Health Effects After Anthracycline and Radiation Therapy (HEART): Dexrazoxane and Prevention of Anthracycline-related Cardiomyopathy

• Differences in serum biomarkers [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Particularly cardiac troponins and natriuretic peptides associated with acute changes following anthracycline exposure will be examined. Analyses involving markers of inflammation (hs-CRP, TNF, IL6) and more novel markers associated with heart failure in the general population (galectin-3, ST2, growth differentiation factor-15) are exploratory.
• Quality of Life [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Based on self-report instruments will be factored into QALY estimates to answer the secondary aims.
• Update primary disease relapse and second cancer rates [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  Given additional elapsed time since last follow-up used in the prior published analyses,11-13 primary disease relapse and second cancer rates will be updated.

We will determine echocardiographic and serum biomarkers of cardiac injury in a study of long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 with certain features. Our primary aim will be to determine whether patients randomized to the experimental dexrazoxane (DRZ) arms have decreased markers of myocardial injury compared with patients treated without dexrazoxane (DRZ). This will include a one-time measurement of an echocardiographic index of pathologic left ventricular (LV) remodeling (wall thickness-dimension ratio), complemented by serum biomarkers and a physical examination for signs and symptoms of cardiomyopathy/heart failure (CHF). We will also evaluate whether DRZ's cardioprotective effect is modified by anthracycline dose, chest radiation, and selected demographic factors (age at cancer diagnosis, current age, sex).

Given the critical role anthracyclines have in many effective cancer treatments and the risk for subsequent cardiotoxicity associated with this class of agents, development of an effective cardioprotective strategy is of great importance. Although adult studies have shown that dexrazoxane (DRZ) is effective in minimizing cardiomyopathy/heart failure (CHF) after anthracycline therapy, short and long-term data in children are much more limited. Furthermore, concerns regarding DRZ's interaction with cancer therapies and possible association with an increased risk of second cancers have limited its use among children despite possible protection against premature CHF. To address these gaps in knowledge, using a cross-sectional study design, we propose to ascertain echocardiographic and serum biomarkers of cardiac injury in a cohort of long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 that featured upfront DRZ randomization and a range of anthracycline exposures commonly used in contemporary therapy (100-360 mg/m2 doxorubicin). Our primary aim will be to determine whether patients randomized to the experimental DRZ arms have decreased markers of myocardial injury compared with patients treated without DRZ. Specifically, this will include a one-time measurement of an echocardiographic index of pathologic left ventricular (LV) remodeling (wall thickness-dimension ratio), complemented by serum biomarkers and a physical examination for signs and symptoms of CHF. We will also evaluate whether DRZ's cardioprotective effect is modified by anthracycline dose, chest radiation, and selected demographic factors (age at cancer diagnosis, current age, sex). In secondary analysis, we will also update the overall- and event-free survival rates between patients on the DRZ and non-DRZ arms. Finally, we will determine whether projected quality-adjusted life years differed by randomization status, accounting for premature cardiac disease, primary disease relapse, and second cancers.

Long-term pediatric T-cell leukemia and Hodgkin lymphoma survivors enrolled on 3 front-line Children's Oncology Group (COG) clinical trials (POG 9404, 9425, 9426) between 1996-2001 that featured upfront DRZ randomization and a range of anthracycline exposures commonly used in contemporary therapy (100-360 mg/m2 doxorubicin).

• T-cell Acute Lymphoblastic Leukemia
• Intermediate/Advanced Hodgkins
• Early Hodgkins

• Other: Diagnostic/symptom checklist
  The local PI or their designee (e.g. clinician, research nurse, or clinical research associate) will be asked to complete a diagnostic and symptom checklist (see Forms Packet on COG website) related to study outcomes. A copy of the participant's most recent clinic note and current medication list also are requested.
• Other: Anthropometry

  Easily determined in-office physical exam parameters requested include:

  • Height
  • Weight
  • Waist circumference
  • Blood pressure (BP)
  • Heart rate
• Procedure: Echocardiogram
  Study participants will undergo a one-time standard 2D, M-mode, and Doppler echocardiogram per AHA/ACC task force practice guidelines at participating institutions (or their adult affiliates depending on patient age and institutional practice).
• Procedure: Serum Biomarkers

  All participants will have the following analytes collected under standardized conditions and processed centrally.

  • Cardiac troponins have been associated with acute anthracycline-related cardiotoxicity, and newer high-sensitivity cTnT and cTnI assays may be predictive of late-occurring LV dysfunction. Natriuretic peptides (BNP, NT-ProBNP) are produced in response to myocardial wall stress and are used to monitor CHF progression. Levels, if persistently elevated, correlate well with echocardiographic indices of myocardial dysfunction. In exploratory analyses, we will also examine the effects of selected inflammatory biomarkers.
  • Fasting lipid profile (total cholesterol, HDL, LDL, triglyceride), glucose, insulin, and hemoglobin AIC)
  • Provide optional consent to have DNA banked for future research related to analysis of possible genetic polymorphisms associated with differential risk of cardiomyopathy.
• Other: 6 minute walk test (6MWT)
  Ambulatory participants will be asked to undergo this simple test of functional exercise capacity. Contraindications include: 1.) history of angina or myocardial infarction within the past month, 2.) resting heart rate >120 bpm, 3.) systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg. Any other reason for patient inability to perform this test should be documented in the respective Report Form.
• Behavioral: Participant Questionnaires (ages ≥14 years only)
  The time to complete questionnaires is estimated less than 45 minutes. General health status and quality of life will be assessed using the Short-Form-36. Participants also will be administered the Minnesota Living with Heart Failure questionnaire. Questionnaires will ascertain family history of cardiovascular and related diseases (e.g. diabetes). Physical activity will be assessed using questions from the Centers for Disease Control & Prevention's (CDC) Behavioral Risk Factor Surveillance System exercise & physical activity modules. Smoking history (current & lifetime) will be assessed using questions from Health and Nutritional Examination surveys.

• Stratum 1 with diagnostic interventions

  Required observations are designed to be collected at one visit:

  Diagnostic/symptom checklist Anthropometry Echocardiogram Serum biomarkers Troponins (cTnT, cTnI) Natriuretic peptides (BNP, NT-ProBNP) Inflammation (hs-CRP, IL-6, TNF, Galectin-3, ST2, GDF15) Fasting glucose, lipid profile, insulin, hemoglobin AIC DNA 6 minute walk test Participant Questionnaires: Quality of life, family history, physical activity, and smoking Fasting for at least 10 hours prior to the study blood draw.

  Interventions:

  • Other: Diagnostic/symptom checklist
  • Other: Anthropometry
  • Procedure: Echocardiogram
  • Procedure: Serum Biomarkers
  • Other: 6 minute walk test (6MWT)
  • Behavioral: Participant Questionnaires (ages ≥14 years only)
• Stratum 2 Relapse and subsequent malignancy status

  Patients not eligible for Stratum 1 may still contribute data to the Secondary Aims:

  Relapse and subsequent malignancy status

Inclusion Criteria:

• Previously enrolled and randomized on POG 9404, 9425, or 9426
• Alive and in continuous first complete remission from their original cancer (T-cell leukemia/lymphoma [POG 9404] or Hodgkin lymphoma [POG 9425/9426])
• Not have been diagnosed with any subsequent malignancy, with the exception of non-melanomatous skin cancer(s). Patients with history of only subsequent non-melanomatous skin cancers remain eligible.
• All patients and/or their parents or legal guardians must sign a written informed consent (see Stratum 1 sample consent).
• Among patients who have relapsed or have experienced a subsequent malignancy other than non-melanomatous skin cancer since their original diagnosis, the study committee will review the available data (both from COG's Statistics and Data Center (SDC) and the participating institution) to determine if individual patients are to be selected for secondary aim arm only. The study will petition the IRB specifically for a waiver of consent to include any relapse and subsequent cancer data obtained from existing records for analysis of the secondary aims. Patients selected for Stratum 2 will be those for whom late relapse or subsequent cancer is reported but who lack clear confirmation in existing records (either at SDC or at the local institution).

Exclusion Criteria:

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• The Leukemia and Lymphoma Society
• St. Baldrick's Foundation
• National Cancer Institute (NCI)