Willman, Cheryl L.

Importance Decentralized clinical trials (DCTs) aim to increase trial access for underrepresented populations (URP) and ensure study outcomes, conclusions, and policy-related decisions are applicable to diverse populations. Objective To assess trends in the percentage of accrued participants from more than 120 miles from the research site upon DCT program implementation. Design, Setting, and Participants This descriptive quality improvement study was conducted from January 2024 to March 2025 at Mayo Clinic, a US multiregional, academic medical center (AMC) comprising 3 sites and an affiliated, community-based health care system. All individuals who consented and/or accrued to an institutional review board–approved clinical trial were included. Exposure DCTs are defined as trials with at least 1 decentralized capability beyond remote consent. DCT program development began July 2022. By January 2024, remote consent, video telehealth visits, remote phlebotomy, and device services were implemented across all sites and departments. Remote monitoring and oral medication delivery were available on a limited basis. Prospective automated program and DCT participant data collection and quarterly reporting began in January 2024. Main Outcomes and Measures Percentage of all DCT accrued participants with a residential zip code more than 120 miles from 1 of 3 AMC sites. Results There were 7469 participants (median [IQR] age, 62 [51-70] years; 3594 [48.1%] female; 241 [3.2%] Asian, 391 [5.2%] Black or African American, and 6347 [85.0%] White individuals) accrued to 765 DCTs. During the study period, the percentage of DCT participants residing more than 120 miles from an AMC site ranged from 18.9% in the first quarter (Q1) of 2024 (383 of 2032 participants) to 29.6% in Q1 of 2025 (346 of 1170 participants). Of those accrued, 1147 (15.4%) were of a racial or ethnic URP, ranging from 12.5% in Q1 of 2024 (253 participants) to 17.4% in Q1 of 2025 (204 participants). There were 1554 (20.8%) participants from a rural location, ranging from 16.6% in Q1 of 2024 (338 participants) to 24.9% in Q1 of 2025 (291 participants). Additionally, by geospatial distance from an AMC site, the male-to-female ratio was nearly 50:50, and the age distribution appeared similar. Conclusions and Relevance In this quality improvement study of a DCT program implementation, DCT accruals trended favorably among those residing more than 120 miles from an AMC site and those of rural or URP populations. While these findings cannot be directly attributed to program implementation, they are reassuring that this strategy may address some barriers to clinical trial access. Future studies should assess the sustained effectiveness and scalability of DCT models in improving equitable trial access.

817 Background: Universal germline sequencing is increasingly utilized in practice, but existing evidence and guidelines are based on studies in predominantly white populations. This study aims to compare the prevalence of genetic alterations in white vs underrepresented minority (URM) populations and assess incremental findings discovered with universal testing beyond current guidelines. Methods: This prospective, multicenter study analyzed genetic alterations in white and URM cohorts with primary GI malignancies receiving care at Mayo Clinic cancer centers between April 2018 and April 2025. Patients underwent germline sequencing using a next-generation sequencing (NGS) platform targeting over 80 genes. We compared the distribution of results between white and URM populations. Concordance with NCCN testing guidelines and incremental findings were assessed. Results: A total of 1128 patients were studied, of which 758 were white and 370 were URM, (47.6% Hispanic, 22.7% Black, 13.8% Asian, 10.5% American Indian, 0.8% Pacific Islander, and 6.8% other). Pathogenic variants (PGV) were more common in the white population (16.1% vs 9.2% P < 0.001). Variants of uncertain significance (VUS) were more common in the URM population (53.2 vs 43.5%, P<0.001). A total of 156 patients were found to have a PGV. PGVs outside primary cancer genes were more common in white patients (57.4% vs. 32.4%; p=0.0241). Incremental findings from universal testing were higher in white patients (66.4% vs 35.3%; p=0.0011). Conclusions: This study reveals a significant difference in the prevalence of PGV and VUS between white and URM patients with primary GI malignancies. The higher rate of PGVs in white patients and VUS in URM patients highlights potential inequities in both detection and interpretation of genetic results. These findings emphasize the need for broader representation in genetic databases to ensure equitable access to precision oncology. Screening guidelines met by patients with PGV. White (N=122) URM (N=34) Total (N=156) p value Did they meet NCCN testing guidelines for their primary cancer? 0.0991 Yes 87 (71.3%) 29 (85.3%) 116 (74.4%) No 35 (28.7%) 5 (14.7%) 40 (25.6%) Was the PGV outside of the primary genes recommended for their primary cancer? 0.0241 Yes 70 (57.4%) 11 (32.4%) 81 (51.9%) No 47 (38.5%) 22 (64.7%) 69 (44.2%) Incremental Finding 0.0011 Yes 81 (66.4%) 12 (35.3%) 93 (59.6%) No 41 (33.6%) 22 (64.7%) 63 (40.4%)

Abstract Introduction:A comprehensive integration of significantly mutated genes and pathways with molecular subgroups is lacking in adult B-ALL. Furthermore, the genomic drivers underlying each subgroup remain to be identified.We aimed to perform genomic analysis on a large cohort of patients with adult B-ALL, and to correlate genomic markers with achievement of MRD negativity enabling blinatumomab randomization, and with subsequent response to blinatumomab. Methods:For genomic analysis, we studied 569 adults with newly diagnosed B-ALL registered for initial screening on the ECOG-ACRIN-led E1910 trial (NCT02003222), which evaluated the addition of blinatumomab to standard consolidation chemotherapy. The median age was 52 yrs (range 30 to 71 yrs), with 52% males. Analysis was performed on tumor and matched-normal samples using whole transcriptome sequencing (RNA-seq; tumor only; n=569), whole exome sequencing (n=490), whole genome sequencing (n=131), and single nucleotide polymorphism array (n=445). B-ALL cases were classified into 22 molecular groups. Outcome analysis was limited to patients enrolled and treated on E1910 (n=319). Results: Driver genes (n=268) were identified by the mutation-significance detection tool dNdScv or by the presence of pathogenic variants in known cancer genes, with NUP188 identified as a novel driver gene. Recurrently mutated pathways included: B-cell development (46%), cell cycle (44%), epigenetic regulation (30%), other transcriptional regulation (27%), Ras signaling (25%), RNA machinery (17%) and JAK-STAT signaling (8%). A high frequency of high-risk subtypes was observed including BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A (12%). Using tSNE analysis, we identified a new cluster of cases (n=20, 3.5%) lacking a known subgroup driver, with overexpression of CEBPA (n=13) or CEBPB (n=7), distinct from CEBPE/ZEB2, termed “CEBP-altered” ALL (CEBPalt). Five of 13 cases with high CEBPA expression harbored an IGH::CEBPA rearrangement and one harbored a RXRA::CEBPA enhancer hijacking alteration. Of the 7 cases with high CEBPB expression, 5 harbored IGH::CEBPB, and two of these had concomitant clonal BCR::ABL1 fusions. To identify additional mechanisms of CEBP deregulation, in situ Hi-C coupled to H3K27 acetylation immunoprecipitation (HiChIP) was performed on 5 cases. Four cases showed evidence of de novo CEBPA enhancer activity. In two cases, we identified novel insertions (12 and 34nt) ~2kb downstream of CEBPA. A novel translocation and enhancer hijacking event between LINC00426 and the 5' UTR of CEBPB was identified in the remaining case. Overall, we confirmed genomic alterations of CEBPA or CEBPB in 16 of 20 cases with available material. Thus, we have identified a new molecular subgroup of adult B-ALL characterized by genomic alterations that drive enhancer hijacking and oncogenic deregulation of CEBPA/CEBPB. Several subgroups were enriched in patients that failed induction chemotherapy (n=62) or were MRD-positive (n=63) compared to those that achieved MRD-negative status (n=194): BCR::ABL1-like (30 vs 14%, p&lt;0.001), KMT2A (18 vs 9%, p=0.03) and BCL2/MYC (5 vs 1%, p=0.06). Conversely, the following subgroups were enriched in patients that achieved MRD-negativity: PAX5alt (6 vs 18%, p=0.002), TCF3::PBX1 (0 vs 5%, p=0.01) and ZNF384 (2 vs 6%, p=0.08) Within each molecular subgroup we compared the survival of patients who achieved MRD-negative status after induction and were randomized to receive blinatumomab plus chemotherapy (n=93) or chemotherapy only (n=91). Although numbers were low, blinatumomab improved relapse-free survival for patients with hyperdiploid, PAX5alt, BCR::ABL1-like and KMT2A ALL compared to chemotherapy alone. Clonal hematopoiesis of indeterminate potential (CHIP)-related gene mutations were identified in 121 of 417 cases analyzed (29% total: somatic 74%, remission 31%, both 5%). TP53 mutations were most frequent (n=65 patients), with the majority identified in patients with low hypodiploid (n=52). Interestingly, patients with CRLF2 rearrangements collectively harbored the highest number of other CHIP gene mutations (n=13), including DNMT3A (n=4), TET2 (n=3) and ASXL1 (n=3). Conclusions:We provide a comprehensive landscape of genomic alterations in adult B-ALL and identify a new group characterized by deregulation of CEBPA/CEBPB (CEBPalt). We also provide insights into the efficacy of blinatumomab in different molecular subgroups of adult B-ALL.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Abstract Next-generation sequencing has transformed cancer care by providing essential insights for diagnosis, prognosis, and treatment. However, variability in testing timing, reporting practices, and interpretation challenges limits its clinical impact. This article highlights key opportunities to optimize somatic reporting, emphasizing the importance of timely testing throughout the cancer care continuum to maximize the diagnostic and therapeutic relevance of findings. Technical factors such as test design, sequencing depth, and the use of liquid biopsy substantially influence result accuracy and interpretation, underscoring the need for careful integration with clinical history. Standardized reporting practices that clearly delineate diagnostic, prognostic, and therapeutic findings can enhance the clinical utility of next-generation sequencing results. Streamlined formats and curated clinical trial data further support actionable decision making. Additionally, direct patient engagement and education are essential for empowering patients to navigate genomic testing and make informed decisions about their care. By leveraging multidisciplinary tumor boards, decision-support tools, and emerging artificial intelligence technologies, clinicians can better navigate the complexities of somatic reports. Standardization and clarity in reporting are critical to advancing precision oncology, empowering providers and patients to make informed treatment decisions and improve outcomes.

LBA1551 Background: Traditional cancer therapy is primarily delivered in clinical settings, imposing logistical, emotional, and financial burdens, particularly on rural and underserved patients. While international studies have demonstrated the safety of home-based chemotherapy, no randomized U.S. trials have evaluated this approach. Mayo Clinic’s CCBW program aims to expand access to high-quality cancer care by providing in-home cancer treatment, lab testing, telemedicine, remote patient monitoring, command center and paramedic support. This pragmatic randomized controlled trial evaluates feasibility and impact of home-based versus in-clinic cancer directed therapy on patient preference, acceptability, safety, and patient-reported outcomes. Methods: Adult patients (ECOG 0-2) receiving chemotherapy or hormonal therapy at Mayo Clinic Florida were randomized 1:1 after confirmation of treatment tolerance in clinic to receive (1) home-based care for 24 weeks or (2) in-clinic care for 8 weeks followed by home-based care for 16 weeks. Target accrual is 200 patients. A planned interim analysis after 50 enrollments assessed accrual, data completeness, technical challenges, safety, and study outcomes. The primary endpoint is patient ratings of their overall cancer care experience (0–10 scale, CAHPS Cancer Care Survey) at 8 weeks. 200 patients provide 80% power to detect a 0.45 standard deviation difference in mean ratings between arms with a 2-sided 2-sample t-test (α=0.05) and 20% missing data rate. Secondary endpoints are patient preference, comfort with home infusions, treatment worthwhileness, functional/symptom assessments (EORTC QLQ-F17, PRO-CTCAE, GP5), grade ≥3 AEs, hospitalizations, and overall survival. Cost is a tertiary endpoint. The trial is IRB-approved (#23001719) and registered (NCT05969860). Results: Enrollment began 8/23/23. As of 2/21/25, 52 patients (26 per arm) were enrolled and 36 started protocol treatment. Common cancers were breast (38%), colorectal (21%), prostate (19%), and multiple myeloma (14%). 64% (28/44) of patients were female; 84% identified as White, 14% as Black, and 2% as multiple races. Median distance to clinic was 20 miles (range 2-66). After 8 weeks, patients in both arms rated their overall cancer care experience highly (mean [SD]=9.69 [0.85] versus 9.54 [0.66] for home-based vs. in-clinic care, n=26). After 24 weeks, 73% preferred home-based care, 18% had no preference, and 9% preferred in-clinic care; 100% felt comfortable with home infusions. No grade ≥3 AEs related to location of care have occurred. Conclusions: Early findings support the feasibility, safety, and high patient acceptability of home-based cancer therapy. No safety concerns related to care location were observed and most patients preferred home-based treatment. Ongoing accrual and analysis will assess clinical outcomes and cost implications. Clinical trial information: NCT05969860 .

TPS1657 Background: Cancer treatments are traditionally administered in clinical settings, which can isolate patients from their familiar environments and exacerbate physical, psychosocial, and financial burdens. Travel requirements further amplify these challenges, particularly for underserved populations. Studies indicate that patients prefer receiving care at home, and international models have demonstrated the safety of home-delivered chemotherapy since the 1990s; however, no U.S. clinical trial data exists. In response, Mayo Clinic has developed the Cancer CARE (Connected Access and Remote Expertise) Beyond Walls (CCBW) program, a distributed cancer care delivery model that expands access to quality cancer care by bringing it to the home environment, providing in-home cancer treatment, lab testing, telemedicine, and community paramedic support. This trial evaluates the safety, acceptability, and impact of home-based subcutaneous (SC) nivolumab (Nivo) administration compared to in-clinic treatment within the CCBW initiative. Methods: This open-label, single-arm trial evaluates the impact of SC Nivo administration location—home versus infusion center—on patient reported cancer care experience, patient-preferred treatment location, acceptability, safety, and patient-reported outcomes. Eligible adult patients (ECOG 0-1) receiving IV Nivo for an FDA-approved indication and residing within 75 miles of Mayo Clinic Florida will transition to SC Nivo, receiving two initial in-clinic cycles. If tolerated without injection reactions, four cycles will be administered at home before resuming in-clinic treatment. Exclusion criteria include concurrent investigational/standard treatments or contraindications to immunotherapy. Fifty patients will be enrolled, with an estimated 75% (n=38) providing cancer care ratings after 8 weeks in-clinic and 8 weeks at-home, offering 85% power to detect a mean difference in ratings of 0.50 standard deviations. The primary endpoint is within-patient change in cancer care rating (0–10 scale, CAHPS Cancer Care Survey) comparing 8 weeks of in-clinic vs. at-home care. Secondary endpoints include patient-preferred treatment location, comfort with home injections, safety (grade 3+ adverse events), function (EORTC QLQ-F17), symptoms (PRO-CTCAE), side effect impact (GP5), and healthcare utilization (ER visits, hospitalizations). Cost will be assessed as a tertiary endpoint. The trial has FDA approval (IND #170079), Mayo Clinic IRB approval (#23009663), and ClinicalTrials.gov registration (NCT06265285). Enrollment began in April 2024, with an expected accrual period of 24 months. To date, 10 patients have been enrolled, and final analysis is expected 2.5 years after trial activation. Clinical trial information: NCT06265285 .

NPM1 mutations (NPM1+) are found in about 30% of adult AML. While NPM1+ are generally associated with favorable risk, prior studies have shown that NPM1+ older patients, defined as ≥ 65 years, have significantly worse outcomes. The updated European Leukemia Net 2022 (ELN22) now classifies NPM1+ AML patients with FLT3-ITD (ITD+) and MDS-associated mutations (MDSm+) as adverse-risk, while NPM1+/ITD-/MDSm+ patients remain favorable-risk unless they have an adverse-risk karyotype. A recent report (Chan et al., Blood Adv 2024) found MDSm+ conferred worse OS only in patients ≥ 60 years; however another report (Othman et al., Blood 2024) did not find MDSm+ were significantly associated with adverse outcomes in a larger cohort of NPM1+ patients. To further assess this question, we examined the mutational landscape in a large cohort of pre-treatment, diagnostic specimens from 456 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112) and 126 patients from the UW/FHCC Hematopoietic Repository (Total N=582). Patients were treated with curative intent as per standard practice or clinical trials. Out of the 582 patients, 191 were NPM1+ (33%), of which 148 patients had cytogenetic and long-term outcome data. Kaplan-Meier and cumulative incidence estimates were estimated. C-statistics and AUC for Cox, cause-specific and logistic regression models for overall survival (OS), event-free survival (EFS), time to relapse (TTR, calculated in n=106 who achieved complete remission [CR], death in remission analyzed as a competing risk) and CR were calculated for age, ELN17, and ELN22, as well as ELN17 and ELN22 adjusting for age. ELN17 favorable-risk patients reclassified as adverse-risk (N=5 of 108) demonstrated significantly shorter EFS (HR=2.50, p=0.05) and CR rate (OR=0.20, p=0.024), although with similar OS (HR 1.30, p=0.66) and TTR (HR=1.20, p=0.86). ELN17 favorable-risk patients reclassified as ELN22 intermediate-risk (N=23 of 108) did not show a significant difference in OS (HR 1.47, p=0.20), EFS (HR 1.35, p=0.12), CR rate (OR 0.75, p=0.46), or TTR (HR=1.64, p=0.11) compared to ELN22 favorable-risk. For ELN17 intermediate-risk (N=40), 5 patients were reclassified as ELN22 adverse-risk (12.5%) and had significantly shorter EFS (HR 2.89, p=0.037) compared to ELN22 intermediate risk, although there was not a significant difference in CR rate (OR 0.31, p=0.23) or OS (HR 0.81, p=0.67). We next compared the prognostic significance of age relative to ELN risk classification. Age was associated with higher C-statistics (OS=0.65, TTR=0.57 and EFS=0.60) and AUC (CR=0.64) compared to both ELN17 (OS=0.56, TTR=0.54, EFS=0.54, CR=0.54) or ELN22 (OS=0.57, TTR=0.57, EFS=0.57, CR=0.58). The combination of age and ELN22 resulted in the highest C-statistics for OS, TTR, and EFS (OS=0.68, TTR=0.60, EFS=0.64). To further assess the impact of MDSm on risk-stratification of NPM1+ AML, we performed multivariable analyses adjusting for FLT3-ITD, MDSm, and age in patients without adverse-risk disease. These analyses showed MDSm did not have a significant association with OS when controlling for age or FLT3-ITD. We also compared ELN22 favorable-risk patients with and without MDSm (MDSm+ N=18; MDSm- N=61). Compared with the MDSm-, there was a trend toward an inferior OS (HR 1.85, p=0.054) for MDSm+ patients but not EFS (HR 1.38, p=0.3) or TTR (HR 1.2, p=0.64). When stratified by age (&lt;65, N=53 vs. ≥65, N=26), MDSm+ in younger patients did not show a difference for OS (HR 0.96, p=0.96), EFS (HR 0.63, p=0.53) or TTR (HR 0.4, p=0.37). Older ELN22 favorable-risk patients (≥65) had similarly poor OS (MDSm- HR 3.33 and MDSm+ 3.27, respectively, p=0.001 for both) and EFS (MDSm- HR 3.11 and MDSm+ 2.39, p=0.001 and 0.01) compared to younger MDSm- patients. In our study, the ELN22 guidelines incrementally improve risk stratification for EFS in NPM1+ patients. However, age remains the most prognostic factor, and patients ≥ 65 years have similar adverse clinical outcomes, whether classified as favorable risk by ELN17, ELN22, or incorporating MDSm. Moreover, MDSm do not confer a worse prognosis in NPM1+ patients when accounting for age or FLT3-ITD status. These findings differ from a recent report by Chan et al. and are in keeping with the report by Othman et al. Therefore, further understanding of the underlying biology of age and its effect on NPM1+ AML is needed to improve outcomes for older patients.