Stanisic, Alexander V.

Introduction: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) Prognosis is highly variable due to underlying biological and molecular heterogeneity. The first-line (1L) treatment paradigm for MCL continues to evolve with increasing use of bruton tyrosine kinase inhibitors (BTKi) and decreasing use of autologous stem cell transplant (ASCT). TP53 alterations are associated with inferior outcomes in MCL. The aim of this retrospective study is to determine treatment strategies and clinical outcomes in MCL patients based on TP53 gene mutation status. Methods: Retrospective data were collected from 19 institutions in the United States from 1/1993 to 1/2024. We examined treatment patterns and outcomes among MCL patients >18 years of age with known TP53 mutation status by sequencing. Patients who did not receive treatment were excluded. The analysis was stratified based on presence of TP53 mutations. Systemic therapies were categorized as chemo-immunotherapy (CIT), non-chemotherapy (including monoclonal antibodies, lenalidomide, venetoclax, and novel agents on clinical trial), and regimens containing BTKi. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS) and time to next treatment (TTNT). OS and PFS were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups. Results: 645 patients were included in the study, with 468 men (72.6%) and median age was 64 years (range 30-89). 230/645 patients (35.7%) had a TP53 mutation, of which 182 (79%) were identified prior to 1L. While the male/female distribution was the same between the mutated and unmutated groups, median age at diagnosis and MIPI risk score was higher in the TP53 mutated group (age 65.9 vs 63.1 yrs, p= 0.015; MIPI 6.4 vs 6.1, p<0.001). TP53 unmutated patients had a median of 1 line of therapy vs. 2 for the mutated group (p<0.001, range 1-8). Blastoid histology and higher ki67 were also associated with the TP53 mutated group (p=0.045, 0.01 respectively) The median OS was 14.2 years for TP53 unmutated and 8.3 years for TP53 mutated patients (p<0.0001). PFS in 1L was 0.95 years in TP53 mutated compared to 2.02 years in TP53 unmutated group (p<0.0001). Selection of 1L therapeutic strategy was not associated with presence of TP53 mutation (Χ2 p= 0.21) although more patients in the TP53 unmutated group underwent ASCT (119/415 vs 38/230; Χ2 p=0.0006) TP53 mutation was associated with inferior survival compared to TP53 unmutated patients for CIT in 1L but the difference did not reach statistical significance when non-chemotherapy regimens and regimens containing BTKi were used. For CIT in 1L, 5 year OS was 78% [71-84%] for unmutated compared to 58% [48-67%] for the mutated group (p=0.0001 ). For non-chemotherapy regimens, 5 year OS for unmutated patients was 73% [52- 86%] compared to 52% [25-73%] for the mutated group (p=0.09). For regimens containing BTKi, 5 year OS for unmutated was 93% [81-97%] compared to 57% [28-78%] for mutated (p=0.07). Within the TP53 mutated group, there were no differences in any clinical outcomes between those receiving CIT, non-chemotherapy, or BTKi in 1L. While median OS appeared numerically longer in the BTKi group (14.4 yrs vs 8.8 yrs for CIT and 6.8 yrs for non-chemotherapy), the difference did not reach statistical significance (p=0.58). In contrast,TP53 unmutated patients who received CIT in 1L had better TTNT (p=0.0039) compared to those in non-chemotherapy and BTKi groups. There was no improvement in PFS (p=0.79) or OS (p=0.47). Conclusions To our knowledge this is the largest retrospective real world dataset of MCL treatment outcomes stratified by TP53 mutation. As in prior studies, TP53 mutation portends a worse prognosis in MCL compared to TP53 unmutated patients, but outcomes are better than historically reported. CIT in 1L was not associated with improved OS in either group. Irrespective of TP53 mutation status, incorporation of BTKi in first line was not associated with improved clinical outcomes. The gap in OS between TP53 mutated and unmutated MCL may be narrowing as treatment paradigms shift away from intensive induction chemotherapy and ASCT, and due to an increasing number of effective therapies for relapsed patients. Clinical trials of novel agents are needed to further improve the OS of TP53 mutated MCL patients.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

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.