Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease.
OBJECTIVE
Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs).


METHODS
Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low-dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ (n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes.


RESULTS
Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors (osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% +/- 1.0% with DRZ versus 0.85% +/- 0.6% in the non-DRZ group (P = .160). For any SMN, the CIR for DRZ was 3.43% +/- 1.2% versus CIR for non-DRZ of 0.85% +/- 0.6% (P = .060). Among patients receiving DRZ, the standardized incidence rate (SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ (P = .0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ (P = .0231).


CONCLUSIONS
DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.
Tebbi
Cameron K
CK
Children's Oncology Group, Statistics and Data Center, Arcadia, CA, USA.
London
Wendy B
WB
Friedman
Debra
D
Villaluna
Doojduen
D
De Alarcon
Pedro A
PA
Constine
Louis S
LS
Mendenhall
Nancy Price
NP
Sposto
Richard
R
Chauvenet
Allen
A
Schwartz
Cindy L
CL
D000208:Acute Disease; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002614:Chelating Agents / Q000009:adverse effects*; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases / Q000139:chemically induced / Q000517:prevention & control; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D015994:Incidence; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000453:epidemiology; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000453:epidemiology; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000453:epidemiology; D012516:Osteosarcoma / Q000139:chemically induced; D011929:Razoxane / Q000009:adverse effects*; D018570:Risk Assessment; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000139:chemically induced; D013997:Time Factors; D059005:Topoisomerase II Inhibitors
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D011929:Razoxane