Ip, Andrew

Abstract Introduction: Older adults (OAs) with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients (pts). NAVD has been widely adopted in clinical practice for frontline (1L) treatment of OAs with advanced stage cHL based on the subset analysis of S1826 study (Rutherford et al, JCO 2025) showing a 1-year progression-free survival (PFS) of 93% and 1-year overall survival (OS) of 95% after NAVD (n = 50) which remained durable on longer-term follow up. Another phase 2 study (Torka et al, JCO 2025) showed that NAVD is a highly effective and well-tolerated 1L regimen in OAs with cHL (n=40) across a wide range of geriatric impairments. Adverse events (AEs) and efficacy have not been reported in OAs treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of OAs with cHL treated with 1L NAVD in a real-world setting (RWS). Methods This is a multicenter retrospective cohort study of adults (≥18 years) with cHL treated with 1L NAVD between 2023 and 2025 at 20 US academic sites. Baseline characteristics and outcomes of pts ≥60 years were evaluated as a pre-planned subset analysis. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who had not yet completed treatment. The efficacy evaluable cohort had completed 6 cycles of treatment including end of treatment (EOT) PET-CT and included pts who intended to complete treatment but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and OS. PFS and OS were analyzed using the Kaplan Meier method. Results Among 311 pts, 81 were OAs (26%). Median age of the OA cohort was 70 (range 60-88) yrs, 65% male, 84% Caucasian, 71% nodular sclerosis subtype, 58% stage 4 disease, 59% B symptoms, 14% bulky disease (>7.5 cm), 69% extranodal sites, 41% EBV positive, 54% hypoalbuminemia, 49% IPS ≥ 4 and10% had an autoimmune disease. G-CSF was given in 81% pts. All 81 pts were evaluable for safety; 74% experienced a grade 3+ (≥G3) AE, 54% had ≥G3 hematological AE, 48% had ≥G3 neutropenia, 17% had febrile neutropenia. Infection rate was 28% with 10% ≥G3, neuropathy rate was 23% with 4% ≥G3. One infusion reaction was noted. Treatment related hospitalizations rate was 23% with median duration of 7 (range 1-16) days. There were 24 immune related AEs (IrAE) (30%) of which 5 were ≥G3. Most common IrAE was hypothyroidism (n=5), followed by inflammatory arthritis (n=4), pneumonitis (n=2, ≥G3, n=1), hepatitis (n=2, both ≥G3), adrenal insufficiency (n=2, ≥G3, n=1), colitis (n=2), and rash (n=2). One patient each had autoimmune neutropenia, sarcoidosis of lung/skin and myocarditis (≥G3). Overall, 15% pts required steroids with resolution of IrAEs in 56% cases, 30% (n=7) pts required continued therapy (levothyroxine in 4 pts, steroids in 3 pts, medical tx for heart failure in 1 pt). Treatment was interrupted in 22%, reduced in 22%, and discontinued in 23% pts. Nivolumab was discontinued in 14% pts. Among all pts (n=81), 81% had an interim PET-CT after 2-4 cycles. The ORR and CR rate at interim PET-CT were 100% and 81%, respectively. In the efficacy evaluable pts (n=52; 24 still on therapy), the EOT ORR and CRR were 93.2% and 84% in OAs compared to 96.8% and 91.7% in pts <60yrs, respectively. At a median follow up of 10.2 mo (range 0.27-28.52), the 1-yr PFS was 90.6% (95% CI: 82.7%-99.3%) in OAs and 95.5% (95% CI: 91.6%- 99.6%) in pts <60 yrs (p=0.044). 1-yr OS was 97.5% (95% CI: 94.1-100%) and not evaluable in pts <60yrs (p=0.017). None of the baseline features were predictive of response, additional analysis to understand impact on AEs and survival is ongoing. Among the 5 pts with progression/relapse, 4 were primary refractory. 4 pts received 2nd line (2L) therapy.79 pts are alive at data cut off, 2 deaths occurred- 1 infection-related and other unknown; both after the 1st cycle. Conclusions In this largest RWS cohort of OAs treated with NAVD we showed comparable response rates, AEs and 1-year survival outcomes to those in the pivotal S1826 trial. Notably, rates of ≥G3 AEs including infections, neuropathy and IrAEs remained low and manageable. Although survival significantly improved with NAVD compared to historical data, outcomes of OAs remained inferior compared to pts <60 yrs. Our data reinforces the use of NAVD as the preferred 1L option for OAs with advanced stage cHL.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

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: Epcoritamab (Epcor) is a novel subcutaneous CD3xCD20 bispecific antibody (bsAb) that is currently approved as monotherapy for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after ≥2 systemic therapies. The combination of Epcor with standard treatment regimens has been shown to be safe and efficacious; Epcor in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival outcomes in a transplant-ineligible R/R diffuse large B-cell lymphoma (DLBCL) patient (pt) population, of which 99% were from the US and Europe (EPCORE NHL-2; NCT04663347). Another CD3xCD20 bsAb, intravenous glofitamab, has been studied in combination with gemcitabine and oxaliplatin (Glofi+GemOx) in the randomized STARGLO trial (NCT04408638) and demonstrated benefit over rituximab plus GemOx (R-GemOx), despite not demonstrating superiority over R-GemOx in patients from the US and Europe. In the absence of head-to-head data, this study used matching-adjusted indirect comparisons (MAICs) to assess the comparative efficacy of Epcor+GemOx vs R-GemOx and vs Glofi+GemOx. Methods: Individual pt-level data from EPCORE NHL-2 arm 5 and aggregated data from pts in each of the STARGLO arms were used to conduct an MAIC. Logistic propensity score models were used to weight Epcor+GemOx-treated pts to create matched cohorts with the R-GemOx and Glofi+GemOx arms separately. Weighting was conducted based on the distribution of baseline characteristics and prognostic factors such as age, sex, Eastern Cooperative Oncology Group performance status, previous therapies, and primary refractory status. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx, and vs Glofi+GemOx. Results: A total of 103 pts treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 91 pts treated with R-GemOx and 183 pts treated with Glofi+GemOx (median follow-up: 20.7 months), although differences in median follow-up time limited comparisons of longer-term survival outcomes. Match-adjustment mitigated differences in baseline characteristics across the 3 cohorts. After adjustment, Epcor+GemOx demonstrated a significant 44.8% advantage in ORR over R-GemOx (85.4% vs 40.7%), with a 110% increase in the likelihood of achieving a response (odds ratio [OR] 2.1; 95% CI 1.6-2.8; P<0.0001). Epcor+GemOx also demonstrated a significant 43.2% advantage in CR rate over R-GemOx (68.5% vs 25.3%), with a 170% increase in the likelihood of achieving a CR (OR 2.7; 95% CI 1.8-4.1; P<0.0001). With the current follow-up, Epcor+GemOx demonstrated superior PFS vs R-GemOx (hazard ratio [HR] 0.37; 95% CI 0.22-0.63; P<0.001), corresponding to a 63% reduction in the risk of progression. Median OS was not reached [NR] for Epcor+GemOx vs 13.9 months for R-GemOx, corresponding to a 43% reduction in the risk of mortality (HR 0.57 [95% CI 0.33-0.98]; P=0.04). After adjustment, Epcor+GemOx demonstrated a significant 15% advantage in ORR over Glofi+GemOx (83.3% vs 68.3%), with a 20% increase in the likelihood of achieving a response (OR 1.2; 95% CI 1.0-1.4; P=0.021). Epcor+GemOx demonstrated a trend toward higher CR rate than Glofi+GemOx (66.8% vs 58.5%; OR 1.1; 95% CI 0.90-1.5; P=0.277). Adjusted median PFS and OS for Epcor+GemOx, with limited follow-up and substantial censoring, was 12.9 months and NR, respectively. For Glofi+GemOx with longer follow-up, PFS and OS were 13.8 months and 25.6 months, respectively. Conclusions: Results show significantly superior efficacy for all outcomes with Epcor+GemOx vs R-GemOx from STARGLO. Epcor+GemOx also provided superior ORR and a trend toward higher CR rates vs Glofi+GemOx, indicating potential for better long-term efficacy outcomes. The Epcor+GemOx survival data are still maturing given shorter follow-up time, preventing a robust comparison of survival vs Glofi+GemOx. Findings support the efficacy of Epcor+GemOx as an alternative therapeutic regimen in transplant-ineligible patients with R/R DLBCL.

Introduction: Epcoritamab, a novel subcutaneously administered CD3xCD20 bispecific antibody (bsAb) being developed as a core therapy across several lymphoma subtypes, is currently approved for the treatment of adults with different types of R/R LBCL after ≥2 systemic therapies. The combination of epcoritamab with standard treatments has been shown to be safe and efficacious; epcoritamab in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival benefits in a transplant-ineligible R/R DLBCL study population, of which 99% was from the United States and Europe (EPCORE NHL-2; NCT04663347). The rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen has been a widely used treatment for patients with R/R DLBCL ineligible for transplant, albeit with suboptimal efficacy outcomes. In the absence of direct comparisons of these regimens, this study assessed the comparative efficacy of Epcor+GemOx vs R-GemOx in patients with R/R DLBCL ineligible for transplant. Methods: Individual patient-level data (IPD) from EPCORE NHL-2 arm 5 were compared to 2 sources of clinical practice data for patients with R/R DLBCL treated with R-GemOx: published data from Cazalles et al (2021) and IPD from the US-based COTA electronic health record database. The Cazalles study reports the results of a large retrospective analysis of patients with R/R DLBCL treated in 2 academic centers in France. The COTA database includes de-identified IPD with demographic and clinical information from numerous academic and community clinical sites in the US. For the comparison to Cazalles, logistic propensity score models were used to weight the Epcor+GemOx cohort to create match-adjusted distributions of baseline characteristics with the R-GemOx cohort in Cazalles. For the comparison to COTA, inverse probability of treatment weighting was employed to balance covariates between the Epcor+GemOx and R-GemOx cohorts. Analyses were restricted to chimeric antigen receptor T-cell therapy (CAR T)-naive patients from EPCORE NHL-2, as the comparator cohorts did not include patients treated with CAR T. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx. Results: A total of 74 patients treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 196 R-GemOx-treated patients from Cazalles et al (median follow-up: 22 months). After match-adjustment, Epcor+GemOx (ORR 86.8%) demonstrated significantly higher ORR, corresponding to a 48.5% advantage over R-GemOx (ORR 38.3%) with an odds ratio (OR) of 2.3 (95% CI 1.8-2.9; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx vs R-GemOx (71.2% vs 32.7%; 38.6% difference; OR 2.2 [95% CI 1.6-3.0]; P<0.0001). Median PFS was significantly longer with Epcor+GemOx (26.7 months) vs R-GemOx (4.8 months; hazard ratio [HR] 0.38 [95% CI 0.22-0.67]; P<0.001). Median OS was not reached (NR) for Epcor+GemOx vs 10.0 months with R-GemOx (HR 0.54 [95% CI 0.29-1.0]; P=0.05), corresponding overall to a 62% reduction in the risk of a progression event and a 46% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. A total of 72 patients were treated with R-GemOx in COTA (median follow-up: 7.5 months) and compared to 74 Epcor+GemOx patients. After adjustment, ORR was significantly higher with Epcor+GemOx vs R-GemOx (88.5% vs 35.6%; OR 2.5 [95% CI 1.8-3.4]; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx (63.9% vs 10.2%; OR 6.3 [95% CI 3.1-12.7]; P<0.0001). Adjusted median PFS was significantly longer with Epcor+GemOx (11.2 months) vs R-GemOx (2.4 months; HR 0.23 [95% CI 0.15-0.36]; P<0.0001). Adjusted median OS was also significantly longer with Epcor+GemOx (21.6 vs 8.3 months; HR 0.47 [95% CI 0.30-0.74]; P=0.002), corresponding overall to a 77% reduction in the risk of a progression event and a 53% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx. Conclusions: In this indirect treatment comparison analysis,Epcor+GemOx provided significantly superior efficacy benefits in terms of ORR, CR, PFS, and OS vs standard-of-care R-GemOx. While subject to the limitations of comparisons outside of controlled trials, findings indicate the compelling efficacy of Epcor+GemOx as a novel therapeutic option for transplant-ineligible patients with R/R DLBCL.