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Background: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is a standard of care in patients (pts) with relapsed or refractory (RR) large B-cell lymphoma (LBCL). However, it remains underutilized in elderly pts due to limited efficacy and safety data. We therefore evaluated real world outcomes of CART in such pts. Methods: Seven academic centers participated in this retrospective study. Pts aged ≥65 years with RR LBCL who received a commercial CART product were included. Baseline characteristics, treatment data, CART toxicity, and clinical outcomes were collected. Progression-free survival (PFS; time from infusion to disease progression or death) and overall survival (OS; time from infusion to death from any cause) were analyzed using Kaplan-Meier method. Cumulative incidences of non-relapse mortality (NRM) and disease relapse/progression were estimated accounting for competing risks. Statistical analyses were performed in JMP v15 and XLSTAT v2022.1.2. Results: 209 pts were identified. Baseline characteristics and treatment pattern are shown in Table. Median age at infusion was 71 years (range 65-89), and 25 (12%) were ≥80 years. 131 (63%) were male, 188 (90%) were white, and 27 (13%) had ECOG PS of ≥2. The median HCT-CI was 1 (range 0-6), and 39 (22%) pts had a score of ≥3. 165 (84%) had stage III-IV disease, 131 (70%) had extranodal involvement, 24 (18%) had bulky disease, and 24 (11%) had high grade B-cell lymphoma (HGBL; double- or triple-hit lymphoma, n=15; HGBL, NOS, n=9). The median number of prior lines of therapy was 2 (range 1-8), and 99 (48%) pts had ≥3 prior lines of therapy, 45 (22%) had prior bendamustine, and 44 (21%) had prior stem cell transplant (SCT; auto-SCT, n=41; allo-SCT, n=2; both auto- and allo-SCT, n=1). Bridging therapy was given to 100 (52%) pts; among those, 57 had chemotherapy, 20 had radiotherapy, 6 had both chemotherapy and radiotherapy, 10 had lenalidomide-based regimen, and 7 had CD20 antibody and/or corticosteroids. Axicabtagene ciloleucel (axi-cel) was most frequently used (63%, n=131), followed by lisocabtagene maraleucel (liso-cel) (24%, n=49) and tisagenlecleucel (tisa-cel) (13%, n=27). Cytokine release syndrome (CRS) occurred in 75% of pts, and a minority (6%) had grade ≥3. Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 55%, and 29% had grade ≥3. The management of CRS and ICANS included corticosteroids in 101 (49%) pts, tocilizumab in 116 (56%) pts, and other biologic agents (anakinra, siltuximab, basiliximab) in 8 (4%) pts. Day 30 response was evaluable in 195 pts with an objective response rate (ORR) of 84%, and a complete response rate (CR) of 52%. 82% of the responders continued to have a response at 3 month follow up. The ORR/CR rates were 86%/53% for axi-cel, 64%/44% for tisa-cel, and 89%/52% for liso-cel, respectively. At a median follow up of 19.1 months (95% CI 16.1-23.6) after infusion, the median PFS was 6.7 months (95% CI 5.1-11.5), with 6- and 12-month PFS rates of 54% (95% CI 47-61) and 43% (95% CI 35-50), respectively. The median OS was 16.5 months (95% CI 13.2-26.7), and the 6-and 12-month OS rates were 70% (95% CI 64-77) and 61% (95% CI 54-68), respectively. The NRM rate was 17% (95% CI 11-24) at 1 year, primarily due to infections including 5 COVID-19 related deaths. In univariate analysis, ECOG PS ≥2, bulky disease, elevated LDH, and the need for bridging therapy were associated with inferior PFS and OS. No significant difference in PFS and OS was seen based on age at infusion with a median PFS of 6.4 vs 9.6 vs 6.4 vs 6.0 months ( P=0.93) (Figure) and OS of 16.4 vs 19.2 vs 28.5 vs 12.7 months ( P=0.85) in age groups ≥65-69 vs ≥70-74 vs ≥75-79 vs ≥80-89. In addition, there was no statistically significant difference in PFS and OS based on type of CART with a median PFS of 6.4 vs 5.6 vs 12.7 months ( P=0.16) and OS of 15.1 vs vs 16.1 vs NR months ( P=0.24) in pts treated with axi-cel vs tisa-cel vs liso-cel. Conclusions: In this large multicenter study of elderly pts with RR LBCL, CART therapy demonstrated favorable efficacy and safety profile comparable to that in pivotal registration trials. Survival outcomes appeared similar regardless of patient age, including those aged ≥80 years, and type of CART product used. Similar to younger pts, high tumor burden and poor performance status at CART infusion were associated with inferior survival. This analysis confirms that older pts should not be excluded from receiving CART therapy solely due to chronological age.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.