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Abstract Rationale Alpha-1 antitrypsin (AAT) deficiency, primarily caused by homozygous SERPINA1 Z mutation, increases the risk of COPD. Individuals carrying one Z and one normal M allele (MZ) have higher COPD risk than MM individuals, although many never develop disease. COPD is a polygenic condition influenced by numerous genetic factors across the genome and by environmental exposures such as smoking. We aimed to examine how polygenic factors and smoking modify risk of airflow obstruction in MZ compared with MM. Methods We included participants with the MZ and MM genotypes from the Framingham Heart Study. We first tested the association between AAT genotype (MZ coded as 1 and MM as 0) and FEV1/FVC, stratified by ever-smoking status, and further evaluated interactions between AAT genotype and smoking pack-years. Next, for each participant we calculated a polygenic risk score (PRS) for FEV1/FVC, which was derived from external genome-wide association studies in the UK Biobank and SpiroMeta Consortium. To reflect risk for airflow limitation, higher PRSs correspond to lower FEV1/FVC. We then tested the interaction between the PRS and AAT genotype, stratified by ever-smoking. Models were adjusted for age, sex, height, current smoking, pack-years (among ever-smokers), familial relatedness, and in PRS models, principal components of genetic ancestry. Results Among 4,220 participants (mean age 53.7 years, 54.2% female, 50.2% ever-smokers, mean FEV1/FVC 74.6%), 133 (3.2%) had MZ genotype. In never-smokers, MZ individuals had 1.72% higher FEV1/FVC compared with MM (P = 0.032), whereas no difference was observed among ever-smokers (β= -0.39%; P = 0.65). Cumulative smoking modified the effect of MZ genotype on FEV1/FVC (interaction β= -0.13% per pack-year; P = 0.003); this interaction persisted among ever-smokers (β= -0.11% per pack-year; P = 0.044). A one-standard-deviation increase in the FEV1/FVC PRS was associated with lower FEV1/FVC in both never- (β= -2.37%; P < 0.0001) and ever-smokers (β= -2.46%; P < 0.0001). A higher PRS was disproportionately associated with reduced FEV1/FVC in MZ compared to MM (interaction β= -1.87% per standard-deviation PRS increase, P = 0.027) among ever-smokers, but not in never-smokers (P = 0.15). Conclusions In this community-based cohort, the AAT MZ genotype was associated with higher FEV1/FVC among non-smokers compared to MM. The interaction between MZ genotype and pack-years suggested a dose-dependent modifying effect of smoking on the MZ-related COPD risk. Among ever-smokers, higher polygenic risk further amplified susceptibility to airflow obstruction in MZ compared with MM. These findings highlight the roles of both polygenic and environmental risk factors in COPD susceptibility in MZ. Replication of the results is needed. This abstract is funded by: This work is supported by an Alpha-1 Foundation Grant and a Boston University Department of Medicine Career Investment Award

Abstract Introduction: The prognosis of patients (pts) with histological transformation (HT) of Waldenström macroglobulinemia (WM) remains dismal with standard chemoimmunotherapy. CD19-targeted chimeric antigen receptor T-cell therapies (CAR-T) can lead to durable responses in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and are approved in the second or third line settings. Pts with HT-WM were largely excluded from CAR-T trials. We previously reported high response rates in a series of 23 pts. The aim of the present study was to evaluate a larger cohort of pts with R/R HT-WM treated with CAR-T with a longer follow-up. Methods: We performed a multicenter retrospective study of pts with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with CAR-T in the French DESCAR-T registry (NCT04328298), 4 centers from ECWM and 4 US centers. This study includes updated data from previously published cases (Durot et al, Blood, 2024). Responses were assessed according to the Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Progression-free survival (PFS) and overall survival (OS) were calculated from the date of CAR-T infusion and estimated using the Kaplan-Meier method. Results: 50 pts were included (39 from DESCAR-T centers, 7 from US centers and 4 from ECWM centers). Median age was 60 (range: 32-72) and 68 (range: 42-82) years at WM diagnosis and CAR-T infusion, respectively. MYD88L265P and CXCR4 mutations were present in 79% (23/29) and 15% (2/13) of patients with available data, respectively. The median time from WM to HT diagnosis was 5.3 years (range: 0-32). Median prior lines of therapy was 1 (range: 0-9) for WM and 2 for HT (range: 0-4). Twenty (40%) pts previously received a BTK inhibitor for WM or HT, 12 (24%) underwent prior autologous SCT and 1 pt allogeneic SCT. 40% of pts presented primary refractory disease and 44% were refractory to last treatment before CAR-T. 40 pts (80%) received bridging therapy, of whom 17 (44%) responded (7 complete responses (CR)). 35 (70%), 10 (20%), and 5 (10%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), respectively. The best overall response rate (ORR) was 94%, with 44 (88%) pts reaching CR. With a median follow-up of 25.7 months (range: 1-69) from CAR-T infusion, the median PFS was 1.2 years (95% CI: 0.5-4.5) and median OS was 4.2 years (95% CI: 1.2-not reached). Median duration of response was 1.5 years (95% CI: 0.4-4.4), with a median of 4 years (95% CI: 1.5-NR) for pts still in CR at 6 months after CAR-T. 22 pts experienced relapse/progression after CAR-T, 19 related to LBCL and 3 to WM. Median survival after relapse was 7.9 months (95% CI: 3.8-25.3). At LBCL relapse after CAR-T, salvage therapy consisted of CD20xCD3 bispecific antibodies for 9 pts, lenalidomide +/- anti-CD20 or anti-CD19 antibody for 6 pts, and BTKi for 3 pts. Among 19 pts who died, 14 (74%) were due to progressive disease and 5 (26%) from infections. 37 (76%) pts experienced CRS, including 2 (4%) grade 3 events, and 22 (45%) had ICANS, with 2 (4%) ≥ grade 3 events. 17 (35%) pts presented infections, including 12 ≥ grade 3. 21 (43%) pts developed ≥ grade 3 prolonged cytopenias (ie, not resolved within 30 days post infusion). CNS involvement due to LBCL was present in 11 pts (22%) at the time of CAR-T. 6 of them had ICANS, with 1 grade 4. The best ORR was 91% (best CR 91%). Only 1 patient did not obtain a response, with stable disease at 1 month and progression at 3 months. The median PFS was 1.2 year (95% CI: 0.2-NR) and median OS was NR (95% CI: 0.5-NR). On univariate analysis, only elevated LDH was correlated with worse PFS (HR 2.5, p=0.04) and OS (HR 3.3, p=0.04). Other variables, including number of prior lines of therapy, MYD88 mutation status, primary refractory disease, refractory to last treatment, CNS involvement before CAR-T, response after bridging therapy and type of CAR-T received, were not associated with inferior PFS or OS. Conclusion: This cohort represents the largest series of pts with transformed WM treated with anti-CD19 CAR-T. We confirm the high efficacy previously reported with an acceptable safety profile, including for pts with CNS involvement due to LBCL at CAR-T infusion.

ImportanceChronic obstructive pulmonary disease (COPD) is often undiagnosed. Although genetic risk plays a significant role in COPD susceptibility, its utility in guiding spirometry testing and identifying undiagnosed cases is unclear.ObjectiveTo determine whether a COPD polygenic risk score (PRS) enhances the identification of undiagnosed COPD beyond a case-finding questionnaire (eg, the Lung Function Questionnaire) using conventional risk factors and respiratory symptoms.Design, Setting, and ParticipantsThis cross-sectional analysis of participants 35 years or older who reported no history of physician-diagnosed COPD was conducted using data from 2 observational studies: the community-based Framingham Heart Study (FHS) and the COPD-enriched Genetic Epidemiology of COPD (COPDGene) study.ExposuresModified Lung Function Questionnaire (mLFQ) scores and COPD PRS.Main Outcomes and MeasuresThe primary outcome was spirometry-defined moderate to severe COPD (forced expiratory volume in the first second of expiration/forced vital capacity [FEV1/FVC] <0.7 and FEV1 [percent predicted] <80%). The performance of logistic models was assessed using the PRS, mLFQ score, and PRS plus mLFQ score for predicting spirometry-defined COPD.ResultsAmong 3385 FHS participants (median age, 52.0 years; 45.9% male) and 4095 COPDGene participants (median age, 56.8 years; 55.5% male) who reported no history of COPD, 160 (4.7%) FHS and 775 (18.9%) COPDGene participants had spirometry-defined COPD. Adding the PRS to the mLFQ score significantly improved the area under the curve from 0.78 to 0.84 (P < .001) in FHS, 0.69 to 0.72 (P = .04) in COPDGene non-Hispanic African American, and 0.75 to 0.78 (P < .001) in COPDGene non-Hispanic White participants. At a risk threshold for spirometry referral of 10%, the addition of the PRS to the mLFQ score correctly reclassified 13.8% (95% CI, 6.6%-21.0%) of COPD cases in FHS, but not in COPDGene.Conclusions and RelevanceA COPD PRS enhances the identification of undiagnosed COPD beyond a conventional case-finding approach in the general population. Further research is needed to assess its impact on COPD diagnosis and outcomes.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Abstract Rationale In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case–control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10−95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10−87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Abstract INTRODUCTION Central nervous system (CNS) relapse is a challenging situation in diffuse large B-cell lymphoma (DLBCL). High CNS-International Prognostic Index (IPI), activated B-cell (ABC) subtype and MYD88 L265P mutation, features often found in transformed Waldenström macroglobulinemia (WM), are associated with a higher risk for developing CNS relapse. This study was aimed to describe CNS involvement in a large cohort of transformed WM. METHODS This international multicenter retrospective study included patients with a diagnosis of WM and a concurrent or sequential histological diagnosis of DLBCL. CNS disease was diagnosed by detection of DLBCL cells in the cerebrospinal fluid and/or by brain biopsy. Patients with CNS involvement by lymphoplasmacytic cells (Bing-Neel syndrome) were excluded. Of 254 identified patients with a diagnosis of histological transformation (HT) between 1988 and 2020, 19 were excluded due to lack of data on extranodal involvement. The first part of the analysis focused on baseline CNS involvement. Clinicobiological characteristics were compared between groups using Chi-square or Fisher's exact tests or Mann Whitney tests as appropriate. We analyzed CNS recurrence in the second part of the study. Forty-eight additional patients were excluded due to baseline CNS involvement (n = 25), absence of treatment at HT (n = 14) and lack of details on follow-up (n = 9). Cumulative incidence of CNS relapse was analyzed using competing-risk models that accounted for other events like systemic relapse or death from any cause, reporting sub-hazard ratio (SHR). RESULTS Baseline CNS involvement was present in 25 patients (11%) with transformed WM, including 10 (4%) with parenchymal disease, 10 with leptomeningeal, 4 (2%) with both, and 1 with unspecified CNS involvement. Characteristics associated with baseline CNS involvement were performance status 2-4 (P=0.03) and ≥2 extranodal sites (P=0.02). Median survival after HT was 1 year [0.7-2.5], comparable to the one of patients without CNS disease (1.8 year [1.2-2.6], P=0.74). We observed no difference in survival based on isolated CNS involvement (n = 10) compared to CNS and systemic involvement (n = 15) (P=0.94). Twenty-three CNS relapses occurred (12%). The 2-year and 3-year rates of CNS relapse were 9% (95% CI, 6-14) and 11% (95% CI, 7-16) (Figure 1). The median time to relapse in the CNS was 11 months (95% CI, 7-25). Thirteen CNS recurrences (57%) occurred during the first year of follow-up. Seventy percent were isolated CNS relapses. The location was leptomeningeal in 43% of cases, parenchymal in 35%, both in 17%, and unspecified in 4%. According to CNS-IPI risk groups (data available for 20 patients), 9 patients (45%) belonged to the high-risk group, 10 (50%) to the intermediate-risk group and 1 (5%) to the low-risk group. Prior to CNS relapse, 87% of patients had received rituximab, and 39% had received CNS prophylaxis (30% intrathecal chemotherapy, 4% high-dose methotrexate (HD-MTX), and 4% both). After CNS recurrence, 96% of patients received salvage treatment: combination of HD-MTX and HD-cytarabine (48%), HD-MTX alone (30%), or HD-cytarabine alone (9%). Four patients underwent consolidative autologous stem cell transplantation. The median survival after CNS relapse was 5.6 months. Factors associated with 3-year cumulative incidence of CNS recurrence in univariate analysis were involvement of kidney/adrenal glands (HR, 4.4; P=0.01) and MYD88 L265P mutation (P=0.01) (Figure 2A and B). Of note, among 74 patients (over 187, 40%) with data available for MYD88 mutation status, 11 CNS relapses occurred in patients with MYD88 L265P mutation (n = 54, 20%) whereas no relapse were observed in MYD88 WT cohort (n = 20). A trend toward higher risk of CNS relapse for ≥2 extranodal sites (HR, 2.3, 95% CI 0.98-5.3; P=0.06) was observed. Cumulative incidence according to CNS-IPI risk groups (0% in the low-risk, 9% in the intermediate-risk and 14% in the high-risk group) was not statistically significant (P=0.47). CONCLUSION CNS involvement occurs frequently in transformed WM. Rate of CNS relapse seems similar to DLBCL patients belonged to the CNS-IPI high-risk group. Special attention should be paid to patients with kidney/adrenal involvement and MYD88 L265P mutation. Figure 1 Figure 1. Disclosures Vos: Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Travel reimbursement. Treon: X4: Research Funding; Janssen: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos: Janssen: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria. Kapoor: Cellectar: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

TPS3616 Background: METamp is a secondary, or co-driving, genetic change in pts with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant pts with mCRC and METamp, MET inhibition + an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US for NSCLC harboring MET exon 14 skipping. Tepotinib + gefitinib demonstrated improved outcomes in pts with EGFR-mutant METamp NSCLC and acquired EGFR TKI resistance vs chemotherapy (INSIGHT: NCT01982955). In these pts, progression-free survival (PFS) was 16.6 vs 4.2 months (HR = 0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). In pts with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib + anti-EGFR antibody cetuximab may be active and provide an effective therapeutic option. Methods: This Phase II, multicenter, single-arm, open-label study will assess preliminary safety and tolerability, antitumor activity, and explore pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). A safety run-in (6–12 pts) will evaluate the recommended Phase II dose of tepotinib to be used in combination with cetuximab (endpoint: dose-limiting toxicities). Enrollment is based on a confirmed advanced left-sided CRC diagnosis ( RAS/BRAF wild-type), documented previous anti-EGFR therapy and acquired resistance on most recent anti-EGFR antibody and METamp confirmed by liquid and/or tissue biopsy. Pts must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. The study will screen sufficient pts to account for setting-specific heterogenecity in reported METamp incidence. Approximately 42 pts are planned to receive study treatment: ̃22 in Cohort A (second-line, outside US) and 20 in Cohort B (≥third-line, US only). Primary endpoint: investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR), PFS (RECIST 1.1) and OS, tolerability and safety (NCI-CTCAE v5.0), and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab PK profiles, and expression of biomarkers of resistance (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial information: NCT04515394.