scholarly journals Cardiac Cell Therapies for the Treatment of Acute Myocardial Infarction: A Meta-Analysis from Mouse Studies

2017 ◽  
Vol 42 (1) ◽  
pp. 254-268 ◽  
Author(s):  
Cajetan Immanuel Lang ◽  
Markus Wolfien ◽  
Anne Langenbach ◽  
Paula Müller ◽  
Olaf Wolkenhauer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Mouse Model ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cell Therapies ◽  
Positive Effects ◽  
Advanced Therapies

Aims: Stem cell-based regenerative therapies for the treatment of ischemic myocardium are currently a subject of intensive investigation. A variety of cell populations have been demonstrated to be safe and to exert some positive effects in human Phase I and II clinical trials, however conclusive evidence of efficacy is still lacking. While the relevance of animal models for appropriate pre-clinical safety and efficacy testing with regard to application in Phase III studies continues to increase, concerns have been expressed regarding the validity of the mouse model to predict clinical results. Against the background that hundreds of preclinical studies have assessed the efficacy of numerous kinds of cell preparations - including pluripotent stem cells - for cardiac repair, we undertook a systematic re-evaluation of data from the mouse model, which initially paved the way for the first clinical trials in this field. Methods and Results: A systematic literature screen was performed to identify publications reporting results of cardiac stem cell therapies for the treatment of myocardial ischemia in the mouse model. Only peer-reviewed and placebo-controlled studies using magnet resonance imaging (MRI) for left ventricular ejection fraction (LVEF) assessment were included. Experimental data from 21 studies involving 583 animals demonstrate a significant improvement in LVEF of 8.59%+/- 2.36; p=.012 (95% CI, 3.7–13.8) compared with control animals. Conclusion: The mouse is a valid model to evaluate the efficacy of cell-based advanced therapies for the treatment of ischemic myocardial damage. Further studies are required to understand the mechanisms underlying stem cell based improvement of cardiac function after ischemia.

Abstract 1111: Embryoinc Stem Cell Derived Cardiovascular Progenitor Cells Improve Function More Than Hemangioblasts in a Mouse Model of Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Eric Adler ◽  
Vincient Chen ◽  
Anne Bystrup ◽  
Wilson Young ◽  
Steve Giovannone ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Myocardial Function ◽  
Es Cells ◽  
Fluorescent Microscopy ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

BACKGROUND: Intramyocardial transplantation of stem cells improves left ventricular ejection fraction (EF) in animal studies and preliminary clinical trials. The mechanism may involve either replacement of myocytes or improved vascular supply to existing myocytes. We recently identified an Embyronic Stem cell derived cardiovascular progenitor cell (ES-CPC) that is the common precursor of cardiomyocyte and vascular cell lineages. To determine whether myocyte transplantation improves myocardial function more than angiogenesis alone does, we compared the effect of ES-CPCs to hemangioblasts (vascular/hematopoetic progenitor cells) on EF in a mouse model of myocardial infarction. METHODS: ES-CPC and hemangioblasts were isolated from a doxycycline-responsive, Notch-inducible ES cell line containing Notch 4 cDNA under the control of a tetracycline-inducible promoter. Notch induction of mesoderm-derived ES cells resulted in a CPC phenotype, whereas non-induced cells developed into hemangioblasts. Mice underwent transplantation of 500,000 ES-CPC (n=20), hemangioblasts (n=16), or an equal volume of serum-free media (n=12) 30 minutes after surgically-induced myocardial infarction. All cell lines constitutively expressed green fluorescent protein (GFP). EF was assessed two weeks post-transplantation using 9.4 Tesla MRI. Mice were then euthanized and frozen heart sections were examined using fluorescent microscopy. RESULTS: The mean EF was 59Â ± 15, 46Â ± 17, and 39Â ± 13% in the ES-CPC, hemangioblast, and control groups, respectively (p<0.05 for the differences among all 3 groups; ANOVA). GFP + cells were detected in frozen sections of both the ES-CPC and hemangioblast groups. GFP + cells in ES-CPC treated hearts expressed markers associated with both cardiomyocyte and vascular phenotypes, whereas the GFP + cells in the hemangioblast group expressed markers associated with vascular phenotypes. CONCLUSIONS: Both hemangioblast and ES-CPC transplantation improves EF in a mouse model of myocardial infarction, but ES-CPC transplantation was more effective. This suggests that enhancement of myocardial function by transplantation of both cardiomyocyte and vascular phenotypes exceeds that with vascular phenotypes alone.

Abstract 355: Heart Failure Impairs Bone Marrow Mesenchymal Stem Cell Renewing Capacity and Migration

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Victoria Florea ◽  
Cristina Sanina ◽  
Darcy Difede ◽  
Krystalenia Valasaki ◽  
Aisha Khan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Bone Marrow ◽  
Growth Rate ◽  
Clinical Trials ◽  
Stem Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Healthy Donors

Background: Clinical trials have shown a sustained beneficial effect of bone marrow mesenchymal stem cells (MSCs) as a therapy for acute and chronic heart failure (HF). Clinical grade cell manufacturing of autologous and allogeneic MSCs is becoming a standard procedure. This study investigates the differences of bone marrow MSC isolation and expansion in favorable in vitro conditions. We compared MSC production from both healthy young donors and chronic HF patients. Methods: We analyzed MSC manufacturing records from five clinical trials: TAC-HFT (Ischemic cardiomyopathy (CMP), patient and donors), POSEIDON (Ischemic CMP, donors), POSEIDON DCM (Dilated CMP, donors), TRIDENT (Ischemic CMP, donors), and CRATUS (Frailty, donors). Results: All cells expressed CD105, CD90 and lacked hematopoietic marker CD45. The age of healthy donors (25.5 ± 0.7 y.o., N=24) and HF patients (56.1 ± 2.5, y.o., N=23), was significantly different (P<0.0001). Collectively, the number of mononuclear cells (MNCs) isolated from bone marrow (volume range 58-125ml) didn’t differ between the groups. However, plated MNCs from healthy adults generated more MSCs than MNCs from HF patients (p0: 5.9x10^6±0.5x10^6, N=23 vs 3.8x10^6±0.4x10^6, N=24, respectively, P=0.003 and p1: 15.4x10^6±2.5x10^6, N=23 vs 10.8x10^6±1.1x10^6, N=24, respectively, P=0.036). No correlation was found between stem cell growth and age (35 to 78y.o.). Left ventricular ejection fraction (LVEF) in patients with HF had a direct correlation with MSC growth rate (P=0.03), particularly, in patients with severely depressed LVEF (<30%), which had a tendency to generate less MSCs overall. Moreover, MSCs from HF patients demonstrated less migration compared to MSCs from healthy donors at 6, 10 and 24 hours (h) relative to baseline (6 h: 9.5±3.0% vs 30.7±2.1%; 10 h: 19.9±13.7% vs 53.1±2.5% and 24 h: 41.5±15.8% vs 88.9±1.6%, N=4, respectively. P=0.03). Conclusions: Despite equivalent numbers of MNCs, healthy young donors generate significantly more MSCs than HF patients, due to increased growth rate and higher number of resident stromal bone marrow stem cells. MSC migration was impaired in HF patients compared to healthy donors. HF appears to be an independent factor for MSC renewal capacity and culture phenotype.

Abstract 16154: Baseline Left Ventricular Diameter Predicts Recovery in New Systolic Heart Failure Syndromes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Daniel Gold ◽  
Nathan Kong ◽  
Matthew Gold ◽  
Tess Allan ◽  
Anand Shah ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Medical Decision ◽  
Left Ventricular Ejection ◽  
Internal Diameter ◽  
Event Free Survival ◽  
Short Term Treatment ◽  
Ventricular Ejection Fraction ◽  
Free Survival ◽  
Advanced Therapies

Introduction: It is unknown how often patients with very advanced left ventricular (LV) dilation at initial presentation demonstrate meaningful recovery with medical therapy. Understanding short term treatment outcomes may impact medical decision making and counseling. Hypothesis: Patients with left ventricular end diastolic internal diameter (LVEDD) > 6.5cm will be less likely to recover left ventricular ejection fraction (LVEF) as compared to patients with LVEDD < 6.5cm. Methods: Patients were retrospectively identified by a database search of echocardiogram studies obtained at the University of Chicago between 2008-2018. Manual review was performed to ensure new diagnosis of systolic dysfunction with LVEF ≤ 35% and follow up echocardiogram study within 3 to 9 months of index study. LVEDD was determined from parasternal long axis views per routine. LVEF recovery was specified as LVEF > 35%. Chart review was done to assess for composite death, hospice, transplant, left ventricular assist device, and sustained ventricular tachycardia. Chi-square, multivariable logistic regression, and Kaplan-Meier survival were used for analysis. Results: Out of 100 patients included for analysis, mean age was 59.7 years, 41 were female and 82 were African American. 17.7% of patients’ with LVEDD > 6.5 cm had LVEF recovery compared to 53.0% of patients’ with LVEDD ≤ 6.5 cm (p = 0.008). LVEDD > 6.5 cm was associated with less LVEF recovery even when adjusted for age, gender, hypertension, and diabetes (adjusted odds ratio 0.18, 95% CI 0.04 to 0.65). LVEDD > 6.5cm was associated with worse event free survival (p = 0.004) with a median follow-up time of 2.4 years. Conclusions: An LVEDD of > 6.5cm is associated with diminished LVEF recovery and event free survival when compared to those patients with an LVEDD ≤ 6.5cm. Delaying consideration for advanced therapies and device based therapies in hopes of recovery may be inappropriate for many such patients.

scholarly journals PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2965
Author(s):  
Francesca Oppedisano ◽  
Rocco Mollace ◽  
Annamaria Tavernese ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Dietary Supplementation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Related Factor ◽  
Ventricular Ejection Fraction ◽  
Pufa Supplementation ◽  
Positive Effects ◽  
Mitral Annulus Velocity

Heart failure (HF) characterized by cardiac remodeling is a condition in which inflammation and fibrosis play a key role. Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) seems to produce good results. In fact, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and antioxidant properties and different cardioprotective mechanisms. In particular, following their interaction with the nuclear factor erythropoietin 2 related factor 2 (NRF2), the free fatty acid receptor 4 (Ffar4) receptor, or the G-protein coupled receptor 120 (GPR120) fibroblast receptors, they inhibit cardiac fibrosis and protect the heart from HF onset. Furthermore, n-3 PUFAs increase the left ventricular ejection fraction (LVEF), reduce global longitudinal deformation, E/e ratio (early ventricular filling and early mitral annulus velocity), soluble interleukin-1 receptor-like 1 (sST2) and high-sensitive C Reactive protein (hsCRP) levels, and increase flow-mediated dilation. Moreover, lower levels of brain natriuretic peptide (BNP) and serum norepinephrine (sNE) are reported and have a positive effect on cardiac hemodynamics. In addition, they reduce cardiac remodeling and inflammation by protecting patients from HF onset after myocardial infarction (MI). The positive effects of PUFA supplementation are associated with treatment duration and a daily dosage of 1–2 g. Therefore, both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) define dietary supplementation with n-3 PUFAs as an effective therapy for reducing the risk of hospitalization and death in HF patients. In this review, we seek to highlight the most recent studies related to the effect of PUFA supplementation in HF. For that purpose, a PubMed literature survey was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2015 to 2021.

scholarly journals Elevated heart rate in hypertension and coronary artery disease: risk factor or risk marker in patients with preserved left ventricular ejection fraction

2019 ◽  
Vol 25 (4) ◽  
pp. 389-406 ◽  
Author(s):  
E. V. Kokhan ◽  
G. K. Kiyakbaev ◽  
Z. D. Kobalava
Keyword(s):  
Coronary Artery Disease ◽  
Heart Rate ◽  
Coronary Artery ◽  
Ejection Fraction ◽  
Prognostic Significance ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Positive Effects ◽  
Artery Disease

Numerous studies have demonstrated the negative prognostic value of tachycardia, both in the general population and in specific subgroups, including patients with coronary artery disease (CAD), arterial hypertension (HTN) and heart failure with preserved ejection fraction (HFpEF). In the latest edition of the European guidlines for the treatment of HTN the level of heart rate (HR) exceeding 80 beats per minute is highlighted as a separate independent predictor of adverse outcomes. However, the feasibility of pharmacological reduction of HR in patients with sinus rhythm is unclear. Unlike patients with reduced ejection fraction, in whom the positive effects of HR reduction are well established, the data on the effect of pharmacological HR reduction on the prognosis of patients with HTN, CAD and/or HFpEF are not so unambiguous. Some adverse effects of pharmacological correction of HR in such patients, which may be caused by a change in the aortic pressure waveform with its increase in late systole in the presence of left ventricular diastolic dysfunction, are discussed. The reviewed data underline the complexity of the problem of clinical and prognostic significance of increased HR and its correction in patients with HTN, stable CAD and/or HFpEF.

scholarly journals The continuous heart failure spectrum: moving beyond an ejection fraction classification

2019 ◽  
Vol 40 (26) ◽  
pp. 2155-2163 ◽  
Author(s):  
Filippos Triposkiadis ◽  
Javed Butler ◽  
Francois M Abboud ◽  
Paul W Armstrong ◽  
Stamatis Adamopoulos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Ejection Fraction ◽  
Statistical Power ◽  
Structural Changes ◽  
Randomized Clinical Trials ◽  
New Technologies ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Abstract Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

scholarly journals Cardiovascular phenotyping of the first mouse model of Sarcoidosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Bueno Beti ◽  
C Lim ◽  
A Protonotarios ◽  
A Kiss ◽  
M.N Sheppard ◽  
...  
Keyword(s):  
Mouse Model ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Cell Junctions ◽  
Left Ventricular Ejection ◽  
Unknown Etiology ◽  
Funding Source ◽  
Ventricular Ejection Fraction ◽  
Arrhythmogenic Substrate ◽  
Inflammatory Infiltrates

Abstract Introduction Sarcoidosis is a potentially life-threatening, inflammatory, granulomatous disease that affects multiple organs including the heart. Heretofore, its unknown etiology had hindered the creation of experimental models and the understanding of the molecular mechanisms of pathogenesis behind it. Purpose To extensively phenotype the heart of the first mouse model of sarcoidosis created through deletion of the tuberous sclerosis 2 (Tsc2) gene in the CD11c-positive macrophage population. Methods Tsc2 fl/fl CD11c Cre+ (Tsc2-KO; n=7) and Tsc2 fl/fl CD11c Cre- (Tsc2-WT; n=7) mice were subjected to echocardiography at 25 weeks of age (woa) to assess myocardial dimensions and function. Hearts of 13 and 25woa animals were subjected to histological and immunological stains to assess tissue changes, subtype inflammatory infiltrates and examine the localization of key proteins shown to be re-distributed in patients. Results At 13 woa, Tsc2-KO animals show inflammatory infiltrates; subtyped mainly as macrophages as well as evidence of myocyte destruction. At 25 woa, the number of inflammatory cells is significantly higher and there is heavy fibrotic replacement primarily in the septum and trabeculae. Older animals also show giant cells and non-necrotizing granulomas. The hearts show heterogeneous gap junction remodeling known to constitute an arrhythmogenic substrate and lack of immunoreactive signal for the desmosomal protein plakoglobin from the cell-cell junctions just as described in patients. The left ventricular ejection fraction and LV morphology was not significantly different between the two groups (EF: 64±4% in Tsc2-KO vs 64±2% in Tsc2-WT; LV end-systolic diameter: 4.51±0.54 mm in Tsc2-KO vs 4.59±0.29 mm in Tsc2-WT). However, there was a strong trend towards increasing filling pressure (E/e'ratio; 14.24±4.01 vs 12.15±2.54) and mean pulmonary pressure (21±6 vs 18±3 mmHg) in Tsc2-KO mice compared to controls suggesting diastolic dysfunction. Conclusion Hearts of the Tsc2 fl/fl CD11c Cre+ animals show a phenotype highly reminiscent of cardiac sarcoidosis in patients. We anticipate that this model will be very useful in deciphering molecular mechanisms of pathogenesis as well as testing much-needed mechanism-based therapies. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation - PG/18/27/33616

Safety analysis from PACS 04—A phase III trial comparing 6 cycles of FEC100 with 6 cycles of ET75 for node-positive early breast cancer patients, followed by sequential trastuzumab in HER2+ patients: Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 632-632 ◽  
Author(s):  
M. Spielmann ◽  
H. Roché ◽  
T. Delozier ◽  
G. Romieu ◽  
H. Bourgeois ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Safety Data ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Ventricular Ejection Fraction ◽  
Phase Iii Trial ◽  
Post Surgery

632 Background: Following the BCIRG 001, PACS 01 and HERA trials, this randomised, multicentre, open-label, Phase III trial was designed to demonstrate the benefit of concomitant docetaxel and epirubicin versus anthracyclines, and evaluate the use of sequential trastuzumab. Methods: Patients (pts) with localised, resectable, unilateral breast cancer who met the following criteria were eligible: age <65 years, ≥1 positive node, M0, adequate heart and organ functions. Pts were randomised to receive either 6 cycles of 5-fluorouracil-epirubicin-cyclophosphamide (FEC100: F and C, 500 mg/m2, E 100 mg/m2) (Arm A) or epirubicin-docetaxel (ET75: E 75 mg/m2, T 75 mg/m2) (Arm B). Primary prophylaxis with G-CSF was not planned. Radiotherapy was mandatory after conservative surgery and tamoxifen was required in pts with hormone receptor-positive tumours. Pts with HER2-positive disease were then further randomised to observation only or to 1 year of trastuzumab monotherapy (6 mg/kg iv every 3 weeks). In HER2-positive pts receiving trastuzumab, left ventricular ejection fraction (LVEF) was determined at Cycles 2, 4, 8, 13, 18 and after 2 years. Otherwise, LVEF was determined at baseline and at 1 year post-surgery. Results: Of the 3010 pts recruited (2622 evaluable for safety to date), 1518 received FEC100 and 1492 received ET75 after the first randomisation. Haematologic toxicity was the most frequent toxicity in both arms. Grade 3–4 toxicities were similar for Arms A and B, except febrile neutropenia (10.3% and 31.4%, respectively) and nausea/vomiting (13.2% and 7.5%, respectively). Grade 2 clinical cardiac toxicity (decreased LVEF) was observed in 4 pts in Arm A and 5 in Arm B, with median LVEF scores of 63% in both arms at the end of chemotherapy. HER2-positive pts (n=500) were then randomised to either receive trastuzumab (n=259) or observation only (n=241). Conclusions: These preliminary safety data indicate that FEC100 and ET75 were both well tolerated, with acceptable cardiac safety values. The trial is ongoing and further analysis regarding the use of trastuzumab in this setting will be presented. [Table: see text]

A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 579-579 ◽  
Author(s):  
L. A. Kutteh ◽  
T. Hobday ◽  
A. Jaffe ◽  
B. LaPlant ◽  
D. Hillman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Troponin T ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Tnf Alpha ◽  
Ventricular Ejection Fraction ◽  
Pre Treatment ◽  
Positive Breast Cancer

579 Background: N9831 and other clinical trials have demonstrated the additive survival benefit of trastuzumab (H) therapy with chemotherapy for patients with resected HER-2 positive breast cancer. Cardiac toxicity (CTox) is increased by this strategy. Prediction of or early detection of CTox is important. Methods: 95 patients provided informed consent. Brain natriuretic peptide (BNP), C-reactive protein (CRP), troponin T (TnT) and I (TnI), TNF-alpha, IL-1b, and IL-6 were to be drawn at baseline, after initiation of doxorubicin/cyclophosphamide (AC), after initiation of paclitaxel (T), and after the initiation of H (may have been given concurrently with T). 67 patients with at least a baseline sample, a post-treatment sample, and a baseline and subsequent evaluation of LVEF were studied. No patient in this group had a grade 3 decline in LVEF. Only 3 of these patients did not receive H. Values above the 99th percentile were considered abnormal for troponin. 40 ng/ml was considered elevated for BNP. Results: Values of CRP, TNF-alpha, IL- 6 and IL1b changed in very few patients and without a discernible pattern. For further evaluation of BNP, TnI, and TnT, 2 definitions of CTox were tested: 1. a >10% drop in LVEF from baseline (n=27) and 2. a drop in LVEF of 10–15% to less than the institutional lower limit of normal (LLN) OR a >15% decline in LVEF (n=14). No pre-treatment marker appeared to predict a > 10% decline in LVEF (definition 1). For patients fulfilling definition 2, pre-treatment BNP > 40 was seen in 21% of patients vs 8% of normals (nls) (p= 0.18) and an abnormal TnI (>0.04) was seen in 21% vs 6% of nls (p=0.10). Only doubling of BNP appeared promising as a serial marker of CTox using definition 2 (27% vs 7% for nls (p = 0.09). Conclusions: Baseline BNP and TnI and serial measures of BNP may be promising for further investigation for the prediction and detection of treatment-related CTox. Due to limitations of the study including the small numbers of patients analyzed, the difficulty in defining CTox, and the variation in the timing of sample procurement and assessment, these data are considered exploratory. Supported by CA-25224, CA-2115, CA 38926, CA31946. No significant financial relationships to disclose.

Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 517-517 ◽  
Author(s):  
Lorena De La Pena ◽  
Javier Cortes ◽  
Alexey Manikhas ◽  
Laslo Roman ◽  
Vladimir Semiglazov ◽  
...  
Keyword(s):  
Nyha Class ◽  
Metastatic Breast ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Class Iii ◽  
Ventricular Ejection Fraction ◽  
Phase Iii Trial

517 Background: M in combination with T has shown promising activity and cardiac safety in MBC patients (pts). We conducted a randomized Phase III trial of first-line M plus T and P (MTP) versus T plus P (TP) in HER2+ MBC pts. Methods: Pts with HER2+ (by FISH) MBC ≥ 18 years and ECOG 0-1, who had received no prior chemotherapy for metastatic disease, were eligible. Left ventricular ejection fraction should be within normal institutional limits. Prior (neo-) adjuvant anthracyclines, T or P were permitted, if completed >1 year before the start of the study. Pts received M 50 mg/m2 q3w for 6 cycles, T 4 mg/kg loading dose followed by 2 mg/kg qw, and P 80 mg/m2qw, or T+P at the same doses until progression or toxicity. Primary outcome was progression-free survival (PFS). Enrollment of 332 pts would provide 80% power with a 5% significance to detect an improvement in PFS with MTP, assuming a median PFS of 8 months in TP and a hazard ratio (HR) of 0.70. Results: 363 pts enrolled (MTP 181, TP 183), 360 received treatment. The two groups were well balanced for demographics, pretreatment characteristics and extent of disease. One third of the pts had prior exposure to anthracyclines, but almost none to trastuzumab (1% and 2% in MTP and TP arms, respectively). Six cycles of M could be given to 72% of the pts. With a median follow-up of 31 months, median PFS was 16.1 and 14.5 months with MTP and TP, respectively (HR 0.84, P=0.174). In pts with ER and PR-negative tumors, PFS was 20.7 and 14.0 months, respectively (HR, 0.68; 95% CI 0.47–0.99). Median overall survival (OS) was 33.6 and 28.9 months, respectively (HR, 0.79, P=0.083). In ER and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR, 0.63; 95% CI 0.42–0.93). The incidence of NYHA Class III/IV congestive heart failure was 3% with MTP and there were 2 cardiac deaths with TP. The frequency of adverse events was higher with MTP, especially myelosuppression, stomatitis and gastrointestinal intolerance. Conclusions: The trial failed to demonstrate a significant clinical improvement with the addition of M to TP. The clinical benefit observed in an exploratory analysis in the ER and PR-negative population deserves consideration for further clinical trials. Clinical trial information: NCT00294996.

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