib and ≥ 6 mo after completing R were evaluated for serologic response ≥ 2 weeks after the final dose of vaccine using the Roche Elecsys® Anti-SARS-CoV-2 S assay against the spike protein receptor binding domain. Results: Twenty pts began therapy between Feb 2017 and January 2020. All had grade I/II FL and FLIPI score was 2 in 20% and ≥ 3 in 20%;FLIPI score in all other patients was 0 or 1. Eleven (55%) pts met GELF criteria for high tumor burden disease including 6 (30%) pts with a tumor mass ≥ 7 cm. Median follow-up was 32.1 months (range 5.7 - 51.6). The ORR by Lugano criteria was 35% (CR 5%) during the ixazomib window and 65% (CR 45%) overall. At data cut (June 15, 2021) all patients were alive and 8 (40%) remained progression-free on treatment (Figure 1). By KM estimate, median PFS was 25.8 mo and median DOR was not reached at a median follow-up of 29.6 mo. As expected, high-grade treatment-related AEs were infrequent for ixazomib and R, including grade ≥ 3 events in 3 unique pts (15%;diarrhea, transaminitis, and cytopenias). No grade ≥ 4 or serious AEs were observed. Toxicities led to study-directed drug interruptions in 4 (20%) pts and dose reduction to ixazomib 3 mg weekly in 2 pts (10%). Higher ORR to ixazomib monotherapy was associated with FLIPI > 1 (p = 0.04) and, by exploratory GEP, downregulation of components of proteasomal degradation and upregulation of NF-KB and chemokine signaling (Figure 2). High tumor burden by GELF (p = 0.89) and tumor mass ≥ 7 cm (p = 0.26) were not associated with ORR to ixazomib. All 6 of 6 patients evaluated to date for response to COVID-19 vaccination, administered at a median of 32.5 mo (range 7.0 - 41.0) after last dose of R, achieved positive anti-spike protein antibodies (median anti-S 163.8 AU/mL, range 13.3 - 1139);none was diagnosed with COVID-19. Conclusions: The simple outpatient regimen of weekly oral ixazomib and the addition of 4 doses of R shows significant long-term activity with low toxicity in untreated FL. Extended DOR is achievable especially in patients who respond to ixazomib monotherapy. Ixazomib efficacy was associated with higher FLIPI scores and gene expression signatures implicated in proteasomal degradation and B-cell signaling pathways. Ixazomib deserves further investigation as a biomarker-driven therapeutic in untreated FL, particularly as an option that prioritizes outpatient management and serologic responsiveness to im unization. (Figure Presented).

Zanubrutinib in patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib

Introduction: Bruton tyrosine kinase inhibitor (BTKi) therapy is remarkably effective in a number of B-cell malignancies;however, its continuous use is limited by adverse events (AE) leading to discontinuation. Zanubrutinib is a potent and selective BTKi with the potential to be a safe and effective therapy after intolerance to previous BTKi therapy. Here, we report preliminary results of a phase 2 study of zanubrutinib in patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib based on a median follow-up of 6 months. Methods: Patients meeting protocol criteria for intolerance to ibrutinib, acalabrutinib, or both (without documented progressive disease on ibrutinib or acalabrutinib) were given zanubrutinib monotherapy (160mg twice daily or 320mg once daily at investigator's discretion). Recurrence of adverse events that led to intolerance to prior BTKi and additional safety measures were assessed based on the Common Terminology Criteria for AEs v5.0. Investigators determined responses using disease status at study entry as baseline and standard established disease response criteria. Results: As of 1 March 2021 (cutoff), 64 patients (n=48 chronic lymphocytic leukemia/small lymphocytic lymphoma, n=10 Waldenström macroglobulinemia, n=3 mantle cell lymphoma, n=3 marginal zone lymphoma) were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. The median age was 71 y (range, 49-91);the median duration of treatment was 5.9 months (range, 0.6-16.6). The median number of prior regimens was 2 (range, 1-12). Regarding prior BTKi, 55 patients had received ibrutinib monotherapy, eight had received ibrutinib combination therapy, and seven had received acalabrutinib monotherapy. The median number of ibrutinib- or acalabrutinib-intolerant adverse events per patient was 2 (range, 1-5). Most ibrutinib- (75%) and acalabrutinib-intolerant events (75%) did not recur with zanubrutinib (Table 1). A majority (90%) of the recurrent ibrutinib-intolerant events were less severe with zanubrutinib than with ibrutinib. Ibrutinib intolerance events present in >1 patient that did not recur on zanubrutinib were alanine aminotransferase increased, aspartate transaminase increased, neutropenia, and pain in extremity. The ibrutinib-intolerant events that recurred were diarrhea, dizziness, insomnia, nausea, constipation, myalgia, stomatitis, arthralgia, headache, muscle spasm, rash, atrial fibrillation, fatigue, hemorrhage, and hypertension. One-third of the recurrent acalabrutinibintolerant events were less severe with zanubrutinib than with acalabrutinib. The acalabrutinib-intolerant events that recurred were myalgia and arthralgia. Two events of arthralgia that induced acalabrutinib intolerance did not recur with zanubrutinib. No ibrutinib- or acalabrutinib-intolerant events recurred at a higher severity while patients were on zanubrutinib. At cutoff, 57 patients remained on treatment;one withdrew consent due to zanubrutinib-unrelated grade 3 syncope. Grade ≥3 adverse events were reported in 14 patients (21.9%), serious adverse events in five patients (7.8%;pain in jaw;COVID-19 pneumonia;anemia;febrile neutropenia and salmonella infection [occurred in the same patient]), adverse events requiring dose interruptions in 15 patients (23.4%), and adverse events leading to dose reduction in three patients (4.7%). Adverse events led to zanubrutinib discontinuation for three patients (4.7%). One death was reported (COVID-19 pneumonia). Among efficacy evaluable patients (n=48), the disease control rate was 89.6% and the overall response rate was 50.0%. Conclusions: In patients with B-cell malignancies intolerant to ibrutinib and/or acalabrutinib, zanubrutinib therapy was effective and controlled patient's disease or induced responses to therapy, and was well-tolerated;most adverse events that led to discontinuation of previous BTKi therapy did not recur while patients were on zanubrutinib.

Randomized, Phase III Study of Early Intervention with Venetoclax and Obinutuzumab Versus Delayed Therapy with Venetoclax and Obinutuzumab in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Evolve CLL/SLL Study (SWOG S1925;NCT#04269902)

Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies in patients with CLL/SLL with non-specific chemoimmunotherapy agents have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax (an oral BCL2 inhibitor;V) and obinutuzumab (an intravenous anti-CD20 monoclonal antibody;O), have provided tolerable/efficacious options for patients with CLL. In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (uMRD)] compared with those receiving chlorambucil and O (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI;Table 1) is a validated prognostic model to predict which patients are at highest risk of a shorter time to first therapy and shorter OS. A score of ≥4 is considered high-risk on this scale. We aim to use VO as early intervention in asymptomatic, high-risk CLL patients, assessed by CLL-IPI, to potentially improve OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study (NCT#04269902 ) for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥4 (Table 1) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL;Hallek 2018) guidelines. Enrolled patients are randomized in a 2:1 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO (Figure 1). VO is administered as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided a=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival;safety;time to second CLL-directed therapy;and quality of life (assessed by FACT-Leukemia). As COVID19 is an infection with particularly high morbidity and mortality in patients with CLL, incidence of this infection and complications including death will be recorded and compared between patients followed on the early versus delayed intervention arms. The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Secondary translational objectives include describing the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Current Status: At the time of submission, 7 patients have been registered and randomized per protocol. Accrual is ongoing. [Formula presented] Disclosures: Stephens: Adaptive: Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Epizyme: Membership on an entity's Board of Directors or advisory committees;Beigene: Membership on an entity's Board of Directors or advisory committees;Innate Pharma: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Consultancy;CSL Behring: Consultancy;Celgene: Consultancy;Novartis: Research Funding;Abbvie: Consultancy;JUNO: Research Funding;Arqule: Research Funding;Mingsight: Research Funding;Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley: BioSight Ltd: Consultancy. Hill: AbbVie: Consultancy, Honoraria, Research Funding;Gentenech: Consultancy, Honoraria, Research Funding;Beigene: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria;Kite, Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding;Karyopharm: Consultancy, Honoraria, Research Funding;AstraZenica: Consultancy, Honoraria;Celgene (BMS): Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Epizyme: Consultancy, Honoraria;Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy;Actinium Pharmaceuticals: Consultancy;Incyte/MorphoSys: Consultancy;BeiGene: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy;AstraZeneca: Consultancy;Gilead: Consultancy;MEI Pharma: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy. Danilov: Genentech: Consultancy, Honoraria, Research Funding;Takeda Oncology: Research Funding;TG Therapeutics: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Beigene: Consultancy, Honoraria;Pharmacyclics: Consultancy, Honoraria;Gilead Sciences: Research Funding;Bristol-Meyers-Squibb: Honoraria, Research Funding;Rigel Pharm: Honoraria;Bayer Oncology: Consultancy, Honoraria, Research Funding;SecuraBio: Research Funding;Astra Zeneca: Consultancy, Honoraria, Research Funding. Mato: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;DTRM BioPharma: Consultancy, Research Funding;Acerta/AstraZeneca: Consultancy, Research Funding;Sunesis: Consultancy, Research Funding;BeiGene: Consultancy, Research Funding;Johnson and Johnson: Consultancy, Research Funding;Genentech: Consultancy, Research Funding;AbbVie: Consultancy, Research Funding;Nurix: Research Funding;Genmab: Research Funding;LOXO: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;AstraZeneca: Consultancy;Adaptive Biotechnologies: Consultancy, Research Funding;MSKCC: Current Employment;TG Therapeutics: Consultancy, Other: DSMB, Research Funding. Brander: Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding;Pfizer: Consultancy, Other: Biosimilars outcomes research panel;TG Therapeutics: Consultancy, Research Funding;Novartis: Research Funding;ArQule/Merck: Consultancy;Verastem: Consultancy;BeiGene: Research Funding;ArQule: Research Funding;NCCN: Other: panel member;AstraZeneca: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding;LOXO: Research Funding;Ascentage: Research Funding;Genentech: Consultancy, Research Funding;DTRM: Research Funding;MEI Pharma: Research Funding;AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Coutre: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees;Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta: Other: Data Safety Monitoring Committee, Research Funding. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding;Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, El Lill: Consultancy. Erba: AbbVie Inc;Agios Pharmaceuticals Inc;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Incyte Corporation;Jazz Pharmaceuticals Inc;Novartis: Speakers Bureau;AbbVie Inc: Other: Independent review committee;AbbVie Inc;Agios Pharmaceuticals Inc;ALX Oncology;Amgen Inc;Daiichi Sankyo Inc;FORMA Therapeutics;Forty Seven Inc;Gilead Sciences Inc;GlycoMimetics Inc;ImmunoGen Inc;Jazz Pharmaceuticals Inc;MacroGenics Inc;Novartis;PTC Therapeutics: Research Funding;AbbVie Inc;Agios Pharmaceuticals Inc;Astellas;Bristol Myers Squibb;Celgene, a Bristol Myers Squibb company;Daiichi Sankyo Inc;Genentech, a member of the Roche Group;GlycoMimetics Inc;Incyte Corporation;Jazz Pharmaceuticals Inc;Kura Oncology;Nov: Other: Advisory Committee. OffLabel Disclosure: The trial studies early intervention with venetoclax and obinutuzumab in patients with CLL/SLL who are asymptomatic and observation would be standardly recommended.

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Background: Bruton tyrosine kinase inhibitors (BTKis) are important tools to treat B-cell malignancies. However, duration of treatment may be limited by adverse events (AEs). Zanubrutinib (zanu) is a BTKi approved for mantle cell lymphoma (MCL) and is in development for other hematologic malignancies. Data from phase 3 head-to-head trials of zanu vs ibrutinib (ibr) in pts with Waldenström macroglobulinemia (WM) or chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) demonstrated that pts treated with zanu showed lower rates of AEs leading to discontinuation (Blood 2020;136(18):2038-50;EHA 2021 LB1900). Preliminary results from BGB-3111-215 (NCT04116437) show that zanu was well-tolerated in pts who discontinued ibr and/or acalabrutinib (acala) treatment due to AEs (EHA 2021 EP642). Here, we report updated results from the BGB-3111-215 study with a median follow-up of 9 months. Methods: This study is an ongoing US, phase 2, multicenter, single-arm, open-label study. The safety and efficacy of zanu monotherapy (160 mg twice daily or 320 mg once daily) were evaluated in pts with B-cell malignancies who met criteria for continued treatment after having become intolerant to prior BTKi therapy. Pts were divided into cohort 1 (pts who were intolerant to ibr only) and cohort 2 (pts who were intolerant to acala alone/and ibr). Pts with documented progressive disease (PD) on prior BTKi therapy were excluded. Efficacy and safety, including recurrence of intolerant AEs to the prior BTKi, were evaluated. AEs were assessed for severity, seriousness, and relation to zanu;as well as dose reductions, holds, or discontinuations. Response was assessed by investigators based on response criteria for their respective indications (Blood 2008;131:2745;J Clin Oncol 2012;30:2820;J Clin Oncol 2014;32:3059;Br J Haemtol 2013;160:171). Disease parameters from study entry were the baseline for response assessment. Mutational analysis was performed on pts who discontinued treatment, and data will be shared once available. To support clinical findings, kinase selectivity was assessed using Kinome profiling at 100X IC50 (against BTK) for zanu, ibr, acala and its major metabolite, M27 (Reaction Biology Corp). Results: As of 7 June 2021 (data cutoff), 57 pts (n=44 CLL/SLL;n=9 WM;n=2 MCL;n=2 marginal zone lymphoma [MZL]) were enrolled in cohort 1, and 7 pts were enrolled in cohort 2 (n=4 CLL;n=1 WM;n=1 MCL;n=1 MZL). All received ≥1 dose of zanu and were analyzed for safety. The median age was 71 years (range, 49-91) in cohort 1 and 71 years (range, 65-76) in cohort 2;median duration of treatment was 8.7 months (range, 0.6-17.9) in cohort 1 and 8.2 months (range, 6.4-11.4) in cohort 2;median number of prior regimens was 1 (range, 1-12) in cohort 1 and 3 (range, 2-5) in cohort 2. Within cohort 2, 5 pts were intolerant to both ibr and acala. Median number of intolerant events per pt for both cohorts 1 and 2 was 2 (range, 1-5). Overall, 73% of pts did not experience recurrence of their ibr or acala intolerant events and 79% of recurrent events recurred at a lower severity (Figure 1). At cutoff, 54 pts remained on treatment. Reasons for treatment discontinuation were AEs (n=4), PD (n=4), physician's decision (n=1), and consent withdrawal (n=1). Grade ≥3 AEs were reported in 18 pts (28%), and serious AEs occurred in 7 pts (11%). AEs requiring dose interruptions occurred in 17 pts (27%), and AEs leading to dose reduction occurred in 3 pts (5%). One death, due to COVID-19, was reported. Pts demonstrated maintained (41%) and improved (53%) response with zanu treatment from their reported best overall response on prior BTKis for a total disease control rate of 94% (including a 42% partial response rate in pts with CLL/SLL, 30% in pts with WM, and a 20% very good partial response rate in pts with WM). Zanu also demonstrated good selectivity by kinase profiling. It showed >50% inhibition on 7/370 kinases, while ibr, acala, and M27 had more off-target binding (17, 15 and 23 kinases, respectively) at their respective 100X IC50 (BTK) c ncentrations (Figure 2). Conclusion: In pts with B-cell malignancies intolerant to ibr and/or acala, zanu treatment resulted in continued disease control or improved response. Zanu was well-tolerated, and most AEs that led to discontinuation of previous BTKi therapy did not recur or recurred at a lower grade. In support of clinical findings, differentiation between BTKi selectivity profiles favor zanu over ibr and acala. [Formula presented] Disclosures: Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding;Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, and Atara Biotherapeutics, Adaptimmune: Membership on an entity's Board of Directors or advisory committees. Flinn: Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding;Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;ArQule: Other: All research funding payments mad to Sarah Cannon Research Institute, Research Funding;Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding;Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Great Point Partners: Consultancy, Other: All consultancy payments made toSarah Cannon Research Institute;BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding;Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Sarah Cannon Research Institute: Current Employment;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute;Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding;Johnson & Johnson: Current holder of individual stocks in a privately-held company;Seattle Genetics: Research Funding. Levy: Epizyme: Consultancy, Other: Promotional speaker;Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau;GSK: Consultancy, Other: Promotional speaker;Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Beigene: Consultancy, Honoraria, Speakers Bureau;Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Novartis: Consultancy, Other: Promotional speaker;Dova: Consultancy, Other: Promotional speaker;TG Therapeutics: Co sultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Burke: SeaGen: Consultancy, Speakers Bureau;Beigene: Consultancy, Speakers Bureau;MorphoSys: Consultancy;Bristol Myers Squibb: Consultancy;AstraZeneca: Consultancy;Epizyme: Consultancy;Verastem: Consultancy;Kura: Consultancy;Kymera: Consultancy;AbbVie: Consultancy;Adaptive Biotechnologies: Consultancy;Roche/Genentech: Consultancy;X4 Pharmaceuticals: Consultancy. Cultrera: Beigene: Research Funding. Yimer: Astrazeneca: Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau;Janssen: Speakers Bureau;Beigene: Speakers Bureau;GSK: Speakers Bureau;Sanofi: Speakers Bureau;Amgen: Speakers Bureau;Pharmacyclics: Speakers Bureau;Texas Oncology: Current Employment. Chaudhry: Medical Oncology Associates, PS (dba Summit Cancer Centers): Current Employment;Novartis, Immunomedics: Current holder of individual stocks in a privately-held company. Gandhi: TG Therapeutics: Honoraria;Karyopharm Therapeutics: Honoraria;GlaxoSmithKline: Honoraria. Kingsley: Comprehensive Cancer Centers of Nevada: Current Employment. Tumula: Texas Oncology: Current Employment. Manda: Morphosys: Honoraria;Genmab: Current equity holder in publicly-traded company. Chen: BeiGene: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Cohen: BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: Travel, Accommodations, Expenses. By: BeiGene, Ltd: Current Employment. Xu: Beigene: Current Employment;AstraZeneca: Ended employment in the past 24 months. Liu: BeiGene Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Sharman: TG Therapeutics: 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;BMS: Consultancy;AbbVie: Consultancy;BeiGene: Consultancy;AstraZeneca: Consultancy;Lilly: Consultancy.

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is require to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. [Formula presented] Disclosures: Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding;Celgene/BMS: Research Funding;BeiGene: Research Funding;Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy;BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Takeda: Research Funding;Genentech: Consultancy;AstraZeneca: Speakers Bureau;Roche: Consultancy;Karyopharm: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding;AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharma: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Genmab: Consultancy, Honoraria;Epizyme: Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau;Servier Pharmaceuticals: Consultancy;Seattle Genetics: Speakers Bureau;Sanofi: Speakers Bureau;Pharmacyclics: Consultancy;MorphoSys: Consultancy;Kite (Gilead): Speakers Bureau;KaryoPharm: Consultancy;CSL Therapeutics: Consultancy;Bristol-Myers Squibb: Speakers Bureau;Biogen: Consultancy;Beigene: Consultancy;AstraZeneca: Speakers Bureau;ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;AbbVie: Consultancy. Grover: Genentech: Research Funding;Novartis: Consultancy;ADC: Other: Advisory Board;Kite: Other: Advisory Board;Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months;BMS: Divested equity in a private or publicly-traded company in the past 24 months;Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months;Novatis: Divested equity in a private or publicly-traded company in the past 24 months;Janssen: Divested equity in a private or publicly-traded company in the past 24 months;Morphosys: Divested equity in a private or publicly-traded company in the past 24 months;ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months;Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months;Beigene: Divested equity in a private or publicly-traded company in the past 24 months;Merck: Divested equity in a private or publicly-traded company in the past 24 months;KITE: Divested equity in a private or publicly-traded company in the past 24 months;Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support;Humanigen: Consultancy, Honoraria, Other: Travel support;Celgene: Consultancy, Honoraria, Other: Travel support;Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding;Lonza: Consultancy, Honoraria, Other: Travel support;AbbVie: Consultancy, Honoraria;Precision Biosciences: Consultancy, Honoraria, Other: Travel support;Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support;Nkarta: Consultancy, Honoraria;Axis: Speakers Bureau;Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy;Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.