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Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P< .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

Abstract Background Several BsAbs with different treatment (Tx) approaches have been approved by the FDA for Tx of lymphoma, including: fixed-duration and less frequently dosed mosunetuzumab (mosun) and glofitamab (glofit) (Option 1 Tx approach); and treat to progression and more frequently dosed epcoritamab (epcor) (Option 2 Tx approach). Differences in Tx approaches have implications for time spent receiving care, known as “time toxicity”. We previously reported that mosun and glofit were associated with about 2 weeks lower time toxicity vs epcor over the first year in R/R FL and DLBCL, based on registrational trial protocols (Torka et al. Blood 2024; Ma et al. Value in Health 2025). In this study, we assessed time toxicity from the perspective of patients (pts) receiving BsAbs for R/R FL or DLBCL. Methods An online survey was conducted aiming for input from 120 pts with R/R FL or DLBCL, who have received BsAb for ≥1 month in the US. Time toxicity was measured by pts recalling time spent on healthcare contacts related to BsAb Tx, cancer management, and any other reasons in the past 30 days. Pts' preferences were assessed through direct elicitation of choice between 2 hypothetical Tx profiles with different Tx approaches and time toxicity, assuming the same efficacy and safety. The survey was pre-tested and refined based on input from 3 BsAb pts with R/R DLBCL to ensure relevance and comprehension. Descriptive analyses were performed on pts characteristics, mean and standard deviation (SD) of time spent per pt per month, and the proportion of pts preferring the convenience of different Tx profiles. Results At this interim analysis, 101 pts receiving BsAbs responded to the survey: 48 pts with R/R FL (mosun n=28; epcor n=20) and 53 pts with R/R DLBCL (glofit n=32; epcor n=21). Most pts with R/R FL lived in urban/suburban areas (87.5% vs 12.5% in rural areas) and had a shorter one-way travel time to receive care vs pts in rural areas (mean±SD: 28.2±13.5 vs 60.3±30.2 minutes). The median age was 58 years for both mosun and epcor. Mean±SD Tx duration was 6.2±1.8 months for mosun vs 4.5±1.3 months for epcor. In the past 30 days, pts on mosun had fewer BsAb Tx visits vs epcor (mean±SD: 1.0±0.2 vs 2.0±1.2), and fewer all-cause healthcare contacts vs epcor (mean±SD: 1.7±0.8 vs 3.5±2.0). The mean±SD time spent per BsAb Tx visit was 5.0±1.4 hours for mosun vs 3.8±1.8 hours for epcor. Less time was spent per pt per month on recovery at home after Tx visit for mosun vs epcor (22.7±16.5 vs 43.2±47.6 hours). Less time was spent per pt per month on Tx and cancer management for mosun vs epcor (mean±SD: 30.5±16.9 vs 56.9±59.3 hours). Most pts with R/R DLBCL lived in urban/suburban areas (88.7% vs 11.5% in rural areas) and had a shorter one-way travel time to receive care vs pts in rural areas (mean±SD: 31.4±14.1 vs 103.3±19.4 minutes). The median age was 67 years for glofit and 66 years for epcor. The mean±SD Tx duration was 6.1±2.0 months for glofit vs 5.9±1.8 months for epcor. In the last 30 days, pts on glofit had fewer BsAb Tx visits vs epcor (mean±SD: 1.1±0.2 vs 1.7±0.5), and fewer all-cause healthcare contacts vs epcor (mean±SD: 2.2±1.3 vs 3.0±1.1). Irrespective of the route of administration, the time spent per BsAb Tx visit was similar (mean±SD: 5.1±1.6 hours for mosun; 5.6±1.2 hours for epcor). Less time was spent per pt per month on recovery at home after Tx visit for glofit vs epcor (mean±SD: 34.3±23.8 vs 69.3±39.4 hours). Less time was spent per pt per month on Tx visits and cancer management for glofit vs epcor (mean±SD: 43.0±25.9 vs 85.0±44.2 hours). Regardless of which BsAb pts received, most pts (93%) preferred the convenience of Option 1 Tx approach with less time required over Option 2 Tx approach with more time required. Conclusions This is the first study to directly measure pt-reported time toxicity from pts with R/R FL and DLBCL receiving BsAbs in a real-world setting. Fixed-duration less frequently dosed mosun and glofit (Option 1 Tx approach) had less pt-reported time toxicity, with less healthcare contact and less time spent per pt per month vs treat to progression more frequently dosed epcor (Option 2 Tx approach). Over 90% of pts preferred the convenience of a fixed-duration, less frequently dosed, and less time required Tx option, suggesting that time toxicity is a significant factor in shared Tx decision-making for pts with R/R FL and DLBCL. Analysis is ongoing to comprehensively measure pt-reported time toxicity.

Abstract Introduction Bruton tyrosine kinase inhibitors (BTKis) have changed the treatment algorithm for patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Efficacy was demonstrated for zanubrutinib and ibrutinib in high-risk R/R CLL patients in the ALPINE (NCT03734016) trial, for ibrutinib and acalabrutinib in the ELEVATE-RR (NCT02477696) trial, and for acalabrutinib in the ASCEND (NCT00135226) trial. While there is limited head-to-head comparative trial data of all covalent BTKis in the treatment of high-risk R/R CLL, a previously published network meta-analysis (NMA) used data from the ALPINE, ELEVATE-RR, and ASCEND trials, and reported that zanubrutinib demonstrated significantly improved relative efficacy compared to ibrutinib and acalabrutinib in high-risk R/R CLL (Shadman 2025). Within this NMA, high-risk R/R CLL populations were defined based on the prespecified definitions within each trial, including patients with del(17p) and/or TP53 mutations in the ALPINE and ASCEND trials, and del(17p)/del(11q) in the ELEVATE-RR trial. This study aimed to compare zanubrutinib versus ibrutinib and acalabrutinib in high-risk R/R CLL by calculating the number needed to treat (NNT) to avoid one progression or death. Methods A model was developed to evaluate the NNT among high-risk R/R CLL patients to avoid a progression or death. Progression free survival (PFS) data for zanubrutinib in high-risk patients were extracted from the ALPINE trial. PFS values for ibrutinib and acalabrutinib were derived from the previously published NMA study. PFS for ibrutinib and acalabrutinib were calculated by applying PFS hazard ratio from the NMA results to the zanubrutinib PFS value for the high-risk population in the ALPINE trial. 24-month PFS (72.6% for zanubrutinib, 52.0% for ibrutinib, and 55.9% for acalabrutinib) were used for the base case analysis of the model. Sensitivity analyses were conducted to examine the impact of alternative PFS inputs for ibrutinib, derived directly from the high-risk populations in ALPINE trial (unadjusted). Results The base case results from the NNT model indicate that for the treatment of patients with high-risk R/R CLL over 24-months, every five patients treated with zanubrutinib instead of ibrutinib results in the avoidance of one disease progression or death and every six patients treated with zanubrutinib instead of acalabrutinib results in the avoidance of one disease progression or death. Applying the model result to a hypothetical scenario of 100 patients with high-risk R/R CLL treated with zanubrutinib versus ibrutinib for two years finds approximately 20 patients will avoid disease progression events or deaths. Treating the same population with zanubrutinib versus acalabrutinib for two years will result in the avoidance of 17 disease progression events or death. Sensitivity analysis showed consistent NNT results.Conclusions The NNT analysis suggests that among high-risk R/R CLL patients, zanubrutinib is associated with more favorable clinical outcomes compared to ibrutinib and acalabrutinib. Over 24 months, zanubrutinib demonstrated a NNT of five to prevent one disease progression or death compared to ibrutinib, and an NNT of six compared to acalabrutinib, in high-risk R/R CLL patients. Study findings should be interpreted based on modeling assumptions and potential patient population differences across trials.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Introduction: Epcoritamab (epcor) was the first CD3xCD20 bispecific antibody approved for treatment of R/R DLBCL in May 2023 based on its efficacy and safety in EPCORE NHL-1. Patients (pts) enrolled in clinical trials are highly selected, and those with high-risk features, such as primary refractory disease, early post-CAR T relapse, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and CD20+ status are often underrepresented or excluded. As epcor use expands in more heterogeneous, real-world populations, there is increasing interest in understanding pt characteristics and response outcomes associated with its use outside of clinical trials. In particular, pts with DLBCL that is resistant to, or relapse soon after, CAR T are left with limited treatment options and often present with rapidly progressive, resistant disease, making them especially challenging to manage. Generating real-world evidence is critical for informing optimal use of epcor in routine practice. Methods: Real-EPCOR is a multicenter US retrospective chart review study at >8 academic and community oncology centers designed to evaluate the real-world use of epcor. Eligible pts are adults (≥18 years) with R/R DLBCL and ≥2 prior lines of therapy (LOT) who initiated epcor outside of a clinical trial after 5/19/23. Pt demographic, clinical, and treatment data were collected, including ECOG PS, refractory status, prior CAR T, and CD20+ status. Overall response rate (ORR) was evaluated during epcor treatment and defined as the proportion of pts achieving complete response (CR) or partial response among pts with ≥1 evaluable response assessment or who died due to disease progression before response assessment. ORR and CR rate were calculated for the entire cohort, for pts receiving ≥2 cycles of epcor (full cycle is 28 days), and for pts who received prior CAR T. Results: This interim analysis included 34 pts from 2 centers. Data collection and analysis is ongoing and updated results with additional pts and longer follow-up may be included at time of presentation. Median age was 67 years; 68% pts were male and 85% were White. Median time from DLBCL diagnosis to initiation of epcor was 15.5 months. The most common comorbidities were cardiovascular disease (59%) and diabetes mellitus (29%). ECOG PS was ≥2 in 29% of pts, and 85% of pts had Ann Arbor stage 3-4 disease. Nearly all (97%) had CD20+ DLBCL. High-risk features were common at time of epcor initiation, including 53% with International Prognostic Index (IPI) ≥3, 26% with double-hit, and 24% with non-GCB subtype. Among pts who received ≥2 cycles of epcor (n=15), 20% had ECOG PS ≥2 and 33% had IPI ≥3; in post-CAR T pts, 22% had ECOG PS ≥2 and 57% had IPI ≥3. Median number of prior LOT was 3 (range: 2–9); 44% of pts initiated epcor as 3L therapy. Prior to epcor, 41% had primary refractory disease. Following their most recent therapy, 72% had refractory disease, and 43% had DLBCL that was refractory to all prior LOT in those with known refractory status. Most pts (68%) received prior CAR T, with a median interval of 4.6 months from infusion to epcor initiation, and 23% initiated epcor ≤2 months from CAR T. 15 pts (44%) received CAR T in the LOT immediately prior to epcor, 9 (60%) of whom were refractory to CAR T. The ORR was 50% and CR rate was 29% in the overall evaluable population (n=24). 10 pts were not evaluable, as they did not undergo a response assessment either because they remained alive without assessment or experienced a non-progression-related event. Among pts who received ≥2 cycles of epcor, ORR was 85% and CR rate was 54% in the evaluable population (n=13). Among 23 post-CAR T pts, ORR was 53% and CR rate was 33% in the evaluable population (n=15). Conclusion: In this real-world interim analysis, pts with R/R DLBCL treated with epcor had a high proportion of CD20+ disease, higher-risk clinical features, greater comorbidity burden, and more complex treatment histories, including a substantial proportion with prior CAR T, compared to pts in EPCORE NHL-1. Therefore, the ORR remains highly meaningful in the overall cohort despite being lower than the trial. Encouraging ORRs among those who received ≥2 cycles of epcor or had prior CAR T suggest that epcor monotherapy may provide clinical benefit even in difficult-to-treat pts in the real-world setting. Ongoing real-world survival analyses will inform the optimal use of epcor within the evolving treatment landscape of R/R DLBCL.

Abstract Background: Mosunetuzumab, a CD20xCD3 bispecific antibody, can be administered in the outpatient setting for a fixed duration. Mosunetuzumab by intravenous (IV) administration is FDA- and EMA-approved in relapsed/refractory (R/R) FL after ≥2 prior lines of therapy. Interim results from the Phase II MorningSun study (NCT05207670) demonstrated promising efficacy and manageable safety of mosunetuzumab SC in pts with previously untreated HTB FL (Flinn et al. ASCO 2025). We report 12-month follow-up efficacy and safety data of mosunetuzumab SC in pts with previously untreated HTB FL in the MorningSun study, including pts who received optional maintenance therapy. Methods: Pts with previously untreated HTB FL, per Groupe D'Etude des Lymphomes Folliculaires criteria, and Eastern Cooperative Oncology Group performance status of 0–2 were enrolled, primarily from United States (US) community sites. Mosunetuzumab SC was administered as step-up dosing in Cycle (C)1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg) followed by 45mg on D1 of each 21-day cycle, for up to 17 cycles (1 year). Pts with a partial or complete metabolic response (CMR) after C17 could receive optional mosunetuzumab maintenance treatment (45mg every 8 weeks for up to 1 year). The primary endpoint was progression-free survival (PFS) rate at 1 year. Key secondary endpoints included objective response rate (ORR), duration of response (DOR), duration of complete response (DOCR) and safety. Exploratory analysis of ctDNA levels was performed using the AOA-NHL assay. Results: As of February 10, 2025, 103 pts were enrolled (n=82 pts from community sites, n=21 pts from academic sites). Overall, the median age was 65 years (range: 24–86), 51.5% of pts were female and most pts had Ann Arbor stage III/IV disease (91.3%) and a FLIPI score ≥2 (78.6%). In total, 69 pts completed initial treatment (17 cycles), 33 discontinued (primarily due to progressive disease [PD; n=18] and adverse events [AEs; n=5]), and 1 pt was continuing treatment. After 17 cycles, 68 pts were eligible for maintenance treatment, of whom 46 received maintenance, and 15 were continuing maintenance treatment at the time of data cut-off. Median duration of follow-up was 22.3 months (95% confidence interval [CI]: 20.9–24.1). The 12-month PFS rate was 85.5% (95% CI: 76.2–91.3). The ORR was 87.4% (95% CI: 79.4–93.1); 64.1% of pts had a CMR. The 12-month OS rate was 91.9% (95% CI: 84.5–95.9); the 12-month DOR and DOCR rates were 89.6% (95% CI: 80.2–94.7) and 91.1% (95% CI: 79.4–96.2), respectively. Of the 46 pts who received maintenance, no pts experienced PD, and 1 pt died (reason unknown). Of the 22 pts who were eligible but did not receive maintenance, 1 pt had PD. The most common AEs (≥30%) were injection-site reaction (67.0%), fatigue (44.7%), cytokine release syndrome ([CRS] 34.0%), headache (32.0%), and nausea (32.0%). Grade (Gr) ≥3 AEs and serious AEs were reported in 47.6% and 35.9% of pts, respectively. Five pts experienced Gr 5 AEs: COVID-19 pneumonia (n=2) and cardiogenic shock, unexplained death, pneumonia (n=1 each). Infections occurred in 77.7% of pts and were predominantly Gr 1/2 (Gr 1: 10.7%; Gr 2: 47.6%; Gr 3: 12.6%; Gr 4: 3.9%), with the most common infection being COVID-19 (24.3%). Of 3 (2.9%) Gr 5 infections reported, 1 occurred during initial treatment (COVID-19), 1 during maintenance (pneumonia), and 1 occurred 2.8 months after completion of treatment (COVID-19). AEs were reported in 80.4% of pts in the maintenance phase, mostly Gr 1/2 events. No CRS events occurred during maintenance treatment. Infections were reported in 45.7% of pts during maintenance, with the majority being Gr 1/2 events (37.0%), and were similar types of infection as during initial therapy. ctDNA levels were assessed in a subset of pts who achieved a CMR; 86.4% (19/22) of pts were minimal residual disease (MRD) negative (p-value cut-off 0.005).Conclusions: Longer follow-up of mosunetuzumab SC with optional maintenance treatment continues to demonstrate promising PFS and OS rates, and a manageable safety profile in pts with previously untreated HTB FL. Exploratory analysis of ctDNA in a subset of CMR pts showed MRD negativity in 86.4%, thus supporting fixed treatment duration of mosunetuzumab SC. Overall, these data support the outpatient administration of mosunetuzumab SC in US community practices and further evaluation of mosunetuzumab-based treatment in first-line HTB FL.

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 (>=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.

Abstract Introduction: CLL disease control and survival outcomes have improved since the introduction of Bruton tyrosine kinase inhibitors (BTKis). Since CLL often requires treatments, understanding patient preferences is critical in optimizing adherence and overall satisfaction. However, there are limited published data on how Korean patients prioritize treatment efficacy, safety and the convenience of administration. To address this gap, a discrete choice experiment (DCE) methodology was applied in a comprehensive quantitative analysis to evaluate patient preferences for BTKi treatment attributes among patients with CLL in Korea. Methods: Adult patients (≥18 years of age) with a confirmed diagnosis of CLL in Korea were recruited by The Korea Blood Disease & Cancer Association to participate in an online DCE survey questionnaire from April 30, 2025 to May 22, 2025. Treatment attributes and levels were identified based on published literature and clinical inputs. Efficacy attributes included progression-free survival (PFS); safety attributes included impacts of adverse events (AEs), including diarrhea, headache, atrial fibrillation and hypertension, on quality of life (QoL); convenience attributes included formulation type (including tablet or capsule) and dosing frequency (including once daily or twice daily). Preference data was analyzed using a conditional logistic regression. Relative importance of BTKi treatment attributes were calculated to measure the importance of each attribute in treatment decision-making. Additionally, subgroup analyses were conducted among patients aged <60 years and ≥60 years, those who received 2 or more lines (2L+) of treatments, and those who experienced AEs from CLL treatment. Results: A total of 57 patients completed the survey. The mean age was 61 years, with 46% aged <60 years and 54% aged ≥60 years. Female patients comprise 35% of the sample. Around 33% had a high school education or less, and 23% were employed full-time. More than half (54%) reported no comorbid conditions, and 70% were diagnosed ≥5 years ago (26% diagnosed 1 to <5 years ago; 4% diagnosed less than a year ago). In terms of treatment experience, 11% were treatment naive, while 89% received ≥1 treatment (61% first-line, 21% second-line and 7% third-line or later). In the context of CLL treatment preferences, patients showed a significant preference (P < .05) for therapies that minimized the impact of AEs on QoL, offered longer PFS, and required less frequent dosing. Formulation type did not have a statistically significant impact on treatment choice. Overall, patients placed greater importance on how treatment-related attributes affect their QoL and dosing frequency. The highest-ranked factors were the impact of headache (22%) and diarrhea (21%) on QoL, followed by dosing frequency (19%), the impact of atrial fibrillation (16%) and hypertension (14%) on QoL, PFS (7%), and formulation type (0.6%). Results from the subgroup analyses were generally consistent with the full sample analysis, with impacts of AEs on QoL being the most important factors for treatment decision-making, especially among older patients, although the relative ranking of impacts of AEs varied by age groups and treatment experience. Regarding efficacy, younger patients (<60 years of age) valued PFS slightly more than older patients (≥60 years of age), ranking it 4th and 6th out of the 10 attributes, respectively. Additionally, preference on dosing frequency was more important for 2L+ patients, reflecting the treatment burden experienced from previous regimens. Conclusions: This study provides valuable insights into the treatment preferences of Korean patients with CLL, highlighting the importance of QoL considerations for treatment decision-making. Among the evaluated attributes, patients placed the greatest weight on minimizing the impacts of AEs, particularly headache and diarrhea, on daily functioning, followed by dosing frequency. These preferences underscore the need for patient-centered care that prioritizes not only clinical efficacy but also tolerability and convenience. These insights can inform shared decision-making and support the development of personalized treatment strategies that better align with patient needs and expectations in Korea.

Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment landscape for CLL, offering significant improvement in patient outcomes. Despite the widespread adoption of BTKis and their proven clinical benefits, data on the treatment preferences and priorities of patients with CLL in Asia, particularly in Japan, are limited. Understanding patient preference is critical for optimizing clinical decision-making and tailoring treatment strategies for Japanese patients. A comprehensive quantitative analysis was conducted to evaluate patient preferences for covalent BTKi treatment attributes and trade-offs among these attributes. Methods: An online survey applying discrete choice experiment (DCE) methodology was administered between April 29 and June 30, 2025 to Japanese adults (≥18 years of year) diagnosed with CLL. The design of DCE attributes and levels was informed by literature review and clinical consultations. Treatment attributes included efficacy (i.e., progression-free survival [PFS]), safety (i.e., impacts of diarrhea, headache, atrial fibrillation, and hypertension on quality of life [QoL]), and convenience (i.e., formulation type including tablet or capsule, and dosing frequency including once daily or twice daily). A conditional logistic regression was applied to estimate preference weights, which were used to calculate the relative importance as well as willingness-to-tradeoff between BTKi treatment attributes. Results: The study included 50 patients (mean age: 62 years; 30% female; 38% employed full-time; 60% reported no comorbid conditions). More than half (60%) were diagnosed ≥5 years ago. Around one quarter (24%) were treatment naive, and 76% received ≥1 treatment (40% first-line, 26% second-line and 10% third-line or later). Most patients (82%) reported living with or near their caregiver. In terms of travel time to obtain CLL medication, 46% reported travel time of one hour, 40% traveled less than 30 minutes, and 14% traveled more than two hours. The majority of patients (66%) were using High-Cost Medical Expense Benefit, while an additional 10% were either currently applying or planning to apply. In general, patients preferred treatments with less impact of AEs on QoL, higher efficacy, and less dosing frequency (P<.05). The top three treatment attributes with the highest relative importance were the impact of atrial fibrillation (24.7%) and diarrhea (21.0%) on QoL, and PFS (15.8%), followed by impact of headache (15.7%) and hypertension (14.1%) on QoL, dosing frequency (7.8%), and formulation type (capsule or tablet) (0.9%). Patients were willing to trade off PFS for improved quality of life: accepting reductions of 3.1 years for less impact from atrial fibrillation, 2.7 years for diarrhea, 2.0 years for headache, and 1.8 years for hypertension (none or mild vs. significant impact). Additionally, they were willing to accept a reduction of 1.0 years of PFS to receive a treatment given once daily rather than twice daily.Conclusions: This is the first quantitative assessment of treatment preferences among Japanese patients with CLL using a DCE approach. Findings from this study provide valuable Japan-specific insights, highlighting that although efficacy is important, patients prioritize safety factors, such as the impact of atrial fibrillation and diarrhea on QoL. These findings support the integration of patient perspectives into treatment planning to enhance shared decision-making, personalize care, and promote better adherence to long-term therapies in CLL management.