Vose, Julie M.

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.

Abstract Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL–not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881–R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.

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 Background: ZUMA-1 is the registrational Phase 1/2 study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pts with refractory LBCL. In ZUMA-1 Cohorts 1+2 (C1+2; N=101), rates of Grade (Gr) ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) were 13% and 28%, respectively, at the 6-mo primary analysis; the objective response rate (ORR) was 82% (54% complete response [CR]; Neelapu et al. NEJM. 2017). ZUMA-1 safety management C6 assessed whether prophylactic and earlier corticosteroids and/or tocilizumab could reduce incidence and severity of CRS and NEs. With a median follow-up of 8.9 mo (N=40) for C6, there were no Gr ≥3 CRS, a low rate of Gr ≥3 NEs (13%), and high response rates (Oluwole et al. BJH. 2021). Here, we present a 1-yr updated analysis of C6 supported by propensity score matching (PSM) analysis to compare outcomes for pts in C6 vs C1+2. Methods: Eligible pts could receive optional bridging therapy after leukapheresis. Pts received conditioning chemotherapy for 3 d prior to a single axi-cel infusion. Pts received once-daily oral dexamethasone 10 mg on Days 0 (before axi-cel), 1, and 2; corticosteroids and/or tocilizumab for adverse event (AE) management were given earlier vs C1+2. The primary endpoints were incidence and severity of CRS and NEs. Other endpoints included efficacy outcomes and biomarker analyses. To ensure comparability for pts in C6 and C1+2, an exploratory PSM analysis was performed after balancing for key baseline disease characteristics (tumor burden, IPI score, no. of prior lines of chemotherapy, disease stage, and LDH level). Results: As of December 16, 2020, the median follow-up time was 14.9 mo. Gr ≥3 AEs were reported in all 40 treated pts, and the most common were neutropenia (45%), neutrophil count decreased (33%), and white blood cell count decreased (23%). No Gr ≥3 CRS occurred. Gr ≥3 NEs were reported in 15% of pts. Median time to CRS and NE onset was 5 and 6 d, respectively, after axi-cel infusion. Infections of any grade occurred in 50% of pts (20% Gr ≥3). Since the 6-mo analysis, no new cases of CRS were observed. Four new axi-cel-related NEs occurred in 2 pts (pt 1: Gr 2 mental status changes and seizure-like phenomena both on Day 441; pt 2: Gr 1 dementia [occurred on Day 93 but was reported late] and Gr 5 toxic encephalopathy on Day 369 [resultant from a Gr 4 event that started on Day 351]). Two new infections of Gr 2 pneumonia and Gr 1 bronchitis were observed; the latter was axi-cel-related. One death due to progressive disease occurred. The investigator-assessed ORR was 95% (80% CR). Median DOR, PFS, and OS were not reached. Kaplan-Meier estimates of the 12-mo DOR, PFS, and OS rates were 60%, 63%, and 82%, respectively. At data cutoff, 53% of pts were in ongoing response. Median peak CAR T-cell levels were comparably high in pts with ongoing response and relapse (64 cells/µL [n=21] and 66 cells/µL [n=15], respectively) at 12 mo and considerably lower in nonresponders (18 cells/µL [n=2]). In all, 32 matched pts each in C6 and C1+2 were identified during PSM analysis; 8 pts from C6 were not included due to nonavailability of matched pts in C1+2. No Gr ≥3 CRS was observed in C6 vs 13% of pts in C1+2. Incidence of Gr ≥3 NEs was comparable in C6 and C1+2 (19% and 22%, respectively), with median time to onset of 12 d in C6 vs 7 d in C1+2. The ORR was 94% in both C6 and matched C1+2 (75% and 78% CR rates, respectively); 47% and 59% of pts were in ongoing response at 12 mo. The Kaplan-Meier estimate of the 12-mo PFS rate was 61% in both C6 and matched C1+2. Median peak CAR T-cell levels were 65 and 43 cells/µL, respectively, in C6 and C1+2. Serum levels of inflammatory biomarkers associated with CAR T-cell treatment-related AEs (IFN-γ, IL-2, GM-CSF, and ferritin) were lower in C6 vs C1+2. Median cumulative corticosteroid dose including prophylaxis was 1252 mg in C6 (n=32) and 7418 mg in C1+2 (n=6). Conclusion: With ≥1-y follow-up, prophylactic and earlier corticosteroid and/or tocilizumab intervention continued to demonstrate a manageable safety profile, absence of new safety signals, and high, durable response rates, which was corroborated by PSM analysis. Although fewer pts in C1+2 received corticosteroids after matching, the median cumulative corticosteroid dose was 4-fold lower in C6 vs C1+2. These findings suggest that the C6 AE management strategy can improve long-term safety of axi-cel in R/R LBCL without compromising durability of responses. Disclosures Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Forcade: Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support; Gilead: Other: Travel Support, Speakers Bureau; Novartis: Consultancy, Other: Travel Support, Speakers Bureau. Muñoz: Targeted Oncology: Honoraria; Seagen: Consultancy, Honoraria, Speakers Bureau; Physicians' Education Resource: Honoraria; Kyowa Kirin: Consultancy, Honoraria, Speakers Bureau; OncView: Honoraria; 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. de Guibert: Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Bartlett: Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Lin: Juno: Consultancy; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy; Merck: Research Funding; Sorrento: Consultancy; Legend: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. McSweeney: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Autolus: Research Funding; Allovir: Research Funding. Goy: Acerta: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Xcenda: Consultancy, Honoraria; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; MorphoSys: Honoraria, Other; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LLC(Targeted Oncology): Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Rosewell Park: Consultancy; 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; 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; Celgene: Consultancy, Honoraria, Research Funding; Xcenda: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Hoffman la Roche: Consultancy; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Kersten: Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support. Jacobson: Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Farooq: Kite, a Gilead Company: Honoraria. Minnema: Cilag: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; Alnylam: Consultancy. Thieblemont: Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: 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; Novartis: 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; Gilead Sciences: 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 . Timmerman: Spectrum Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; TG Therapeutics: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Corvus: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Merck: Research Funding. Stiff: Macrogenics: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Research Funding; Seagen: Research Funding; Gamida Cell: Research Funding; Janssen: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Cellectar: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; BioLineRX: Research Funding; Cellectar: Research Funding; MorphoSys: Consultancy, Honoraria; Actinium: Research Funding. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Tzachanis: Fate Therapeutics: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Magenta: Consultancy; Kyowa Kirin: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Partner: Consultancy. Kim: Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng: Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Shen: Gilead Sciences: Current equity holder in publicly-traded company; Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Vardhanabhuti: Kite, a Gilead Company: Current Employment, Other: Travel support, Research Funding; Gilead Sciences: Current equity holder in publicly-traded company. Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy.

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.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

SummaryIn young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

Abstract Purpose: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non–Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. Experimental Design: We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Results: Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT–mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA–mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T–B-cell interaction. Conclusions: Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.

SummaryZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.