Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment

PRIMARY OBJECTIVES:

I. To determine whether leukemia and lymphoma patients from P9404, P9425, P9426, and Dana
Farber Cancer Institute (DFCI) 95-01 randomized to the experimental dexrazoxane hydrochloride
(DRZ) arms have decreased markers of cardiomyopathy/heart failure (CHF) compared with
patients on the standard arm.

II. To determine whether osteosarcoma patients from P9754 (all received DRZ) have decreased
markers of cardiomyopathy/heart failure (CHF) compared with similarly treated osteosarcoma
patients diagnosed during the same time period, but who did not receive DRZ.

III. To evaluate whether the cardioprotective effect of DRZ is modified by anthracycline
(anthracycline analogue GPX-150) dose, chest radiation, and demographic factors (age at
cancer diagnosis, current age, sex).

SECONDARY OBJECTIVES:

I. To determine whether leukemia and lymphoma patients from P9404, P9425, P9426, and DFCI
95-01 on the DRZ arms experienced differential rates of overall-survival and event-free
survival compared with the standard therapy arms.

II. To determine whether projected quality-adjusted life years (QALY) differed by DRZ status,
accounting for premature cardiac disease, primary disease relapse, and second cancers.

OUTLINE:

Patients complete a diagnostic symptom checklist, undergo a physical exam, echocardiogram,
collection of serum for biomarker testing, and a 6 minute walk test, and complete quality of
life, family history, physical activity, and smoking questionnaires.

Inclusion Criteria:

- STRATUM I AND STRATUM II: LEUKEMIA AND LYMPHOMA SURVIVORS

- Previously enrolled leukemia and lymphoma survivors, randomized to + or - DRZ on
P9404, P9425, P9426, or DFCI 95-01 (high-risk patients only)

- STRATUM I: Alive and in continuous first complete remission from their original cancer
(leukemia/lymphoblastic lymphoma [P9404, high-risk DFCI 95-01] or Hodgkin lymphoma
[P9425/P9426])

- STRATUM I: Did not have progressive disease or induction failure requiring
off-protocol therapy including hematopoietic cell transplantation

- STRATUM I: Must not have been diagnosed with any subsequent malignancy that required
additional cardiotoxic therapies (i.e., radiotherapy to the chest [also includes
fields directed towards the neck, upper abdomen, or spine], or additional
anthracyclines or anthraquinones); patients with history of subsequent malignancy that
did not require such therapies remain eligible

- STRATUM I: All patients and/or their parents or legal guardians must sign a written
informed consent

- STRATUM II: Among leukemia and lymphoma patients randomized to + or - DRZ on P9404,
P9425, P9426, and DFCI 95-01 (high risk patients only) who have relapsed or have
experienced a subsequent malignancy that precludes eligibility since their original
diagnosis, the study committee will review the available data (both from Children's
Oncology Group's [COG?s] Statistics and Data Center [SDC] and the participating
institution) to determine if individual patients are to be selected for Stratum 2; in
recognition that local institutions sometimes have more updated relapse/subsequent
cancer data than SDC, in cases where local data is more updated, local data will be
used preferentially; the study will petition the Institutional Review Board (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)

- STRATUM II: Alive, but have experienced relapse of their original cancer and/or have
developed a subsequent cancer (other than non-melanomatous skin cancer) since their
original diagnosis

- STRATUM II: All patients and/or their parents or legal guardians must sign a written
informed consent

- STRATUM III: OSTEOSARCOMA SURVIVORS

- Previously enrolled osteosarcoma survivors treated on P9754 who are alive and able
(themselves and/or parents/legal guardian) to provide written informed consent; note
that relapse and subsequent malignancy are not exclusion criteria for P9754 survivors

- Comparison subjects for P9754 survivors will be eligible to be enrolled from any
ALTE11C2 participating COG site (even if that institution did not participate on
P9754), according to the following criteria:

- Newly diagnosed, previously untreated biopsy-proven moderate or high grade
osteosarcoma without metastasis; patients with low grade osteosarcoma, parosteal
or periosteal sarcoma are ineligible

- < 31 years of age at time of initial osteosarcoma diagnosis

- Diagnosis occurred between January 1, 1999 through December 31, 2002; duration of
therapy can extend beyond 2002

- No evidence of poor or low cardiac function at time of initial osteosarcoma
diagnosis; if reports from the time are available: shortening fraction >= 28% by
echocardiogram and within the institutional normative range for age, or
radionuclide angiogram ejection fraction >= 50%; if imaging reports from the time
are no longer available, there must be no documentation within available medical
records that suggest poor or low cardiac function at time of diagnosis

- Comparison subject must have institutional records (e.g., clinic note, treatment
summary, chemotherapy roadmap) documenting lifetime receipt of 450 to 600 mg/m^2
of doxorubicin (doses within 10% are acceptable); this includes initial therapy
as well as any subsequent therapy for relapse or second cancer, if relevant; as
such, comparison subjects who have had osteosarcoma relapse or subsequent
malignancies remain eligible so long as they meet all other eligibility criteria

- No anthracycline or anthraquinone aside from doxorubicin was ever given as part
of initial or subsequent therapies

- No exposure to DRZ at any point in time

- All patients and/or their parents or legal guardians must sign a written informed
consent

- For all participants, all institutional, Food and Drug Administration (FDA), and
National Cancer Institute (NCI) requirements for human studies must be met