Besien, Herman van

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.

Introduction Emerging evidence suggests that responses to CPI in Hodgkin lymphoma (HL) may be adversely affected by the reductions in microbiome diversity associated with concomitant antibiotic (abx) exposure. Given the increasingly key role that CPI-based regimens (CPI+) appear to have on improving post-ASCT outcomes, we evaluated the potential impact of abx exposure on CPI+ efficacy and post-ASCT outcomes in RRHL patients treated with CPI+ prior to ASCT. Methods This retrospective study of RRHL patients at 11 US academic centers included patients ≥18 who received CPI+ between 1/2012-12/2022. Patient/disease characteristics, treatment histories, outcomes, and abx exposure (2 weeks prior to and 30 days after CPI+) were collected by participating sites and analyzed centrally. Primary and key secondary objectives were overall response rate (ORR) to CPI+ by Lugano criteria, and PFS/overall survival (OS) by abx exposure. PFS/OS were estimated by Kaplan-Meier and compared by log-rank tests. Univariate and multivariate regression models evaluated the impact of abx exposure on ORR/complete response rate (CR)/PFS/OS. Results 237 patients with median follow-up of 3.20 and 2.73 years from CPI+ initiation and ASCT, respectively, were evaluated. At diagnosis: median age 30.6 (range 7.8 - 71.7) years, female (53.6%), nodular sclerosing (75.1%), and stages I-IIB/bulky and III/IV (73.4%). 1L regimens were ABVD/ABVD-like (75.5%), brentuximab vedotin (BV)+AVD (15.2%), and other (9.3%). 65.8% received 6 cycles of chemotherapy, and 10.5% received 1L radiation. End of 1L responses were CR (39.7%), partial response (PR; 13.1%), refractory disease (37.6%), and unknown (8.0%). Median time to first relapse from diagnosis was 0.95 (range 0.15 - 22.2) years. All patients underwent ASCT after 1 (58.2%), 2 (22.8%), or 3+ (19.0%) lines of salvage. CPI+ was given as 1st (65.8%), 2nd (21.5%), or 3rd+ (12.5%) salvage therapy. CPI+ included BV-nivolumab (44.3%) + ipilimumab (7.2%), pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD; 24.5%), and CPI-monotherapy (20.2%). ORR to CPI+ was 88.0% (CR 68.4%) in all lines; as 1st salvage ORR was 91.7% (CR 76.3%). 75.1% of patients underwent ASCT in CR (PR 19.4%) increasing to 91.1% CR after ASCT. At 3-years, PFS was 88.0% (95% CI: 83.5% - 92.8%) and OS was 94.8% (95% CI: 91.3% - 98.3%) for the full cohort. Overall, 46.8% patients were abx exposed during CPI+, 22.8% fluoroquinolone/beta-lactams (BL) prophylaxis (ppx) and 38.8% abx [BL 29.5%, carbapenems (CB) 12.2%, vancomycin (VM) 19.8%, anti-pseudomonas (PA) 24.9%, anti-MRSA (SA) 22.4%, anti-anaerobe (AN) 16.5%] for suspected/documented infection. Use of ppx, BL, CB, VM, PA, SA were significantly higher with CP1+ as 2nd+ vs 1st salvage. At 3-years, PFS (87.0% vs 88.4%, p=0.91) and OS (92.5% vs 95.8%, p=0.47) were similar for abx exposed vs naïve patients, respectively. On univariate analysis, line of salvage and CPI+ regimen (Cytotoxic vs Monotherapy) were associated with ORR/CR, while overall abx exposure was not associated with inferior ORR (OR 0.62; p=0.24), CR (OR 0.85, p=0.56), PFS (HR 0.95, p=0.91), or OS (HR 1.58, p=0.47). When adjusted for line of salvage and CPI+ regimen, exposure to BL, CB, VM, PS, SA, or AN, abx indication (ppx vs treatment), duration of abx exposure (<7 vs ≥7 days) by class were all not associated with ORR/CR or PFS/OS. Conclusion In this large cohort abx exposure does not appear to adversely affect ORR/CR to CPI+ or PFS/OS following ASCT, when adjusted for line of CPI+ salvage and CPI+ regimen. Our findings may be related the high proportion of patients (79.8%) receiving CPI-combinations compared to CPI monotherapy (20.2%), whereas in previous series all patients received CPI without cytotoxic agents. This observation could be related to intrinsic antimicrobial activities of some cytotoxic agents (e.g. gemcitabine and doxorubicin) that may overshadow impact from concomitant abx exposure. Alternatively, the lack of effect could be related to the inherent fitness of patients with RRHL who undergo ASCT, compared to those treated with CPI+ following ASCT or those with solid tumors receiving where abx exposure may indicate an overall sicker/higher-risk population. Overall, our findings demonstrate that combination of CPI with BV or chemotherapy may overcome any adverse impact of abx on the efficacy of CPI+ prior to ASCT.

Introduction: Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin (P-GVD) has become a commonly employed regimen for the treatment of relapsed or refractory classical Hodgkin lymphoma (CHL), often preceding autologous stem cell transplant in patients with good response. The utilization of P-GVD is based on a 38-evaluable patient prospective trial (Moskowitz et al. JCO 2021). There remains minimal data regarding the efficacy of this regimen in a larger, real-world cohort. Methods:Patients with CHL who received P-GVD at 9 United States centers were retrospectively evaluated to estimate efficacy and safety, with a focus on the second line use of this regimen. Demographic and clinical data were extracted from medical records. Responses reflected Lugano criteria per local investigator assessment. Study objectives were overall response rates (ORR), complete response rates (CRR), progression free survival (PFS), overall survival (OS), and safety. PFS and OS were estimated by Kaplan-Meier. Results: Patients and Treatment: We identified 65 CHL patients who received P-GVD between July 2019 and June 2024, including 43 who were treated in the second line. Enrolled patients included a median age of 31 years (range 17-69 years), 36.9% (24) females, 75.4% (49) nodular sclerosing subtype, and 60% (39) stage III-IV at diagnosis. Patients included 64.6% (42) White and non-Hispanic, 15.4% (10) Hispanic or White and Hispanic, 10.8% (7) Black, 3.1% (2) Asian/Pacific Islander, 3.1% (2) other, and 3.1% (2) unknown. The median number of prior regimens was 1 (range 0-12); these included 3.1% (2) who had prior checkpoint inhibitor (CPI), 50.8% (33) who had prior brentuximab vedotin (BV), and 3.1% (2) who had prior transplant. Patients with primary refractory disease [no initial complete response (CR)] comprised 58.5% (38), and 35.4% (23) had relapse within 1 year of completing initial therapy. The median number of cycles received was 3 (range 1-5). Treatment in a community practice setting was noted for 21.5% (14) patients. Efficacy: At a median follow up of 17.7 months, ORR and CRR after P-GVD were 95% (62/65) and 74% (48/65), respectively. This increased to 95% ORR and 81% CRR when limited to 43 patients who were treated 2nd line. Responses by line included: 1st [n=1; 100% ORR and CRR]; 3rd [n=15; 100% ORR, 73.3% CRR], 4th [n=3; 100% ORR, 33.3% CRR], 5th [n=2; 100% ORR, 0% CRR], and 13th [n=1; SD]. CRR in BV- and CPI-exposed patients were 60.6% and 50%, respectively. Ninety one percent (39) of 2nd line treated patients proceeded to autologous transplant, as well as all 3 patients > age 60. Among 41 response-evaluable second-line patients, CR was achieved in 94% (30/32) who received 2 or 3 cycles of P-GVD, and 56% (5/9) who received 4 cycles of P-GVD. For the entire cohort at 12 and 24 months after starting P-GVD, PFS was 95% (95% CI: 89-100%), 91% (95% CI: 83-100%) and OS was 98% (95% CI: 94-100%), 94% (95% CI: 86-100%), respectively. Ninety five percent (41) of 2nd line transplanted patients remain alive and in remission at a median of 18.5 months (range 3.5-38.7 months). In the primary refractory subset, PFS and OS at 24 months were 91% and 97%, respectively. For the cohort with 2 or more prior lines of therapy, PFS and OS at 24 months were 91% and 94%, respectively. Safety: Immune-related adverse events (IRAEs) were reported in 20% (13) of patients, of which grade 3 IRAEs per NCCN criteria version 1.2024 comprised 38.5%; all others were grades 1-2. Non-IRAE grade 3-4 toxicities per CTCAE version 5.0 were reported in 22% (14) patients. Of 29 patients evaluable for treatment-related interruptions, 7% (2) had therapy discontinued, and 34% (10) had holds, dose reductions, and/or delays. No deaths were attributed to P-GVD treatment. Conclusions:This retrospective study confirms the utility of P-GVD in treating relapsed/refractory CHL in a real-world population. Though fewer CRs and higher rates of grade 3 adverse events were observed, the vast majority of patients were able to proceed to transplant, and outcomes to date are highly encouraging.