Citations

Abdominal aortic aneurysm (AAA) is a significant vascular condition characterized by the dilation of the abdominal aorta, presenting a substantial risk of rupture and associated high mortality rates. Current management strategies primarily rely on aneurysm diameter and growth rates to predict rupture risk and determine the timing of surgical intervention. However, this approach has limitations, as ruptures can occur in smaller AAAs below surgical thresholds, and many large AAAs remain stable without intervention. This review highlights the need for more precise and individualized assessment tools that integrate biomechanical parameters such as wall stress, wall strength, and hemodynamic factors. Advancements in imaging modalities like ultrasound elastography, computed tomography (CT) angiography, and magnetic resonance imaging (MRI), combined with artificial intelligence, offer enhanced capabilities to assess biomechanical indices and predict rupture risk more accurately. Incorporating these technologies can lead to personalized medicine approaches, improving decision-making regarding the timing of interventions. Additionally, emerging treatments focusing on targeted delivery of therapeutics to weakened areas of the aortic wall, such as nanoparticle-based drug delivery, stem cell therapy, and gene editing techniques like CRISPR-Cas9, show promise in strengthening the aortic wall and halting aneurysm progression. By validating advanced screening modalities and developing targeted treatments, the future management of AAA aims to reduce unnecessary surgeries, prevent ruptures, and significantly improve patient outcomes.

SummaryThe age‐associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy. Thoughtful consideration is needed to design trials that are both clinically relevant and avoid overmedicalization. Here, we summarize clinical studies of CH to date and provide suggestions and guidance on how to approach designing CH‐focused therapeutic clinical trials. These recommendations are derived from discussions among clinical researchers and scientists emanating from the Inaugural Meeting on Somatic Mutations and Predisease in October 2021.

Background Migraine is associated with obesity. These analyses evaluated weight change with atogepant used as a preventive migraine treatment. Methods Five atogepant clinical trials in adults with migraine (one phase 2b/3; four phase 3) were included: Three 12-week, randomized, placebo-controlled trials (episodic migraine: two; chronic migraine: one); one 40-week, open-label extension trial and one 52-week, standard care, randomized, long-term safety trial in episodic migraine. Change from baseline in body weight was measured. Results Mean baseline body mass indexes were 30.0–30.7 kg/m 2 (pooled episodic migraine [United States only]) and 25.0–25.5 kg/m 2 (chronic migraine [East Asia, Europe, and North America]). More participants treated with atogepant 60 mg once-daily compared to placebo experienced ≥7% weight loss at any time in the pooled episodic migraine placebo-controlled trials (4.9% vs. 2.8%), chronic migraine placebo-controlled trial (5.8% vs. 2.0%), and pooled open-label extension and long-term safety trials (24.0% vs.14.7% in standard care [long-term safety only]). In the placebo-controlled trials, weight loss with atogepant 60 mg once-daily was observed at week 2 (pooled episodic migraine: −0.32%; chronic migraine: −0.39%), increasing at week 12 (pooled episodic migraine: −1.02%; chronic migraine: −1.50%); compared to weight gain with placebo at week 12 (pooled episodic migraine: +0.49%; chronic migraine: +0.10%). In the long-term episodic migraine studies, weight loss with atogepant 60 mg once-daily was observed at week 4 (long-term safety: −0.42%; open-label extension: −0.76%), increasing at week 40 (long-term safety: −2.38%; open-label extension: −2.09%). Conclusion Atogepant was associated with modest dose- and duration-dependent weight loss. Trial registration ClinicalTrials.gov identifiers: NCT02848326 (CGP-MD-01); NCT03777059 (3101-301-002); NCT03700320 (long-term safety trial); NCT03939312 (open-label extension trial); NCT03855137 (3101-303-002).

OBJECTIVE To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring. RESEARCH DESIGN AND METHODS At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks. RESULTS Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI −0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by >0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by >0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects. CONCLUSIONS In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia.

Abstract Background: MCL is a B-cell non-Hodgkin lymphoma for which auto-HCT is often employed in first CR, based on non-randomized phase 2 trials, and a randomized trial (Dreyling et al, Blood 2005) conducted before the advent of more effective induction and maintenance regimens. The TRIANGLE trial (Dreyling et al, Lancet 2024) suggested that auto-HCT may not add benefit to more effective induction and maintenance regimens containing high-dose cytarabine, rituximab and BTK inhibitors. E4151 explored whether auto-HCT benefits pts achieving deep first remission, as measured by a highly sensitive immunoglobulin high throughput sequencing minimal residual disease (MRD) assay. Methods: EA4151 is a four arm trial conducted through the U.S. National Clinical Trials Network (NCTN) and Blood and Marrow Transplant Clinical Trials Network (BMT-CTN). Pts with MCL between the ages of 18 and 70 and in first remission were eligible. After induction, pts underwent PET/CT, bone marrow biopsy, and the clonoSEQ® MRD assay from peripheral blood. Pts in CR with uMRD at 1 in 10-6 sensitivity (uMRD6) were randomized 1:1 to Arm A (auto-HCT + 3 years of maintenance rituximab [MR]) or Arm B (3 years of MR alone), stratified by MIPI-c score and intensive vs non-intensive induction. Pts with either MRD-positive (MRD+) CR or MRD-indeterminate CR (Arm C and Arm D, respsectively) both received auto-HCT + 3 years of MR. Pts who were MRD+ pre-transplant had MRD repeated at day 100. Primary endpoint was to compare overall survival (OS) in Arms A and B, with secondary endpoints including progression-free survival (PFS). Primary analysis population included all randomized pts. As some pts refused their assigned treatment (N=65 [25.3%] for arm A and N=2 [0.8%] for arm B), a “treated as assigned” analysis was also performed. Stratified logrank test was used to compare survival distributions. P-values are two-sided. Results: From Aug 2017 to July 2024, 650 pts were assigned to a treatment arm with 257, 259, 49, and 85 pts enrolled on Arms A, B, C, and D, respectively. Pts were 79% male and 92% white race. Median age was 60 years (range 27-70). MIPI-c was low/low-intermediate (LI) in 63% and high/ high-intermediate (HI) in 37%. Induction was intensive (defined as high-dose cytarabine-containing) in 73% and non-intensive in 27%. A BTK inhibitor was given during induction in 7.2% of pts, and during maintenance in 0.3% of pts. The third pre-planned interim analysis was based on data as of 7/15/24, with median follow up of 2.7 years. The futility boundary was an OS hazard ratio (HR) of 0.984 for Arm A vs B. The estimated OS HR for Arm A vs B in all randomized (n=516) and pts treated as assigned (n=375) were 1.11 (CI 0.71-1.74, p=0.66) and 1.00 (CI 0.58-1.74, p=0.99), respectively and crossed the futility boundary. The 3 year (yr) OS for Arms A and B were 82.1% and 82.7% in all randomized pts, and 86.2% and 84.8% in pts treated as assigned. The estimated PFS HR for Arm A vs B in all randomized and pts treated as assigned were 1.05 (CI 0.71-1.56, p=0.79) and 0.95 (CI 0.59-1.54, p=0.84), respectively. The 3 yr PFS for Arms A and B were 76.6% and 77.4% in all randomized pts, and 81.5% and 80.4% in pts treated as assigned. For Arm C, 3 yr OS and PFS were 81.9% (CI 69.6-96.4%) and 76.9% (CI 64.4-91.7%), respectively. For Arm D, 3 yr OS and PFS were 85.1% (CI 76.0%-95.4%) and 73.4% (62.7-85.9%), respectively. For the MIPI-c low/LI group, 3 yr OS was 84.6% vs 85.7% for Arm A vs B (p=0.96), while in the MIPI-c high/HI group, 3 yr OS was 77.4% vs 77.6% for Arm A vs B (p=0.71). For the intensive induction group, 3 yr OS was 83.0% vs 86.2% for Arm A vs B (p=0.30), while in the non-intensive induction group, 3 yr OS was 79.5% vs 72.8% for Arm A vs B (p=0.48). Exploratory analysis of MRD+ pts (Arm C) showed that pts who converted to uMRD6 post auto-HCT (n=17) had 3 yr OS of 100% and PFS of 100%, whereas those who remained MRD+ (n=13) post auto-HCT had 3 yr OS of 63.6% and PFS of 48.8%. Causes of death (COD) in Arm A were 4.7% lymphoma, 5.1% COVID-19, and 5.0% other/unknown. COD in Arm B were 3.5% lymphoma, 6.6% COVID-19, and 4.6% other/unknown. In Sept 2024, the DSMC recommended termination of accrual and release of trial findings based on these results. Conclusion: In this interim analysis, in the era of highly effective induction and maintenance regimens, MCL pts in first CR with uMRD6 did not benefit from consolidative auto-HCT. Pts who remain MRD+ after induction may benefit from auto-HCT. Longer follow-up will be important to confirm these findings.

Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking. Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)]. In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p<.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p<0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21) and in another study of 186 patients, the 10-year cumulative incidence was 14%Click or tap here to enter text.. In this report, we focus on risk factors for transformation as well as clinical characteristics and outcomes of transformed SMZL (tSMZL). Patients and methods: Adults diagnosed with SMZL in 2000-2018 were identified through regional or nationwide population-based registries or from hospital registries. Only patients likely to have SMZL as defined by Matutes et al. were included. Those with discordant lymphoma and/or transformation at diagnosis were excluded. Medical records were reviewed by local clinicians with experience in hematology/oncology, and detailed information on clinical characteristics, treatment lines, and outcomes was collected. Only histologically confirmed high-grade transformations (HT) were included. OS was defined as the time from transformation to death or censoring at last follow-up. Additional analyses stratified by treatment exposure prior to HT and treatment of HT were conducted. Multivariable Cox analyses were performed to determine clinicopathological features associated with transformation and OS. Results: Out of 940 patients with SMZL, 111 developed HT during a median follow-up of 9.1 years. The median time from diagnosis to HT was 3.4 years with an interquartile range of 1.6-7.4 years. Median age at HT was 71 years. Patients with HT shared similar baseline characteristics to those without in terms of age at diagnosis (66.4 vs 67.6), f:m ratio (1.5 vs 1.1) and ECOG ³2 (7.2% vs 7.4%). The 5-yr OS from the time of HT was 42% (CI 95%, 32-54). Of the 111 patients with tSMZL, a complete treatment history from SMZL diagnosis until HT was available for 88 included in the following analyses. By the time of HT, 46 had not received any prior systemic therapy (37 only splenectomy, 9 no therapy), 6 patients had received rituximab alone or combined with splenectomy, and 36 patients had received chemotherapy alone or as part of combined modality treatment. In a uni- and multivariable models for HT, we assessed age, treatment at diagnosis, sex, extra-hilar lymphadenopathy, and extranodal involvement. In both the uni- and multivariable model, age >70 (HR 1.9, 95% CI: 1.1-3.4), immediate treatment including splenectomy (HR 2.0, 95% CI: 1.05-3.6), and extra-hilar lymphadenopathy (HR 1.9, 95% CI: 1.1-3.3) were associated with higher HT hazard, while extranodal involvement (HR 0.23, 95% CI: 0.06-0.84) was associated with a lower HT hazard. At the time of first-line treatment, multivariable analysis revealed similar results and with no association between risk of transformation and treatment strategy (i.e splenectomy alone, rituximab monotherapy or chemotherapy with /without rituximab or splenectomy, and other). At the time of HT, patients who had been previously treated with chemotherapy had an inferior 5-year OS of 24% (95%CI: 13-44%) versus 54% (95%CI: 41-71%) for those who had not received chemotherapy prior to HT. In contrast, there was no difference in the survival of patients that transformed less than or more than 24 months from diagnosis with 5-year OS after HT of 35% (95%CI 20-60%) and 45% (95%CI, 33-61%) respectively. In a multivariable Cox regression analyses of age at time of HT, sex, time since last treatment <24 months, chemo-exposure in previous treatment lines and anthracycline-containing therapy (+/-R) at the time of HT, only prior chemo-exposure was borderline associated with poorer OS (HR 1.8, 95%CI: 0.9-3.5). Conclusion: Patients with SMZL face a notable risk of developing tSMZL over time. Patients in need of immediate treatment at first SMZL diagnosis, age >70 and extrahilar lymphadenopathy had a higher risk of tSMZL and outcomes at the time of HT were poor if patients had been exposed to prior chemotherapy after adjustment for age, sex, and time since last treatment.

Introduction: WM is a rare subtype of lymphoma, identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the somatic mutation, MYD88 L265P, which is observed in over 90% of WM patients. We previously identified two rare variants at 6p25.3 (EXOC2) and 14q32.13 (TCL1) that were significantly associated with an increased risk of WM/LPL (PMID: 30305637). However, the genetic basis for WM/LPL predisposition remains largely unknown. We conducted the largest WM/LPL GWAS to discover further germline susceptibility loci for WM/LPL. Methods: Our meta-analysis discovery set included 1,707 cases and 58,328 controls of European ancestry from the InterLymph Consortium, genotyped on a high-density SNP array and imputed to TOPMed, providing over 10 million common variants for association testing. Germline genetic loci with suggestive significance (P<5x10-6) were selected for replication in four independent sets (570 cases and 771,770 controls; UK Biobank, Copenhagen Hospital Biobank, FinnGen, Mayo Clinic), giving us a total of 2,277 WM/LPL cases and 831,098 controls. Conditional and sensitivity analyses were performed considering family history and sex. A transcriptome-wide association study (TWAS) was performed using FUSION with expression quantitative trait loci (eQTL) data from GTEx and Young Finns Study in whole blood, lymphocytes, and other tissues. Functional annotations were done using FUMA, F-MAGMA, FORGE, and OpenTarget. Colocalization was measured using CoLoC with whole blood gene expression data. Results & Discussion: We identified 11 germline genetic loci associated with WM/LPL risk that replicated and reached genome-wide significance (P< 5x10-8), including the two known loci on 6p25.3 and 14q32.13 and nine novel loci in the following regions: 6p25.3 (n=2 independent loci), 2q37.1, 9p13.2, 6p21.32, 10q23.31, 16q21, 1p31.1, and 15q15.1. Four of the discovered variants showed strong associations with WM/LPL [odds ratios (ORs) >10]. Enrichment was observed for enhancer and promoter elements in B-cells (FDR q < 0.01), and gene-based and colocalization analyses identified several potential biological pathways. Colocalization analyses show the intronic PAX5 risk variant on 9p (OR=1.5, P= 2.3x10-25) associated with whole blood eQTL expression of PAX5, which plays an essential role in regulating lymphoid progenitors to the B-lymphocyte lineage, as well as RP11-297B17.3 (RNA gene, antisense to PAX5). In addition, GWAS have shown this variant is in linkage disequilibrium (LD) with GWAS loci for CD20 on IgD+ CD38- B cell that represents a specific immunophenotype that helps identify and characterize B cells involved with WM and other similar conditions. The 2q37.1 (SP140) locus (OR=1.6, P=1.2x10-33) contains variants linked to chronic lymphocytic leukemia (CLL) and autoimmune diseases, including multiple sclerosis and Crohn's disease. This locus is important in chromatin-mediated gene regulation, suggesting a significant role in the immune system. The specific variant influences exon-skipping and potentially protein expression, altering the gene's function. The variants on 10q23.31 in FAS (OR=1.3, P=4.4x10-13) and 15q15.1 (OR=1.2, P=8.5x10-11) in BCL2 modifying factor (BMF), are in strong LD with known CLL susceptibility variants. The 15q variant is also linked with multiple lymphoid leukemia GW significant SNPs. Sex-specific analyses identified one novel locus at 20q13.33 associated with the expression of ZGPAT and UCKL1 in males (OR=1.9, P=9.5x10-10). TWAS identified associations with CRHR1 and CDKN2A; overexpression of both are shown to be associated with an increased risk of WM/LPL. Expression of CDKN2A has been linked to childhood acute lymphoblastic leukemia, while CRHR1 has been associated with breast cancer risk. Conclusions: Our study, the largest GWAS of WM to date, has identified 11 susceptibility loci, including two previously known and nine novel regions. The findings underscore the genetic complexity of WM, with the PAX5 and SP140 loci implicated in both chromatin-mediated gene regulation and immune system functions. These insights not only enhance our understanding of WM predisposition but also pave the way for future research focused on functional understanding of these loci, potentially leading to new therapeutic strategies.

Introduction: Patients with non-Hodgkin Lymphoma (NHL), especially adolescents and young adults, can face late effects from treatment, including decreased fertility. Due to time constraints prior to treatment initiation and sometimes financial limitations, implementing fertility counseling and referral-based guideline care remains challenging. We aim to understand the occurrence and predictors of fertility counseling and preservation in patients with NHL in the Lymphoma Epidemiology of Outcomes (LEO) cohort study. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with NHL from 2015-2020 at 8 academic medical centers in the US. Clinical. Treatment data were abstracted from medical records, pathology was reviewed and classified by a LEO pathologist, and participants completed a self-administered questionnaire. Participants were then prospectively followed to identify outcomes and collect additional patient reported data, including a survivorship questionnaire at follow-up 3 years (FU3) after diagnosis that included items on fertility counseling and preservation. The questionnaire contained two fertility questions analyzed: whether healthcare providers discussed the impact of lymphoma treatment on fertility, and whether providers discussed the process of fertility preservation. This analysis was based on participants aged 18-50 years at enrollment and who completed the fertility questions at FU3. Women who had undergone natural or procedural menopause and men who had undergone vasectomy pre-treatment were excluded. We estimated the association of demographic and clinical factors with fertility preservation using odds ratios (ORs) and 95% confidence intervals (CI) from univariate and multivariable logistic regression models. Results: Seventy-seven patients were included in the analysis: 36 females (46%) and 41 males (53%). The median age of diagnosis was 40 years (IQR 30-45), and 36 (47%) participants were in the age 18-39-year category. Participant self-identified race/ethnicity was 69% non-Hispanic White, 22% Hispanic, 4% Black and 3% Asian. Sixty (78%) patients were treated with alkylators, 12 (15.6%) with non-alkylators, and 5 (6.5%) with radiation. Fifty-five (71%) of the patients were classified as having aggressive lymphoma, with follicular, extranodal marginal zone, primary cutaneous follicle center, and nodal marginal zone B-cell lymphoma defined as indolent and remaining subtypes aggressive. Around 6% of female patients underwent fertility preservation after lymphoma diagnosis, compared to 12.2% of male patients. All the patients who had undergone fertility preservation after lymphoma diagnosis were in the 18-39-year age group. On univariate analysis, females were more likely to have undergone fertility toxicity and preservation discussions compared to males, with 72% of females and 59% of males recalling a discussion regarding fertility (OR 1.8, 95% CI 0.7-4.9, p=0.21). Those age 18-39 were significantly more likely to have undergone fertility discussion compared to those aged 40-50 (OR 10.2, 95% CI 3.3-39.2, p<0.001). Patients treated with alkylating therapy were significantly more likely to undergo fertility discussion when compared to those on non-alkylating therapy (OR 9.0, 95% CI 2.3-45.5, p<0.01). In addition, 75% of those with aggressive lymphoma compared to 41% of patients with indolent lymphoma had fertility discussion (OR 4.2, 95% CI 1.5-12.4, p=0.01). White patients were significantly less likely than Hispanic, Black and Asian patients to have fertility discussion (OR 0.2, 95% CI 0.04-0.6, p<0.01). In the multivariable analysis, alkylating therapy (OR 8.9, 95% CI 1.6-66.7) and age 18-39 years (OR 10.9, 95% CI 2.9-55.3) remained significant predictors of fertility discussion; White race was also trending towards significance (OR 0.2, 95% CI 0.04-1.0, p=0.08). Aggressive lymphoma subtype was not a significant predictor of fertility discussion. Conclusions: In this cohort of lymphoma survivors 3 years post-diagnosis, we found that Hispanic patients, those diagnosed at a younger age and exposed to alkylating chemotherapy agents were significantly more likely to undergo discussions regarding the effects of lymphoma treatment on fertility. Our study highlights the importance of all cancer patients of childbearing age having the opportunity to address fertility concerns during clinic visits.

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.