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Blood, 1 January 2007, Vol. 109, No. 1, pp. 46-51.
Prepublished online as a Blood First Edition Paper on September 19, 2006; DOI 10.1182/blood-2006-01-023101.
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Submitted January 17, 2006
Accepted July 27, 2006
Therapy-related myelodysplasia and acute myeloid
leukemia after Ewing sarcoma and primitive
neuroectodermal tumor of bone: a report from the
Children's Oncology Group
Smita Bhatia*, Mark D. Krailo, Zhengjia Chen, Laura Burden, Frederic B. Askin, Paul S. Dickman, Holcombe E. Grier, Michael P. Link, Paul A. Meyers, Elizabeth J. Perlman, Aaron R. Rausen, Leslie L. Robison, Teresa J. Vietti, and James S. Miser
Division of Pediatric Oncology, City of Hope National Medical Center, Duarte, CA, USA
Keck School of Medicine, University of Southern California, USA
Children's Oncology Group, Arcadia, CA, USA
Johns Hopkins Medical Center, Baltimore, MD, USA
Phoenix Children's Hospital, Phoenix, AZ, USA
Dana Farber Cancer Institute and Children's Hospital, Boston, MA, USA
Stanford University School of Medicine, Stanford, CA, USA
Memorial Sloan-Kettering Cancer Center, NYC, NY, USA
Johns Hopkins Hospital, Baltimore, MD, USA
New York University Medical Center, NYC, NY, USA
University of Minnesota, Minneapolis, MN, USA
Washington University Medical Center, St. Louis, MI, USA
* Corresponding author; email: sbhatia{at}coh.org.
This study describes the magnitude of risk of therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) in 578 individuals diagnosed with Ewing sarcoma and enrolled on Children's Oncology Group therapeutic protocol, INT-0091. Between 1988 and 1992, patients with or without metastatic disease were randomized to receive doxorubicin, vincristine, cyclophosphamide and dactinomycin (Regimen A) or these four drugs alternating with etoposide and ifosfamide (Regimen B). Between 1992 and 1994, patients with metastatic disease were non-randomly assigned to receive high-intensity therapy (Regimen C: Regimen B therapy with higher doses of doxorubicin, cyclophosphamide and ifosfamide). Median age at diagnosis of Ewing sarcoma was 12 years, and median length of follow-up, 8 years. Eleven patients developed t-MDS/AML, resulting in a cumulative incidence of 2% at 5 years. While patients treated on Regimen A and B were at a low risk for development of t-MDS/AML (cumulative incidence: 0.4% and 0.9% at 5 years, respectively), patients treated on Regimen C were at a 16-fold increased risk of developing t-MDS/AML (cumulative incidence: 11% at 5 years), when compared with those treated on Regimen A. Increasing exposure to ifosfamide from 90 to 140 gm/m2, cyclophosphamide from 9.6 to 17.6 gm/m2 and doxorubicin from 375 to 450 mg/m2, increased the risk of t-MDS/AML significantly.
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