Rapoport, Aaron P.

Background: Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product administered as a fresh formulation to patients (pts) with relapsed/refractory Diffuse Large B Cell Lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis of 59 evaluable patients and 69 patients in the safety population. Methods: Eligible adults had r/r DLBCL after at least 2 prior lines of treatment including anti-CD20 monoclonal antibody and anthracycline-containing regimen and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to-vein time and administered as a fresh formulation. Lymphodepletion chemotherapy was initiated during the manufacturing process (either cyclophosphamide/ fludarabine or bendamustine) prior to receiving a single dose of zamto-cel at a dose of 2.5x106 CAR T cells/kg on Day 0. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse. Results: As of March 29th, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. Sixteen pts (27%) received 3 or more lines of prior treatment. The majority of pts (53%) had elevated LDH at study entry, and 49% had ≥ 2 extranodal lesions, indicative of a study population with advanced disease. No pts received any bridging therapy, in the week after apheresis and before lymphodepletion. Only 7 pts (12%) received bendamustine as lymphodepleting regimen. Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. Four patients received a cryopreserved formulation to permit time for comorbid condition management. The mean viability of the final product was 96.0% with 29.4 % transduction efficacy. No patient died or withdrew during the manufacturing process. The ORR in the evaluable patient population (n=59) as assessed by an Independent Radiology Committee (IRC) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83). The median DOR was 11.4 months. All 69 treated pts were assessed for safety outcomes. Treatment-emergent adverse events (TEAEs) were mostly of grade 1-2, the majority of grade ≥ 3 were hematological. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days. Biopsies at progression were available in 24 pts. CD19-negative relapse (defined as H Score <100) was seen in 2 pts, CD20-negative relapse was observed in 3 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating that most lymphomas maintain target antigen expression at relapse after treatment with zamto-cel. Conclusion: This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The trial plans to enroll 100 evaluable patients and the final data will be presented upon study completion. Among the 59 evaluable patients at the interim analysis, there is encouraging activity and a favorable safety profile in DLBCL patients treated with zamto-cel. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time of 14 days with lymphodepletion initiated during the manufacturing process. With a manufacturing success rate of 91% we have demonstrated the feasibility of this process among high-risk patients with r/r DLBCL.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS Among axi-cel–infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse ( P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Abstract During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

Introduction: Historically, older patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL) were often deemed ineligible for curative-intent autologous stem cell transplant (ASCT) due to age and concern for increased toxicity related to comorbidities. We previously demonstrated in the pivotal ZUMA-7 study that older pts with R/R LBCL can safely receive axicabtagene ciloleucel (axi-cel) as second-line (2L) therapy with improved event-free survival (EFS), response rate, and quality of life compared with standard of care (SOC) based on results from the primary EFS analysis (Westin, et al. Clin Cancer Res. 2023). At a median follow-up of 47.2 months (mo), results from the ZUMA-7 primary overall survival (OS) analysis demonstrated superior OS in the intention-to-treat (ITT) analysis (hazard ratio [HR], 0.73; 95% CI, 0.54-0.98; stratified two-sided log-rank P=0.03; Westin, et al. N Engl J Med. 2023; NCT03391466). We now report updated efficacy and safety results from the primary OS analysis among ZUMA-7 pts aged ≥65 years (y) and ≥70 y. Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based chemoimmunotherapy; responding pts proceeded to high-dose chemotherapy with ASCT). The primary OS analysis occurred 5 y after the first pt was randomized (01/25/2018) per protocol. Other endpoints included progression-free survival (PFS) per investigator assessment and safety. A planned subgroup analysis of pts aged ≥65 y was conducted in addition to an analysis for those ≥70 y. Multivariate analyses were performed to examine treatment efficacy with axi-cel compared with SOC after adjusting for multiple covariates, including sex, disease type, molecular subgroup, lactate dehydrogenase (LDH), tumor burden, and age; strata for these analyses included second-line age-adjusted International Prognostic Index (aaIPI), and relapsed vs refractory disease. Exploratory analyses were conducted to determine the association between OS and axi-cel product characteristics for pts aged ≥65 y. Results: A total of 109 pts were included in the analysis (axi-cel: 51 were ≥65 y, 26 of whom were ≥70 y, maximum age was 80 y; SOC: 58 were ≥65 y, 27 of whom were ≥70 y, maximum age was 81 y). Compared with SOC pts at baseline, more axi-cel pts had high-risk features, including aaIPI 2-3, elevated LDH, and high-grade B-cell lymphoma. At a median follow-up of 46.6 mo, OS was prolonged in the axicel vs SOC arm in pts aged ≥65 y (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). Similar results were observed using the piecewise Cox regression model. The median OS for axi-cel and SOC pts was 43.5 mo (95% CI, 20.9-not estimable [NE]) and 19.6 mo (95% CI, 12.3-NE), respectively, among those aged ≥65 y, and 24.7 mo (95% CI, 12.8-NE) and 11.2 mo (95% CI, 6.1-NE), respectively, among those aged ≥70 y. In the SOC arm, 57% and 52% of pts received subsequent cellular immunotherapy off protocol in pts aged ≥65 y and ≥70 y, respectively. Multivariate analyses demonstrated an even greater OS benefit with axi-cel over SOC when adjusting for differences in baseline characteristics in pts aged ≥65 y (HR, 0.526; 95% CI, 0.266-1.041) and in pts aged ≥70 y (HR, 0.184; 95% CI, 0.045-0.755). PFS assessed by investigator confirmed benefit of axi-cel over SOC in pts aged ≥65 y (HR, 0.406; 95% CI, 0.230-0.715) and in pts aged ≥70 y (HR, 0.206; 95% CI, 0.078-0.547). The median PFS for axi-cel and SOC pts was 28.7 mo (95% CI, 5.1-NE) and 5.0 mo (95% CI, 2.8-7.2), respectively, for those aged ≥65 y, and 11.4 mo (95% CI, 4.1-NE) and 2.7 mo (95% CI, 1.7-5.0), respectively, for those aged ≥70 y. No new treatment-related deaths occurred since the primary EFS analysis. There were no manufacturing failures for any pt who underwent leukapheresis. Similar associations between product characteristics and outcomes were observed among the elderly and overall populations, including improved OS associated with a greater (&gt;median) proportion of juvenile or stem memory T-cell phenotype cells (CCR7+CD45RA+ T cells) in the axi-cel product among pts aged ≥65 y (HR, 0.369; 95% CI, 0.138-0.984). Conclusion: Axi-cel as 2L therapy prolonged survival over SOC in pts aged ≥65 y, including in pts aged ≥70 y. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy, supporting the use of axi-cel as a curative-intent 2L therapeutic option for older pts with R/R LBCL.

Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 63.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 5-year OS and PFS (progression-free survival) estimates of 42.6% (95% CI, 32.8-51.9) and 31.8% (95% CI, 22.9-41.1), respectively (Neelapu, Blood 2023). We previously reported outcomes of axi-cel patients treated with standard of care therapy, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 58 months, as well as late outcomes of interest. Results The US Lymphoma CAR-T Consortium is comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel (n=298) as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After a median follow-up of 58 months, median OS was 34.9 months (95% CI 23.4 - 44.8) with the OS at 3, 4, and 5 years of 49.1% (95% CI 42.9 - 54.9%), 43% (95% CI 36.8 - 48.9%), and 40.3% (95% CI 34.2 - 46.4%), respectively. The median PFS was 8.7 months (95% CI 5.87 - 16.6) and the 3-,4-, and 5- year PFS were 36.1% (95% CI 30.4 - 41.8%), 30.7 (95% CI 25.2 - 36.4%), and 28.5% (95% CI 23 - 34.2%), respectively. Results of multi-variable modeling were similar to our prior analysis: male sex (HR 1.56, 95% CI 1.08 - 2.27, p =0.02); LDH above the upper limit of normal (HR 1.6, 95% CI 1.12 - 2.30, p = 0.01); ECOG status of 2-4 (HR 2.02, 95% CI 1.33 - 3.07, p = &lt;0.001); and elevated bilirubin &gt; 1.5 (HR 5.68, 95% CI 2.21 - 14.6, p = &lt;0.001) were associated with decreased OS. Factors associated with decreased PFS included male sex (HR 1.68, 95% CI 1.20 - 2.37, p = 0.003), LDH above the upper limit of normal (HR 1.82, 95% CI 1.31 - 2.53, p = &lt;0.001), ECOG status of 2-4 (HR 1.93, 95% CI 1.30 - 2.86, p = 0.001), elevated bilirubin (HR 3.68, 95% CI 1.45 - 9.37, p = 0.006) and receipt of 3 or more prior lines of therapy (HR 1.49, 95% CI 1.03 - 2.13, p = 0.032). We also assessed events of interest including late PFS events and causes of non-relapse mortality (NRM). One hundred and ninety-one PFS events occurred after axi-cel infusion during the follow-up period, 151 due to lymphoma progression and 40 NRM. In the first 12 months post infusion, 131 progression events occurred,13 between 1 and 2 years post infusion, and 7 relapses after 2 years with the latest occurring 46.4 months after infusion. Thirteen NRM events occurred in the 1st year post infusion, 6 between 1- and 2-years post infusion and 21 occurring later than 2 years after infusion. Of the 40 NRM events, 21 were secondary to infection including fungal infections (n = 3, 2 candidemia, 1 candidemia and pneumocystis jiroveci pneumonia), JC encephalitis (n=1) and COVID-19 (n = 2). Nine deaths were attributed to secondary malignancy. Other causes of NRM included cerebral edema (n=1), HLH (n=1), intracranial hemorrhage (n=1), suicide (n=1), and unknown (n=6). The 5-year cumulative risk of relapse was 55.2% and the 5-year risk of non-relapse mortality was 16.2%. Excluding non-melanoma skin cancers, twenty-three of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=11), AML (n=2), CMML (n=1)); other malignancies included anal squamous cell carcinoma (ca) (n=1); histiocytic sarcoma (n=1); prostate ca (n=1); endometrial ca (n=1); lung ca (n=1); merkel cell ca (n = 1), mesothelioma (n=1), B-ALL (n = 1), and AITL (n=1). Conclusion This multi-center retrospective study showed similar 5-year results to the ZUMA-1 trial with a 5-year PFS and OS of 28.5% and 40.3%, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Non-relapse mortality was primarily due to infection and secondary malignancy. This report supports the curative potential of axi-cel but highlights the competing risk of NRM in this high-risk patient population.

Abstract Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P &lt; 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P &lt; 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P &lt; 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and &lt;65 years. Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.

PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.