Magnetic Resonance Imaging:A Window to Anthracycline Toxicity

This is a pilot study with a descriptive study design.

Anthracycline induced late onset cardiotoxicity, defined in terms of abnormal findings on echocardiography, has been reported to occur in 57% of childhood cancer survivors. Serial monitoring of cardiac function by means of echocardiography detects cardiac toxicity only when many of the cardiomyocytes have already been damaged. Given the lack of evidence to support the reliability of serum markers of cardiotoxicity, many recommend modifying the dose of anthracyclines only when there is objective evidence of myocardial dysfunction by echocardiograph. This approach could be responsible for the increasing frequency of dilated cardiomyopathy occurring 10-15 years after treatment. Non invasive imaging methods are thus critically needed to more precisely detect cardiotoxic changes in children receiving anthracyclines. CMRI has become the gold standard for the assessment and quantification of ventricular volumes, myocardial mass and global and regional wall function. CMRI also allows morphologic analysis of the myocardium as well as detection and characterization of pathological myocardium. In this study, the investigator therefore proposes to use serial MRI parameters in conjunction with a battery of serologic markers, obtained at intervals determined by cumulative anthracycline dose, to monitor changes in systolic function during chemotherapy and one year after the end of chemotherapy. The investigator will use a combination of a serum cardiac biomarker of inflammation (CRP), myocyte injury (Troponin, Caspases), heart failure (BNP), and extracellular matrix remodeling (PICP, CITP, Bone Alkaline Phosphatase, MMPs, TIMPs). The investigator will then correlate these findings with CMRI parameters of myocyte dysfunction. Results will be compared with standard echocardiography. The investigator predict that CMRI is a better indicator of early anthracycline cardiotoxicity in children with solid tumors and hematologic malignancies.

Patients who are of age 9 years of age or older, newly diagnosed with a malignancy that is anticipated to receive high dose anthracyclines as part of their chemotherapy (such as but not limited to solid tumors, high risk Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, and lymphomas) will be invited to participate in the study.

Specific Aim 1: To use CMRI to detect occult asymptomatic cardiotoxicity over time and in relation to cumulative dose among pediatric cancer patients treated with anthracyclines.

Specific Aim 2: To quantitate serologic biomarker profile for several functional pathways including the inflammatory cascade, MMP/TIMP remodeling pathways, signaling, cell viability and growth domains over time and in relation to cumulative dose among pediatric cancer patients treated with anthracyclines.

Specific Aim 3: To compare changes over time detected by CMRI and serologic markers of cardiac toxicity to echocardiographic indices of systolic and diastolic function and determine their ability alone or in combination to predict freedom from left ventricular dysfunction defined as change in ejection fraction at one year post chemotherapy.

These aims will test the hypothesis that CMR imaging and serologic biomarkers of inflammation, apoptosis and progressive extracellular matrix remodeling will precede echocardiographic indices of systolic and diastolic function among children receiving high dose anthracyclines as part of their chemotherapy protocol.

Study Outcome Measures

Myocardial edema in the acute phase measured by the following parameters:

• Increased myocardial mass.
• Focal areas of high signal intensity T2 weighted spin echo imaging and myocardial delayed enhancement. Significant enhancement will be defined as signal intensity increases of greater than two standard deviations above the mean value of remote normal myocardium.
• Increased myocardial T2 relaxation time in the myocardium compared to baseline as measured by T2 mapping technique
• Changes in myocardial T1 relaxation time in the myocardium pre and post-contrast compared to baseline as measured by T1 mapping technique (Modified Look-Locker inversion recovery (MOLLI). Myocardial T1 (msc).
• Decrease in myocardial strain and strain rate compared to baseline calculations: Mid wall left ventricular circumferential strain (ECC), Maximum longitudinal left ventricular strain (ELL).
• Decrease in myocardial T2* indicative of presence of Iron in the myocardium (reflecting anthracycline-Fe complexes)(ms).
• The following markers were measured: Matrix/Fibrosis pathway:

Plasma levels of MMPs (all soluble MMP types) and TIMPs (all 4 TIMPs); Inflammatory domain: cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2, TGF βII)),cytokine receptors (sTNF RI, sTNF RII, sSt2, sgp130, siL1-RII/sCD121b, siL-2Rα/CD25, siL-4R, siL-6R, Endoglin); Signaling pathway: growth factors (GDP-15, GCSF, VEGF, sVEGFR2 TGFβ1, IGF-1;). Changes in regional myocardial function and elevation of serologic markers may predict freedom from left ventricular dysfunction defined as ejection fraction ≥55% at 1 year.

The following tests and procedures will be done for this study:

1. CMRI tests
2. Blood tests
3. Echocardiograms

These tests noted above will be done:

1. Prior to or at before the cum dose of anthracyclines = 60 mg/m2
2. Cumulative anthracycline doses:

• 125-175 mg/m2
• 200-250 mg/m2
• 275-325 mg/m2
• After maximal anthracycline treatment
• One year after completion of maximal anthracycline therapy

The blood tests being done are:

Matrix/Fibrosis pathway:Plasma levels of MMPs (all soluble MMP types) and TIMPs, (all 4 TIMPs); Inflammatory domain: cytokines (TNFα, interleukins, interferon gamma (IFNG), TGF β2, TGF βII)), Cytokine receptors (sTNF RI, sTNF RII, sSt2, sgp130, siL1- RII/sCD121b, siL-2Rα/CD25, siL-4R, siL-6R, Endoglin); Signaling pathway: growth factors (GDP-15, GCSF, VEGF, sVEGFR2 TGFβ1, IGF-1;