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TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

e19023 Background: Undetectable measurable residual disease (uMRD) is associated with prolonged progression free survival in patients with chronic lymphocytic leukemia (CLL) (Rios-Olais et al., 2024). Peripheral blood (PB) MRD testing is less invasive and allows more frequent MRD monitoring than bone marrow (BM) MRD testing. As MRD testing and MRD-guided time-limited therapies become more common, there is a need to determine the concordance between rates of uMRD in the PB and BM. Methods: We performed a systematic review and meta-analysis of studies in CLL to determine the concordance between rates of uMRD in the PB and BM. Prospective clinical trials evaluating first-line, time-limited treatment of CLL with targeted agents or anti-CD20 monoclonal antibodies (mAbs) were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception until December 15 th , 2025. Studies were included if they reported rates of BM and PB uMRD at the same timepoint using the same method of MRD testing. Study arms evaluating chemotherapy, single-agent targeted therapy or single-agent anti-CD20 mAbs were excluded. Study sample size, number of patients receiving MRD testing, rates of uMRD in PB and BM, time and method of MRD testing, depth of MRD testing, and treatment arm were extracted. The agreement of uMRD rates between PB and BM was assessed using intraclass correlation coefficients (ICC). Results: 3128 studies were identified on initial search. After study selection criteria were applied, 24 timepoints across 12 prospective clinical trials were analyzed. Across all timepoints, 3121 PB and 2782 BM MRD measurements were included. All timepoints defined uMRD at a depth of under 0.01% CLL cells (10^-4). 20/24 timepoints utilized flow cytometry for MRD testing, 3 utilized allele-specific oligonucleotide PCR (ASO-PCR), and one utilized next-generation sequencing (NGS). 8 timepoints evaluated patients treated with a BTK inhibitor + venetoclax, 10 evaluated patients treated with venetoclax + an anti-CD20 mAb, and 6 evaluated patients treated with triplet therapy. The ICC between rates of uMRD in PB and BM was 0.925 (95% CI: 0.89, 0.95), indicating an excellent degree of agreement between the two methods of testing.(Koo & Li, 2016) The mean uMRD rates in PB and BM were 70.1% and 64.3%, respectively. The mean rate of uMRD in the PB was 5.87% (95% CI: -7.05, 18.80%) higher than in the BM; indicating a consistent slight bias of higher PB uMRD rates compared to BM across timepoints. Conclusions: Overall, we demonstrate that in patients with CLL treated with modern, time-limited therapy, there is high concordance in uMRD rates between PB and BM. Rates of uMRD in the PB are typically slightly higher than in BM.

1503 Background: CAR T-cell therapy has revolutionized treatment outcomes in hematological malignancies, but has traditionally required inpatient post-infusion monitoring, which is associated with significant cost and time toxicity. Outpatient CAR T infusion and monitoring has been the standard approach at Mayo Clinic site in Rochester, MN, with demonstrated feasibility and safety (Bansal et al., ASCO 2023). We present data comparing healthcare utilization between CAR T recipients who underwent outpatient remote monitoring and those with traditional inpatient monitoring. Methods: Electronic medical records were retrospectively analyzed for 293 patients who received CAR T-cell therapy for a hematological malignancy at any of the 3 Mayo Clinic sites (MN, AZ, FL) between 2020 and 2024 . Healthcare utilization was compared between patients who received outpatient CAR T with remote patient monitoring in Rochester, MN (N = 125) and those who received inpatient CAR T in the Arizona (n = 90) and Florida (n = 78) sites. Per protocol, patients in the inpatient group underwent mandatory inpatient monitoring for 7 days, with extension per provider discretion. Data was analyzed through Chi-Square and Wilcoxon tests. P values < 0.05 were considered statistically significant. Results: There was no significant difference in baseline sex, age, ethnicity, LDH, platelets, or neutrophils among the 293 patients. Diagnoses included lymphoma (n = 175), multiple myeloma (n = 106), and B-ALL (n = 12). The most common CAR T-cell products used were axicabtagene ciloleucel (n = 138) idecabtagene vicleucel (n = 56), and ciltacabtagene autoleucel (n = 50). Median hospital days were lower in the outpatient group vs the inpatient group at 30 days (4.4 vs 13.3, P < 0.001) and 90 days (4.6 vs 13.6, P < 0.001). ICU admission occurred in 1 outpatient patient ( < 1%) vs 18 inpatient patients (11%) in the first 30 days (P < 0.001). In the first 30 days, 22% of patients in the outpatient group did not require hospitalization, while 56%, 15%, and 6% required 1, 2, and 3 hospitalizations, respectively. Similarly, only 11 (8.8%) patients in the outpatient group had ≥1 ED visit in the first 30 days compared with 32 (20%) pts in the inpatient group (P = 0.009). At 30 days, there was no difference in patient portal use, with 58% of patients using the portal at least once and a median of 1 message in both groups. Within the first 30 days, 53% and 2% of patients in the outpatient group required 1 and 2 outpatient visits, respectively, vs 29% and 2% in the inpatient group (P < 0.001). There was no difference in 30-day mortality (1.6% outpatient vs 2.4% in inpatient) between the 2 groups (P = 1.00) Conclusions: Outpatient CAR T-cell therapy monitoring was associated with significantly fewer hospital days without increased ED visits, ICU stays, portal use, or 30-day mortality. This demonstrates lower healthcare utilization for outpatient CAR-T therapy.

1056 Background: Resistance to HER2-directed therapies remains a major challenge in HER2-positiveMBC. In preclinical models, HER2+ tumors overexpress poly (ADP-ribose) polymerase (PARP), and PARP inhibition induces apoptosis through NF-κB suppression even in the absence of pathogenic mutations in BRCA 1/2 . We evaluated the safety, efficacy, and translational correlates of niraparib combined with trastuzumab in patients (pts) with refractory HER2+ MBC. Methods: This open-label Phase 1b/2 trial (NCT03368729) enrolled pts with HER2+ MBC (IHC 3+ and/or FISH amplified), measurable disease, LVEF ≥50%, and progression on ≥1 prior HER2-targeted therapy; stable CNS disease was allowed. Pts with germline BRCA1/2 mutations or prior PARP inhibitor exposure were excluded. Niraparib 300 mg orally was administered on Days 1–21 of a 21-day cycle with trastuzumab 6 mg/kg IV every 3 weeks (loading dose 8 mg/kg on cycle 1). The Phase 2 portion used a Gehan/Simon two-stage design with early stopping for futility (P0=24%); ≥1 response among the first 20 patients triggered expansion to 40 patients. ORR was assessed by RECIST v1.1, meeting the primary endpoint and allowing response rate estimation with <7% standard error and a two-sided 95% exact CI width of 0.28. Gene expression profiling of paired tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed using the NanoString nCounter Tumor Signaling 360 panel at pretreatment compared to cycle 2. Results: Forty-six pts were enrolled (9/2019–2/2025); 41 were evaluable for response. Pts were heavily pretreated (median 3 prior regimens), including trastuzumab deruxtecan in 22 pts; 33% had brain metastases. Treatment-related adverse events were predominantly grade 1–2 and manageable. Clinical benefit rate (CBR) was 44% (18/41) including 1 complete response, 2 partial responses, and 15 stable disease. Eleven patients achieved disease control ≥ 6 months; 1 patient remained on treatment at data cutoff. Tumor profiling revealed enrichment of a B-cell–driven tertiary lymphoid structure signature with reduced hypoxia signaling in responders. Matched PBMC analyses demonstrated coordinated downregulation of interferon signaling, DNA damage response, metabolic activation, angiogenesis, and resistance pathways in clinical responders, whereas non-responders retained signatures of chronic stress and immune exhaustion. Conclusions: Niraparib plus trastuzumab demonstrated a favorable safety profile and durable clinical benefit in heavily pretreated HER2+ MBC. Integrated tumor and blood-based analyses identify immune-organized tumor microenvironments and systemic immune normalization as key correlates of prolonged response, supporting further investigation of PARP inhibition strategies. Clinical trial information: NCT03368729 .

Abstract Background Human granulocytic anaplasmosis (HGA) can cause severe illness requiring intensive care, but factors associated with critical illness among hospitalized patients are incompletely described. Method We performed a retrospective multicenter cohort study of adults hospitalized with PCR-confirmed HGA at Mayo Clinic Rochester and affiliated Mayo Clinic Health System sites in Minnesota and Wisconsin from 2014 through 2024. Patients who required ICU-level care were compared with those managed on general medical wards using exploratory univariate analyses (Fisher exact and Kruskal–Wallis tests). Results Among 101 hospitalized patients, 12 (12%) required ICU-level care. Symptoms documented at hospital presentation/admission were more frequent in ICU patients, including vomiting (64% vs 30%) and abdominal pain (55% vs 26%). On admission, ICU patients had lower sodium (mean 128.8 vs 132.3 mmol/L) and higher total bilirubin (mean 1.3 vs 0.8 mg/dL). Platelet nadir during hospitalization was lower in ICU patients (mean 54.8 × 109/L vs 84.1 × 109/L). Peak ferritin, measured in a subset, was markedly higher in ICU patients (median 21 666 vs 961 µg/L). The composite endpoint of HGA-related complications or serious treatment-related adverse events occurred more often in ICU patients (75% vs 17%); one death occurred in the ICU group. Conclusions In hospitalized adults with HGA, ICU-level care was associated with gastrointestinal symptoms at presentation/admission, admission hyponatremia and hyperbilirubinemia, lower platelet nadir, and marked hyperferritinemia when measured. Because these findings were derived from univariate group-level comparisons with substantial overlap between groups, they should be viewed as hypothesis-generating rather than individually predictive or sufficient as stand-alone triage criteria.

Abstract Rationale Interstitial lung abnormalities (ILA) are abnormal findings on chest CT scans that may represent early-stages of interstitial lung disease. The presence of fibrosis (traction bronchiectasis and/or honeycombing) identifies those with ILA at an increased risk for mortality, however, determining who will progress remains a challenge, and the role of blood-based biomarkers in ILA risk-stratification is unknown. Methods Data from four prospective cohort studies were used to identify associations between plasma proteins measured with DNA aptamers (SomaScan) and ILA, fibrosis, and mortality. The Genetic Epidemiology of COPD Study (COPDGene) was used to identify protein associations, and findings were replicated by meta-analysis of the Age, Gene/Environment Susceptibility-Reykjavik study (AGES-Reykjavik), SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS), and Framingham Heart Study (FHS). Protein associations with ILA and with fibrotic ILA compared to non-fibrotic ILA were performed using multivariable logistic regression; among those with ILA, Cox proportional hazards models were used to identify protein associations with mortality. Models were adjusted for age, gender, race, BMI, smoking status, pack-year smoking history, and for mortality, COPD. Benjamini-Hochberg false discovery rate p-values &lt;0.05 were considered significant. Results 524 (10.7%) of 4,899 COPDGene participants had ILA, of whom 57 (10.9%) had fibrosis; of 8,146 AGES-Reykjavik, SPIROMICS and FHS participants included in the meta-analysis, 666 (8.2%) had ILA, of whom 198 (29.7%) had fibrosis. In COPDGene, 230 proteins were associated with ILA; the most significant of which were SFTPD (adjusted odds ratio per standard deviation [SD] of protein [OR]=2.21, p = 3.7E-41) and SFTPB (OR = 1.82, p = 7.9E-37). In the meta-analysis, 159 of the ILA-associated proteins were replicated. Of the 230 ILA-associated proteins in COPDGene, 9 were associated with fibrosis, and 5 of these 9 proteins were associated with mortality among those with ILA. The 5 proteins associated with all three outcomes were WFDC2 (ORILA=1.90, p = 2.6E-34; ORFibrosis=2.00, p = 0.0001; adjusted hazards of mortality per SD of protein [HR]=1.59, p = 3.4E-05), GDF15 (ORILA=1.67, p = 3.6E-23; ORFibrosis=1.78, p = 0.0006; HR = 1.63, p = 1.4E-06), SCGB3A1 (ORILA=1.52, p = 4.5e-14; ORFibrosis=1.80, p = 0.0002; HR = 1.25, p = 0.02), TREM1 (ORILA=1.44, p = 1.4e-14; ORFibrosis=1.62, p = 0.001; HR = 1.25, p = 0.02) ICAM5 (ORILA=1.42, p = 1.2e-11; ORFibrosis=1.79, p = 0.0001; HR = 1.31, p = 0.002). In the meta-analysis, 6 of the 9 fibrosis-associated proteins and all 5 ILA mortality-associated proteins replicated. Conclusion This represents the first plasma proteomic screen demonstrating reproducible biomarker associations not only with ILA presence, but also with measures of severity and adverse outcomes. These results provide compelling targets for further study, including their prospective evaluation as clinical biomarkers for early disease identification and prognostication. This abstract is funded by: Multiple Sources

Augmented cardiovascular responses to spontaneous nocturnal arousals were previously shown in chronic short-sleeping adults, without known sex differences. Sustained 4-h sleep restriction produced a sex-dependent alteration in heart rate responses to arousals and resulted in a prolonged reduction in postarousal pulse transit time in females only. These findings yield the first sex-specific characterization of nocturnal cardiovascular responses to spontaneous arousals following sleep restriction, and may place females at greater sleep truncation-related cardiovascular disease risk.

PURPOSE Remote symptom monitoring using patient-reported outcomes (PROs) has been shown to improve symptom control and physical function among patients with advanced cancer. However, it is unclear whether these benefits are similar across demographic groups. This exploratory analysis of the PRO-TECT trial examined whether the effects of electronic symptom monitoring varied by race, age, sex, and educational attainment. METHODS PRO-TECT was a cluster randomized trial conducted across 52 US community oncology practices comparing weekly electronic symptom monitoring with usual care (UC). Adult patients with metastatic solid tumors receiving systemic therapy were enrolled (N = 1,191). Participants in the PRO arm completed weekly symptom surveys including the PRO-CTCAE, triggering alerts to the care team for severe or worsening symptoms. Patients chose whether to complete weekly PROs online or via telephone-based interactive voice response not requiring Internet access. Outcomes were measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 symptom control and physical function scales. Subgroup analyses were performed by race (Black v White), age (<65 v ≥65 years), sex (male v female), and educational attainment (≤high school v >high school). RESULTS From baseline to 3 months, PRO participants showed greater improvements in symptom control (+2.37 v −0.20, P = .002) and physical function (+1.54 v −0.93, P = .02) versus UC. Benefits were most pronounced among younger, female, Black, and less educated participants. Black participants in the PRO arm were more likely to report that symptom reporting made them feel more in control of their care compared with White participants. CONCLUSION Electronic symptom monitoring improved quality-of-life outcomes overall, including among groups who have historically experienced higher symptom burden or barriers to communication. Remote PRO systems may represent an equitable strategy to enhance cancer care delivery.

Background: Preliminary evidence examining ibogaine in neuropsychiatric and substance use disorders is accumulating. As patient interest and off-label use grow, clinicians require an understanding of emerging dosing strategies, investigational protocols, and reported adverse effects to appropriately counsel patients and contextualize potential risks and benefits. Methods: Databases were searched for human studies of ibogaine, noribogaine, or 5-MeO-DMT with relevant clinical outcomes, prioritizing randomized controlled trials (RCTs), microdosing paradigms, and sequential protocols. Results: Only three RCTs were identified. First, a double-blind pilot study in 20 cocaine-dependent adults found that a single 1800 mg dose of ibogaine was associated with reduced craving versus placebo over follow-up of up to 24 weeks. Second, an ascending-dose trial in 36 healthy volunteers showed that noribogaine doses of 3–60 mg were safe and well-tolerated, without opioid-agonist effects. Third, a randomized crossover trial in 27 opioid-dependent patients receiving noribogaine 60–180 mg demonstrated dose-dependent heart rate-corrected QT interval (QTc) prolongation with non-significant reductions in withdrawal symptoms. Thus, two RCTs enrolled substance-dependent populations, while one focused on safety and pharmacokinetics in healthy volunteers. Microdosing and escalating sequential protocols remain experimental, lack standardized definitions, and are supported only by preliminary observational data. Adverse effects include neurologic, psychiatric, and cardiac events, including QTc prolongation; fatalities have occurred in the presence of medical and substance use comorbidities. Conclusions: The available evidence is confined to case reports, observational analyses, and small early-phase or proof-of-concept studies. Given ibogaine’s cardiotoxicity and narrow therapeutic margin, clinical use cannot be recommended without confirmation from larger, well-controlled trials.

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: &gt;50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of &lt; 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 &lt; 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)