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Purpose: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO). Patients and Methods: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, Results: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7–67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%. Conclusions: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

Supplementary Data from Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase II Study of an MRD-Driven Approach

Purpose:Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO).Patients and Methods:Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, –4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation.Results:Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7–67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%.Conclusions:This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; PCONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).

Most patients with advanced-stage indolent non-Hodgkin lymphoma have multiple relapses. We assessed axicabtagene ciloleucel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory indolent non-Hodgkin lymphoma.ZUMA-5 is a single-arm, multicentre, phase 2 trial being conducted at 15 medical cancer centres in the USA and two medical cancer centres in France. Patients were eligible if they were aged 18 years or older, with histologically confirmed indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide at 500 mg/mBetween June 20, 2017, and July 16, 2020, 153 patients were enrolled and underwent leukapheresis, and axicabtagene ciloleucel was successfully manufactured for all enrolled patients. As of data cutoff (Sept 14, 2020), 148 patients had received an infusion of axicabtagene ciloleucel (124 [84%] who had follicular lymphoma and 24 [16%] who had marginal zone lymphoma). The median follow-up for the primary analysis was 17·5 months (IQR 14·1-22·6). Among patients who were eligible for the primary analysis (n=104, of whom 84 had follicular lymphoma and 20 had marginal zone lymphoma), 96 (92%; 95% CI 85-97) had an overall response and 77 (74%) had a complete response. The most common grade 3 or worse adverse events were cytopenias (104 [70%] of 148 patients) and infections (26 [18%]). Grade 3 or worse cytokine release syndrome occurred in ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Serious adverse events (any grade) occurred in 74 (50%) patients. Deaths due to adverse events occurred in four (3%) patients, one of which was deemed to be treatment-related (multisystem organ failure).Axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma.Kite, a Gilead Company.

To evaluate the trend in cytogenetic/molecular testing rate in chronic lymphocytic leukemia (CLL) and assess the clinical and economic burden of first-line (1 L) treatment with chemoimmunotherapy (CIT) by risk status.This retrospective cohort study identified patients with CLL from a U.S. managed care population. Medical records were obtained for eligible patients who initiated 1 L CIT between 1/1/2007 and 7/31/2019 and underwent prognostic testing to classify them as high risk (del(17p),Among the 1,808 patients with CLL, 612 were FISH orHigh-risk CLL patients treated with 1 L chemoimmunotherapy have poorer clinical and economic outcomes compared to non-high risk patients. Assessment of genetic risk remains suboptimal.

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher’s exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt’s, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.

Lymphoma patients are at greater risk of severe consequences from COVID-19 infection, yet most reports of COVID-19-associated outcomes were published before the advent of COVID-19 vaccinations and monoclonal antibodies (mAbs). In this retrospective study, we report the real-world outcomes of 68 lymphoma or CLL patients who developed COVID-19 infection during the omicron surge in the US. We found that 34% of patients were hospitalized as a result of COVID-19 infection. The death rate due to COVID-19 was 9% (6/68) in the overall population and 26% (6/23) in hospitalized patients. During the preintervention COVID-19 era, the mortality rate reported in cancer patients was 34%, which increased to 60.2% in hospitalized patients. Thus, the death rates in our study were much lower when compared to those in cancer patients earlier in the pandemic, and may be attributed to modern interventions. In our study, 60% (18/30) of patients with serology data available did not develop anti-COVID-19 spike protein antibodies following vaccination. Most patients (74%, 17/23) who were hospitalized due to COVID-19 infection did not receive COVID-19 mAb treatment. Our results pointed to the importance of humoral immunity and the protective effect of COVID-19 mAbs in improving outcomes in lymphoma patients.

7548 Background: Elderly pts with R/R LBCL are at risk of inferior outcomes, increased toxicity, and inability to tolerate second-line (2L) SOC treatment (Tx) (Di M, et al. Oncologist. 2021). Further 2L SOC Tx is often associated with poor health-related quality of life (QoL) (Lin V, et al. J Clin Oncol . 2020;38:e20070). In the pivotal Phase 3 ZUMA-7 study, we assessed outcomes, including PROs, of 2L axi-cel (an autologous anti-CD19 CAR T-cell therapy) versus SOC in elderly pts with R/R LBCL. Methods: Pts aged ≥65 y were assessed in a planned subgroup analysis. Pts with ECOG PS 0-1 and R/R LBCL ≤12 mo after 1L chemoimmunotherapy (CIT) were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based CIT; pts with partial or complete response [CR] proceeded to HDT-ASCT). PRO instruments, including the EORTC QLQ-C30 (Global Health [GH] and Physical Functioning [PF]) and the EQ-5D-5L VAS, were administered at timepoints including baseline (BL; prior to Tx), Day (D) 50, D100, D150, and Month (M) 9, then every 3 mo up to 24 mo or time of event-free survival event (EFS), whichever occurred first. The QoL analysis set included all pts who had a BL PRO and ≥1 completed measure at D50, D100, or D150. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score, 7 points for EQ-5D-5L VAS score. Results: As of 03/18/2021, 51 and 58 elderly pts were randomized to the axi-cel and SOC arms, respectively, with median ages (range) of 70 y (65-80) and 69 y (65-81). At BL, more axi-cel versus SOC pts had high-risk features, including 2L age-adjusted IPI 2-3 (53% vs 31%) and elevated LDH (61% vs 41%). EFS was superior with axi-cel versus SOC (HR, 0.276, P< 0.0001), with higher CR rates (75% vs 33%). Grade ≥3 Tx-emergent adverse events (AEs) occurred in 94% and 82% of axi-cel and SOC pts, respectively, and Grade 5 Tx-related AEs occurred in 0 and 1 pt. In the QoL analysis set comprising 46 axi-cel and 42 SOC pts, there were statistically significant and clinically meaningful differences in mean change of scores from BL at D100 favoring axi-cel for EORTC QLQ-C30 GH ( P

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

7567 Background: Despite the success of axi-cel, ≈60% of patients (pts) have no response or relapse within ̃2 y after Tx (Jacobson C, et al. ASH 2021. #1764), highlighting the need for more therapeutic strategies. In preclinical studies, Rtx augmented CD19 CAR T-cell function and increased tumor reduction and survival in murine models via synergistic targeting with CAR T-cells (Mihara K, et al. Br J Haematol. 2010). Here, we report outcomes of ZUMA-14, a Phase 2, multicenter study of axi-cel in combination with Rtx in pts with R-LBCL after ≥2 lines of systemic therapy. Methods: Eligible pts were ≥18 y with R/R LBCL. Pts received one Rtx dose (375 mg/m2) on Day -5, a conditioning regimen of cyclophosphamide and fludarabine on Days -5, -4, and -3, and a single axi-cel infusion of 2×106 CAR T cells/kg on Day 0. Starting on Day 21 post–axi-cel infusion, pts received 1 Rtx dose every 28 d for up to 5 doses. The primary endpoint was investigator-assessed complete response (CR) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and biomarker assessments. The analysis reported here occurred after all treated pts had ≥12 mo of follow-up. Results: As of 12/2/21, 27 pts were enrolled, and 26 received axi-cel and ≥1 Rtx dose (15 pts received all 6 Rtx doses); 1 pt discontinued Tx due to an adverse event (AE). Median age was 63 y (range, 38-82), 54% of pts were male, 81% had stage III/IV disease, 62% had extranodal disease, 38% had elevated LDH, and 85% had an aaIPI ≥1 (35% aaIPI 2). The CR rate was 65% (95% CI, 44-83), and the ORR was 88% (95% CI, 70-98). With a median follow-up of 17 mo, 65% of the pts had ongoing response, with 57% ongoing in CR. Medians for DOR, PFS and OS were not reached. The estimated DOR and PFS rates at 12 mo were 64% and 56%, respectively. The estimated 12 mo OS rate was 76%, and 6 pts (23%) died of progressive disease. Most pts (92%) experienced Grade ≥3 AEs. Grade ≥3 cytopenias were reported in 85% of pts, with 38% ongoing on Day 30. Grade ≥3 neurologic events (NEs) occurred in 4 pts (15%), and there was no Grade ≥3 cytokine release syndrome (CRS). Median times to onset of CRS and NEs were 4 d (range, 1-7) and 6 d (range, 3-32), respectively, with median durations of 5 d (range, 2-15) and 7 d (range, 1-39). No pts experienced myelodysplastic syndrome. Median peak CAR T-cell levels were comparable to the ZUMA-1 pharmacokinetic profile. Immune-modulating cytokines, including granzyme B, IL-6, CXCL10, IFN-g and IL-2, were induced in pts following axi-cel and Rtx infusion and were more prominently elevated in responders vs non-responders. Peak Rtx levels were also elevated in responders vs non-responders. Conclusions: Results from ZUMA-14 demonstrated that axi-cel in combination with Rtx elicited a high CR rate with no new safety signals detected in pts with R-LBCL. Clinical trial information: NCT04002401.

Background: Early reports suggested that cancer patients have a 1.7-fold increased risk of contracting SARS-CoV-2 and higher rates of severe events and mortality compared with general population. Patients with hematologic malignancies may have worse COVID-19 outcomes, due to an impaired humoral immune response from their underlying malignancy and concurrent anticancer therapy. In this multi-center, retrospective, observational study, we evaluate the associations of COVID-19 outcomes with patient and lymphoma disease characteristics. Methods: EMRs at 10 study centers across the USA identified 519 patients with a diagnosis of lymphoma, CLL, or other lymphoid malignancies, who had a documented positive result of SARS-CoV-2 PCR or nucleocapsid antibody testing. Descriptive statistics were used to summarize the demographic and clinical characteristics. Logistic regression was used to evaluate the associations of individual characteristics with COVID-19 outcomes, adjusted for center (NYU vs. other). The interactions between each of the variables was also included in these models; since the interactions were generally small and non-significant, only the main effect of center was included. Two-sided p-values ≤0.05 were considered significant; there were no adjustments for multiple variables or endpoints. Each analysis was based on complete data for that analysis. Results: Tables 1 and 2 provide demographic and clinical characteristics, respectively, of the 519 patients. The mean age was 61.9 years, with 296 (57%) male and 374 (72%) white patients. NYU had the largest cohort (318 patients), with the remaining centers contributing a range of 3 to 69 patients (median 14). Logistic regression models for the association of each COVID-19 outcome with individual clinical and patient characteristics included adjustments for the center (NYU/other). While center effects were statistically significant, center by covariate interaction effects were not and are not included in the final models. The odds ratio (OR) estimates and p-values for each patient and CLL/lymphoma clinical variable are shown in Tables 3 and 4, respectively. The risks of experiencing a severe event, death, and hospital admission increased with age; for each 10 years of age increase, the ORs were 1.58 for experiencing severe events, 1.78 for death, and 1.65 for hospital admission. The risks of poor outcome were higher in males than in females (OR 1.93 for severe events, 1.85 for death, and 1.47 for hospital admission). Patients with Charlson Comorbidity Index (CCI) >5 had a higher risk of severe events (OR 2.46), mortality (3.30) and hospital admission (2.73) compared to patients with CCI ≤5. Compared to patients with HL, patients with aggressive NHL had a higher risk of severe events (OR 4.05), mortality (4.68) and hospital admission (4.65). Patients with CLL similarly had a higher risk of severe events (OR 4.64), mortality (4.65) and hospital admission (5.93) compared to HL patients. Patients with indolent NHL had a higher risk of hospital admission (OR 3.95) but not a higher risk of mortality compared to HL. Patients in remission at the time of COVID-19 diagnosis had a lower risk of severe events (OR 0.42), mortality (0.36) and hospital admission (0.40) relative to those who were not in remission. Patients who received cytotoxic chemotherapy within 28 days of their COVID-19 diagnosis had a higher risk of severe events (OR 2.54), mortality (2.79), and hospital admission (2.31). Patients who received an anti-CD20 monoclonal antibody within 6 months of COVID-19 diagnosis had a higher risk of severe events (OR 2.60), mortality (2.17) and hospital admission (3.28). Conclusions: In addition to demographic and comorbidity risk factors identified in previous studies, our study shows that patients with aggressive NHL and CLL, or patients who have received recent cytotoxic chemotherapy or anti-CD20 mAB, may be at risk for poor COVID-19 outcome. The difference in risk between NHL and HL patients is likely associated with young age of HL patients but may also be related to differences in underlying innate and adaptive immune defects. Patients at high risk for poor outcome should be a priority for studies of monoclonal antibody prophylaxis. If defects in humoral immunity are at the root of poor outcome, this may be compounded by poor response to vaccination. Multivariate analysis of this data will be completed in advance of the meeting. Figure 1 Figure 1. Disclosures Olszewski: Celldex Therapeutics: Research Funding; PrecisionBio: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Barta: Daiichi Sankyo: Honoraria; Seagen: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Hernandez-Ilizaliturri: AbbVie: Other: Advisory Boards; Incyte: Other: Advisory Boards; Celgene: Other: Advisory Boards; BMS: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; Amgen: Other: Advisory Boards; Kite: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Leslie: Janssen: Consultancy, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; AbbVie: Research Funding; Trillium: Research Funding; IGM Biosciences: Research Funding; IMab: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of R/R large B-cell lymphoma and follicular lymphoma (FL), both after ≥2 lines of systemic therapy. ZUMA-5 is a Phase 2, multicenter, single-arm study evaluating axi-cel in patients with R/R iNHL (including FL and marginal zone lymphoma [MZL]). In the primary analysis of ZUMA-5 (N=104; 17.5 months median follow-up), the overall response rate (ORR) was 92% (76% complete response [CR] rate), and median peak CAR T-cell levels were numerically greater in patients with FL who were in ongoing response at data cutoff than in those who relapsed (Jacobson et al. ASH 2020. Abstract 700). Here, we report updated clinical and pharmacologic outcomes from ZUMA-5. Methods: Adult patients with R/R FL or MZL after ≥2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) underwent leukapheresis and conditioning chemotherapy followed by a single axi-cel infusion at 2×10 6 CAR T cells/kg. The primary endpoint was centrally assessed ORR per Lugano classification. The updated efficacy analysis occurred when ≥80 consecutively treated patients with FL had ≥2 years of follow-up post-infusion and included patients with MZL who had ≥4 weeks of follow-up post-infusion. Results: As of March 31, 2021, 149 patients with iNHL (124 FL; 25 MZL) were treated with axi-cel. Of those, 110 patients (86 FL; 24 MZL) were eligible for efficacy analyses. Among eligible patients with FL, median follow-up was 30.9 months (range, 24.7-44.3). Centrally assessed ORR was 94% in patients with FL (79% CR rate). At data cutoff, 57% of eligible patients with FL had ongoing responses; 68% of patients who achieved a CR had ongoing responses. The estimated duration of response (DOR) and progression-free survival (PFS) medians were 38.6 months and 39.6 months in patients with FL, respectively. Among patients with FL who progressed Among eligible patients with MZL, median follow-up was 23.8 months (range, 7.4-39.4). The ORR was 83% in patients with MZL (63% CR rate), with 50% of eligible patients in ongoing response and 73% of patients with a CR in ongoing response at data cutoff. Medians for DOR and TTNT were not reached in patients with MZL; 24-month rates were not estimable and 51%, respectively. Median PFS was 17.3 months in patients with MZL and median OS was not reached (70% OS rate at 24 months). Common Grade ≥3 AEs in all treated patients with iNHL were consistent with prior reporting: neutropenia (33%), decreased neutrophil count (28%), and anemia (25%). Grade ≥3 cytopenias present ≥30 days post-infusion were reported in 34% of patients with iNHL (33% FL; 36% MZL). Consistent with previous reports, Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 7% of patients (6% FL; 8% MZL) and 19% of patients (15% FL; 36% MZL), respectively. Most CRS cases (120/121) and NEs (82/87) of any grade resolved by data cutoff. Among patients with FL who had evaluable samples, 76% (65/86) had detectable CAR gene-marked cells at low levels by 12 months post-infusion; 53% (23/43) had detectable cells 24 months post-infusion. Among evaluable patients with MZL, 67% (8/12) had detectable CAR gene-marked cells 12 months post-infusion; 60% (3/5) had detectable cells 24 months post-infusion. B-cell reconstitution was detectable in 59% of evaluable patients with FL (49/83) and 42% of those with MZL (5/12) by 12 months post-infusion. By 24 months, B cells were detectable in 61% of evaluable patients with FL (25/41) and 50% of those with MZL (2/4). Conclusions: With long-term follow-up in ZUMA-5, axi-cel demonstrated substantial and continued benefit in patients with iNHL. In FL, high response rates translated to durability, with a median DOR of 38.6 months and 57% of eligible patients in ongoing response at data cutoff. In MZL, efficacy outcomes appeared to improve with longer follow-up, with the median DOR and OS not yet reached. Axi-cel maintained a manageable safety profile, with no new safety signals . Disclosures 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, 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. Chavez: Merk: Research Funding; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Speakers Bureau. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Munshi: Kite, a Gilead Company, and Incyte: Honoraria; Kite, a Gilead Company, and Incyte: Speakers Bureau. Casulo: Genentech: Research Funding; BMS: Research Funding; Verastem: Research Funding; Gilead: Research Funding. Maloney: Kite, a Gilead Company, Juno, and Celgene: Research Funding; A2 Biotherapeutics: Consultancy; BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Juno: Patents & Royalties. Reshef: Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Gilead and Novartis: Honoraria. Leslie: Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Rosenblatt: Synergys: Patents & Royalties; BioGraph 55: Research Funding. Sherman: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Dong: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company; GliaCure/Tufts: Consultancy, Patents & Royalties. Giovanetti: Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Yang: Kite, a Gilead Company: Current Employment. Lui: Gilead Sciences: Other: stock or other ownership; Kite, a Gilead Company: Current Employment, Other: travel support. Bashir: Kite, a Gilead Company: Ended employment in the past 24 months; OmniacPharmConsult Ltd: Other: stock or other ownership. Jung: Amgen, Kura, Gilead, and Turning Point: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Jacobson: Lonza: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau.

Introduction: Liquid biopsy has been reported to be useful in predicting residual disease in patients with diffuse large B-cell lymphoma (DLBCL). Most of the studies focused on quantifying the level of circulating lymphoma-specific DNA. We explored the clinical relevance of the specific mutated genes in predicting progression in patients with DLBCL. Method: Peripheral blood samples were collected from patients with DLBCL based on their visit to clinic without other specific selection. Median age of patients is 69 (range 28-91), with 51% of the patients being male. These patients were treated on multiple protocols including R-CHOP, R-EPOCH, Magrath, HCVAD, CAR-T (#2 patients), and others. cfDNA was extracted and sequenced by next generation sequencing using 177 gene panel. The panel uses single primer extension (SPE) approach with UMI. Sequencing depth is increased to more than 2000X after removing duplicates. Low level mutations are confirmed by inspecting BAM file. Results: A total of 86 sample from 61 patients were collected post clinical remission at different time points (median 28 weeks, range: 1-994 weeks). Of these samples, 56 (65%) from 46 patients (75%) were positive. However, 6 of these samples from 4 patients had germline mutations or mutations in TET2, ASXL1, or DNMT3A that are consistent with CHIP (clonal hematopoiesis of indeterminate potential). The remaining 50 positive samples from 42 patients had 8 repeats on the same patients collected at different time points. Comparing the 19 negative patients with the 42 positive patients post-remission, patients with residual molecular disease were significantly older than patients without residual disease (P=0.01). However, there was no significant difference between the two groups in gender, ethnic background, LDH, cell of origin classification, or TP53 positivity by IHC. Patients with residual disease showed tendency for short progression-free survival (P=0.08). Focusing on patients with specific mutations detected in the cfDNA showed that 14 (23%) patients had mutations either in TP53 or MYD88. There was no significant difference in age between these two groups or any of the other clinical variables. However, patients with TP53/MYD88 mutations had significantly shorter survival (P=0.04). Conclusion: Post-remission residual disease as measured by circulating cfDNA is an independent predictor of potential relapse in patients with DLBCL. However, presence of it is important to determine the aggressiveness of the residual circulating clone. Residual circulating lymphoma DNA with TP53 or MYD88 mutations is a strong predictor of earlier relapse. Figure 1 Figure 1. Disclosures Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Goy: Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Honoraria, Other; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Acerta: Consultancy, Research Funding; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Michael J Hennessey Associates INC: Consultancy; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; 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; Medscape: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xcenda: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; LLC(Targeted Oncology): 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; Xcenda: Consultancy; Hoffman la Roche: Consultancy; Incyte: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; 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; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment.

Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an "add-on" approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ε] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity; U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10^-4 for uMRD). Umbralisib (administered daily at 800mg) and ublituximab (administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6) were added to ibrutinib, and patients were monitored serially for MRD starting on Cycle 3 Day 1. Once uMRD was achieved and confirmed 4 weeks later, patients entered a period of TFO. Patients who did not attain uMRD continued treatment for up to 24 cycles followed by TFO. The primary objective of the study was rate of uMRD, with a prespecified MRD conversion rate of 25% defined as promising. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: In this fully accrued study, U2 was added to ibrutinib in 26 patients. Median age was 63 years (range, 48-81) and 77% were male. Disease characteristics included del(17p) in 8%, del(11q) in 12%, and unmutated IGHV in 31%. Median duration of ibrutinib treatment prior to addition of U2 was 22 months (range 7-66 months). The swimmer plot in Figure 1 depicts time on ibrutinib prior to enrolling in this study, the duration of treatment with triplet therapy, achievement of uMRD, and TFO. MRD has been assessed in 24 patients; 71% (17/24) had uMRD in at least 1 assessment. Median time to first uMRD result was 5 months (range 2 - 12). A total of 16 patients (67%) entered TFO; 15 had 2 consecutive uMRD assessments and 1 completed 24 cycles with detectable MRD. TFO appears durable, with a median of 242 days off therapy (range 5-538 days) as of the data cutoff. 73% remain uMRD at last follow up. No patient has progressed or required re-treatment per iwCLL criteria. U2 plus ibrutinib was well tolerated. All-causality grade 3/4 adverse events of special interest included ALT/AST increase (4%), diarrhea (4%), and hypertension (8%). Two patients discontinued all therapy due to rash; both were uMRD at the time of treatment discontinuation and remain uMRD. One patient died due to complications of COVID-19. Conclusions: This is the first MRD-driven approach utilizing the combination of BTKi, PI3Ki, and anti-CD20 monoclonal antibody. This novel agent combination therapy was well tolerated and effective, with achievement of uMRD in 71% of evaluable patients. This "add-on" approach for patients on continuous ibrutinib resulted in deep remissions that allowed for a tailored, time-limited therapy and sustained treatment-free observation. Figure 1 Figure 1. Disclosures Roeker: Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Loxo Oncology: Consultancy. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Merck: Consultancy; Janssen: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Soumerai: Abbvie: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Zelenetz: MorphoSys: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; NCCN: Other; Gilead: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; Amgen: Honoraria; Pharmacyclics: Honoraria; MethylGene: Research Funding; Genentech/Roche: Honoraria, Research Funding; Novartis: Honoraria. Falchi: Abbvie: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding; Genmab: Consultancy, Research Funding. Park: Curocel: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Minerva: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy; Kite Pharma: Consultancy; Autolus: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Intellia: Consultancy. Battiato: Janssen Pharmaceutical: Other: Advisory Board July 2020; Abbvie Pharmaceuticals: Other: CLL Steering Committee November 2020-present. Thompson: VJHemOnc: Honoraria; Curio Science: Honoraria; MJH Life Sciences: Honoraria. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; AstraZeneca: Consultancy; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genmab: Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Background: The standard of care (SOC) treatment (Tx) in the curative setting for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after 1st-line (1L) chemoimmunotherapy (CIT) is high-dose therapy with autologous stem cell rescue (HDT-ASCT) if responsive to 2L CIT; however, as many pts do not respond to or cannot tolerate 2L CIT, or are not intended for HDT-ASCT, outcomes remain poor. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for R/R LBCL after ≥2 prior systemic therapies. Since CAR T-cell therapy may benefit pts in earlier lines of therapy, we conducted ZUMA-7 (NCT03391466), a global, randomized, Phase 3 trial of axi-cel vs SOC in pts with 2L R/R LBCL, and report here the results of the primary analysis (PA). Methods: Eligible pts were ≥18 y with LBCL, ECOG PS 0-1, R/R disease ≤12 mo of adequate 1L CIT (including anti-CD20 monoclonal antibody and an anthracycline), and intended to proceed to HDT-ASCT. Pts were randomized 1:1 to axi-cel or SOC, stratified by 1L Tx response and 2L age-adjusted IPI (sAAIPI). In the axi-cel arm, pts received a single infusion of 2×10 6 CAR T cells/kg after conditioning (3 d; cyclophosphamide 500 mg/m 2/day and fludarabine 30 mg/m 2/day). Optional bridging Tx was limited to corticosteroids (CIT was not allowed). In the SOC arm, pts received 2-3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen; pts with partial response or complete response (CR) proceeded to HDT-ASCT. Disease assessments by PET-CT per Lugano Classification occurred at timepoints specified from randomization. Although there was no planned trial crossover between arms, pts not responding to SOC could receive CAR T-cell therapy off protocol. Axi-cel was hypothesized to result in a 50% improvement in event-free survival (EFS: time to earliest date of disease progression, death from any cause, or new lymphoma Tx) vs SOC. The PA was event-driven, and the primary endpoint was EFS by blinded central review. Key secondary endpoints, tested hierarchically, were objective response rate (ORR) and overall survival (OS; interim analysis); safety was also a secondary endpoint. Level of CAR T cells was an exploratory endpoint. Results: As of 3/18/21, 359 pts were enrolled globally. The median age was 59 y (range, 21-81; 30% ≥65 y). Overall, 74% of pts had primary refractory disease and 46% had high sAAIPI (2-3). Of 180 pts randomized to axi-cel, 170 (94%) were infused; of 179 pts randomized to SOC, 64 (36%) reached HDT-ASCT after 2L CIT. The primary endpoint of EFS was met (HR: 0.398; P Conclusions: ZUMA-7, the first randomized, global, multicenter Phase 3 study of axi-cel vs 2L SOC in R/R LBCL, demonstrated a statistically significant and clinically meaningful improvement in EFS. Axi-cel showed superiority over SOC with >4-fold greater median EFS, 2.5-fold greater EFS at 2 y, double the CR rate, and more than double the percentage of pts receiving definitive Tx. Safety of axi-cel was manageable and at least consistent with 3L axi-cel therapy. Axi-cel may replace CIT/HDT-ASCT as the SOC for 2L R/R LBCL. These data are reported on behalf of all ZUMA-7 investigators and contributing Kite members. Disclosures Locke: Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Legend Biotech: Consultancy, Other; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Cowen: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; 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. 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; 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: Patents & Royalties. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Perales: Cidara: Honoraria; Omeros: Honoraria; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria; Takeda: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Kite/Gilead: Honoraria, Other; Novartis: Honoraria, Other; Incyte: Honoraria, Other; Equilium: Honoraria; Karyopharm: Honoraria; NexImmune: Honoraria; Celgene: Honoraria; Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Bristol-Myers Squibb: Honoraria. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support. Oluwole: Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Pfizer: Consultancy; Curio Science: Consultancy. Ghobadi: Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara Biotherapeutics: Consultancy; Wugen: Consultancy; Celgene: Consultancy. McGuirk: Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding. Pagel: Incyte/MorphoSys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Pharmacyclics/AbbVie: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy. Muñoz: Targeted Oncology, OncView, Kyowa, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics, Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosun Kite, Innovent, Seagen, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, and Servier: Consultancy; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics, Janssen, Seagen, Acrotech, Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/Bristol Myers Squibb, Genentech, and Roche: Speakers Bureau; Bayer, Kite, a Gilead Company, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seagen, and Janssen, Millennium: Research Funding; OncView: Honoraria; Kyowa Kirin: Honoraria; Physicians' Education Resource: Honoraria. Farooq: Kite, a Gilead Company: Honoraria. Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy. Reagan: Genentech: Research Funding; Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seagen: Research Funding. Sureda: Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Vandenberghe: Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Research Funding; Gilead Sciences: Consultancy, Other: Travel support; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy. Song: GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Kite, a Gilead Company: Honoraria; Sanofi: Honoraria. Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria. Minnema: Janssen: Consultancy; Alnylam: Consultancy; Kite/Gilead: Consultancy; Cilag: Consultancy; Celgene: Other: Travel expenses; BMS: Consultancy. Riedell: Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Xencor: Research Funding; MorphoSys: Research Funding. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Chaganti: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Yang: Kite, a Gilead Company: Current Employment. Filosto: Tusk Therapeutics: Patents & Royalties: or other intellecular property; Gilead Sciences: Other: stock or other ownership ; Kite, a Gilead Company: Current Employment. Schupp: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. To: NantWorks: Ended employment in the past 24 months; Kite, a Gilead Company: Current Employment, Other: stock or other ownership . Cheng: Kite, a Gilead Company: Current Employment, Other: Travel support; Gilead Sciences: Other: stock or other ownership . Gordon: Bristol Myers Squibb: Honoraria, Research Funding; Zylem Biosciences: Patents & Royalties: Patents, No royalties. Westin: Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Curis: Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Background Patients with hematologic malignancies have poor outcomes from COVID infection with associated mortality of up to 30-40%. Studies have shown that these patients are less likely to mount an antibody response after COVID infection 1. The Pfizer-BioNTech and Moderna COVID mRNA vaccines have been shown to be 94% effective in preventing severe disease in the general population. There is limited data on the efficacy of these vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. Methods This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/2020 and 04/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Additional outcomes of interest included key variables, such as lymphoma subtype and treatment with anti-CD20 monoclonal antibodies. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. Results One-hundred thirty-seven patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was older at a median age of 69 (IQR 59-78) years old, 52% of patients were male, and 72% of patients were white. The most frequent comorbidities were cardiovascular disease (39%) and former smoking history (34%), and 45 (33%) patients were obese (BMI >= 30). Testing for anti-COVID spike protein antibodies occurred at a median 48 (IQR 25-62) days [range 6-120] after second vaccination. Lymphoma subtypes in our cohort were: indolent lymphomas (35%), CLL/SLL (20%), 27 (20%) patients with Burkitt's, DLBCL, PMBCL combined, and 25 (18%) patients with Hodgkin's and T-cell lymphomas (HL/TCL) combined. Majority of patients received COVID mRNA vaccines, and we were able to confirm the specific type in 71 (52%) patients. Only 1 person received the COVID adenovirus vaccine. Ninety-two patients (67.2%) developed anti-COVID spike protein antibodies after receiving a COVID vaccine. Of 27 patients who received an anti-CD20 monoclonal antibody-containing regimen in the last 12 months prior to vaccination, 14 (52%) patients produced antibodies. This rate was numerically lower than 72% (26/36) of those who developed antibodies and received an anti-CD20 antibody greater than 12 months prior to vaccination. There were differences observed in the ability to produce serology towards the COVID vaccine amongst lymphoma subtypes. Of 28 patients with CLL, 12 (43%) produced antibodies. There were 6 CLL patients receiving anticancer treatment at the time of vaccination, of which 2 patients produced antibodies. CLL/SLL patients were less likely to mount an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this difference was significant on UVA (OR 0.270, 95% CI 0.112-0.648), p=0.003) and MVA (OR 0.259, 95% CI 0.104-0.643, p=0.004). For patients with HL/TCL, 22 of 25 (88%) patients produced antibodies. Among the 3 HL/TCL patients that did not produce antibodies, 1 patient had HIV/AIDS post-transplant, 1 had relapsed AITL, and 1 received rituximab. All HL/TCL patients who received anticancer treatment in the last 6 months (10 of 10) produced antibodies at a median titer of 120 AU/mL (reference >=15 AU/mL), with 4 patients having a robust response of antibody titers >400 AU/mL. On statistical analysis, HL/TCL patients were more likely to elicit an antibody response to the COVID vaccine when compared to those with other types of lymphoma, and this response was significant on UVA (OR 4.084, 95% CI 1.149-14.515, p=0.03) and MVA (OR 4.442, 95% CI 1.219-16.191, p=0.024). Conclusion Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. CLL/SLL appears predictive of a negative antibody response to the COVID vaccine, while HL/TCL histologies appeared to correlate to a positive antibody response, even with treatment within 6 months of vaccination. Our study suggests anti-CD20 monoclonal antibody therapy in the last 12 months may affect the ability to produce serology towards a COVID vaccine. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population. 1. Passamonti et al, Br J Haematol 2021 Figure 1 Figure 1. Disclosures Leslie: Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy. Goy: Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; 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; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; 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; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Michael J Hennessey Associates INC: Consultancy; Hoffman la Roche: Consultancy; Xcenda: Consultancy; Medscape: Consultancy; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: 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; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Xcenda: Consultancy, Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; 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; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment; Janssen: Consultancy, 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; Infinity/Verastem: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator.

Background: Cirmtuzumab (Cirm) is a humanized monoclonal antibody that inhibits the tumor promoting activity of ROR1 and has demonstrated additive/synergistic activity with many anticancer agents, including ibrutinib (Ibr). Methods: Patients (Pts) with relapsed or refractory (RR) MCL or treatment-naïve (TN) or RR CLL were enrolled. In Part 1 (Dose Escalation), doses of Cirm IV q2wks x5 then q4wks of 2-16 mg/kg and 300 or 600 mg were examined. Safety of Cirm alone was assessed during the first 28 days, then Ibr was started at approved doses for each indication. Cirm 600 mg IV q2wks x3 then q4wks in combination with Ibr starting day 0 was chosen as the recommended dosing regimen for use in Part 2 (Expansion) and Part 3 (CLL only, Cirm/Ibr vs. Ibr). MCL Part 1 is closed, and Part 2 is open for enrollment. CLL Parts 1, 2 & 3 are closed for enrollment. Results: As of 18Jun2021 data cutoff, 28, 34 and 28 pts were treated in MCL Parts 1 & 2, CLL Parts 1 & 2, and CLL Part 3 (Cirm/Ibr (n=18) or Ibr (n=10)). In Parts 1 & 2 MCL, the median number (#) of prior systemic regimens was 1.5 (1-4) including pts relapsing after Ibr (n=4), auto-SCT (n=6), auto-SCT/allo-SCT (n=1), or auto-SCT/CAR-T (n=1). Ki-67 ≥30% and extra-nodal disease was present in 54% and 68% of pts, respectively. The median # of prior systemic regimens for CLL Parts 1 & 2 and CLL Part 3 (RR), was 2 (1-15) including auto-SCT (n=1), and 2 (1-6). Pts entered with Rai staging ≥ Grade 2 in 71% and 64%. Safety (MCL and CLL): Most frequent treatment emergent (TEAEs) (≥30%) for both MCL and CLL pts treated with Cirm/Ibr (N=80), (all grades; regardless of causality) included contusion & fatigue (both 40.0%), and diarrhea (37.5%). Most frequent (≥5%) Grade ≥3 TEAEs, regardless of causality included hypertension (10.0%), fatigue, neutropenia, pneumonia, and atrial fibrillation (all 6.3%), leukocytosis and anemia (both 5.0%). Grade ≥3 TEAEs of myelosuppression, regardless of causality, include anemia (5.0%), thrombocytopenia (1.3%), and neutropenia (6.3%). Most TEAEs in MCL or CLL pts were considered related by Investigator to Ibr alone 64% or 84% vs. Cirm alone 14.3% or 16%. Efficacy (MCL): The best response of 20 evaluable pts in Parts 1 & 2 included CR 35%, PR 45%, SD 10%, and 10% PD. At a median follow-up of 14.9 mos., the objective response rate (ORR), clinical benefit rate (CBR) and median duration of response (DOR) for overall, ≥30% Ki-67, and >1 prior systemic regimen subgroups, were 80%, 90% and (not reached) NR (95% CI: 11.9, NR), 81.8%, 81.8% and 13.8 (95% CI: 8.7, NR), and 90%, 100% and NR (95% CI: 8.7, NR). Responses occurred in all evaluable pts who received prior SCT+/- CAR-T (4CR, 2PR) or prior Ibr (2CR, 2PR). The median PFS (mPFS) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were all NR with varying 95% CI: (16.5, NR), (0.03, NR), and (0.03, NR). Efficacy (CLL): The best response of 34 evaluable pts in Parts 1 & 2 included 94.1% ORR, 11.8% CR, 82.3% PR/PR-L, and 5.9% SD for a CBR of 100%. In Part 3, evaluable Cirm/Ibr TN (n=8) or RR (n=7) and Ibr TN (n=4) or RR (n=3) arms achieved 100% or 85.7% and 100% or 100% ORR, 12.5% or 0% and 0% or 0% CR, 87.5% or 85.7% and 100% or 100% PR/PR-L, 0% or 14.3% and 0% or 0% SD. No pts had PD as best response. All pts had a CBR of 100%. For Parts 1 & 2, at a median follow-up of 24.8 mos., the DOR for overall and >1 prior systemic regimen subgroups, was NR (8.3, 35.9) and NR (12.0, 29.6). In Part 3, at a median follow-up of 14.7 mos., the DOR for TN or RR Cirm/Ibr and Ibr arms is NR (7.7, 18.6) or NR (9.2, 14.8) and NR (11.2, 18.5) or NR (8.3, 14.2). The mPFS (Parts 1 & 2) for overall, pts achieving CR, and >1 prior systemic regimen subgroups were NR (9.1, 35.8), NR (95% CI: 22.5, NR), and NR (9.1, 35.2). In Part 3, mPFS for TN or RR Cirm/Ibr and Ibr arms is all NR. Conclusions: Cirm/Ibr is well-tolerated. ORR, CR, DOR, and mPFS were similar across all subgroups of MCL and CLL pts regardless of number of prior systemic regimens or poor risk factors. Striking responses were observed in patients with MCL as evidenced by a mPFS that was NR (95% CI: 16.5, NR), CR of 35%, and a DOR of NR (95% CI: 11.9, NR) within the study period. These data compare very favorably to the mPFS of 12.8 mos, CR of 20%, and a DOR of 18.6 mos., reported for Ibr alone (Rule 2017). For CLL pts treated with Cirm/Ibr, results continue to be encouraging as they mature. The study is ongoing, with MCL enrollment expanded to include Cirm + Ibr in pts who have had an inadequate response to an Ibr regimen, or who are refractory to approved BTKi agents. Figure 1 Figure 1. Disclosures Lee: Oncternal: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Seagen: Research Funding; BMS: Honoraria, Research Funding; Aptitude Health: Honoraria; Guidepoint: Honoraria; Century Therapeutics: Consultancy; Pharmacyclics: Research Funding; Janssen: Honoraria. Choi: Abbvie: Other: Institution: Research Grant/Funding; Pharmacyclics: Other: Institution: Research Grant/Funding; Oncternal: Other: Institution: Research Grant/Funding; Velosbio: Other: Institution: Research Grant/Funding; Merck: Other: Institution: Research Grant/Funding; Geron: Other: Institution: Research Grant/Funding. Siddiqi: Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Speakers Bureau; Oncternal: Research Funding; TG Therapeutics: Research Funding. Wierda: Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Karyopharm: Research Funding; Xencor: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; KITE Pharma: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Juno Therapeutics: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; Loxo Oncology, Inc.: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding. Leslie: Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy. Breitmeyer: Oncternal Therapeutics: Current Employment, Membership on an entity's Board of Directors or advisory committees. Yazji: Oncternal Therapeutics: Current Employment. Wang: Oncternal Therapeutics: Current Employment. Wang: OMI: Honoraria; Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; Newbridge Pharmaceuticals: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; InnoCare: Consultancy, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Lilly: Research Funding; Physicians Education Resources (PER): Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Molecular Templates: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Juno: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Bayer Healthcare: Consultancy; BGICS: Honoraria; CAHON: Honoraria; Oncternal: Consultancy, Research Funding; CStone: Consultancy. Jamieson: Forty Seven Inc.: Patents & Royalties. Kipps: Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; Genentech/Roche: Honoraria; European Research Initiative on CLL (ERIC): Honoraria; Genetech: Honoraria, Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Bionest Partner: Other; DAVA Pharmaceuticals: Speakers Bureau; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding.

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of lymphomas associated with poor outcomes following anthracycline-based chemotherapy, even when consolidative autologous stem cell transplantation (ASCT) is used. CD30 expression is universal in anaplastic large cell lymphoma (ALCL) and is frequently expressed in other PTCL subtypes. Brentuximab vedotin (BV) is a CD30-directed antibody drug conjugate that prolongs progression-free survival (PFS) and overall survival (OS) when combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as compared to CHOP chemotherapy (Horwitz, 2020). Although a majority of pts treated with BV-CHP remained in durable remission (5y PFS 51%), there is room for improvement. Based on retrospective studies that demonstrated improved outcomes in younger pts, the addition of etoposide to CHOP (CHOEP) is commonly used as initial therapy for PTCL. We performed a multicenter phase 2 trial to evaluate the safety and efficacy of adding etoposide to BV-CHP (CHEP-BV) followed by BV consolidation in pts with newly diagnosed CD30-expressing PTCL. Methods: Adults with newly diagnosed CD30+ (≥ 1% of tumor cells by local pathology) PTCL were eligible, including pts with ALK+ ALCL and IPI score ≥ 2, ALK-negative ALCL, PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma (ATLL), among others. After accrual of 28 pts, the protocol was amended to allow enrollment of 20 additional pts with CD30+ non-ALCL PTCL (with ALCL allowed in Canada). Pts could receive prephase steroids and/or 1 cycle of CHOP-equivalent chemotherapy prior to study entry. 6 pts were treated in a safety lead-in cohort and all pts received CHEP-BV at the recommended phase 2 dose: 6 x 21-day cycles of CHP+BV (1.8mg/kg) on d1 and etoposide 100mg/m2 on d1-3. G-CSF prophylaxis was mandatory. Pts in response after CHEP-BV could receive BV consolidation (1.8mg/kg q3w) for up to 10 additional cycles (16 total BV cycles) either after ASCT or CHEP-BV if no ASCT was performed. The co-primary endpoints were safety and the CR rate (Deauville score 1-3) by PET-CT after CHEP-BV assessed by investigators according to the 2014 Lugano classification. Secondary endpoints were PFS and OS. Results: Accrual has completed and 48 pts were enrolled; all were evaluable for toxicity, 46 were evaluable for efficacy. 16 pts had ALCL (13 ALK+, 3 ALK-) and 32 had non-ALCL PTCL subtypes, including 18 with AITL, 11 with PTCL NOS, 2 with T-follicular helper PTCL, and 1 with ATLL. Baseline characteristics are shown in Table. 43 pts completed CHEP-BV, 2 had progressive disease (PD) prior to completion, 1 pt discontinued CHEP-BV early (MD discretion), 1 pt died due to COVID-19, and 1 remains on CHEP-BV. Of 43 pts who completed CHEP-BV, 24 proceeded to ASCT and 19 did not. 33 (74%) pts received BV consolidation (20 after ASCT, 13 directly after CHEP-BV) and completed a median 8 of the planned 10 cycles (range, 1-10). 13 pts completed all cycles of consolidation; 19 pts discontinued early - 12 due to adverse events (AE), 5 due to PD, and 2 due to patient/physician choice. The most frequent CHEP-BV related AEs (all grades, G) include fatigue (73%), peripheral sensory neuropathy (67%), anemia (62.5%), nausea (56%), neutropenia (50%), lymphopenia (44%), leukopenia (42%), thrombocytopenia (40%), elevated transaminases (33%). The most common G3+ AEs were neutropenia (37.5%), febrile neutropenia (23%), lymphopenia (21%), anemia (19%), thrombocytopenia (19%). There were 5 deaths, 4 due to PD and 1 due to COVID-19 infection during C3 of CHEP-BV. The interim (n=46) ORR and CR rates (after 3 CHEP-BV cycles, except 1 pt after 2) were 96% and 59% (27 CR, 17 PR), respectively. At completion of CHEP-BV (n=46), the ORR was 91% with 80% CR (37 CR, 5 PR, 4 PD). The ORR/CR rates in ALCL (n=16) vs non-ALCL (n=30) pts were 94%/94% vs 90%/73%, respectively. The ORR/CR rates in pts with CD30 expression 1-9% (n=15) vs 10+% (n=31) were 93%/67% and 90%/87%, respectively. The median follow-up in surviving pts is 16.1 months (range, 0.9-32.5). The overall 18mo PFS and OS were 61% and 89%; 18mo PFS by subgroup: ALCL 81%, non-ALCL 49%, CD30 1-9% 48%, CD30 10+% 67%. Landmark 1y PFS from end of CHEP-BV in responding pts (n=41) was 82% in pts who underwent ASCT vs 48% in pts who did not. Conclusions: In a cohort of pts with mostly non-ALCL CD30-expressing PTCL, CHEP-BV (+/- ASCT) followed by BV consolidation was tolerable and effective. Figure 1 Figure 1. Disclosures Herrera: Genentech: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy, Research Funding. Zain: Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria; Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy. Savage: Astra-Zeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Popplewell: Hoffman La Roche: Other: Food; Novartis: Other: Travel; Pfizer: Other: Travel. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Mei: Morphosys: Research Funding; Janssen: Honoraria; TG Therapeutics: Research Funding; EUSA: Honoraria; BMS: Research Funding; Epizyme: Research Funding; Beigene: Research Funding. Leslie: Merck: Consultancy; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Karyopharm Therapeutics: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.