Abramson, Jeremy S.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

7503 Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval [CI] 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% CI 0.532–0.863]). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.

Abstract Background: High grade B-cell Lymphoma with rearrangements of MYC and BCL2 and/or BCL6, also known as double hit lymphoma (DHL), and double expressing lymphomas (DEL; DLBCL with IHC expression of MYC and BCL2, but without double hit cytogenetics) are highly aggressive B cell non-Hodgkin lymphomas and patients (pts) often develop relapsed/refractory disease following standard first-line chemoimmunotherapy. DA-EPOCH-R is widely used in patients with DHL, and a phase 1 trial of venetoclax + DA-EPOCH-R established the dose of 600 mg for 5 days with each cycle as the recommended phase 2 dose (Rutherford, et al. Proc ASCO 2020). A051701 is a phase II/III randomized trial evaluating chemoimmunotherapy +/- the BCL2 inhibitor venetoclax in a DHL cohort (pts with DHL with BCL2 rearrangement and/or expression), and a DEL cohort. Here we report the initial results from the DHL cohort of A051701. Methods: Pts age ≥ 18 years with newly diagnosed DHL were stratified on International Prognostic Index (IPI) score and receipt of a single cycle of chemotherapy prior to registration, which was permitted, and randomized 1:1 to receive DA-EPOCH-R (Arm 1) or DA-EPOCH-R with venetoclax (Arm 2). Enrollment was based on local pathology results which were centrally confirmed. DA-EPOCH-R was administered as previously published. Venetoclax was dosed at 600 mg po daily on days 4-8 of cycle 1 and on days 1-5 of subsequent cycles for up to 6 total cycles. All cycles were supported by GCSF or peg-GCSF. For the interim analysis at the end of phase II, 53 events ensured 90% power to detect an improvement in 24-month progression-free survival (PFS) from 40% in Arm 1 to 60% in Arm 2 (HR=0.557) using a one-sided stratified log-rank test with type I error rate of 20%. The Alliance Data and Safety Monitoring Board approved the data release after accrual was stopped early due to excess toxicity in Arm 2. These data were frozen July 8, 2021. Results: 73 pts were registered (36 in Arm 1 and 37 in Arm 2) between 8/7/19 and 9/18/20. Analyses were performed for the modified intent-to-treat (mITT) population, defined as eligible pts with DHL histology confirmed (n=66; 30 Arm 1, 36 Arm 2). Median age was 65 years in both arms (range 37-80) and baseline demographic factors were well balanced. An allowed pre-protocol chemoimmunotherapy cycle was administered in 60% and 56% of Arm 1 and Arm 2 pts, respectively. The majority of pts had advanced stage disease (Arm 1 87%, Arm 2 86%), GCB immunophenotype (Arm 1 100%, Arm 2 88%), ECOG PS 0-1 (Arm 1 90%, Arm 2 86%), and high-intermediate/high risk IPI score (Arm 1 63%, Arm 2 64%). Therapy was completed per protocol in 70% and 47% of pts, respectively, for Arm 1 and 2, and disease progression on therapy occurred in 10% and 3%. Treatment was discontinued due to adverse events in 7% of pts in Arm 1 and 11% of pts in Arm 2. Consent was withdrawn after beginning treatment in 3% and 11% in Arm 1 and 2, respectively. Death on treatment occurred in 1 patient (3%; PJP pneumonia) in Arm 1 and 6 pts (17%; sepsis (n=4), cardiac arrest (n=2)) in Arm 2. The observation of excess deaths on Arm 2 prompted suspension of accrual to the DHL cohort. Treatment was discontinued for other reasons in 3 (10%) and 4 (11%) pts in Arms 1 and 2, respectively. Venetoclax was dose-reduced and/or omitted in 15 (42%) pts. Grade 4 neutropenia was not significantly different between arms (Arm 1 67%, Arm 2 71%), nor was grade ≥3 neutropenic fever (Arm 1 36%, Arm 2 40%). Sepsis occurred more frequently in Arm 2 (14% vs. 23%). The end of treatment overall and complete response rates in the mITT population were 73% and 67% in Arm 1, and 58% and 50% in Arm 2. The end of treatment overall and complete response rates among only pts evaluated for response (n=52) were 79% and 71% in Arm 1, and 88% and 75% in Arm 2. With a median follow-up of 7.4 months, the median PFS was not reached (NR) in Arm 1 (95% CI 6.1-NR) and was 6.7 months in Arm 2 (95% CI 4.5-NR) (two-sided p=0.13). The median OS was NR in Arm 1 and was 8.5 months in Arm 2 (95% CI 5.2-NR) (two-sided p=0.004). Conclusions: DA-EPOCH-R plus venetoclax in DHL pts resulted in excess treatment-related mortality compared to DA-EPOCH-R alone, prompting early discontinuation of accrual and venetoclax treatment for the study cohort. Based on these data, we recommend against combining venetoclax with DA-EPOCH-R in DHL. Robust accrual to this study shows that prospective trials are feasible in DHL, and the favorable outcome thus far in the DA-EPOCH-R arm may serve as a benchmark for future trials Figure 1 Figure 1. Disclosures Abramson: Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Ruppert: Telios Pharma: Consultancy. Hsi: Seattle Genetics: Honoraria; Cytomx: Honoraria; Eli Lilly: Research Funding; AbbVie: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Kahl: AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy; AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding. Friedberg: Acerta: Other: DSMC ; Novartis: Other: DSMC ; Bayer: Other: DSMC . Bartlett: Millennium: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Bristol Myers Squibb: Research Funding; Roche/Genentech: Consultancy; Autolus: Research Funding; Seagen: Consultancy, Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. OffLabel Disclosure: venetoclax in double hit lymphoma

Abstract Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p<0.0001; Arm 3 vs 1 HR 0.36, 95% CI 0.25-0.51, p<0.0001; Arms 3 vs 2 HR 0.99, 95% CI 0.66-1.48, p=0.96]. 48-month PFS estimates were 47%, 76% and 76% in Arms 1, 2, and 3 respectively (Figure 1). At this time, there are no significant differences in overall survival (OS) among arms (p=0.49). 48-month OS estimates were 84%, 85%, and 86% in Arms 1, 2, and 3, respectively (Figure 2). The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p<0.001). Thus in Arm 1, PFS was significantly worse for those with TP53 abnormalities vs without (HR 5.32, 95% CI 3.05-9.27, p<0.0001), but in Arms 2 and 3 combined, there was no significant difference in PFS by presence/absence of TP53 abnormalities (HR 0.99, 95% CI 0.51-1.91, p=0.98). Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; 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. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

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

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 Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-501A is a genetically modified anti-CD19 AlloCAR T™ cell product that uses TALEN ® gene editing to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD). Here we present an update on the preliminary safety, efficacy, and correlative data. ALLO-501A uses Cellectis technologies. Methods ALPHA2 (NCT04416984) is a single-arm, open-label, Phase 1/2 trial of ALLO-501A in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL including [R/R] diffuse LBCL [DLBCL], transformed follicular lymphoma [tFL], marginal zone lymphoma [tMZL], primary mediastinal B-cell lymphoma [PMBCL], follicular lymphoma grade 3B [FL3B]) who received ≥2 prior lines of therapy (including an anthracycline and anti-CD20 mAb), have an ECOG performance status of 0 or 1. Subjects with donor specific antibodies are excluded. Following LD with ALLO-647, fludarabine 30 mg/m 2/d x 3d (F), and cyclophosphamide 300 or 500 mg/m 2/d x 3d (C), either a single (40 [DL1] or 120 [DL2] x 10 6 viable CAR T cells) or consolidation dose of ALLO-501A (DL2) are given. For consolidation dose, pts with ≥stable disease (SD) at day 28 receive consolidation with second ALLO-647 (no chemo) for LD and ALLO-501A (DL2) cell infusion. Results As of July 9, 2021, 20 pts were enrolled; 15 pts were treated with ALLO-501A (12 evaluable and 3 pending D28 assessment); 3 pts pending treatment; 2 pts withdrew due to adverse event (AE)/progressing disease (PD) prior to dosing. Patients were heavily pretreated with advanced-stage disease (Stage III: 4 [22.2%], Stage IV: 8 [44.4%]), median number of prior treatments was 3 with a high of 7. Three pts (16.7%) had primary refractory disease. Safety profile was manageable in both single dose and consolidation cohorts. Events of interest in the single dose cohort have been previously reported (ASCO 2021). In the consolidation cohort (13 enrolled, 9 pts dosed thus far), no cytokine release syndrome (CRS), no GvHD, no immune effector cell-associated neurotoxicity syndrome (ICANS), no dose-limiting toxicities (DLTs), no dose reductions, no Grade (Gr) 3+ infections and no related serious adverse events (SAEs) occurred, and infusion-related reactions were Gr 1. Among all treated, cytopenias were the most common AE and occurred in 72% of pts. Of the 12 evaluable pts (6 each treated in the single dose and consolidation dose cohort), both the overall response rate (ORR) and complete response (CR) were 50% (95% CI: 21.1, 78.9). In the consolidation cohort, both ORR and CR rate were 66.7% (95% CI: 22.3, 95.7) with 3/3 partial responses (PRs) converting to CR after consolidation; 1 pt had CR at days 28 and 56 post consolidation and 2 pts had PD at month 1 and did not receive consolidation. In single dose cohort, 2 pts have ongoing CR at 9 and 12+ months. CAR T expansion was greater in pts who achieved a CR with a geometric mean area under the curve (AUC) at D1-28 of 206,990 copies/ug*days (n=6; GSD 4.94) compared to pts who did not achieve a CR with AUC at D1-28 of 3,571 copies/ug*days (n=3; GSD 2.41). Pts who received the consolidation dose continued to have CAR T expansion after the 2 nd CAR T infusion with geometric mean AUC from D30-56 of 92,893 copies/ug*days (n=4; GSD 5.42). Conclusions ALLO-501A with consolidation dosing demonstrated comparable safety and an improved efficacy profile compared to single dosing with all 4 pts who received consolidation remaining in CR. Persistence of CAR T at D28 and expansion after consolidation dose was observed in addition to the observed deepening of responses in pts whose initial response was PR. Additional follow up is needed to determine whether consolidation also improves the durability of response. Consolidation was well tolerated and given the generally favorable overall safety profile, ALLO-501A may have the potential to be given in the outpatient setting. Enrollment is ongoing. Updated efficacy and follow-up will be presented at the meeting. Currently, an ALLO-501A Phase 2 trial is planned. Disclosures Locke: Cowen: Consultancy; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Legend Biotech: Consultancy, Other; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. 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; 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; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Popplewell: Novartis: Other: Travel; Pfizer: Other: Travel; Hoffman La Roche: Other: Food. Abramson: Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genentech: Consultancy. Munoz: Pharmacyclics/Abbvie: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Debiopharm: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding, Speakers Bureau; Millennium: Research Funding; Targeted Oncology: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Roche: Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau. Shin: Allogene Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Loomis-Navale: Allogene: Current Employment, Current equity holder in publicly-traded company. Miklos: 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; 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: Patents & Royalties. OffLabel Disclosure: Discussion of fludarabine and cyclophosphamide in combination with ALLO-647 as conditioning regimen prior to administration of ALLO-501A in patients with R/R LBCL.

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.