Independent Adjudication Committee Research Articles

Accuracy of healthcare systems data for identifying cardiovascular outcomes after stroke due to intracerebral haemorrhage in the United Kingdom

BackgroundHealthcare systems data (HCSD) could improve the efficiency of clinical trials, but their accuracy and validity are uncertain. Our objective was to assess the accuracy of HCSD as the sole method of outcome detection in the REstart or STop Antithrombotics Randomised Trial (RESTART; ISRCTN71907627) compared with adjudicated questionnaire follow-up and compare estimates of treatment effect.MethodsRESTART was a prospective, open, assessor-blind, parallel-group randomised controlled trial (RCT) of antiplatelet therapy after intracerebral haemorrhage (ICH) in the UK.We included 496 (92%) of 537 RESTART participants, who were resident in England or Scotland at randomisation. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy.RESTART used annual questionnaires to detect its primary outcome (recurrent ICH) and secondary outcome (a composite of haemorrhagic or ischemic major adverse cardiovascular events [MACE]) over a median of 2.0 years; an independent adjudication committee verified outcomes using medical records and brain imaging. We obtained ICD10-coded HCSD on hospital admissions and deaths in England and Scotland to identify primary and secondary outcomes. We compared HCSD with a reference standard of adjudicated outcomes. We estimated the effects of antiplatelet therapy using HCSD alone in a Cox proportional hazards model adjusted for minimisation variables.ResultsIn the original RESTART trial, 31 people experienced a primary outcome event. HCSD had sensitivity of 84% (95% CI 66 to 95%) and positive predictive value of 68% (51 to 82%) for recurrent ICH. HCSD estimated an effect of antiplatelet therapy (adjusted hazard ratio [aHR] 0.51, 95% CI 0.27 to 0.98; p = 0.044) that was almost identical to adjudicated outcomes (aHR 0.51, 95% CI 0.25 to 1.03; p = 0.060). HCSD had sensitivity of 84% (76 to 91%) and positive predictive value of 78% (69 to 85%) for MACE, on which HCSD estimated an effect of antiplatelet therapy (aHR 0.81, 95% CI 0.56 to 1.16; p = 0.247) that was similar to adjudicated outcomes (aHR 0.65, 95% CI 0.44 to 0.95; p = 0.025).ConclusionsIn a RCT of antiplatelet therapy for people with ICH, HCSD was reasonably accurate and provided similar estimates of treatment effect compared with adjudicated outcomes.Trial registrationISRCTN71907627. Registered on 25 April 2013.

HIV DNA Levels in Persons Who Acquired HIV in the Setting of Long-Acting Cabotegravir for HIV Prevention: Analysis of Cases from HPTN 083 and 084.

We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected <LLOD; one near the LLOD (4.2 copies/106 PBMCs); in 2/4 cases, the DNA level was still <10 copies/106 PBMCs ≥40 weeks after the first HIV-positive visit. In contrast, only 3/14 (21.4%) of the TDF/FTC cases had a low or negative initial DNA test result (one not detected; two <10 copies/106 PBMCs). In this study, the time between the first HIV-positive visit and the first DNA test was longer in the CAB-LA cases than the TDF/FTC cases. Despite this difference, low or undetectable DNA levels were more frequently observed in the CAB-LA cases. This suggests that CAB-LA exposure may limit seeding of the HIV reservoir in early infection.

Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7-14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI -0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority=0·0003). Superiority was not identified (psuperiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, -0·004 to 0·006; p=0·78). Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. British Heart Foundation.

Unravelling the Causal Relationship between Endometriosis and the Risk for Developing Venous Thromboembolism: A Pooled Analysis.

To investigate the effect of endometriosis on venous thromboembolism (VTE) in oral contraceptive (OC) users. Pooled analysis on a harmonized dataset compromising international patient-centric cohort studies: INAS-VIPOS, INAS-SCORE, and INAS-FOCUS. Eleven European countries, the United States, and Canada. Individuals being newly prescribed an OC with or without an endometriosis and no VTE history. Detailed information was captured using self-administered questionnaires at baseline and every 6 to 12 months thereafter. Self-reported VTEs were medically validated and reviewed by an independent adjudication committee. Incidence rates (IRs) were calculated per 10,000 woman-years. The association of endometriosis on VTE was determined in a time-to-event analysis, calculating crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) using stabilized inverse probability of treatment weighting (IPTW). A total of 22,072 women had an endometriosis diagnosis, and 91,056 women did not. Women with endometriosis contributed 78,751 woman-years during which 41 VTE events occurred (IR: 5.2/10,000, 95% CI: 3.7-7.1) compared to 127 VTEs during 310,501 woman-years in women without endometriosis (IR: 4.1/10,000, 95% CI: 3.4-4.9). The hazard ratio of VTE in women with endometriosis was 1.79 (95% CI: 1.24-2.57) using stabilized IPTW controlling for age, body mass index, smoking, education, age at menarche, and family history of VTE. Subgroup and sensitivity analyses showed similar results. These results highlight the importance of considering endometriosis as a potential factor contributing to VTE in women using OC; however, further research on the relationship between endometriosis and VTE is warranted.

Adjudication of Self-reported Symptomatic Stone Recurrence in the Prevention of Urinary Stones With Hydration Trial

ObjectiveTo assess accuracy of self-reported stone events in a large clinical trial by adjudication against the weight of documentation for spontaneous stone passage or surgical intervention. MethodsParticipants in the Prevention of Urinary Stones with Hydration (PUSH) trial were randomized to a multi-component behavioral intervention or control arm to increase and maintain high fluid intake. The primary endpoint was urinary stone events including symptomatic stone passage or procedural intervention. An independent adjudication committee blinded to randomization assignments reviewed all events. Confirmed clinical stone events required typical stone symptoms and documentation of stone passage (e.g., via photograph, clinical record) and/or surgical intervention. Events with typical symptoms and self-described stone passage but without objective documentation of passage were also considered as meeting the primary endpoint and classified separately as patient-reported passage. Non-events did not meet either criteria. ResultsAt time of this blinded analysis, a total of 1658 participants were randomized and had a median follow-up of 19 months. Self-reported stone events (n=217) were adjudicated by the committee as either confirmed clinical events (134; 61.8%), patient-reported passage (71; 32.7%), or non-events (12; 5.5%). Confirmed clinical events consisted of stone passage in 66/134 and procedural interventions in 68/134 (53 for symptoms and 15 without symptoms). ConclusionsRigorous adjudication revealed that self-reported stone events in the PUSH trial overwhelmingly represented clinically documented passage, surgical intervention, and patient-reported passage outside healthcare settings, with only 5.5% failing to satisfy adjudication criteria. Similar adjudication and classification processes warrant consideration for implementation in future stone trials. Clinical Trials RegistrationNCT03244189

789. EFFICACY AND SAFETY OF CRYOBALLOON-180 ABLATION FOR THE TREATMENT OF DYSPLASTIC BARRETT ESOPHAGUS: PRELIMINARY RESULTS FROM A PROSPECTIVE MULTICENTER STUDY

Abstract Background Cryoballoon-ablation is a relatively novel method for the eradication of dysplastic Barrett esophagus (BE). While the focal cryoballoon-ablation system has shown to be efficacious for BE of limited extent, the cryoballoon180-ablation system (CBAS180) is developed to treat longer BE segments by semi-circumferential ablation over 3cm, in a single step. A first-in-human study demonstrated the feasibility of CBAS180 treatment, yet the optimal dose needs to be determined. The current prospective, multicenter study, investigates CBAS180 at lower dosages for patients with dysplastic BE. Methods A total of 62 patients with ablation naïve BE (C≤3 and M≥1) will be enrolled in six Dutch Barrett expert centers. Treatment consists of a full circumferential ablation over 3 cm of length, using two semi-circumferential ablations at a dose of 1.2 mm/sec. Follow-up consisted of phone calls at days 1, 7 and 30, a symptom diary during 14 days, and an endoscopy after 3 months. Outcomes included (1) technical success rate; (2) BE regression percentage at follow-up scored by an independent adjudication committee; (3) incidence of adverse events; (4) post-procedural pain (scored on a scale of 0-10); and (5) post-procedural dysphagia (scored on a validated scale of 0-4). Follow-up treatment consisted of focal cryoballoon-ablation until complete eradication of visible BE was achieved, confirmed by biopsies from the neo-Z-line. Results So far, 25 patients (80% male; mean age 67) with a median BE length of C0M2 (p25-p75 C0-1M2-4) were included. Technical success rate was 92% (23/25; 95% CI 74-99%). In two patients, treatment was technically unsuccessful due to unstable positioning of the balloon (n=1) or a device malfunction (n=1). Median procedure time was 14 (p25-p75 11-16) 4) minutes and median ablation time was 5 (p25-p75 3-5) minutes. All 23 successfully treated patients completed follow-up endoscopy at 3 months. Median BE regression was 90% (p25-p75 75%-100%) evaluated by the independent adjudication committee. Overall, CBAS180 adverse event rate was 8% (2/23); one patient developed esophageal stricture (1/23; 4% [95% CI 1-16%]) resolved after a single endoscopic dilation. Another patient (1/23; 4% [95% CI 1-16%]) experienced post-procedural bleeding, with re-endoscopy without intervention. The CBAS180 procedure was well tolerated with low post-procedural pain (median 2 [p25-p75 1-4] at day 1 and 0 [p25-p75 0-1] at day 7) and dysphagia (56% and 70% of patients with score 0 at days 1 and 7, respectively) scores. So far, 22/23 (95%) patients were additionally treated with focal cryoballoon-ablation and 18/22 (82%) achieved a complete endoscopis and histologic eradication of BE after median 1 (p25-p75 1-3) treatment, the other 4 are still under treatment. After focal cryoballoon-ablation, 2/22 patients developed strictures, resolved after 1 and 2 endoscopic dilatations. Conclusion Based on these preliminary results, circumferential ablation with CBAS180 at 1.2 mm/sec, followed by focal cryoballoon-ablation, emerges as an effective and safe procedure for dysplastic BE eradication in the hands of expert endoscopists. Further avenues for exploration should encompass the assessment of multiple CBAS180 ablations stacked on top of each other in larger segments and the validation of outcomes in a larger patient cohort.

Adverse myocardial and vascular side effects of immune checkpoint inhibitors: a prospective multimodal cardiovascular assessment.

Immune checkpoint inhibitors (ICIs) can induce cardiovascular toxicities. To prospectively assess the incidence of major cardiovascular events (MACE) on ICIs in solid cancer patients: myocarditis, pericarditis, acute coronary syndrome, heart failure, high-degree conduction abnormalities or sustained ventricular arrhythmias, or cardiovascular death at 6weeks (early MACE), including asymptomatic clinical changes by an independent adjudication committee using current recommended diagnostic criteria. The secondary objective was the incidence of the above-mentioned events adding atrial fibrillation (AF) at 6months (late MACE). Participants underwent pre-ICIs and repeated multimodality cardiac imaging (echocardiogram, cardiac magnetic resonance (CMR)), serum biomarkers (ultrasensitive troponin I), and rhythm surveillance (ambulatory ECG monitoring) at 6weeks and 6months. Forty-nine patients (38 (77.6%) male; mean age 64.3 (SD 11.0) years old) were included (June 2020-December 2021). Early MACE were observed in 9 (18.4%) patients at mean 40.1 (SD 5.9) days, with heart failure (HF) in 5 (10.2%), ventricular arrhythmias, or new conduction disorders in 4 (8.2%) patients. History of AF (HR 4.49 (CI 1.11-18.14), P = 0.035) predicted early MACE. At 6months follow-up, 18 MACE were observed in 15/49 (31%) patients, with 6 (12.2%) HF events, 5 (10.2%) significant ventricular arrhythmias, or conduction disorders, and 4 (8.2%) AF. There was a significant decline in LVEF (P < 0.001) in patients with no MACE (P = 0.003) or HF (P = 0.0028). Higher creatinine at inclusion (HR 0.99 [0.98-1.00], P = 0.006) predicted HF on multivariate analysis. There were no significant T1 or T2 mapping changes in our study cohort on repeated CMR. Cardiotoxicity on ICIs is more frequent than previously described when using a thorough detection strategy, consisting mainly in HF and asymptomatic rhythm disorders.

Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET).

The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) &amp;lt; 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr &amp;lt; 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin &amp;gt;4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

Swissped-RECOVERY: masked independent adjudication for the interpretation of non-randomised treatment in a two-arm open-label randomised controlled trial (methylprednisolone vs immunoglobulins) in Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) involving 10 secondary and tertiary paediatric hospitals in Switzerland

ObjectivesIn trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of...

Mental health outcomes in patients with moderate to severe psoriasis treated with bimekizumab: Analysis of phase 2/3 randomized trials

Patients with psoriasis have increased risk of suicidal ideation and behavior (SIB) and depression. Bimekizumab, a biologic that inhibits interleukin (IL)-17A and IL-17F, received Food and Drug Administration approval in 2023 for moderate to severe plaque psoriasis, following 2021 European Medicines Agency approval. To report SIB and depression in patients with moderate to severe psoriasis treated in bimekizumab clinical trials. Mental health changes, including neuropsychiatric events, were actively monitored across 9 bimekizumab clinical trials in psoriasis phase 2/3 trials. The patient-reported electronic Columbia-Suicide Severity Rating Scale (measuring SIB) and Patient Health Questionnaire-9 (measuring depression) were administered, monitored by an independent Neuropsychiatric Adjudication Committee. Throughout 7166 patient-years (PY) of bimekizumab exposure, the adjudicated SIB rate was 0.13/100PY; SIB ranges for the general psoriasis population and patients receiving anti-IL-17A/anti-IL-23 therapies are 0.09 to 0.54/100PY and 0.09 to 0.19/100PY, respectively. At week 16, 92.9% vs 81.1% of bimekizumab- vs placebo-treated patients had no/minimal depression. Newonset positive electronic Columbia-Suicide Severity Rating Scale responses and mean Patient Health Questionnaire-9 scores were low for bimekizumab-treated patients. Patient exclusion for significant/severe prespecified SIB/depression history. The long-term adjudicated SIB rate with bimekizumab was low and within ranges reported in the general psoriasis patient population and psoriasis patients treated with anti-IL-17A/anti-IL-23 biologics. Screening/monitoring questionnaires reported low SIB and depression levels.

Ultrashort VIBE-Dixon versus Cine and late gadolinium enhancement MRI sequences for cardiac thrombus detection

PurposeTo determine the diagnostic accuracy of volumetric interpolated breath-hold examination sequences with fat suppression in Dixon technique (VIBE-Dixon) for cardiac thrombus detection. MethodFrom our clinical database, we retrospectively identified consecutive patients between 2014 and 2022 who had definite diagnosis or exclusion of cardiac thrombus confirmed by an independent adjudication committee, serving as the reference standard. All patients received 2D-Cine plus 2D-Late-Gadolinium-Enhancement (Cine + LGE) and VIBE-Dixon sequences. Two blinded readers assessed all images for the presence of cardiac thrombus. The diagnostic accuracy of Cine + LGE and VIBE-Dixon was determined and compared. ResultsAmong 141 MRI studies (116 male, mean age: 61 years) mean image examination time was 28.8 ± 3.1 s for VIBE-Dixon and 23.3 ± 2.5 min for Cine + LGE. Cardiac thrombus was present in 49 patients (prevalence: 35 %). For both readers sensitivity for thrombus detection was significantly higher in VIBE-Dixon compared with Cine + LGE (Reader 1: 96 % vs.73 %, Reader 2: 96 % vs. 78 %, p < 0.01 for both readers), whereas specificity did not differ significantly (Reader 1: 96 % vs. 98 %, Reader 2: 92 % vs. 93 %, p > 0.1). Overall diagnostic accuracy of VIBE-Dixon was higher than for Cine + LGE (95 % vs. 89 %, p = 0.02) and was non-inferior to the reference standard (Delta ≤ 5 % with probability > 95 %). ConclusionsBiplanar VIBE-Dixon sequences, acquired within a few seconds, provided a very high diagnostic accuracy for cardiac thrombus detection. They could be used as stand-alone sequences to rapidly screen for cardiac thrombus in patients not amenable to lengthy acquisition times.

Real-world experience with trastuzumab deruxtecan among patients with gastric cancer: 4 month-interim analysis of an all-patient post-marketing surveillance study in Japan.

273 Background: Interstitial lung disease (ILD) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, all-patient post-marketing surveillance (PMS) is underway to investigate the risk of ILD among patients with gastric cancer treated with T-DXd in a real-world setting. We present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT2001200001) with an observation period of 12 months that enrolled all patients treated with T-DXd for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. This interim analysis is based on safety data from the first 4 months of all enrolled patients. All potential ILD (identified based on the pre-specified list of AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee (ILD-AC). The incidence of ILD was calculated from adjudicated drug-related ILD. Results: The interim analysis set included 1074 patients with median age of 70 years (range: 23-100). Of the 1074 patients, 1051 (97.9%) received T-DXd as third-line or later treatment. One hundred and eight patients (10.1%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, and 32 (3.0%), 3 (0.3%), and 23 (2.1%) patients had severe renal impairment (15≤ creatinine clearance (CL) &lt;30 mL/min), end-stage renal disease (CL &lt;15 mL/min), and ILD/radiation pneumonitis at baseline, respectively (all of which were defined as exclusion criteria in clinical trials of T-DXd). Median initial dose of T-DXd was 6.4 mg/kg (range: 3.1-6.4). Median treatment duration of T-DXd was 4.0 months (range: 0.7-4.0). During the first 4 months from the initial treatment, T-DXd was discontinued in 50.9% (547/1074) of patients. The most common reasons for treatment discontinuation were disease progression (n=390, 71.3%), adverse events other than ILD (n=76, 13.9%), and ILD (n=56, 10.2%). All potential ILD that occurred during the first 4 months were adjudicated by ILD-AC, and the incidence of all grades, grade ≥3, and grade 5 adjudicated drug-related ILD were 5.2% (n=56), 1.5% (n=16) and 0.7% (n=7), respectively. Of the 56 patients with adjudicated drug-related ILD, 54 (96.4%) discontinued T-DXd. The incidence of adjudicated drug-related ILD by time from initial treatment of T-DXd were 0.7% (7/1074) at ≤ 1 month, 2.0% (19/949) at 1-2 months, 2.7% (22/829) at 2-3 months, and 1.2% (8/652) at 3-4 months. Conclusions: The interim analysis revealed patient experiences and treatment profiles of T-DXd and the incidence of ILD during the first 4 months since initial treatment in a real-world setting in Japan. The final analysis including a risk factor analysis for ILD of the ongoing PMS is planned.

Diagnostic Accuracy of Contrast-Enhanced Thoracic Photon-Counting Computed Tomography for Opportunistic Locoregional Staging of Breast Cancer Compared With Digital Mammography: A Prospective Trial.

Accurate locoregional staging is crucial for effective breast cancer treatment. Photon-counting computed tomography (PC-CT) is an emerging technology with high spatial resolution and the ability to depict uptake of contrast agents in tissues, making it a promising tool for breast cancer imaging. The aim of this study was to establish the feasibility of locoregional staging of breast cancer through contrast-enhanced thoracic PC-CT, assess its diagnostic performance, and compare it with that of digital mammography (DM). Patients with newly diagnosed breast cancer, DM, and indication of thoracic CT staging were prospectively enrolled in this clinical cohort study over a period of 6 months. Participants underwent contrast-enhanced thoracic PC-CT and breast magnetic resonance imaging in prone position. After blinding to patient data, 2 radiologists independently rated PC-CT and DM regarding the following 6 characteristics: (1) diameter of the largest mass lesion, (2) infiltration of cutis/pectoral muscle/thoracic wall, (3) number of mass lesions, (4) presence/absence of adjacent ductal carcinoma in situ (DCIS), (5) tumor conspicuity, and (6) diagnostic confidence. Reference standard was generated from consensus reading of magnetic resonance imaging combined with all histopathological/clinical data by an independent adjudication committee applying TNM eighth edition. Among 32 enrolled female subjects (mean ± SD age, 59 ± 13.0 years), diagnostic accuracy for T-classification was higher for PC-CT compared with DM (0.94 vs 0.50, P < 0.01). Moreover, the correlation of the number of detected tumor masses with the reference standard was stronger for PC-CT than for DM (0.72 vs 0.50, P < 0.01). We observed that PC-CT significantly ( P < 0.04) outperformed DM regarding not only sensitivity (0.83 and 0.25, respectively) but also specificity (0.99 and 0.80, respectively) for adjacent DCIS. The κ values for interreader reliability were higher for PC-CT compared with DM (mean 0.88 vs 0.54, respectively; P = 0.01). Photon-counting computed tomography outperformed DM in T-classification and provided higher diagnostic accuracy for the detection of adjacent DCIS. Therefore, opportunistic locoregional staging of breast cancer in contrast-enhanced thoracic PC-CT is feasible and could overcome limitations of DM with the potential to improve patient management.

Predicting Major Bleeding in Patients with Venous Thromboembolism on Extended Anticoagulation Therapy Using Follow-up Data and Long Short-Term Memory Based Recurrent Neural Network

Background: It is often challenging for physicians to decide on the duration of anticoagulation treatment for patients with venous thromboembolism (VTE), as they need to weigh the risk of recurrent thrombosis and bleeding at the same time. Several clinical models have been developed to help physicians identify patients with high risk of bleeding. However, these tools use only the baseline clinical information and are not able to incorporate the clinical conditions and events that occur over time that may influence the risk of bleeding. Therefore, capturing the patterns and relationships in the continuously changing time series of clinical data could be a more powerful approach to developing predictor models than just relying on the baseline clinical information. Nonetheless, creating predictive models from follow-up clinical information is challenging given that time series clinical data are non-uniform, high-dimensional, multivariate observations. Here, we present the first attempt at creating a model that uses the time series follow-up information to predict major bleeding over time using a Recurrent Neural Network (RNN) with Long Short-Term Memory (LSTM) cells. Methods: 2542 patients diagnosed with VTE were enrolled in a prospective cohort study over 8 years. In addition to recording their clinical information at baseline, 6-month follow-up interviews were conducted using a standard script to monitor bleeding status and record clinical information. Major bleeding was defined by the International Society on Thrombosis and Haemostasis, with suspected bleeding events classified by an independent adjudication committee. Overall, 118 patients had major bleeding - a 4.6% incidence rate. The median and mode of the clinical variables were used to impute missing numerical and categorical values, respectively, and for patients who had no follow-up information, for whom bleeding occurred before the first follow-up, an artificial follow-up data point was generated from their corresponding baseline data. Thereafter, the data was divided into two stratified sets: 70% for training, and 30% for testing. Five supervised neural network-based machine learning models with different architectures were trained on the baseline dataset, or the follow-up dataset, or both to predict major bleeding. After training, these machine learning models were tested on the testing set and compared to the conventional clinical models, modified to make them compatible with the available predictor variables in our dataset, including the CHAP, the HAS-BLED, the VTE-BLEED, the RIETE, the ACCP, and the OBRI, which only use the baseline information. Results: Overall, the models that used the follow-up information had a higher area under the Receiver Operating Curve (AUROC) or c-statistic compared to the other models that only relied on the baseline dataset. In particular, the LSTM RNN model was able to achieve AUROC of 81.3% that is more than 10% higher compared to the best performing clinical model. We discovered that the LSTM RNN model mostly relied on features such as number of concomitant medications, years since baseline visit, use of specific antibiotics or antiplatelet agents, and presence of new hypertension to predict bleeding from the follow-up dataset. Furthermore, half of the bleeding events occurred within the first year after patients' baseline visits - a trend reflected in the predictions made by LSTM RNN model. Finally, the models that used both the baseline and the follow-up datasets showed different results depending on their architectures; that is, the simpler ensemble model achieved AUROC of 82.5% while the more complex model had AUROC of 70.8% due to overfitting. Conclusion: We have shown that using time series follow-up data can improve bleeding risk prediction in patients with VTE who are on extended anticoagulant therapy compared to just using the baseline data, and clinicians might benefit from using such an approach. Furthermore, our results indicate that LSTM RNN is a suitable architecture to model routine clinical follow-up data. Finally, we believe using time series data could improve the performance of the other clinical models that are currently based on one-time baseline measurements.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score &amp;lt;7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of &amp;lt;24 hours. While patients scheduled for surgery in &amp;lt;12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

Bimekizumab in Patients with Moderate to Severe Plaque Psoriasis: Analysis of Mental Health and Associated Disorders

Introduction: Patients (pts) with psoriasis have a greater risk of depression and suicidality than the general population.1 Here, we report Week (Wk)16 and longer-term depression and suicidal ideation and behavior (SIB) data in bimekizumab (BKZ)-treated pts with moderate to severe plaque psoriasis.&#x0D; Procedure/study: The Patient Health Questionnaire (PHQ)-9, scored 0–27, measured depression severity monthly to Wk16 (regular intervals during BE BRIGHT open-label extension);2,3 higher scores indicate worse depression. PHQ-9 data were pooled from Wk0–16 of BE VIVID/BE READY (BKZ 320mg every 4 weeks [Q4W] vs. placebo [PBO]);4,5 3-year BE BRIGHT data are also reported.3 An independent Neuropsychiatric Adjudication Committee evaluated potential SIB treatment-emergent adverse events (TEAEs) and elevated PHQ-9 scores. Adjudicated SIB (suicide completion/attempt/ideation) incidence/100 pt-years (yrs; PY) was pooled from nine BKZ phase 2/3/3b trials in psoriasis, including up to 5 yrs’ exposure.3–11&#x0D; Results: At Wk16, mean reduction from baseline in PHQ-9 with BKZ Q4W (N=670) vs. PBO (N=169) was 1.3 vs. 0.3; overall mean Wk16 scores were 1.2 and 2.4 for BKZ and PBO. Low mean BKZ PHQ-9 scores were maintained over 3 yrs of BE BRIGHT following the feeder studies (Wk144: 1.2). At Wk16, 92.9% of BKZ pts scored 0–4 in PHQ-9 (no/minimal depression) vs. 81.1% of PBO pts; 1.3% vs. 6.3% scored ≥10 (moderate–severe depression). Through Wk16, 0.7% BKZ vs. 4.1% PBO pts scored ≥15 (moderately severe–severe) in PHQ-9 at any visit. Over 7,166 PY of BKZ exposure (N=2,480), the rate of adjudicated SIB TEAEs was 0.126/100 PY.&#x0D; Conclusion: PHQ-9 scores were low through Wk16 and remained low with longer BKZ exposure. The vast majority of BKZ pts had no/minimal depression at Wk16. The long-term incidence rate of adjudicated SIB with BKZ was low and similar to the general psoriasis population (range: 0.09–0.54/100 PY).1,12&#x0D; Funding: UCB Pharma.

The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): rationale and design.

Postoperative atrial fibrillation (POAF) is the most common complication of cardiac surgery and has been associated with increased postoperative morbidity and hospital costs. The Posterior left pericardiotomy for the prevention of AtriaL fibrillation After Cardiac Surgery (PALACS) trial found that posterior pericardiotomy significantly reduced the incidence of POAF (17% vs. 32%, P < 0.001). We present the protocol for The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): a prospective, extended follow-up of the original PALACS trial. The aim of PALACS-EF is to gain more data regarding the effect of posterior pericardiotomy on postdischarge clinical outcomes. The primary outcome is the time to the first occurrence of the composite of all-cause mortality or hospital cardiovascular readmission. The key secondary outcome is the time to the first occurrence of the composite of all-cause mortality and all-cause hospital readmission. Hospital readmission, myocardial infarction, stroke, transient ischaemic attack, heart failure, systemic embolism, or new arrhythmias with onset since 30-day follow-up will also be recorded. All 420 patients enrolled in the PALACS trial will be included; extended follow-up will be conducted via telephone by blinded research personnel utilizing a standardized script to ensure uniformity and completeness of follow-up. If an event has occurred, documentation will be obtained, and an independent adjudication committee blinded to group assignment will adjudicate outcome events. Results will be reported when a median follow-up of 5 years is achieved. PALACS-EF will provide data to answer the question of whether posterior pericardiotomy improves postdischarge outcomes in patients undergoing cardiac surgery, and it will provide information on the relationship between POAF and adverse postdischarge outcomes including mortality, hospitalization, heart failure, and stroke. PALACS: NCT02875405, PALACS-EF: NCT05903222.

Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up

Introduction: Lovo-cel gene therapy uses autologous transplantation of hematopoietic stem and progenitor cells (HSPC) transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an anti-sickling hemoglobin (Hb), HbA T87Q. The phase 1/2 HGB-206 (NCT02140554) and phase 3 HGB-210 (NCT04293185) studies of lovo-cel are the largest clinical trials of gene therapy in SCD to date. We report efficacy and safety from these studies, including the first data from adult and pediatric patients (age 12 to &amp;lt;18 years) in HGB-210, and HRQOL data from HGB-206. Methods: This analysis includes patients from HGB-206 Group C and HGB-210 who received lovo-cel using the current HSPC mobilization and manufacturing process. Patients with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. After 24 months of follow-up post lovo-cel infusion, patients enrolled in the long-term study LTF-307 (NCT04628585). Lab evaluations, SCD-related outcomes (eg, resolution of VOEs), globin response (a composite endpoint evaluating HbA T87Q percentage and total Hb), and safety are reported up to 60 months. An independent Event Adjudication Committee confirmed VOEs met protocol criteria. HRQOL data from Patient-Reported Outcomes Measurement Information System (PROMIS)-57 domains of pain interference, fatigue, and pain intensity are reported up to 48 months. Results:This analysis includes47 patients (HGB-206 Group C, n=36; HGB-210, n=11; male, 59.6%; median [range] age, 23 y [12-38]) who received a lovo-cel infusion as of Feb 13, 2023. Median (range) follow-up was 35.5 months (0.3-61.0). Median (range) time to neutrophil and platelet engraftment was 20 days (12-35) and 35 days (19-136). Peripheral blood vector copy number remained stable (median &amp;gt;1 c/dg through follow-up). Median HbA T87Q levels were ≥4.5 g/dL from 6 months post infusion to last study visit. Median (range) total Hb level increased from 8.7 g/dL (6.1-12.5) at relative baseline to 11.8 g/dL (8.4-15.0) at last visit; median percent HbA T87Q of nontransfused total Hb was ≈40% or more ( Figure). Of 33 evaluable patients (ie, ≥18 months follow-up and ≥4 VOEs in the 2 years before enrollment), 30 (90.9%) and 32 (97.0%) had complete resolution of VOEs and severe VOEs during the 6-18 months post infusion, vs a median (range) of 3.5 (1.5-16.5) and 3.0 (0.5-13.0) events/year in the 2 years before enrollment. Additional efficacy analyses in subgroups (eg, stroke history, α-globin genotype) will be presented. Among patients who had globin response or who had ≥18 months follow-up (n=38), 33 (86.8%) achieved globin response. Hemolysis markers (eg, reticulocytes, total bilirubin, lactate dehydrogenase) approached normal levels. Among all 47 patients, 44 (93.6%) had ≥1 AE of grade ≥3 after lovo-cel infusion; the most common of which were stomatitis (33 [70.2%] patients) and thrombocytopenia (28 [59.6%]). Serious AEs were reported for 26 (55.3%) patients, the most common of which was chronic pain/acute exacerbation of chronic pain (3 [6.4%]; 2 chronic neuropathic pain and 1 chronic pain associated with anxiety). One patient with -α3.7/-α3.7 genotype was diagnosed with myelodysplastic syndrome with stable complete blood counts 30 months post infusion; updated data to be presented. No veno-occlusive liver disease, graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis was observed. Lovo-cel treatment regimen largely reflected known side effects of HSPC collection and busulfan conditioning regimen. A total of 25 patients (all from HGB-206 Group C; age ≥18 y) had evaluable HRQOL data. Mean scores for PROMIS-57 domains of pain intensity, pain interference, and fatigue improved (ie, decreased) over time up to 48 months ( Table). Conclusion: One-time treatment with lovo-cel resulted in sustained HbA T87Q production and near-complete resolution of VOEs and severe VOEs up to 18 months post treatment; the safety profile was consistent with underlying SCD and myeloablative conditioning. Patients reported sustained improvements in pain intensity, pain interference, and fatigue. Ongoing long-term follow-up will continue to provide important information on efficacy, safety, and patient experience post lovo-cel treatment.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of &amp;gt;24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.