Morschhauser, Franck

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

SummaryProgression‐free survival (PFS) has been the regulatory primary end‐point for recent phase III trials in first‐line follicular lymphoma (FL), but requires prolonged follow‐up. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end‐point for PFS. Our objective was to further evaluate surrogacy of CR measured by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial‐level surrogacy examining the association between treatment effects on EoI‐PET‐CR and PFS was evaluated using linear regression () and bivariate Copula () models. Although EoI‐PET‐CR strongly predicted PFS at a prognostic level, the trial‐level assessment did not show strong correlation (, confidence interval [CI]: 0.20–0.88; , CI: 0.0–0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI‐PET‐CR end‐point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET‐CR based surrogate end‐points is still warranted.

Abstract Background: Standard of care (SOC) for second-line (2L) therapy (tx) of relapsed/refractory aggressive B-cell non-Hodgkin lymphomas (R/R aNHL) includes platinum-based chemotherapy (PCT) followed by autologous hematopoietic cell transplantation (aHCT) in responders. Outcomes are poor for patients (pts) with R/R aNHL who experience progression during or within 12 months (mo) of 1L tx. Tisagenlecleucel (tisa-cel) is an autologous chimeric antigen receptor (CAR) T-cell tx targeting CD19 approved for pts with large B-cell lymphoma (LBCL; US) and diffuse LBCL (non-US) after ≥2 lines of tx. BELINDA (NCT03570892) is a Phase III, randomized, global (18 countries) study of tisa-cel vs SOC as 2L tx for R/R aNHL. Methods: Adults with confirmed R/R aNHL within 12 mo after 1L chemo-immunotherapy were eligible. All pts underwent leukapheresis for tisa-cel production and were randomized 1:1 to receive tisa-cel (Arm A) or SOC (Arm B) and stratified by 1L duration of response, International Prognostic Index (IPI), and geographic region. Arm A received optional bridging tx (investigator choice of protocol-defined PCT regimens) followed by lymphodepletion (LD; generally, fludarabine 25 mg/m 2/day [d] + cyclophosphamide 250 mg/m 2/d for 3 d) and followed by a single tisa-cel infusion (0.6-6×10 8 CAR-T cells). Arm B received investigator choice of PCT regimen followed by aHCT in responders or a second PCT in nonresponders. Disease assessments were performed at 6 and 12 weeks (wk), then planned every 3 mo for year (y) 1 and every 6 mo for y 2. The primary endpoint was event-free survival (EFS), defined as time from randomization to stable disease (SD) or progressive disease (PD) at or after wk 12 assessment or death at any time. SD/PD at wk 6 was not considered an event on either Arm. Arm A's wk 6 assessment evaluated disease burden before tisa-cel infusion and after bridging if administered. Arm B's wk 6 assessment determined if response was sufficient for aHCT or if a second PCT regimen was needed prior to aHCT. Results: As of May 6, 2021, 322 pts were randomized: 162 to Arm A and 160 to Arm B. In Arms A and B, 33% and 29% were ≥65 y, and 66% and 67% had primary refractory disease, respectively. Baseline characteristics indicated imbalances with more high-grade B-cell lymphomas (24% vs 17%) and IPI ≥2 (65% vs 58%) in Arm A vs B. In Arm A, 47% received ≥2 cycles of bridging PCT, 36% received 1 cycle, and 17% received 0. In Arm A, 96% received tisa-cel; the median dose was 2.9×10 8 cells. In Arm B, 96% received ≥2 PCT cycles and 54% received ≥2 different PCT regimens; 33% received aHCT, including 10% requiring ≥2 different PCT regimens before aHCT. Median time from randomization to aHCT was 92 d (range, 61-158 d). Median follow-up was 10 mo (range, 2.9-23.2 mo). At wk 6 assessment, 26% had PD in Arm A vs 14% in Arm B. Median EFS in Arms A and B was 3 mo (HR 1.07; 95% CI, 0.82-1.40; P=0.69); Arm A pts with PD at wk 6 had shorter EFS. Overall response rate (ORR) at wk 12 in Arm A was 46% vs 43% in Arm B; complete response rate in both arms was 28%. Some pts responded to tisa-cel after SD/PD at wk 12 without additional tx but were counted as an event in EFS analysis. In Arm B, 81 pts (51%) crossed over to receive tisa-cel, 71 without receiving aHCT. Of 72 crossover pts with response assessment, ORR to tisa-cel was 40%. Overall survival was immature at data cutoff. In Arm A, 84% had a grade ≥3 adverse event (AE; vs 90% in Arm B), including grade ≥3 cytokine release syndrome in 5% (CRS; Lee 2014) and grade ≥3 neurologic events (NE) in 3% (CTCAE v5.0), with no grade 5 CRS/NE. Median times to CRS and NE onset were 4 and 5 d, respectively; median time to resolution was 5 and 9 d. Fifty-two (32%) and 45 (28%) pts in Arms A and B died on study, including 42 (26%) and 32 (20%) deaths due to PD, respectively. Ten pts in Arm A and 13 in Arm B died of AEs. Conclusions: Tisa-cel as 2L tx in R/R aNHL pts did not have a higher EFS vs SOC. Possible contributing factors include study design elements, such as optional PCT bridging tx in Arm A with potential delay of tisa-cel infusion until after wk 6 assessment, allowance of a different PCT regimen to reach aHCT in Arm B after inadequate response to first PCT, and imbalances in relevant pt characteristics. Insights from this randomized Phase III study will inform use of cellular tx in the 2L R/R aNHL setting and the design of future CAR-T trials. Figure 1 Figure 1. Disclosures Bishop: Arcellx, Autolus, Bristol-Myers Squibb, CRISPR, Kite/Gilead, and Novartis: Consultancy, Research Funding; Bristol-Myers Squibb and Kite/Gilead: Other: fees for non-CME/CE services . Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Amgen: Honoraria. Purtill: Novartis: Honoraria; Gilead: Honoraria; BMS Celgene: Honoraria. Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding. Santoro: Arqule: Consultancy, Speakers Bureau; Sanofi: Consultancy; Takeda: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kato: Abbvie: Consultancy, Research Funding; AstraZeneca: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dainippon-Sumitomo: Honoraria; Eisai: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Honoraria; Mundi: Honoraria; Novartis: Consultancy, Research Funding; Ono: Honoraria, Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Morschhauser: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Janz: Janssen: Honoraria, Other: Meeting Fees; Novartis: Honoraria; Takeda: Honoraria, Other: Travel Accommodations, Expenses, Meeting fees; Roche: Honoraria; Gilead: Other: Travel Accommodations, Expenses, Meeting fees. Flinn: 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 equity holder in publicly-traded company; Seattle Genetics: Research Funding; Sarah Cannon Research Institute: Current Employment; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: 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; Teva: 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; Portola Pharmaceuticals: Other: All 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; Novartis: Consultancy, Other: All consultancy and 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; Loxo: Other: All 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; Infinity 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; IGM Biosciences: Other: All 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; Forma Therapeutics: Other: All 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; Constellation Pharmaceuticals: Other: All 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; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: 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; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and 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; TG Therapeutics: Consultancy, Other: All consultancy and 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; Seagen: Consultancy, Other: All consultancy and 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; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and 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; Juno Therapeutics: 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; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Gilead Sciences: Consultancy, Other: All consultancy and 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; BeiGene: 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; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding. Kwong: Novartis: Consultancy, Honoraria, Research Funding. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; BMS/Celgene: Consultancy, Honoraria. Minnema: Janssen: Consultancy, Honoraria; Celgene: Other: Travel expenses; BMS: Consultancy; Kite/Gilead: Consultancy; Alnylam: Consultancy. Holte: Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Incyte Corporation: Consultancy, Honoraria; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Allovir: Consultancy, Research Funding; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Vor Pharma: Other: Data and Safety Monitoring Board. McGuirk: Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Dreyling: Amgen: Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Gilead Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Research Funding; BeiGene: Consultancy, Speakers Bureau; Genmab: Consultancy; MorphoSys: Consultancy. Harigae: Bristol Myers Squibb: Honoraria; Novartis Pharma: Honoraria, Research Funding; Chugai Pharma: Honoraria; Janssen Pharma: Honoraria; Ono pharma: Honoraria, Other: Subsidies or Donations; Astellas Pharma: Other: Subsidies or Donations; Kyowakirin: Other: Subsidies or Donations. Bond: Kite/Gilead: Honoraria. Andreadis: Merck: Research Funding; BMS: Research Funding; 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. McSweeney: Kite-Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida: Consultancy, Honoraria; TG Theraputics: Consultancy, Honoraria; Autolous Limited: Research Funding; Novartis: Research Funding; NKARTA: Research Funding; Allovir: Research Funding. Newsome: Novartis: Current Employment. Degtyarev: Novartis: Current Employment, Current equity holder in publicly-traded company. Del Corral: Novartis: Current Employment. Andreola: Novartis: Current Employment, Current holder of stock options in a privately-held company. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Schuster: AbbVie, Acerta, Celgene/Juno, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics: Research Funding; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene/Juno, Genentech/Roche, LoxoOncology, Novartis, and Tessa Therapeutics: Consultancy; Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech/Roche, LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics;: Honoraria; Novartis: Other: Personal fees, Patents & Royalties; AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer: Other: Steering Committee Participation. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Abstract Background: Pts with LBCL primary refractory to or relapsed ≤ 12 mo after first-line (1L) therapy may have poor outcomes with SOC, including salvage CT and ASCT, which underscores a critical unmet need. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the TRANSCEND NHL 001 study (NCT02631044) in pts with R/R LBCL (≥ 2 prior lines of therapy), liso-cel treatment resulted in an ORR of 73% (CR rate, 53%), 2% grade ≥ 3 cytokine release syndrome (CRS), and 10% grade ≥ 3 neurological events (NE) (Abramson et al. Lancet 2020). Here we present a prespecified interim analysis of TRANSFORM (NCT03575351; SOC vs liso-cel as 2L therapy in pts with R/R LBCL). Methods: TRANSFORM is a pivotal, global, randomized, multicenter, phase 3 study comparing efficacy and safety of SOC (Arm A; R-DHAP, R-ICE, or R-GDP per investigator choice followed by BEAM + ASCT) vs liso-cel (Arm B). Pts were adults (aged ≤ 75 years), eligible for ASCT, and with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function (LVEF ≥ 40%; serum CrCl > 45 mL/min); pts with secondary CNS lymphoma were allowed. Key exclusion criteria were prior gene or anti-CD19-targeted therapy, and active infection. Pts in Arm A were to receive 3 cycles of CT. Responding pts (CR or PR) were to proceed to BEAM + ASCT. Pts in Arm B were to undergo lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Bridging therapy with an Arm A CT regimen was allowed. Crossover to receive liso-cel was allowed in Arm A for pts not achieving CR or PR after 3 cycles of CT or not in CR after ASCT, or demonstrating PD at any time. Primary endpoint is event-free survival (EFS) based on independent review committee per Lugano 2014 criteria, defined as time from randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks after randomization, or start of new antineoplastic therapy, whichever occurred first. Key secondary endpoints included in the testing strategy are CR rate, PFS, and OS. P value significance threshold for endpoints to reject the null hypothesis was ≤ 0.012. Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were well balanced between both arms (Table). Of 91 treated pts in Arm A (1 pt withdrew consent), 43 received BEAM + ASCT, of which 28 achieved CR with CT. Fifty pts crossed over to receive liso-cel. In Arm B, 90 pts received liso-cel infusion; 58 pts (63%) received bridging therapy. Two Arm B pts were not infused (1 each due to manufacturing failure and rapid progression). Median EFS and PFS were significantly longer, and CR rate was significantly improved for Arm B vs Arm A. For Arms A and B, respectively, median EFS was 2.3 vs 10.1 mo (HR, 0.349; P < 0.0001), median PFS was 5.7 vs 14.8 mo (HR, 0.406; P = 0.0001), and CR rate was 39% vs 66% (P < 0.0001). OS data were immature at the time of this analysis with a median follow-up of 6.2 mo (range, 0.9-20.0), but a numerical trend favored Arm B (HR, 0.509; 95% CI, 0.258-1.004; P = 0.0257). Cellular kinetics in Arm B showed a median t max of 10 d (range, 6‒22). No new liso-cel safety signals were detected in the 2L setting. In Arm B, any-grade CRS was reported in 49% of pts, with grade 1 in 37% and grade 2 in 11%. Only 1 pt had grade 3 CRS (onset at Day 9, which resolved in 2 days). Any-grade NEs were reported in 12% of pts and were also primarily low grade (grade 3, 4%). No grade 4 or 5 CRS or NEs were reported. In Arm B, 24% of pts received tocilizumab, 17% received corticosteroids, and none received vasopressors. The most common TEAEs in both arms were cytopenias. Prolonged cytopenias in Arm B (ie, grade ≥ 3 at 35 d after infusion) were reported in 43% of pts; the majority recovered within 2 mo after infusion. Conclusions: In the TRANSFORM study, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint, EFS, as well as in key secondary efficacy endpoints (CR rate and PFS) compared with SOC as 2L therapy in pts with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Safety results in the 2L setting were consistent with the liso-cel safety profile in 3L or later LBCL, and no new safety concerns were identified. Liso-cel improved outcomes vs SOC and exhibited a favorable safety profile, providing support for liso-cel as a potential new SOC for 2L treatment in pts with R/R LBCL. Figure 1 Figure 1. Disclosures Kamdar: SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Celgene: Other; TG Therapeutics: Research Funding; KaryoPharm: Consultancy; Celgene (BMS): Consultancy; Genetech: Other; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ibrahimi: Karyopharm Theraputics: Divested equity in a private or publicly-traded company in the past 24 months. Mielke: Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Hernandez-Ilizaliturri: Kite: Other: Advisory Boards; Amgen: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; BMS: Other: Advisory Boards; Celgene: Other: Advisory Boards; Incyte: Other: Advisory Boards; AbbVie: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Izutsu: Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Morschhauser: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lunning: Karyopharm: Consultancy; AstraZeneca: Consultancy; Legend: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Acrotech: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy. Maloney: Amgen: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; A2 Biotherapeutics: Honoraria, Other: Stock options; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Celgene: Other: Research funding was paid to my institution, Research Funding; Umoja: Honoraria; Janssen: Honoraria; Legend Biotech: Honoraria; Genentech: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Stepan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mack: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abramson: Bluebird Bio: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Liso-cel is a CAR T cell therapy approved for use in the third line for R/R LBCL. This trial reports data from the pivotal trial in the second line.

Abstract Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.