Citations

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .

3535 Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 349 patients (26.5%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was associated with a greater all-cause mortality than euthyroidism (hazard ratio, 1.19; 95% CI, 1.01-1.38; P=0.04). In this group, the risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level (hazard ratio, 1.27 per 5 mIU/L increase, 95% CI, 1.00-1.53, P=0.04). Conclusions Cardiac resynchronization therapy improves cardiac function in hypothyroid patients. Hypothyroidism has adverse effects on cardiac resynchronization therapy outcomes with reduced survival and increased implantable cardioverter-defibrillator therapies for ventricular arrhythmic events.

Abstract Background: Tumor-associated macrophages have been shown to play a critical role in metastasis, angiogenesis, and immune escape. Cancer associated macrophage-like cells (CAMLs) are circulating stromal cell with macrophage expression subtypes, detected in the peripheral blood of patients with solid tumors. We have previously shown that enlargement of CAML cells is an independent predictor of poorer overall survival and an indication of progression in patients with metastatic breast cancer (MBC). However changes in CAML sizes after induction of therapy has not been investigated. Here we evaluated the association between early changes in numbers and sizes of CAMLs as it relates to clinical response after induction of new therapy. Method: Peripheral blood samples from 29 patients with metastatic breast cancer who failed at least 2 prior lines of therapies were prospectively collected. Baseline (BL) blood samples were taken prior to initiation of a new therapy and the second samples (T1) were taken approximately 30 days after initiation of a new systemic therapy. Blood samples were filtered using CellSieveTM filtration. The quantity and size of CAMLs were measured then compared between the BL and T1 time points. Univariate analysis was used to determine the association of changes in CAML numbers and changes in CAML size, with objective response at the first follow up CT scan with progression free survival (PFS). Results: CAMLs were detected in 97% of BL samples (averaging 20.9 CAMLs/7.5ml blood) and 93% of T1 samples (averaging 18.5 CAMLs/7.5mL blood). At the time of the first follow up CT scan, 17 of 29 patients (58.6%) had progressive disease based on the RECIST criteria. Among those, 14 of 17 patients (82%) had an increase in CAML size (~85% overall enlargement) and 3/17 (18%) had a decrease CAML size (~60% overall shrinkage) in T1 samples compared to baseline. In contrast, 10 of 12 patients (83%) with clinical benefit, including stable disease and partial or complete response, had a 92% reduction in their CAML’s size and 2 of 12 patients (17%) had 61% enlargement in their CAML’s size after treatment. Overall, CAML size change after therapy induction was 83% accurate in predicting clinical benefit based on subsequent scans. Furthermore, patients with enlarging CAML size at T1 had significantly shorter PFS of 4 months compared to 10 months in patients with decreasing CAML size (HR 3.7; 95%CI1.5-10.1; p 0.020). Conclusion: CAMLs can be commonly found in most treatment-refractory metastatic breast cancer patients and their morphological size is clinically correlated to poorer survival. Our data suggests that monitoring the size changes of a patient’s CAMLs after 30 days of new treatment initiation may predict clinical benefit earlier than conventional scans and act as real time monitoring of MBCs response to new therapies. Additional studies are currently ongoing to validate these results. Citation Format: Saranya Chumsri, Markus D. Lacher, William V. Williams, R. K. Alpaugh, Stuart S. Martin, Rena Lapidus, Cha-Mei Tang, Massimo Cristofanilli, Daniel L Adams. Circulating cancer associated macrophage-like cells (CAMLs) are early predictors of response to new line therapies in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-27.

Left bundle branch block may be due to conduction system degeneration or a reflection of myocardial pathology. Left bundle branch block may also develop following aortic valve disease or cardiac procedures. Patients with heart failure with reduced ejection fraction and left bundle branch block may respond positively to cardiac resynchronization therapy. Lead placement via the coronary sinus is the mainstay approach of cardiac resynchronization therapy. However, other options, including physiological pacing, are being explored. In this review, we summarize the salient pathophysiologic and clinical aspects of left bundle branch block, as well as current and future strategies for management.

AbstractBackgroundThe AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real‐world population.Methods and ResultsPatients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013‐2018 were divided into aCRT ON or standard CRT groups based upon device‐stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device‐detected AF episodes of various durations were recorded by the device during follow‐up.A total of 1814 CRT patients with no reported long‐standing AF history at implant were included. Mean follow‐up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate‐adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53‐0.96, P = .028). Mean AF burden during follow‐up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes‐30 days, all P < .001).ConclusionUse of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real‐world, prospective, nonrandomized registry.

Background: The temporal occurrence of arrhythmic complications after alcohol septal ablation (ASA) is unclear. As a result, the appropriate time to monitor patients after ASA is controversial. The purpose of this study is to determine the temporal occurrence of complete heart block (CHB) and ventricular tachyarrhythmia (VT) after ASA to better understand when patients can be safely discharged. Methods: Consecutive patients treated with ASA for hypertrophic cardiomyopathy from 2003 to 2019 at a tertiary referral center were reviewed retrospectively. The incidence and timing of CHB or sustained VT within 30 days post-ASA were assessed. Results: A total of 243 patients were included in this study. Mean maximal septal thickness was 19.0±3.9 mm, and total volume of ethanol injected was 1.7±0.6 mL. CHB occurred in 59 (24.3%) patients, including transient CHB in 33 (13.6%) and permanent in 26 (10.7%). The initial episode of CHB occurred within 24 hours post-ASA in 51 (21.0%) patients, between 24 and 48 hours in 3 (1.2%), between 48 and 72 hours in 3 (1.2%), and after 72 hours in 2 (0.8%). New permanent pacemaker was placed in 46 (18.3%). Presence of baseline bundle branch block and age ≥70 were significantly associated with CHB but not CHB presenting after 24 hours. VT occurred in 3 (1.2%) patients, including 1 (0.4%) within 24 hours, 1 (0.4%) between 24 and 48 hours, and 1 (0.4%) after 72 hours. VT required cardioversion in 2 patients and new implantable cardioverter-defibrillator placement in 2. Conclusions: The incidence of CHB or VT presenting after 72 hours post-ASA was low. These findings suggest that timely discharge of patients without evidence of early conduction disturbances after ASA can be considered as a potentially safe management strategy, especially in patients without preexisting conduction abnormalities.

Background: Mechanical injury in the conduction system requiring permanent pacemaker (PPM) associated with transcatheter aortic valve replacement (TAVR) procedure is a common complication. The objective of this study was to use ambulatory monitor BodyGuardian to assess late occurrence of atrioventricular block (AVB) after TAVR. Methods: This prospective study evaluated 365 patients who underwent TAVR at Mayo Clinic, Rochester, Minnesota between June 2016 and August 2017. Patients who received PPM for bradycardia after TAVR before discharge were considered as the PPM group. Those not requiring PPM received a BodyGuardian system (BodyGuardian group) for 30 days of continuous monitoring. Primary end point was Mobitz II or third-degree atrioventricular block (II/III AVB) at 30-day follow-up. Results: Of 365 patients, 74 who had a PPM or an implantable cardioverter-defibrillator before TAVR and 94 who were enrolled in other studies were excluded. Of 197 patients enrolled in the study, 70 (35.5%) received PPM and 127 had BodyGuardian before the hospital dismissal. Eleven of 127 (8.6%) BodyGuardian group required PPM within 30 days after TAVR for late occurrence of symptomatic bradycardia. In total, 33 of 197 (16.7%) patients developed II/III AVB (24 before and 9 after discharge). Thirty-four patients had preexisting right bundle branch block. Of them, 16 (47%) developed II/III AVB. Of 53 patients who developed new left bundle branch block after TAVR, 14% progressed to II/III AVB within 30 days. Conclusions: In patients without a standard post-TAVR pacing indication, yet a potential risk to develop AVB, a strategy of 30-day monitoring identifies additional patients who require permanent pacing.

Abstract Background Venous stenosis is a well-recognized complication of transvenous leads when patients require lead revisions or device upgrade. In these cases, balloon venoplasty or alternative venous access with subcutaneous tunneling can be performed. Purpose Compare the outcomes of venoplasty vs. tunneling in patients requiring additional transvenous lead implantation. Methods A single center retrospective cohort study of all patients undergoing lead implantation/revision requiring venoplasty or tunneling from 2005–2017. Chi-squared and Wilcoxon Rank-Sum tests were used to compare categorical and continuous variables. Results Ninety five patients met our inclusion criteria (60 venoplasty & 35 tunneling). There was no difference in procedure success rates (p-value=0.98). Tunneling was associated with less fluoroscopy time but higher incidence of acute complications (0% vs. 23%, p-value=0.002) most requiring invasive intervention and/or blood product transfusion. Long term outcomes were comparable and related to lead failure or infection. Outcomes for tunneling vs. venoplasty Variable Tunneling (n=35) Venoplasty (n=60) p-value Age Y 67 (23–84) 70 (29–91) 0.25 Male (%) 24 (69%) 41 (68%) 0.98 Number of existing leads 2.1 (1–4) 2.4 (0–4) 0.1 Age of oldest lead 7.0 (0–21) 7.2 (0–33) 0.73 Number of new leads 1.2 (1–3) 1.4 (1–3) 0.26 Fluoroscopy time (SD) min 29.2 (21.3) 39.7 (21.5) 0.012 Procedure success (%) 35 (100%) 55 (92%) 0.9 Acute complications (%) 8 (23%)1 0 (0%) 0.0002 Pocket hematoma/bleed 4 (11%)2 Hemothorax 2 (6%)3 Pericarditis 1 (3%) Lead compromise 1 (3%) Follow up M 18 (0–76) 28 (0–98) N/A Long term lead issues (%) 6 (17%) 10 (17%) 0.95 Long term complication requiring intervention 4 (11%) 8 (13%) N/A Procedure success: functional lead placed as a result of venoplasty or tunneling. 1Two patients required blood products. 2Two patients required invasive intervention. 3One patient required chest tube and the other ICU admission. Conclusions Balloon venoplasty is associated with similar rates of success and a less incidence of acute complications when compared subcutaneous tunneling. Acknowledgement/Funding NIH T32 Training Grant HL07111-40