Citations

PURPOSE Hematology care delivery is changing rapidly for patients, care teams, and health care institutions. This study simultaneously evaluated utilization data for synchronous/real-time patient appointments, asynchronous/time-delayed patient communications, and provider preferences in a large academic hematology practice to inform sustainable care delivery and workflows in the digital era. METHODS We conducted a retrospective analysis of aggregated adult hematology appointment and patient communication data at Mayo Clinic (Rochester, MN) from January 2023 to January 2025. Data were stratified by appointment modality, patient characteristics, and electronic health record (EHR) message volumes. Additionally, a voluntary, anonymous survey assessed hematology provider preferences regarding appointment modalities, in-basket burdens, and billing practices. RESULTS Among 83,713 completed appointments, 80.8% were in-person, 12.9% video, and 6.4% telephone. Patients age 80 years and older and rural cohorts used virtual modalities at rates comparable with younger and metropolitan cohorts. Asynchronous communication volume was considerable, with 155,036 patient-initiated telephone calls generating a digital cascade of 407,578 EHR messages (a 1:2.6 ratio) and 49,798 patient-initiated advice request in-basket messages generating 343,030 additional EHR messages (a 1:6.9 ratio). Providers (n = 53) strongly preferred in-person appointments for new consults (92.5%) and active therapy management (90.6%) but favored virtual appointments for surveillance (52.8%). Although 86.8% of providers reported spending >30 minutes daily on in-basket management, 94.3% reported not billing for this time. CONCLUSION Telehealth is a substantial component of modern hematology practice, used across all age groups. However, digital cascading and proliferation of asynchronous communications present an invisible and uncaptured workload. Optimizing care delivery could include implementation of a stratified hybrid model, prioritizing in-person appointments for high-acuity needs and virtual appointments for low-acuity needs, alongside standardized workflows to mitigate burdens of the digital era.

Abstract Frailty influences treatment outcomes in older patients with multiple myeloma (MM), yet existing frailty tools capture limited geriatric domains and are incompletely studied in the context of contemporary therapies. We prospectively evaluated patient-reported comprehensive geriatric assessment (CGA) domains and their associations with treatment toxicity and patient-reported outcomes (PRO) in older adults with MM. Patients aged ≥60 years with newly diagnosed or relapsed/refractory MM initiating a new therapy completed electronic CGA and PRO questionnaires at baseline and 4 months. Outcomes included clinician- and patient-reported treatment toxicity, treatment adaptations, health care use, and health-related quality of life (HRQOL). A cumulative deficit frailty index (FI) was derived from CGA and HRQOL domains. Among 90 patients (mean age, 72 years), geriatric impairments were common, particularly physical function domains. High-grade nonhematologic toxicities were significantly associated with older age, comorbidities, patient-reported functional limitations, and anxiety. Toxicity rates on the PRO version of the Common Terminology Criteria for Adverse Events (CTCAE) were higher than on CTCAE, highlighting a discordance between physician- and patient-reported treatment toxicity. Frailty was present in 22% and associated with worse baseline HRQOL and increased high-grade nonhematologic toxicity but not treatment adaptations or health care use. Average CGA and HRQOL scores remained stable over 4 months, although individual trajectories varied. Patient-reported geriatric impairments are prevalent in older adults with MM and strongly associated with nonhematologic toxicities even in the contemporary treatment era. Physician-reported CTCAE may not fully reflect patients' symptom burden. Heterogeneity in individual geriatric trajectories during treatment emphasize the need for longitudinal assessment. This study was registered at www.clinicaltrials.gov as NCT05918185.

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

Abstract Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare blood disorder associated with human T-cell leukemia virus type 1 (HTLV-1) infection. It is generally categorized into four subtypes: smoldering, chronic, lymphoma, and acute. Given the heterogeneity of these subtypes, there is a significant difference in outcomes. Robust and contemporary epidemiological data are lacking for this rare disorder. We present a retrospective cohort study of patients with ATLL, utilizing the National Cancer Database (NCDB) to better characterize the epidemiology and survival trends in the United States. Methods: This is a retrospective cohort study using the NCDB to identify ATLL cases diagnosed from 2004-2020. Descriptive statistics summarized baseline characteristics, while chi-square tests assessed group differences. Overall survival (OS) was estimated using Kaplan-Meier analysis and compared using log-rank tests. Multivariable Cox proportional hazards models identified independent prognostic factors (p < 0.05 considered significant). Results: A total of 635 patients were identified with ATLL, including 344 (54%) males and 291 (46%) females, with a median age at diagnosis of 59 years (range: 19-90). Most patients came from the Middle Atlantic (NY, NJ, PA) region (33%), followed by the South Atlantic (DC, DE, FL, GA, MD, NC, SC, VA, WV) region (20%) and the East North Central (IL, IN, MI, OH, WI) region (8%). Of the 635 patients, 335 (52%) were Black, 247 (39%) White, and 26 (4%) Asian. Sixty-five (10%) patients were of Hispanic origin. Over half of patients with ATLL (54%) had a median income below $46,000. International Prognostic Index (IPI) score was only available for 16 patients: three (19%) patients were in the high-risk group, 7 (43%) in the high-intermediate group, and 6 (37.5%) in the low-intermediate group. Treatment groups included 357 (56%) patients treated with chemotherapy and 29 (4.5%) who received radiation therapy. Thirty-three (5%) patients underwent hematopoietic stem cell transplant (HSCT), including 27 autologous and 16 allogeneic transplants. The median survival time in the cohort was 9 months (95% CI 7.3-10.7). One-year OS rate in the cohort was 43%, while 2-year and 5-year OS rates were 31% and 23.5%, respectively. Patients over the age of 65 had a significantly shorter median OS than those under 65 (4 vs. 11 months, p=0.001) and were significantly less likely to undergo HSCT (p< 0.001). Black patients had significantly shorter median OS compared to White patients (7.8 months vs 13.3 months, p=0.014), despite similar treatment rates with chemotherapy and HSCT. Median OS appeared to improve over time, from 8 months in patients diagnosed between 2004-2009 to 10 months for those diagnosed between 2016-2020, although this was not statistically significant (p=0.145). Treatment with allogeneic HSCT was associated with significantly prolonged median survival, compared to those who did not receive transplant (50 months vs. 7 months, p<0.05). Additionally, receiving chemotherapy and/or radiation compared to not receiving treatment was also associated with significantly prolonged median survival (p<0.05). Patients treated in the Middle Atlantic region had a median survival of 8.8 months, compared to 23.2 months in the West South Central (AR, LA, OK, TX) region (p< 0.001). Increased education and income levels were not significantly associated with improved survival. There were no significant differences in survival between males and females. Conclusions: We provide contemporary estimates on the epidemiology of ATLL. Factors associated with improved prognosis included undergoing HSCT, radiation, or chemotherapy. We report that increased age and Black race are negative prognostic factors. Regional differences in incidence and survival persist in the US. Our study findings underscore the need for increasing access to treatment, including HSCT for those who are good candidates. Additionally, there remains work to be done to address racial disparities in the care of patients with ATLL.

Abstract Introduction: Multiple myeloma (MM) predominantly affects older adults who vary widely in physiological status and treatment outcomes. Comprehensive Geriatric Assessment (CGA) is considered the gold standard for frailty assessment in older cancer patients (pts), but clinical useis limited. Current frailty tools for MM include only select GCA domains, rely on trial datasets, and do not incorporate pt-reported outcomes (PROs). Since their development, treatment strategies have evolved with the use of anti-CD38 MAbs and quadruplets in older pts. The impact of geriatric impairments on treatment tolerance in the era of modern therapy remains unclear and changes in geriatric domains during treatment are not well characterized. Aim: This prospective study evaluates the association between pt-reported CGA and treatment outcomes in older MM pts.Methods: We included MM pts ≥60 years initiating a new treatment at Mayo Clinic from March 2023-June 2024. Pts completed the CARG GCA (Hurria et al 2005) electronically prior to and after 4 treatment cycles. We collected data on toxicity using CTCAE and PRO-CTCAE and quality of life using the PROMIS10-GH SF.Results: Ninety pts were enrolled. Median age was 72 (range: 63-86), 42% female, and >90% non-Hispanic white. Over half (59%) were newly diagnosed with 41% and 56% receiving quadruplets and triplets, respectively. Among newly diagnosed pts, 34% had early stem cell transplant. Baseline median self- and physician- reported KPS were 80% and 90%, respectively, with high correlation (r=0.657). The median number of meds per pt was 9 (range:0-30), 39% had ≥3 comorbidities, 21% reported ≥1 fall in the past 6 months, and 40% reported ≥1 IADL limitation. On the Hospital Anxiety and Depression Scale, 3% and 7% had anxiety and depression, respectively. On the Blessed Orientation-Memory-Concentration test, 19% had mild cognitive impairment, and 1% had severe cognitive impairment. While only 19% had grade (G) ≥3 non-hematologic toxicity by CTCAE, 71% had ≥1 treatment delay, dose reduction, or discontinuation, and 39% had ≥1 ED visit or unplanned hospitalization within the first 4 cycles. This suggests physician grading of non-hem toxicities may inadequately capture toxicity burden from MM therapy. Notably, the rate of G≥3 toxicity by PRO-CTCAE was 49%, highlighting the discrepancy between physician- and pt-reported symptom burden. CGA domains significantly associated with G≥3 non-hem toxicity were: age (74 v 71.5, p=0.032), ≥3 comorbidities (65% v 33%, p=0.015), anxiety (18% v 0%, p=0.006), ≥1 IADL limitation (65% v 33%, p=0.018), physician KPS ≤80 (53% v 27%, p=0.042), limitations in vigorous activities (100% v 78%, p=0.023) and limitations in climbing several flights of stairs (88% v 56%, p<0.001). Predictors of PRO-CTCAE G≥3 toxicity were ≥1 falls (30% v 11%, p=0.030), ≥3 comorbidities (52% v 26%, p=0.011), polypharmacy (≥9 meds) (67% v 43%, p=0.023), and physician KPS ≤80 (43% v 22%, p=0.030). CGA domains associated with ≥1 treatment adjustments were polypharmacy (62% v 33%, p=0.017) and unintentional weight loss (35% v 12%, p=0.028). Polypharmacy was the only domain associated with healthcare utilization (68% v 45%, p = 0.040), which may reflect underlying multimorbidity and greater pain burden. On multivariable logistic regression, any level of limitation in climbing several flights of stairs (OR: 6.0, 95% CI 1.2-30.3; p= 0.030) and older age (OR: 1.1, 95% CI 1.0-1.1; p=0.032) were independently associated with G≥3 non-hem toxicity, reflecting impaired functional status and reduced physiologic reserve, while ≥3 comorbidities only trended toward significance (OR:1.9, 95% CI 1.1-3.9, p=0.051).Compared to baseline, there were no significant changes in CGA domains or PROMIS10 scores after 4 cycles. While there was no significant difference in the proportion of pts reporting limitations in IADLs or physical function, we observed heterogeneity among individual pts, with changes in all 3 directions (improvement, stability, and decline). Conclusions: Geriatric impairments are prevalent in older pts with MM; pt-reported impairments are significantly associated with G≥3 non-hem toxicities, need for treatment modifications, and increased healthcare utilization, even in the era of novel therapies. Physical functional trajectories during treatment are variable among individual pts, underscoring the need for personalized treatment strategies and reassessment of geriatric domains throughout treatment.

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 Background: The landscape of healthcare delivery in hematology has undergone significant transformations with the increasing adoption of telehealth services for appointments and communications in conjunction with the 2016 21st Century Cures Act providing patients complete access to their health information. Digital healthcare services in hematology offer benefits, including convenience and equitable access to those limited by travel or financial burdens. However, they also have inherent risks, including loss of in-person communication, disparities in access to technology, differences in digital literacy, and increased provider workload and burnout. Thus, we analyzed contemporary utilization patterns of hematology healthcare and provider preferences to optimize implementation of evolving hybrid care models. Methods: We analyzed data from the Mayo Clinic (Rochester, MN) Hematology Appointments Office and the Hematology Call Center as well as digital messaging practices using Epic's SlicerDicer tool. Data was collected between January 2023 and January 2025, during which patients had access to the electronic health record (EHR) and direct messaging capabilities. An optional survey was distributed to Hematology providers including physician consultants, fellows, and advanced practice providers (APP) to assess practice preferences. Results: During the analyzed period, a total of 85,899 hematology appointments were completed and captured all adult ages, including 18-34 (4.6%), 35-49 (9.2%), 50-64 (25.3%), 65-79 (48.3%), and 80+ (12.6%). Although in-person, video, and telephone visit options were available, in-person visits predominated across all age groups, with 80.6% of all completed appointments occurring in-person, 12.9% via video, and 6.5% via telephone. Notably, patients aged 80+ had the second highest combined use of video and telephone visits, with over 20% of their appointments conducted virtually. There was a total of 6,893 no-show and cancelled appointments, with 79.9% of these scheduled in-person, 14.8% via video, and 5.3% via telephone. There were over 4,000,000 portal messages in the hematology division with over 1,000,000 sent directly to hematology providers. Patients sent 105,284 new messages, of which 47.2% were new patient advice requests to providers which cascaded to 343,103 additional messages. Patients made 155,036 telephone calls, which cascaded to 407,578 messages over the portal, 78.5% of which were sent directly to providers. Notably, utilization of both portal messaging and telephone calls was similar across all age cohorts, including those 80+ years. Providers only initiated 14,159 new messages to patients yet sent a total of 354,172 messages. The hematology provider survey had a response rate of 42% (53 of 129). Respondents included 45.3% consultants, 45.3% fellows, and 9.4% APPs. 92.5% and 90.6% of providers preferred in-person appointments for new visits and established visits on therapy, respectively. In contrast, 52.8% preferred virtual appointments for established patients not currently receiving therapy. 73.6% and 52.8% of survey respondents either strongly agreed or agreed that virtual appointments are advantageous for patients and providers, respectively. Additionally, only 49.1% felt portal messages were necessary to provide high quality care and 64.2% preferred appointments over communicating through messages. 86.8% of providers reported spending more than 30 minutes daily responding to in-basket messages, however, 94.3% reported not routinely billing for their time. Conclusions: In the digital era, hematology healthcare delivery is multifaceted and increasingly demanding with high rates of patient engagement in their care via various mediums. To our knowledge, this is the largest analysis combining EHR utilization and appointment data with provider preferences to better understand digital hematology care. Digital appointments and communications were common amongst all age groups, including older patients, and had relatively low cancellations rates. Promotion of virtual visits to facilitate patient-provider conversations in addition to standardization of digital communication workflows are low-risk, high-yield interventions to mitigate the cascading of EHR-based communications, especially for those not actively receiving therapy. Together, these could decrease provider burnout while increasing healthcare system operational capacities to provide optimal patient care and satisfaction.

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.