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Dexrazoxane-Associated Risk for Acute Myeloid Leukemia/Myelodysplastic Syndrome and Other Secondary Malignancies in Pediatric Hodgkin's Disease

Cameron K. Tebbi, Wendy B. London, Debra Friedman, Doojduen Villaluna, Pedro A. De Alarcon, Louis S. Constine, Nancy Price Mendenhall, Richard Sposto, Allen Chauvenet, Cindy L. Schwartz

From the Children's Oncology Group, Statistics and Data Center, Arcadia, CA; Tampa Children's Hospital, Tampa; Children's Oncology Group, Statistics and Data Center, University of Florida, Gainesville, FL; University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA; St Jude Children's Research Hospital, Memphis, TN; University of Rochester Medical Center, Rochester, NY; Children's Hospital, Los Angeles, CA; and Brown Medical School, Providence, RI

Address reprint requests to Cindy L. Schwartz, MD, Brown Medical School, RIH/Hasbro Children's Hospital, Multiphasic Building 117, 593 Eddy St, Providence, RI 02903; e-mail: cindy_schwartz{at}brown.edu, cc: pubs{at}childrensoncologygroup.org

Purpose 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).

Patients and 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).

Conclusion 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.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Related Correspondence

• Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without Compelling Evidence
  Steven E. Lipshultz, Stuart R. Lipsitz, and Endel John Orav
  JCO 2007 25: 3179 [Full Text]
• Dexrazoxane-Associated Risk for Secondary Malignancies in Pediatric Hodgkin's Disease: A Claim Without Evidence
  Kurt Hellmann
  JCO 2007 25: 4689-4690 [Full Text]

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