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Abstract Introduction Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggesting their potential anti-inflammatory and anti-proliferative effects as well as cardiovascular benefits. Chronic myeloid leukemia (CML), a myeloproliferative neoplasm, has seen major therapeutic advances with tyrosine kinase inhibitors (TKIs). However, metabolic comorbidities remain widely prevalent in these patients due to both cancer-associated risk factors and the effects of therapy. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with CML, exploring potential interactions between metabolic modulation and disease behaviour. Methods A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with CML and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, ischemic stroke, sepsis, and need for mechanical ventilation and hemodialysis. Results We identified 701,767 patients with CML and obesity who received GLP-1 receptor agonists, and 6,811,928 patients with CML and obesity who did not receive GLP-1 therapy. After propensity matching, each cohort consisted of 700,998 patients with similar baseline characteristics. Our analysis found that over 5 years, patients with CML and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.509, 95% CI: 0.501 to 0.518, p-value <0.001), myocardial infarction (HR: 0.785, 95% CI: 0.769 to 0.801, p-value <0.001), ischemic stroke (HR: 0.665, 95% CI: 0.632 to 0.700, p-value <0.001), hemodialysis (HR: 0.445, 95% CI: 0.430 to 0.461, p-value <0.001) and sepsis (HR: 0.726, 95% CI: 0.714 to 0.738, p-value <0.001). There was no statistically significant difference in the need for mechanical ventilation between the two subgroups. Conclusion Our study revealed that patients with CML and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, ischemic stroke, hemodialysis and sepsis. Further longitudinal cohort studies are warranted to better understand these associations and inform clinical practice guidelines.

Abstract Background: Chimeric Antigen Receptor T-cell therapy (CAR-T) has revolutionized the treatment landscape of hematological cancers, including B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL). However, the cardiac toxicity profile of this therapy is not well described in the literature. The majority of patients receiving CAR-T are older adults who may have pre-existing cardiovascular risk factors, received prior cardiotoxic therapy including anthracycline, alkylators, corticosteroids, proteosome inhibitors, radiation, autologous and allogeneic stem cell transplants. Due to a stricter patient selection for CAR-T clinical trials, cardiac adverse events (AEs) are infrequent. As the survival of patients with hematological malignancies continues to improve with advancements in therapy, it becomes critical to consider the cumulative cardiotoxic effects of these therapies. Therefore, a post-marketing pharmacovigilance analysis of the cardiac AEs reported to the FDA Adverse Event Reporting System (FAERS) for each CAR-T product was conducted to address this knowledge gap. Methods: All individual case safety reports of cardiac AEs listing any of the approved CAR-T therapies [Tisagenlecleucel (Tisa-cel), Axicabtagene ciloleucel (Axi-cel), Lisocabtagene maraleucel (Liso-cel), Brexucabtagene autoleucel (Brexu-cel), Idecabtagene vicleucel (Ide-cel), Ciltacabtagene autoleucel (Cilta-cel) and Obecabtagene autoleucel (Obe-cel)] as the suspected drug were identified from the FAERS database. Patient characteristics, including primary malignancy, age, sex, CAR-T product and AEs were described. Disproportionality analysis was performed using Reported Odds Ratio (ROR) to determine significant associations between CAR-T products and cardiac AEs. Results: There were 1362 cardiac AEs after CAR-T therapy reported in the FAERS database(602 with Axi-cel, 444 with Tisa-cel, 77 with Cilta-cel, 81 with Ide-cel, 128 with Brexu-cel, 30 with Liso-cel and 0 with Obe-cel).Of these, 57% were males, 8.6% occurred in patients <18 yrs, 35.4% in 18–64 yrs, and 32% in >65 yrs. There were 778 reports of arrythmias, 158 heart failures, 184 cardiac arrests, 43 pericardial AEs, 16 valvular AEs, 59 ischemic AEs, 10 cardiogenic shock, 8 myocarditis, and 106 other cardiac disorders (cardiac thrombus, cardiomegaly, cardiac rupture, orthostatic hypotension, hypertensive emergency/crisis etc.). In the entire cohort, males were more likely to develop pericardial (ROR=3.55, p=0.004) and valvular disorders (ROR=9.13, p=0.03), with females developing heart failure (ROR=1.61, p=0.005). Patients <18 years had a higher incidence of pericardial (ROR=3.44, p=0.006) and valvular disease (ROR=12.79, p<0.0001), while adults aged >65 had higher propensity of developing atrial tachyarrhythmias (ROR=2.74, p<0.0001), ventricular arrhythmias (ROR=3.04, p=0.001) and cardiogenic shock (ROR=8.38, p=0.05), and a trend towards higher risk of developing acute coronary syndrome (ACS) (ROR=1.79, p=0.06). For ischemic cardiac AEs, Brexu-cel was associated with increased risk of myocardial infarction (ROR=2.34, p=0.04), and Ide-cel was associated with elevated troponin levels (ROR=6.23, p=0.002). For functional cardiac AEs, Tisa-cel was associated with cardiac arrest (ROR=1.68, p=0.001), pericardial disorders (effusion, tamponade and pericarditis) (ROR=3.56, p<0.001), valvular disorders (ROR=55.97, p<0.0001), myocarditis (ROR=6.2, p=0.012) and heart failure (ROR=2.24, p<0.001). B-ALL was associated with higher odds of cardiac arrest (ROR=1.63, p=0.018). For conduction-related cardiac AEs, Brexu-cel had higher rates of brady-arrythmias (ROR=1.86, p=0.04), Cilta-cel had increased incidence of atrioventricular block (ROR=7.87, p=0.02), and tachy-arrhythmias (ROR=1.71, p=0.0001). Tisa-cel was associated with increased risk of any arrhythmias (ROR=1.68, p<0.001). Axi-cel was associated with higher odds of developing orthostatic hypotension (ROR=2.57, p=0.019). Conclusion: This post-marketing pharmacovigilance analysis highlights patterns of cardiac AEs following CAR-T therapy. Trends in AEs based on CAR-T product, age, and sex support the ongoing need for vigilance for these unique toxicities. As this study is limited by FAERS reporting bias, prospective studies to validate these associations and elucidate the underlying mechanisms are needed, incorporating prior systemic therapies and baseline characteristics of patients undergoing CAR-T therapy.

Abstract The current European Leukemia Net guidelines (ELN22) classify AML patients with intermediate-risk cytogenetics and MDS-associated mutations (MDSm, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse-risk but do not use MDSm+ to alter the risk stratification of patients who otherwise classify as favorable-risk. NPM1 mutations (NPM1+) are one of the most common alterations in AML and remain a favorable-risk biomarker for patients without co-occurring FLT3-ITD mutations or adverse-risk cytogenetics (NPM1+/ITD-/ARcyto-). However, prior studies have shown that older patients (≥65 years) with favorable-risk AML, including NPM1+/ITD-/ARcyto- genotype, have significantly higher relapse rates and decreased survival despite receiving comparable intensive chemotherapy regimens to their younger counterparts. Given that MDSm frequency increases with age in patients with NPM1+ AML, it raises the question as to whether MDSm contribute to poorer outcomes in older patients. To date, there have been differing results in retrospective studies examining the effect of MDSm on NPM1+ AML. Some cohorts demonstrate worse outcomes in those that have NPM1+/MDSm+ AML (Chan et al., Blood Adv. 2024), whereas others do not show a significant difference in NPM1+ AML with or without MDSm (Eckardt et al., Leukemia 2023; Othman et al., Blood 2024; Ruhnke et al., Blood Adv. 2025). We examined the mutational landscape in a large group of pre-treatment, diagnostic specimens from 271 patients, which included 119 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112), 96 patients from the UW/FHCC Hematopoietic Repository, and 56 patients from the BeatAML cohort. All patients were treated with curative intent as per standard practice or on clinical trials and had adequate cytogenetic information and long-term follow-up data. Event-free and overall survival (EFS, OS) were estimated using the Kaplan-Meier method and compared using Cox regression models stratified by cohort. MDSm+ occurred in 17% of patients, with the most common mutations being in SRSF2 (7%) and SF3B1 (3%). To assess the impact of MDSm on outcomes of favorable-risk NPM1+ AML, we performed univariate analyses comparing OS and EFS for NPM1+ AML grouped by ELN22 favorable risk/MDSm-, ELN22 favorable/MDSm+, and ELN22 intermediate/adverse risk. Compared to NPM1+/MDSm- (n=116), favorable-risk NPM1+/MDSm+ (n=33) had worse OS with HR 2.0 [95% CI (1.1, 3.3), p=0.008] and had similar OS to those that are classified as ELN22 intermediate/adverse risk (n=122). There was no significant difference in EFS or complete remission rates between NPM1+ favorable risk with and without MDSm (p=0.36 and p=0.6, respectively). When we grouped the ELN22 favorable risk patients by age (<65 years vs. 65+ years), MDSm+ in younger patients did not show a difference for OS (HR 0.99, p=0.98). Older ELN22 favorable-risk patients (≥65) had poor OS regardless of presence of MDSm compared to younger MDSm- patients: older MDSm- (n=91) with HR 2.4, 95% CI (1.3, 4.6), p=0.005 and older MDSm+ (n=25) with HR 3.5, 95% CI (1.9, 6.3), p<0.0001. There was a trend toward worse OS in MDSm+ compared to MDSm- older patients, but this was not statistically significant (HR 1.42, p=0.33). Since most MDSm are in splicing factor genes (SF3B1, SRSF2, U2AF1, ZRSR2), we examined the effect of splicing factor mutations vs. other MDSm+ in ELN22 favorable risk and did not find a significant difference in OS (HR=1.01, p=0.97). Those with non-splicing MDSm+ had worse EFS compared to MDSm- and splicing MDSm+ (HR 4.12, p=0.0037), although no difference in OS. In this study, MDSm+ in the context of favorable-risk NPM1+ AML are associated with worse OS in a univariate analysis. However, this difference is likely due to the increased prevalence of MDSm with increasing age and overall worse outcomes of NPM1+ AML in older patients. When stratified by age, older NPM1+ AML patients had worse OS than younger NPM1+ patients overall, although presence of MDSm trended toward even worse OS in older patients. In younger patients, MDSm+ are not associated with a significant difference in OS, which is a similar finding compared to prior studies. Our findings suggest that NPM1+ AML is not necessarily “favorable-risk” in older patients, particularly with concurrent MDSm. Therefore, further understanding of the underlying biology of age in the context of NPM1+ AML is needed to improve outcomes for older patients.

Abstract Background: Dissemination and implementation science (D+I) efforts often begin after clinical trial (CT) efficacy data are available. However, delaying this work limits opportunities to identify barriers and facilitators that can enhance adoption of evidence-based practices. Integrating D+I during trial development, activation, and conduct supports more timely, effective, and scalable implementation. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) includes >125 centers, conducting transplant and cellular therapy (TCT) trials with practice-changing potential, with >17,000 patients enrolled since 2001. Data from Center for International Blood and Marrow Transplant Research (CIBMTR) provides a way to measure real-world adoption. With this comprehensive structure in place, the BMT CTN launched a D+I Committee that established a D+I process to better understand uptake of CT findings and to leverage that information to promote adoption. Methods: Informed by established D+I frameworks, a structured, cyclical process to integrate implementation considerations spanning the CT lifecycle was developed. A multidisciplinary team including experts in D+I, clinicians, and investigators iteratively refined the proposed D+I algorithm. The process begins upstream when a trial concept is approved to move forward, it is shared with the D+I Committee for initial assessment. This includes a landscape review for studies in development using CIBMTR data, literature, and expert experience. The Committee then reviews the developing protocol with the BMT CTN protocol team to proactively identify implementation barriers and facilitators to implementation in real-world settings and outline plans for dissemination. The Committee also provides recommendations for integrating relevant implementation data collection and analyses within the protocol. After study completion, both clinical efficacy and implementation outcomes are analyzed, followed by active dissemination. Additional assessment using surveys, qualitative methods, and CIBMTR data occurs after dissemination to understand adoption. Insights gathered also inform further refinement of the process. Tools and templates are in development to build capacity and ensure consistency for Committee members. Results: To date, the Committee has published three peer-reviewed articles addressing implementation implications of three BMT CTN trials (PMC7735536, PMC8578257, PMC9364468) and a fourth is in press. Using the designed D+I process flow, a current effort used a survey sent to US CIBMTR centers, to evaluate factors influencing the implementation of results of the BMT CTN 1703 trial of post-transplant cyclophosphamide as graft-versus-host disease (GvHD) prophylaxis and assessed dissemination and adoption considerations for the upcoming BMT CTN 2203 CT of ruxolitinib as GvHD prophylaxis. CIBMTR data is being analyzed to demonstrate practice patterns before, during, and after BMT CTN 1703 study completion. This effort has allowed for further refinement of the BMT CTN D+I process flow and has highlighted critical opportunities for incorporating dissemination and implementation objectives and endpoints into BMT CTN protocols. We also used the process to guide a review of severe aplastic anemia treatment gaps and ongoing studies. This review underscored how proactive transplant and non-transplant stakeholder engagement and early implementation planning, core elements of this process, can bridge evidence to practice and advance access to care. A complementary survey on current practice patterns in severe aplastic anemia is ongoing. Conclusions: With the existing structure of the BMT CTN and associated practice registry of the CIBMTR, the BMT CTN D+I Committee developed a systematic process to build D+I considerations into trial workflows to increase real-world impact. This process aims to ensure that barriers to uptake of trial results can be identified and addressed appropriately, improving care quality for patients undergoing TCT.

Abstract While the use of NCCN guidelines is essential in lymphoma care, adherence among oncologists remains highly variable. Real-world concordance ranges from 65–80% overall, dropping to as low as 11–46% for certain lymphoma subtypes. Although 88% of clinicians report using NCCN guidelines for Hodgkin lymphoma, adherence to PET-adapted approaches is inconsistent. This gap highlights a critical need for tools that support guideline-concordant care.Large language models (LLMs) such as GPT–4 promise decision support, yet hallucinations and divergence from evidence-based care remain obstacles. We assessed whether retrieval-augmented generation (RAG) with National Comprehensive Cancer Network (NCCN) guidelines improves GPT–4 performance in lymphoma treatment recommendation tasks. To address this, we developed a RAG-enhanced GPT-4 agent (RAG-GPT) by indexing the 2025 NCCN Lymphoma Guidelines into a vector database. Fifty clinical vignettes spanning diverse lymphoma subtypes were compiled from published case reports; this sample provides 80 % power (α = 0.05) to detect a mean score difference of ≥ 0.18 on the modified Generative AI Performance Score (mG-PS). Guideline concordance was assessed based on NCCN guidelines and clinical judgment reflecting real-world oncological decision-making. Scores were normalized between -1.0 and 1.0 for consistent evaluation. Readability and rationale clarity were rated on a 5-point Likert scale. Baseline GPT-4 and RAG-GPT generated treatment plans via standardized prompts. An oncologist scored all outputs with mG-PS, which rates NCCN concordance (0.0–1.0) and penalizes hallucinations (-0.25 to –1.0). RAG-GPT achieved a higher mean mG-PS (0.32) than baseline GPT–4 (0.10) (t(98)=-2.11, p=0.038; mean score difference ΔmG-PS=0.22). Importantly, RAG-GPT eliminated severe hallucinations, reinforcing confidence in the safety of its treatment reccomendations. Fully concordant “gold-standard” plans were produced in 46 % of vignettes with RAG-GPT versus 22 % with baseline. Readability scores favored RAG-GPT modestly without statistical significance. Lymphoma's bimodal age distribution, heterogeneity, and lack of standardized treatment algorithms, coupled with regimen toxicity and the need to account for patient frailty and comorbidities, create complex clinical scenarios that constrain LLM applicability for nuanced decision-making. Non-Hodgkin lymphoma, particularly relapsed/refractory, transformed disease, or rare subtypes, lacks a defined standard of care, leading reviewers to rely on clinical judgment or published case series beyond NCCN guidelines. This underscores a key limitation of LLM-supported tools: their performance is highly dependent on the presence of clear algorithmic consensus within a given disease. Linking GPT-4 to NCCN guidelines via RAG significantly improved treatment accuracy and reduced hallucination severity in lymphoma, though performance remained lower than prior RAG studies in cancers like breast and CNS suggesting a greater impact on hallucination reduction than on retrieval of a consistent gold standard regimen. These findings support continued development and prospective validation of guideline-anchored LLMs for clinical use.

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 Background : Type 2 diabetes and Multiple myeloma are becoming a growing cause of worry among aging populations. Type 2 diabetes and Multiple myeloma share many risk factors like age, obesity, and chronic inflammation. It is also found that diabetes may influence the worsening of multiple myeloma. Hence it becomes crucial to understand the epidemiological intersections between the two conditions in order to optimise treatment and lower death rates. This study assesses the trends in mortality in patients with Type 2 diabetes and Multiple myeloma in the United States from 1999-2023. Methods : We analyzed death certificates of adults aged>45 years' from the CDC-WONDER database with Type 2 diabetes (ICD-10 codes: E10-14) and Multiple myeloma (ICD-10 codes: C90) from 1999-2023. Age-adjusted mortality rates (AAMR) per 100,000 population were stratified by gender, race, census region, year and age. Join-Point analysis was performed to estimate annual percent change (APC) and average annual percent change (AAPC) in mortality trends, along with 95% confidence intervals (CIs). Results: Between 1999 and 2023, Type 2 diabetes and Multiple myeloma caused 22,467 deaths in patients aged>45 years. The overall AAMR increased from 0.647 in 1999 to 0.886 in 2023. Demographically, AAMR among the men increased significantly from 0.827 to 1.205 (AAPC: 1.22; 95% CI: -1.02 to 3.52). Although experiencing a lower mortality as compared to males, females also experienced a surge in mortality from 0.563 to 0.633(AAPC: 0.90; 95% CI: -0.11 to 1.93). In terms of race, mortality increased among the Non-Hispanic (NH) Black or African Americans from 1.942 to 2.158 (AAPC:0.60 ; 95% CI: -0.06 to 1.26), moreover the AAMR in the Hispanics increased from 0.986 to 1.099 (AAPC: 0.84; 95% CI:-0.05 to 1.73) while those among the white community increased from 0.493 to 0.679 (AAPC: 0.87; 95% CI -1.13 to 2.91). Geographically, regions in the South showed the highest overall AAMR (0.760) followed by the West (0.748), followed by the Midwest(0.731), and the Northeast (0.617). Between the urban and rural areas, rural areas had a higher AAMR as compared to the urban areas with an overall AAMR of 0.809. When stratified according to states, AAMRs varied highly from the highest in Columbia to the lowest in California. Conclusion: The overall mortality rates for Type 2 diabetes and Multiple myeloma increased between the years 1999-2023. The greatest change was seen in males, regions in the Northeast, racially in NH Blacks and the rural areas.

Abstract Background Measurable residual disease (MRD) negativity post- autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) is associated with favorable outcomes and may overcome the adverse impact of high-risk cytogenetic abnormalities (HRCAs). However, as the definition of high risk evolves and MRD emerges as a key endpoint, understanding its prognostic value within individual HRCAs is critical for treatment guidance. Methods We retrospectively included patients with NDMM that underwent an ASCT between September 19, 2016, and October 19, 2023, and achieved MRD negativity on Day 100 post ASCT. The MRD testing was conducted using multiparameter flow cytometry with a sensitivity of 2x10. HRCAs were defined as del(17p), 1q21+ gain or amplification (1q21+), t(4;14), t(14;16), t(14;20) and del(1p) and rest were considered standard risk (SRCA). Patients were grouped by the number of HRCAs (0, 1, ≥2). An adaptation of the recently proposed International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) classification for high-risk disease (TP53 mutation unavailable) was also used. Progression-free survival (PFS), measured from stem-cell infusion to progression or death, was estimated using Kaplan–Meier methodology and compared using log-rank test. Results We identified 386 patients with MRD negativity post ASCT, of which 381 had cytogenetic data available for analysis. The median follow-up for the study cohort was 47.3 months (95% CI: 43.2-50). The median age at the time of ASCT was 65.7 (25.4-79.2) years and 58.3% patients were males. A total of 49% (n=189) patients had standard-risk cytogenetics, 31.4 % (n=121) harbored 1 HRCA, 15.3% (n=59) patients had two HRCAs and 3.1% (n=12) had 3 HRCAs. The individual HRCA by their prevalence were: 1q21+ in 35.5%(n=137), del(17p) in 14.3% (n=55), t(4;14) in 10.9% (n=42), t(14;16) in 5.4% (n=21), del(1p) in 4.2% (n=16), and t(14;20) in 1.04% (n=4) of patients. The most common double-hit lesions were1q21+ gain and/or amplification co-occurring with t(4;14) (33.9%, n=20) and del(17p) with 1q21+ (18.6%, n=11). Despite universal MRD negativity at Day 100, several HRCAs remained prognostically significant for PFS. Patients with del(17p) had worse 3-year PFS (71%) than those without (81%) [hazard ratio (HR)=1.85, 95% CI 1.11–3.07, p = 0.0172], though 3-year OS did not significantly differ at data cutoff (80% vs. 92%, p=0.1176). Presence of 1q21+ was associated with an inferior 3-year PFS (73%) compared to those without [84%, HR: 1.96 (95% CI: 1.25–3.06), p=0.0026], while 3-year OS was similar (88% vs. 91%, HR:1.33 p=0.36). Isolated 1q21+ had inferior PFS with comparable OS when compared to SRCA [3-year PFS of 82% vs. 88% respectively (HR:1.97, p=0.0177)]; 3-year OS was 91% vs. 94% (HR:1.38, p=0.44)]. Among 1q21+ patients, those with co-occurring HRCAs had a 3-year PFS of 66% vs. 81% for isolated 1q21+ (HR: 1.47, p=0.21). Patients with t(4;14) had worse 3-year PFS (64%) vs. 82% in non t(4;14) [HR 2.11(95% CI: 1.21-3.67) p=0.0064], and 3-year OS of 82% compared to 91% [HR 2.14 (95% CI: 1.02–4.49), p=0.038]. Isolated t(4;14) showed a 3-year PFS of 59% vs. 87% in standard-risk (p=0.06), and 3-year OS of 90% vs. 93% [HR 3.29, 95% CI 0.95–11.33, p = 0.06]. The presence of t(14;16), t(14;20), and del(1p) did not significantly affect 3-year PFS (all p>0.1), likely due to small subsets. When patients were grouped by the number of HRCAs, PFS declined with increasing cytogenetic complexity. Compared to standard risk, the 3-year PFS was 77% for 1 HRCA vs [HR = 2.11 (95% CI: 1.29–3.46), p = 0.0027], 67% for ≥2 HRCA [HR = 2.64 (95% CI: 1.53–4.57), p = 0.0005]. Maintenance therapy was used in 98% of patients. Patients with HRCAs received a doublet maintenance compared to SRCA (p<0.0001), even in MRD negative disease post ASCT. Conclusion In patients with certain HRCA, achievement of MRD negativity post-ASCT does not overcome the adverse impact of HRCA on PFS. In our cohort, patients with del(17p), t(4;14), or 1q21+ continued to exhibit significantly shorter PFS despite achieving MRD-negative status. These findings underscore the need for ongoing risk-adapted strategies even in patients with MM who attain MRD-negative state. The OS estimates are immature at this time.

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Introduction: While newly diagnosed patients (pts) with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy have prolonged survival outcomes with venetoclax plus azacitidine (VEN+AZA) over AZA alone (2-year overall survival rate: 37.5% vs 16.9%), more can be done to further enhance outcomes (Pratz et al., 2024). CD123 is overexpressed on AML blasts and leukemia stem cells in AML. Pivekimab sunirine (PVEK) is a first-in-class antibody-drug conjugate comprised of a high-affinity anti-CD123 antibody, a cleavable linker, and an indolinobenzodiazepine pseudodimer payload. Previously, in pts with CD123-positive AML, PVEK combined with VEN+AZA demonstrated robust response rates with a manageable safety profile (Daver et al., 2023). Here we report a subgroup analysis from a preliminary cohort of frontline (1L)-treated pts with AML. Methods: Data are from the dose expansion phase of an ongoing, open-label, multicenter, fully enrolled, Phase 1b/2 study of PVEK+VEN+AZA in adults with 1L unfit AML deemed CD123-positive by investigator. Unfit pts were aged ≥75 years (yr), or aged <75 yr with Eastern Cooperative Oncology Group performance status (ECOG PS) score 2–3, or ≥1 defined comorbidity. Pts received PVEK (0.045 mg/kg, intravenous [IV]) on Day (D) 7 plus VEN (400 mg equivalent, oral) daily in a 28-D cycle (cohort 1 received ≥14 D of VEN; cohort 2 received 28 D of VEN) plus AZA (up to 75 mg/m2, subcutaneous or IV) on D1–7. Bone marrow assessments were performed by D12–14 (cohort 1) or D18–21 (cohort 2) to determine VEN duration in cycle 1 and at the end of every subsequent cycle to assess responses and myelosuppression. The primary endpoint was antileukemia activity (complete remission [CR] rate) and measurable residual disease (MRD) assessments. Responses were determined using the modified European LeukemiaNet 2017 criteria (plus CR + partial hematologic recovery [CRh]). MRD-negativity was defined centrally as <0.1% using multiparameter flow cytometry. Safety was assessed as a secondary endpoint. Results: Among 1L unfit pts with CD123-positive AML (n=49), the median (range) age was 77 (58–85) yr, with most pts aged ≥75 yr (n=36 [74%]). Forty-two (86%) pts reported an ECOG PS ≤1, 14% (n=7) had secondary AML, and 20% (n=10) and 51% (n=25) had intermediate or adverse cytogenetic risk, respectively; 65% (n=32) and 35% (n=17) were reported as TP53wt or TP53mut, respectively. Eight (16%) pts bridged to stem cell transplant. The median (range) number of treatment cycles and duration of treatment were 4 (1–20) and 5.5 (0.7–22.7) months (mo), respectively, for PVEK; 4 (1–20) and 5.1 (0.9–22.9) mo for VEN; and 4 (1–21) and 5.7 (0.9–23.4) mo for AZA. For cohort 1 (n=10), the median (range) duration of VEN was 4.5 (2.1–22.9) mo, and for cohort 2 (n=39), the median (range) duration of VEN was 5.7 (0.9–15.2) mo. With a median (range) follow-up of 10 (1.2–26.7) mo, 63.3% (95% CI: 48.3%–76.6%) of pts achieved CR, 79.6% (95% CI: 65.7%–89.8%) achieved CR/CR with incomplete hematologic recovery (CRi), and 73.5% (95% CI: 58.9%–85.1%) achieved CR/CRh; morphologic leukemia free state was achieved in 4% (n=2) of pts. Of pts who achieved CR or CR/CRi with a MRD-evaluable sample, 92% (23/25) and 90% (27/30) achieved flow cytometry MRD-negativity (<0.1%) respectively. The most common (≥50% of pts) any grade treatment-emergent adverse events (AEs) were neutropenia/neutrophil count decreased and thrombocytopenia/platelet count decreased (both 69%); constipation (61%); and peripheral edema (51%). Three pts (6%) experienced AEs leading to discontinuation (myocardial infarction/soft tissue infection/thrombocytopenia) and 2 pts had AEs leading to death (respiratory failure/pancytopenia). Conclusions: Unfit pts with newly diagnosed CD123-postive AML demonstrated high CR rates with PVEK+VEN+AZA. These robust response rates were observed across the select mutational profiles tested. Follow up with duration of response and survival estimates among all pts, by molecular subgroups and MRD negativity status, are being evaluated. Triplet therapy in unfit 1L pts with CD-123–positive AML was well-tolerated, and no new safety signals were observed. These data highlight the need to further evaluate this regimen in a randomized trial.