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;

Inclusion Criteria:

- - Age (≥9years old)

- 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)

- Parental/caregiver consent and subject assent to enrollment

Exclusion Criteria:

- - Contraindications to CMRI.*

- Patients requiring sedation for the CMRI procedure

- Pregnancy tests are done routinely prior to chemotherapy, if test is positive the
patient will be excluded

- Subject is too large to be safely accommodated by MRI

- Serum creatinine higher than the guidelines for adequate renal function