Merryman, Reid W.

Background Follicular lymphoma (FL) is a generally indolent disease where a watch and wait strategy is standard in asymptomatic patients (pts) with a low tumor-burden. Harnessing antitumor immunity through an anti-tumor immunization strategy at this stage may delay or avoid the subsequent need for more toxic and complex therapies. EO2463 is a therapeutic vaccine designed from non-self protein sequences, derived from gut bacteria, including 4 HLA-A2 synthetically produced 9-mer CD8 cytotoxic T cell epitopes, exhibiting molecular mimicry with specific epitopes on the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor). Additionally, EO2463 contains a CD4 helper epitope UCP2 derived from hTERT. The compound expands pre-existing memory CD8 T cells recognizing the non-self protein sequences from gut bacteria which can then cross-react with the selected B cell antigens on tumor cells. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and marginal zone lymphoma (MZL) [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes Cohort 2 of trial EONHL1-20/SIDNEY (NCT04669171) and includes pts with newly diagnosed, previously untreated FL, grade 1-3A, HLA-A2, and not in need of treatment. Pts receive EO2463 (300μg/peptide) SC with adjuvant Montanide ISA 51 VG, q2 weeks (w) x 4, then q4w, for a total of 12 doses (39w; PET-CTs at w6, w19, and w42). Planned accrual for this cohort is 25 pts. Immune responses were assayed on thawed pt peripheral blood mononuclear cells by flow cytometry and EO2463 peptide specific tetramers or by IFN-γ ELISPOT (assaying responses against 9-mer peptides from CD20, CD22, CD37, and CD268; and from peptides of EO2463) without any proceeding in vitro stimulation (ex vivo). Results As of June 2024, 15 pts had started study treatment. Median age was 62 (range 55-66) year, 7 male and 6 female, 2 pts Ann Arbor stage I/II, 5 stage III, and 8 stage IV. Ten of 15 pts were still on treatment; median treatment duration was 18.4 weeks (range 5-39 w) for all pts. Among 13 evaluable pts, best responses by PET-CT using Lugano criteria were 1 pt CR, 5 pts PR (46% objective responses (OR)), 3 pts SD, and 4 pts PD. Of those with PD per Lugano, 2 had isolated increases in FDG-uptake without increase in lesion size/number at w6 and both remain on treatment (per protocol based on LYRIC criteria). OR was first noted w6 in 3 pts and w19 in 3 pts; duration of response is not evaluable at this time due to short follow-up. The pt with CR had isolated increases in FDG-uptake at w6, PR at w19, and CR at w35. Anti-EO2463 immune responses were observed in 4 of 5 tested pts at the 1st testing timepoint (w5) and onwards (currently longest tested up until w31). In an exploratory analysis, the percentage of EO2463 peptide specific CD8 T cells measured by tetramers seemed linked to clinical response (OR 3 pts vs non-OR 2 pts; 2-sided T-test, p=0.02; range of percentages in pts with OR 0.85%-1.39% of all CD8 T cells in peripheral blood, range in pts with non-OR 0.17%-0.27%). Functionality and cross-reactivity of responses were shown by IFN-γ ELISPOT using 9-mer peptides corresponding to the B cell targets in 4 tested pts. Expanded antigen-specific CD8 T cells displayed a memory phenotype; effector/memory (TEM), and terminally differentiated effector memory CD8 T cells (TEMRA). The most common related AEs were grade 1 (7 pts) and grade 2 (5 pts) local administration site reactions (mainly erythema, pruritus, and induration). Other related AEs in > 1 pt were grade 1 headache (2 pts) and grade 1-3 fatigue/asthenia (3 pts). Asthenia lasting 2 days was the only related grade 3 adverse event (AE). Conclusions EO2463 monotherapy is associated with a very manageable safety profile and appears to demonstrate meaningful single-agent efficacy in FL. Consistent with the preclinical hypothesis, expansion of specific CD8 memory T cells may be associated with response. Results will be expanded at the meeting. Study EONHL1-20/SIDNEY also includes cohorts, not covered in this abstract, exploring EO2463 plus rituximab for 1st line FL/MZL, and EO2463 plus lenalidomide/rituximab in relapsed FL/MZL.

Background Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes and a potential for spontaneous remissions indicating immune system intervention. T cell-based therapeutic approaches are therefore an attractive proposition in FL and MZL. EO2463 peptide immunotherapy expands pre-existing memory CD8 T cells recognizing non-self-protein sequences from gut bacteria which cross-react with B cell antigens. The compound includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor immunity against B cell malignancies, and has demonstrated long-lasting, specific CD8-memory T cell responses and clinical activity in relapsed/refractory FL and MZL [J Clinical Oncol 2024, 42 (S16), 7058]. Furthermore, CD8 T cells expanded from samples of patients (pts) treated with EO2463 can kill HLA-A2 expressing lymphoblastoid cell lines presenting the B cell targets [Hematological Oncol 2023, 41 (S2), 581-582]. Methods The current report describes testing of a possible biomarker in the phase 1 portion of the ongoing EONHL1-20/SIDNEY trial (NCT04669171).This part of the trial (“Cohort 1”) included pts (n=9) with relapsed (at least 1, no limit, prior treatments) FL and MZL, stage 1-3A, confirmed to be positive for HLA-A2. Pts received EO2463 (150 [n=3] or 300μg/peptide [n=6]) SC with adjuvant Montanide ISA 51 VG q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) was added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m IV, q1w x 4, then q4w x 4) was also added (ER2). Immune responses and clinical outcomes of Cohort 1 were previously reported [J Clinical Oncol 2024, 42 (S16), 7058]. To assess a possible biomarker, tetramers were used to specifically detect CD8 T cells recognizing the 4 epitopes in the EO2463 compound (derived from gut bacterial proteins exhibiting molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268). The tetramers were all marked with phycoerythrin. Thawed samples of peripheral blood mononuclear cells taken at start of w5 (after 2 administrations of EO2463 monotherapy, each followed by 2w observation) were stained ex vivo (without any in vitro stimulation) with the tetramers and assayed by flow cytometry. Results are presented as percentage of EO2463 specific CD8 T cells among all CD8 T cells in the peripheral blood of the pt. Results Among the 9 treated pts, PET-CT at w6 (after 3 administrations of EO2463 monotherapy) suggested possible clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). By PET-CT at w42 (after 12 administrations of EO2463 monotherapy, 11 cycles of lenalidomide, and rituximab treatment) the Lugano response assessment was complete response in 6/9 pts. A positive biomarker response was assessed in 5/9 pts (percentage of specific CD8 T cells ranged from 0.2-2.1%). EO2463 monotherapy PET-CT activity at w6 (n=4/9 pts): 4 of 4 pts with clinical activity were biomarker positive and 1/5 of the other pts was also positive; this pt had an isolated increase in FDG-uptake at w6, followed by a CR at w19. Four further other pts were biomarker negative. In this limited sample, the biomarker had sensitivity 100% and specificity 80%. EO2463 in combination with lenalidomide/rituximab PET-CT CR at w42 (n=6/9): 5 of 6 pts with CR were biomarker positive and 1 pt with CR was negative; the pt with a negative test had no objective tumor response until after rituximab. In this limited sample, the biomarker showed sensitivity 83% and specificity 100%. Conclusions The current preliminary assessment indicates that direct ex vivo tetramer staining for specific CD8 T cells after short term (5 w) treatment with EO2463 monotherapy could be a possible biomarker for clinical response, both for EO2463 monotherapy response, and for response to EO2463 in combination with lenalidomide/rituximab. We plan to validate these findings in the ongoing study cohorts of the trial; expansion phase 2 cohorts, exploring EO2463 monotherapy in the “watch & wait” setting, EO2463 plus rituximab for 1st line FL/MZL, and EO2463/lenalidomide +/- rituximab in relapsed FL/MZL.

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: Polatuzumab vedotin (Pola) is an antibody drug conjugate targeting CD79b that incorporates the microtubule disrupting monomethyl auristatin E payload. Pola was approved in 2023 for the upfront treatment of diffuse large B cell lymphoma (DLBCL) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (polaRCHP) based on the POLARIX trial. However, the activity of pola appears to vary based on DLBCL cell of origin (COO) subtype, with greater efficacy in activated B cell (ABC) DLBCL compared to germinal center B cell (GCB) DLBCL (Russler-Germain Blood 2023). When outcomes in POLARIX are stratified by COO, polaRCHP demonstrated progression free survival (PFS) and overall survival (OS) benefits over RCHOP in patients with ABC but not GCB subtype DLBCL (PFS HR 0.34 ABC vs 1.03 GCB, OS HR 0.27 ABC vs 1.64 GCB; Morschhauser ASH 2023 and FDA data). Most prospective studies of pola used gene expression to assess COO, which is not readily clinically available. This study aims to examine if COO subtype by Hans algorithm (based on CD10, BCL6, and MUM1 expression by immunohistochemistry) is predictive of pola responses and outcomes in patients with large B cell lymphoma (LBCL). Methods: We conducted a retrospective, multicenter observational study of adults with LBCL who received pola (monotherapy or in combination) from 2015-2024 with Hans algorithm COO data and response assessment available. Patients were stratified by receipt of pola in the frontline vs relapsed/refractory (R/R) setting. The primary endpoint was overall response rate (ORR) to pola-based treatment in GCB vs non-GCB subtypes. Secondary endpoints included complete response rate (CRR), PFS, and OS. For time to event endpoints, patients responding to pola who received CAR T or stem cell transplantation prior to progression were censored at time of cellular therapy. Demographics were summarized by descriptive statistics. Comparative and survival analyses used Chi squared/Fischer exact tests and Kaplan Meier analysis. Data cutoff was July 1, 2024. Results: 718 patients were included. Median follow-up was 15 months (interquartile range [IQR] 8-32). Median age at LBCL diagnosis was 66 years (IQR 56-74); 62% were men; 69 (10%) had double hit lymphoma (DHL); 129 (18%) had underlying low grade lymphoma. Pola was used in the frontline setting in 293 (41%) patients, of whom 139 (47%) had GCB vs 154 (53%) non-GCB COO. Of the 426 patients receiving pola for R/R LBCL (including one patient receiving pola retreatment), 224 (53%) had GCB vs 202 (47%) non-GCB COO. Among patients receiving pola-based regimens in the R/R setting (GCB vs non-GCB: pola monotherapy = 7% vs 4%, pola + R = 26% vs 26%, pola + BR = 55% vs 61%, pola + other = 12% vs 9%; p = 0.44), the ORR in GCB vs non-GCB LBCL was 36% vs 61% (p < 0.001), while CRR in GCB vs non-GCB was 17% vs 36% (p < 0.001). COO remained a significant component of logistic multivariate regression models of ORR (p < 0.001) and CRR (p < 0.001) when incorporating IPI at original LBCL diagnosis, histology, DHL status, and refractory status to frontline therapy. Despite this, no significant PFS or OS differences by COO were seen, potentially due to approximately 1/4 patients being censored due to receiving subsequent cellular therapy (e.g. CAR T) prior to progression. In patients receiving frontline pola-based regimens (of which 275 [94%] included an anthracycline), ORR and CRR were similar in GCB vs non-GCB (ORR 89% vs 88% p > 0.5; CRR 76% vs 77% p > 0.5). While PFS and OS were similar between COO groups in the frontline cohort, follow-up and cohort size were limited. Conclusion: Based on this real-world evidence, COO classification by Hans algorithm is a strong predictor of the activity of pola-containing therapy in R/R LBCL, with significantly higher ORR and CRR in patients with non-GCB compared to GCB COO LBCL. This aligns with the cumulative existing evidence. ORR and CRR to pola-containing therapy in the frontline setting did not differ significantly by COO subtype, but longer follow-up of larger cohorts is needed to clarify the predictive role of COO by Hans algorithm in this setting, especially considering the PFS advantage with polaRCHP in POLARIX was not associated with significant differences in ORR or CRR. Overall, clinicians should consider factoring COO subtype into treatment decisions regarding pola-containing regimens, and studies of pola-based therapies should stratify patients and report outcomes by COO subtype.

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.

7006 Background: Rituximab maintenance (RM) after first-line (1L) bendamustine and rituximab (BR) in MCL did not improve progression-free survival in the MAINTAIN trial (Rummel et al, ASCO 2016) but was associated with improved survival outcomes in a North American observational study (Martin et al, JCO 2023). We sought to examine the potential benefit of RM after BR using a large observational cohort from 26 US academic centers. Methods: Patients with MCL who received 1L BR (without stem cell transplant) outside of clinical trials were included. At the landmark of 3 months after the end of BR, patients who achieved a complete response (CR) or partial response (PR) to BR and had no evidence of progressive disease (PD) or second-line (2L) therapy were deemed eligible for RM. Event-free survival (EFS) was defined as time from landmark to progression, relapse, retreatment, or death. EFS2 was defined as time from landmark to progression, relapse, or retreatment following 2L therapy or death. RM was not considered a line of therapy for either endpoint. OS was defined as time from landmark to death. Survival analysis was done with Kaplan-Meier methods and Cox regression models adjusting for sex and simplified MIPI. Results: Among 796 patients who received 1L BR in 2007-2020, 693 achieved a CR or PR. At the 3-month post-BR landmark, 613 had no evidence of PD, among whom 318 (52%) received RM and 295 did not. The RM group was younger (median age 70 vs 72, p = 0.010) and more predominantly male (78% vs 69%, p = 0.047). There was no statistical difference in stage, simplified MIPI, histology (blastoid or pleomorphic vs classic), Ki-67, TP53 alteration, complex karyotype, year of BR start, or best response to BR between the two groups. The median follow-up after the 3-month post-BR landmark was 61.3 months (95% CI 62.6-70.4). The median number of doses of RM was 10 (IQR 5-12). RM was associated with improved EFS (median 47.1 vs 29.7 months, adjusted HR 0.59, 95% CI 0.48-0.73), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.63, 95% CI 0.50-0.81), and OS (median 136.1 vs 74.3 months, adjusted HR 0.57, 95% CI 0.44-0.75) (all p values < 0.001). In patients with CR to 1L BR (n=527), 271 (51%) received RM, for a median of 11 (IQR 6-12) doses. In this subgroup, RM was associated with improved EFS (median 60.6 vs 31.5 months, adjusted HR 0.56, 95% CI 0.44-0.71), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.62, 95% CI 0.48-0.81), and OS (median 136.1 vs 75.6 months, adjusted HR 0.59, 95% CI 0.44-0.79) (all p values < 0.001). Analysis in patients with PR to 1L BR was limited by the sample size (n=86, 47 received RM). The numeric differences in median EFS (20.8 vs 11.5, log-rank p = 0.370), EFS2 (48.9 vs 30.3, log-rank p = 0.210) and OS (87.3 vs 46.9, log-rank p = 0.067) were not statistically significant. Conclusions: In this large multicenter study, RM after 1L BR was associated with improved EFS and OS, supporting its use in routine practice for patients with newly diagnosed MCL.

7058 Background: Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes anda potential for spontaneous remissions indicating immune system intervention. Therapeutic immunization is therefore an attractive approach but new antigens that evoke a strong immune response are needed. EO2463 expands pre-existing memory CD8+ T cells recognizing non-self protein sequences from gut bacteria which cross-react with B cell antigens and can kill HLA-A2 restricted cells (T2) loaded with target peptides. EO2463 includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor activity against B cell malignancies. Methods: Patients (pts) with FL and MZL, stage 1-3A, and HLA-A2, are eligible. In the safety lead-in pts with relapsed/refractory (R/R) disease were given EO2463 SC q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m2 IV, q1w x 4, then q4w x 4) is also added (ER2). Doses evaluated: 150 μg and 300μg/peptide. Results: 3 pts received 150 μg/peptide and 6 pts 300 μg/peptide (EO2463 1 pat, EL 2 pts, ER2 6 pts): 2 MZL, 7 FL pts with median 2 lines (range 1-4) of prior systemic therapy. No related grade ≥3 adverse events were seen with EO2463 monotherapy. Most common related events were grade 1 to 2 local administration site reactions in 5/9 pts. Adverse events during combination treatment were as expected for R2. PET-CT on w6 after EO2463 monotherapy suggested clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). Overall objective responses (OR) were seen in 6/9 pts (67%; 1st OR on EO2463 1 pat, EL 4 pts, ER2 1 pat), with CR in 5/9 (56%) pts; median time to response was 18w (range 8-43w), response ongoing in 5 pts, range 24-76w. Expansion of specific CD8+ T cells against mimic peptides and targeted B cell antigens were detected in all responding pts, incl. 2 pts with no measurable B cells at baseline (prior anti-CD20). Expansion of specific T cells was detected at w5 in 5/6 pts and was maintained as long as currently tested (up to w94, 43w after last EO2463 dose). No decline in expansions were seen after start rituximab. Conclusions: EO2463 (300 μg/peptide) monotherapy, EL, and ER2 are well tolerated, with encouraging clinical activity with EO2463 monotherapy and with subsequent CR in 5/9 pts on combo. Rapid and durable expansion of specific CD8+ T cells was seen in all responding pts, consistent with the preclinical hypothesis. Additional cohorts investigate EO2463 alone or in combination in newly diagnosed or R/R pts. Results will be reported at the meeting. Clinical trial information: NCT04669171 .

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received &gt;1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p&lt;0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p &lt;0.001), &gt;1 line of salvage treatment prior to ASCT (40% vs 29%, p&lt;0.001), and &lt;CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p&lt;0.001), extra-nodal disease (19% vs 42%, p&lt;0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p&lt;0.001), and BV maintenance (20 vs 31%, p&lt;0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.