Citations

Abstract Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies—often severe and genetically complex—pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research. Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Abstract Systems-based hematology (SBH) is an emerging discipline focused on optimizing care delivery for patients with hematologic disorders within complex health care systems. Despite its growing importance, the field lacks a formal definition, standardized curriculum, and clear career pathway, hindering widespread adoption and training of future SBH experts. We sought to define core principles, competencies, challenges, and future directions of SBH to identify foundational components for a potential educational curriculum. Semistructured interviews were conducted with 8 SBH experts. Expert participants were identified through their committee involvement with the American Society of Hematology. Five overarching themes emerged: (1) The accidental expert: SBH careers have developed organically and reactively in response to pressing institutional needs, not through formal training; (2) Defining the unseen: experts define the field pragmatically by its function and roles; (3) The SBH toolkit: success requires a hybrid skillset combining clinical hematology expertise with health systems science (HSS) principles; (4) The architect's dilemma: the field's growth is hindered by interdependent challenges of building a curriculum, awareness, and securing resources; and (5) Charting the future: the discipline is poised for growth, driven by increasing health care complexity and specialization. SBH represents the nexus of HSS principles and hematology care. Formalizing SBH requires a multipronged approach, including developing a standardized curriculum that equips learners with a hybrid skillset, creating clear value for health systems and patients, and fostering a community of practice through professional societies. These findings provide a foundational framework for developing educational resources and institutional support necessary to continue advancing SBH.

Abstract BACKGROUND Early disease progression within 24 months following chemoimmunotherapy (CIT) is an established adverse prognostic factor for overall survival (OS) in patients (pts) with indolent non-Hodgkin lymphomas. Initially reported in pts with follicular lymphoma, progression of disease (PD) within 24 months in pts with CLL treated with CIT (occurring in ~1-out-of-4 pts) is also associated with inferior OS. The prognostic utility of early event status in pts with CLL treated with targeted therapies is unknown. Recently, we reported worse than expected outcomes with BCL2 inhibitor (BCL2i) treatments in an international cohort of pts with covalent BTK inhibitor (BTKi)-resistant, CIT-naïve CLL. We hypothesize that early disease progression on first-line (1L) targeted agent treatment will identify additional pts with high-risk disease beyond conventional prognostics in the current era. METHODS We identified pts in the Mayo Clinic CLL Database with the following 1L treatments a) BTKi (+/- anti-CD20 monoclonal antibody [CD20mAb]); b) BCL2i + CD20mAb; c) BTKi + BCL2i +/- CD20mAb. PD was defined by a) new or progressive lymphadenopathy or splenomegaly; and/or b) ≥ 50% increase from nadir absolute lymphocyte count (ALC) with persistent (&gt;2 months), and otherwise unexplained ALC ≥ 10x109/L; and/or c) Richter transformation. Logistic regression model evaluated association between clinical factors and POD36 status. OS in pts with PD within 36 months of 1L start (POD36) was evaluated and compared to those without early PD (non-POD36) with analyses: a) starting from time of PD (POD36) and starting from 3 years after 1L initiation (non-POD36); and b) Kaplan-Meier landmark analysis amongst pts alive 3 years post 1L initiation. Cox regression analyses compared a) OS from POD36 by groups and b) OS from 1L treatment with POD36 as a time-dependent covariate. RESULTS A total of 787 pts with CLL initiated 1L targeted therapy (n=538 [68%] BTKi +/- CD20mAb; n=151 [19%] BCL2i + CD20mAb; n=98 [13%] BTKi + BCL2i +/- CD20mAb. The median age at 1L start was 67 years (range 26-92 years), and 67% of pts were male. Among pts with complete CLL-IPI data (n=519), 44% and 15% had high- and very high-risk CLL-IPI risk scores, respectively. Specific pre-1L treatment disease characteristics included TP53 disruption (del17p or TP53 mutation) in 120/639 (19%), del11q in 103/634 (16%), unmutated IGHV in 406/591 (69%), complex karyotype (≥3 clonal structural or numerical abnormalities on karyotype) in 70/273 (26%), and positive CD49d expression in 229/449 (46%). The median pre-treatment beta-2-microglobulin level was 3.3 mcg/mL (range 1.2-24.4 mcg/mL). The median follow-up from 1L start was 50 months (95% CI 46-54 months). 496 pts met criteria for defining POD36 status; 72 (15%) had PD, and 424 did not. TP53 disruption (OR 2.9; 95% CI 1.5-5.7, P=0.001) was associated with POD36 on univariate analysis; complex karyotype, unmutated IGHV status, elevated serum lactate dehydrogenase level, age, sex, and inclusion of CD20mAb were not associated with POD36 status. Median OS from the time of determination of POD36 status was not reached. OS was significantly shorter after POD36 compared to non-POD36 pts (HR 3.5; 95%CI 2.1-6.0, P&lt;0.0001), with 4-year OS estimates of 65% and 88%, respectively. When assessed by landmark analysis at the 3-year timepoint following 1L start (n=50 POD36), OS was also shorter in pts with POD36 compared to non-POD36 pts (HR 3.5; 95%CI 1.8-6.8, P=0.0002). In the overall cohort (n=787), when evaluating OS from 1L treatment with POD36 as a time-dependent covariate, POD36 status was associated with an increased risk of death (HR 4.3; 95% CI 2.6-7.1, P&lt;0.0001) on univariable analysis; and remained an independent marker of shorter OS in multivariable analyses after adjusting for age, sex, TP53 disruption status, and IGHV status (HR 4.2; 95% CI 2.1-8.4, P&lt;0.0001). CONCLUSIONMost pts achieved durable CLL disease control with 1L targeted treatments, and early PD occurs much less frequently than previously reported with CIT. However, among pts who receive 1L targeted therapies for CLL, PD within 36 months is associated with a ~4-fold higher risk of death. These results, if validated in larger data sets, will provide a practical measure for identifying a high-risk subgroup of pts in need of novel treatment strategies in future trials.

Abstract Introduction: Pirtobrutinib, a highly selective non-covalent BTK inhibitor, demonstrated encouraging efficacy in Richter transformation (RT) of chronic lymphocytic leukemia (CLL) in the BRUIN trial (Wierda et al, Lancet Haematology, 2024). However, a control arm was not included in this phase 1/2 trial, and how pirtobrutinib compares to usual care is unknown. To address this gap of knowledge, we sought to compare efficacy outcomes in BRUIN to that in a control cohort consisting of RT patients treated with usual care at Mayo Clinic. Methods: The study was approved by the Mayo Clinic IRB. Patient-level data from BRUIN (n=79; investigator-assessed) were obtained from the study sponsor. Patients with histologically confirmed RT (large B-cell lymphoma) who received at least one line of therapy (n=230) were identified from the Mayo Clinic CLL Database. Multivariable logistic regression was employed to calculate propensity scores for baseline covariates (ie, age at RT treatment line, number of prior lines of CLL treatment [truncated at 3], number of prior lines of RT treatment [truncated at 3], and LDH). For each Mayo patient, propensity scores for each line of RT therapy were calculated, and the line with the highest propensity score was chosen as the index RT treatment line. Using the inverse probability treatment weighting (IPTW) methodology, individual weights were computed, and standardized mean differences (SMDs) were examined for each of the unadjusted and weighted baseline covariates to ensure that balance was obtained between BRUIN cases and Mayo controls. Overall survival (OS; the primary endpoint) and progression-free survival (PFS) were analyzed using unweighted and weighted Cox proportional hazards models. Unweighted and weighted overall response rates (ORRs) and complete response (CR) rates were analyzed using logistic regression. Results: The final analysis dataset contained 79 BRUIN cases (median age 67 [range 26-95], 66% male) and 204 Mayo controls (median age 69 [range 30-89], 74% male). The BRUIN cohort had more patients with ECOG PS ≥1 (61% vs 40%, p=0.001) and elevated LDH (81% vs 63%, p=0.003) than the Mayo cohort. The proportion of patients with TP53 aberration was not statistically different in both cohorts (57% vs. 44%, p=0.15). The index line of RT treatment in the Mayo cohort included chemoimmunotherapy (n=167, 80%) and novel agent-based therapy (eg, cBTKi, venetoclax, PI3Ki, immune checkpoint inhibitor, etc; n=42, 20%). Median lines of prior CLL therapy were 2 (IQR 1-4) vs 1 (IQR 0-3) in the BRUIN and Mayo cohorts, respectively; median lines of prior RT therapy were 2 (IQR 1-2) vs 0 (IQR 0-2). The SMDs of the weighted baseline factors met pre-determined criteria (-0.25≤SMD≤0.25), indicating that balance between the two cohorts was achieved. The median follow-up was 18.3 months (range 0.7-32.9) in the BRUIN cohort and 122.8 months (range 0-280.2) in the Mayo cohort. The unweighted median OS was 12.5 months (95% CI 7.0-20.6) in the BRUIN cohort and 5.7 months (95% CI 3.9-10.7) in the Mayo cohort. The unweighted HR was 0.76 (95% CI 0.54-1.07, p=0.12). After IPTW, the weighted HR was 0.63 (95% CI 0.50-0.78, p&lt;0.001), significantly favoring the BRUIN cohort. The unweighted median PFS was 3.6 months (95% CI 2.8-5.1) in the BRUIN cohort and 3.1 months (95% CI 2.5-4.3) in the Mayo cohort. The unweighted HR was 0.98 (95%CI 0.72-1.34, p=0.92). After IPTW, the weighted HR was 0.78 (95% CI 0.64-0.95, p=0.01), again favoring the BRUIN cohort. Response was evaluable/available in 69 patients in BRUIN and 182 patients in Mayo cohort. The unweighted ORR was 58% vs 53% in BRUIN and Mayo cohorts, respectively (OR=0.83, 95% CI 0.47-1.45, p=0.51), and the CR rate was 16% vs 36% (OR=2.94, 95% CI 1.43-5.88, p=0.003). After IPTW, the weighted OR was 0.65 (95% CI 0.45-0.93, p=0.02) for ORR, favoring the BRUIN cohort, and 1.89 (95%CI 1.23-2.86, p=0.02) for CR rate, favoring the Mayo cohort. Conclusions: This individual patient-level IPTW-based analysis demonstrated that single agent pirtobrutinib is associated with improved OS, PFS, and ORR compared to usual care in patients with RT. These results support the choice of pirtobrutinib over traditional therapies for RT. Although these results are encouraging, the durability of response to pirtobrutinib remains suboptimal. Ongoing trials and other future research will evaluate the efficacy of pirtobrutinib in combination with other treatments in this setting.

Abstract Background: MyeloMATCH is an NCI-sponsored initiative for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) employing a Master Screening and Reassessment Protocol (MSRP) to assign patients (pts) to a pt and disease biology-specific clinical trial. Several trials evaluating initial therapies are currently open, while subsequent trials dedicated to eradicating measurable residual disease during consolidation and including stem cell transplant are being developed. A pt enrolled at diagnosis may be followed longitudinally and be eligible for trials in sequential tiers throughout the treatment course. We report key data concerning the first cohort of pts enrolled on the MSRP. Methods: After pts with suspected AML or MDS consent for the MSRP, blood and marrow are sent to the myeloMATCH Molecular Diagnostics Network (MDNet) of central CLIA labs operating under a single Investigational Device Exemption to rapidly define molecular, cytogenetic, and immunophenotypic characteristics. These data are catalogued by a bioinformatics team (MATCHBox) and reviewed daily to assign participants to an available trial based on pt and disease features. A Tier Advancement Pathway (TAP) allows standard of care therapy with potential for assignment to subsequent myeloMATCH trials. Since activation in May 2024, 550 patients age≥18 were enrolled on the MSRP from 76 institutions: 48 Academic, 14 NCORP, 11 community, 3 VA. There are currently 4 open randomized AML trials (≥age 60 or unfit with mutant FLT3, ≥age 60 IDH2 mutant AML, fit age&lt;60 ELN 2017 intermediate-risk AML, fit age&lt;60 ELN 2017 adverse risk) and 1 MDS trial(IDH2 mutant). Patients not eligible for an open protocol were assigned to TAP. Results: Of the 550 pts consented, 491 completed screening assays; 49 had no or incomplete samples; 10 withdrew before completed analysis. Median cytogenetic turnaround time (TAT) was 69 hours (91% within 72 hours), and median Next Generation Sequencing (NGS) TAT from receipt was 49 hours (95% within 72 hours). Seventy-six pts (of 491 with assay data) were not assigned due to non-AML or non-MDS diagnoses, the most common being: B-ALL [n=11], MPN [9], benign marrow [9], APML [7], and MPAL [6]. The AML/MDS verified cohort was 415 pts, 366 (89.2%) patients with AML (45% age &lt;60) and 49 (11.8%) with MDS. The median age at screening was 63 years (range:18-95) and 186 (45%) were female. Eighty-two percent identified as White, 7.5% Black, 3% Asian, 7% unknown, and 9% as Hispanic. The most frequent mutations in the AML pts were NPM1 (24.0%), DNMT3A (22.7%), TET2 (19.9%), NRAS (18.0%), FLT3 (18.0% ITD, TKD 7.1%), TP53 (14.5%), and CEBPA (8.7%); IDH1/2 mutation rates were 8.2% and 13.7%, respectively. Co-mutations include FLT3/NPM1 (9.8%), NPM1/IDH2 (4.4%), IDH1/2 and any RAS (3.8%). Karyotypes were normal in 40.4%, complex 20.8%, inv(16) 6.0%, MLL/KMT2A 4.6% and t(8;21) 1.9%. 29% had favorable risk disease, 29% intermediate, and 42% adverse (ELN 2017). In MDS, mutations included: TP53 (36.7%), RUNX1 (20.4%) ASXL1 (20.4%), TET2 (18.4%), spliceosome mutations (SRSF2, SF3B1, U2AF1 and ZRSR2, 28.6%) andIDH1/2 in 4.1% and 6.1%, respectively. Karyotypes were normal in 24.5%; complex in 40.8%. By IPSS-R, 2.4% were low, 73.8% intermediate, 2.4% high, and 21.4% very high risk. 82/415 (20%) pts were assigned to initial therapy protocol, with an increase in assignment rate to 44% in the most recent two months. 71/415 pts (16%) were enrolled in one of the MyeloMATCH studies. Three-hundred forty-four pts (80%) were assigned and enrolled to TAP (296 AML, 48 MDS) for potential assignment to subsequent tier trials. In the TAP AML pts, 99 (33%) have completed initial treatment, including intensive chemotherapy (IC) in 62% of pts and hypomethylating agents/venetoclax (HMA/VEN) in 38%. In pts &lt;60 years of age, 87% received IC v. 13% with HMA/VEN, in &gt;60 34% IC v. 66% HMA/VEN and in age 60-75 42% IC v. 58% HMA/Ven. Conclusion: MyeloMATCH has screened over 500 pts from academic and community sites in the US and Canada in 14 months, meeting the TAT goal of sample acquisition to results of &lt;72 hours. Assignment to treatment protocols has substantially increased recently. As additional trials open (12 in development) we expect the percentage of pts enrolled on MSRP who go on to therapeutic trials will markedly increase, thereby allowing a personalized medicine approach for a broad group of US and Canadian adult pts with AML and MDS.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL), a precursor to chronic lymphocytic leukemia (CLL), is an understudied yet common premalignant condition present in ~8 million adults in the United States. Based on flow cytometry, MBL can be classified into two immunophenotypes: CLL-type (CD5, CD23, and CD20 co-expression) and non-CLL-type (CD5-negative). While the majority of the data to date pertains to CLL-type MBL, the available evidence indicates non-CLL-type MBL is also associated with an increased risk of hematologic malignancies. Clonal hematopoiesis of indeterminate potential (CHIP) is another precursor condition associated with hematologic malignancies. The relationship between non-CLL-type MBL and CHIP and their combined effect remains unknown. Herein, we report findings on these two precursor conditions in the largest screening cohort to date. Methods: Using flow cytometry, we screened for MBL in the Mayo Clinic Biobank participants who were 40 years or older with no prior history of hematologic cancers. Using whole-exome sequencing of whole-blood DNA, CHIP was screened on 291 genes related to myeloid (56 genes) or lymphoid malignancies (235 genes). Incident hematologic malignancies were detected during follow-up using International Classification of Diseases (ICD) codes in the medical record. All diagnoses were manually reviewed for confirmation. Multivariable logistic regression was used to evaluate the association between non-CLL-type MBL and CHIP. Time to incident hematologic malignancy was calculated from date of MBL screening to the earliest date of incident malignancy, withdrawal, death, last medical visit, or study end. Overall survival (OS) was calculated from date of MBL screening to date of death or last known alive. Multivariable Cox regression, adjusted for age, sex and residency, was used to investigate associations between non-CLL-type MBL and CHIP with clinical outcomes; with results reported using hazard ratios (HR) and 95% confidence intervals (CI). Results: In total, 8,802 individuals with MBL screening and CHIP data were analyzed. Non-CLL-type MBL was detected in 249 (2.8%) individuals; 121 (49%) were male, and median age was 78 years (range, 47-95). We identified 757 (8.6%) individuals with CHIP in at least one of the 291 genes tested. The most frequently mutated CHIP genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. A total of 47 (0.5%) individuals had both non-CLL-type MBL and CHIP; the four genes with the highest number of CHIP variants in these individuals were DNMT3A (n=16), TET2 (n=10), ASXL1 (n=3), and ATM (n=3). An association between non-CLL-type MBL and any CHIP (OR=1.6, 95%CI:1.2-2.3, P=0.006) was observed. When analyzing CHIP in genes related to myeloid malignancies, the association with non-CLL-type MBL was also significant (OR=1.6, 95%CI:1.1-2.3, P=0.012); however, the association was not statistically significant for genes related to lymphoid malignancies (OR=1.6, 95%CI:0.8-3.3, P=0.165). With a median follow-up of 5.4 years, 104 individuals developed incident hematologic malignancies (66 lymphoid and 38 myeloid malignancies). Non-CLL-type MBL (HR=3.5, 95%CI:1.9-6.5, P&lt;0.001) and CHIP (HR=3.2, 95%CI:2.1-5.1, P&lt;0.001) were each associated with increased risk of incident hematologic malignancies. Co-existence of both precursor conditions was associated with a substantially higher risk of incident hematologic malignancies (HR=10.3, 95%CI:4.0-26.2, P&lt;0.001) compared to individuals with neither precursor condition. Among individuals with non-CLL-like MBL, any CHIP was a borderline significant predictor for incident hematologic malignancy (HR=3.6, 95%CI:1.0-12.9, P=0.049). Compared to individuals with no precursor conditions, OS was not significantly different in those with non-CLL-type MBL-only (HR=1.1, 95%CI:0.8-1.5, P=0.40), those with CHIP-only (HR=1.2, 95%CI:0.99-1.4, P=0.06), or those with both CHIP and non-CLL-type MBL (HR=1.3, 95%CI:0.8-2.1, P=0.39). Conclusions: In the largest screening cohort to date evaluating the relationship of CHIP and non-CLL-type MBL, we found that non-CLL-type MBL and CHIP are associated with each other. Individuals with non-CLL-type MBL were more likely to have CHIP variants in DNMT3A, TET2, ASXL1, and ATM. Among individuals with non-CLL-type MBL, the presence of any CHIP was associated with increased risk of developing hematologic malignancy.

Abstract Background: The synergistic mechanisms of BCL-2 inhibitors and CD20-directed antibodies in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) often lead to deep and durable responses. Although the use of venetoclax-obinutuzumab (Ven-O) in the frontline setting (1L) for CLL/SLL has led to a paradigm shift in the disease management, there are limited data on its efficacy in the relapsed/refractory (R/R) setting. In this study, we evaluated the efficacy and safety of Ven-O in both 1L and R/R CLL among patients treated outside the context of clinical trials at our institution. Methods We used the Mayo Clinic CLL Database to identify patients with CLL who were treated with Ven-O, both in 1L and R/R settings. Patients seen at Mayo Clinic Rochester between 2017 and 2025 were included. Overall survival (OS) was calculated from date of Ven-O initiation until last known alive date. Event-free survival (EFS) was calculated from date of Ven-O initiation until the next line of treatment or last known alive date. Kaplan-Meier methods estimated EFS and OS rates at 1, 3, and 5 years. Cox proportional hazards models were used to explore the association between baseline factors and EFS and OS; results are reported as hazard ratios (HR) and 95% confidence intervals (95%CI). Finally, we compared the OS to the age- and sex-matched general population of the state of Minnesota. Results A total of 154 patients (91 1L, 63 R/R) were included in the study. The median age was 68 years (69 1L, 68 R/R), and 68% were male (64% 1L, 73% R/R). Overall, TP53 disruptions (either del17p by FISH or TP53 mutation) were noted in 22 (15%) patients (9% 1L, 23% R/R). CLL FISH findings demonstrated del11q in 24 (19%) patients (19% 1L, 18% R/R), del13q in 46 (36%) patients (36% 1L, 36% R/R), and trisomy 12 in 21 (16%) patients (16% 1L, 18% R/R). IGHV genes were unmutated in 95 (68%) patients (60% 1L, 80% R/R). The CLL-IPI risk score was high in 54 (51%) patients (51% 1L, 53% R/R) and very-high in 18 (17%) patients (8% 1L, 34% R/R). A total of 121 (89%) patients completed planned treatment (1 year of venetoclax in 73 [90%] 1L and 2 years of venetoclax in 48 [87%] R/R). Median follow-up for the entire cohort was 1.8 years (2.2 1L, 1.5 R/R). Neither median EFS nor OS was reached for the overall cohort or within the 1L and R/R subgroups. The 1, 3, and 5-year EFS estimates for the overall cohort were 91% (86-96%), 85% (78-92%), and 67% (51-89%), respectively; corresponding EFS values for the 1L subgroup were 95% (91-100%), 89% (82-98%), and 67% (47-95%), respectively; and for the R/R subgroup were 85% (76-95%), 77% (65-92%), and 77% (65-92%), respectively. The 1, 3, and 5-year OS estimates were 98% (95-100%), 95% (91-99%), and 88% (76%-100%), respectively; corresponding OS values for the 1L subgroup were 99% (96-100%), 97% (94-100%), and 97% (94-100%) and for the R/R subgroup were 96% (91-100%), 91% (82-100%), and 61% (27-100%), respectively. Univariable analyses showed that TP53 disruption was associated with shorter EFS (HR 3.8, 95%CI 1.4-10.2, p=0.01), although IGHV mutation status was not associated with shorter EFS. A higher level of serum beta-2 microglobulin (HR 1.27, 95%CI 1.01-1.59, p=0.04) and R/R status (HR 4.9, 95%CI 0.9-25.8, p=0.06) were associated with a shorter OS. Interestingly, TP53 mutation status and IGHV mutation status were not associated with inferior OS. There was no difference in the observed and expected OS for both the 1L (p-0.23) and R/R (p=0.14) Ven-O treated cohorts compared to the age- and sex-matched general population of the state of Minnesota. Conclusions Our study shows that Ven-O is a well-tolerated regimen with demonstration of durable treatment responses both in the 1L and R/R groups, when used outside the context of a clinical trial. To the best of our knowledge, these data for the first time demonstrate no difference in OS of patients treated with Ven-O compared to age- and sex-matched general population, in both the 1L and R/R settings.

Abstract Somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis) are known to alter the immune milieu and can result in autoimmune disorders including VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome. There are currently no curative strategies for CH-linked autoimmune disorders besides allogenic hematopoietic stem cell transplantation. Recent work has shown a high prevalence of autoimmune syndromes among patients with IDH1/2 mutant myeloid neoplasms (MN). We thus hypothesized that IDH1/2-mutant CH might drive a subset of autoimmune disorders. To further characterize a possible association between IDH-mutant CH and autoimmune disease, we used data from two observational cohort studies, the UK Biobank (N=454,218) and All of Us (N=414,830). We observed 264 individuals with IDH1/2-mutant CH. IDH1/2 CH was associated with autoimmune disease (OR=1.8, p=4e-3), and, when compared to other CH genes with at least 100 carriers, showed the strongest effect size. When comparing autoimmune subtypes, we observed significant associations with polymyalgia rheumatica (OR=4.0, p=1e-3) and giant cell arteritis (OR=8.1, p=1e-6). IDH1/2 CH carriers had elevated CRP levels compared to other CH-carriers (p=1e-2) and non-carriers (p=8e-3). IDH1/2 CH was associated with lower neutrophil counts and higher monocyte counts. While most (68%) had blood counts outside the normal range, only a minority (11%) had severe cytopenias that met criteria for CCUS. Since IDH1/2 CH is associated with both autoimmune disease and blood count abnormalities, we sought to define the frequency, clinical presentation, and outcomes of IDH1/2-associated autoimmune disease among individuals with bone marrow biopsy confirmed CCUS. We used data from three CCUS cohorts: first, a multi-institutional cohort of CCUS patients with systemic autoinflammatory disease (SAID) who were UBA1-negative, second, a hospital-based cohort at Mayo Clinic, and third, a cohort of IDH1 carriers enrolled on a phase II clinical trial of ivosidenib (NCT05030441). Within 193 SAID patients who were free of myeloid neoplasm at the time of recruitment, IDH1/2 pathogenic variants were the most observed CH driver, occurring in 2% of individuals. These individuals (N=4) all had recurrent fevers and dermatologic manifestations, requiring chronic glucocorticoid treatment with 75% having inflammatory arthritis requiring multiple Disease-Modifying Antirheumatic Drugs (range 1-7, median=5). Within the Mayo Clinic cohort, 275 patients with CCUS were serially ascertained. Among those 8 (2.9%) were IDH1-mutant of whom 50% had autoimmune disease (three with seronegative rheumatoid arthritis and one with Sweet syndrome). At last follow up (median 16 months), 2 (25%) of 8 patients had progressed to MN. Within our open-label decentralized trial of ivosidenib (IDH1 inhibitor) in CCUS, we enrolled 20 patients, of whom 5 (25%) had a diverse array of pre-existing autoimmune disorders, including two cases of seronegative rheumatoid arthritis and one case each of Sweet syndrome, polymyalgia rheumatica, and Sjögren's syndrome. Underlying the clinical presentation of all five cases was episodic joint pain, with half also experiencing episodic dermatologic manifestations. The majority (58%, 11/19) of the IDH1mt-CCUS patients had an elevated hsCRP (&gt;=5; range 6.91–46.2) including all four with co-occurring autoimmune disorders (range 7.97–46.2). Out of the 20 enrolled patients, 17 received at least 8 weeks of therapy, of which 9 had elevated hsCRP at baseline. Most of these (7/9) had normalization of hsCRP (falling below 5 mg/L) while on treatment (median time to hsCRP normalization of 58 days). Among the four patients with autoimmune disease, all had subjective improvement in their autoimmune symptoms following treatment with ivosidenib. In conclusion, we show that IDH1/2 CH is associated with autoimmune disorders and is particularly enriched among IDH1/2 CH carriers with co-occurring cytopenias. IDH1/2-associated autoimmune disease can range from classic rheumatic conditions such as rheumatoid arthritis to more severe VEXAS like presentations. IDH inhibition demonstrates efficacy for improving inflammatory manifestations within an ongoing clinical trial. Together these results nominate IDH mutant CH as a driver of autoimmune diseases with therapeutic implications.