Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group

Blood. 2007 Jan 1;109(1):46-51. doi: 10.1182/blood-2006-01-023101. Epub 2006 Sep 19.

Abstract

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 4 drugs alternating with etoposide and ifosfamide (regimen B). Between 1992 and 1994, patients with metastatic disease were nonrandomly 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 regimens 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 g/m2, cyclophosphamide from 9.6 to 17.6 g/m2, and doxorubicin from 375 to 450 mg/m2 increased the risk of t-MDS/AML significantly.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bone Neoplasms / drug therapy*
  • Child
  • Child, Preschool
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Dactinomycin / administration & dosage
  • Dactinomycin / adverse effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects
  • Etoposide / administration & dosage
  • Etoposide / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Ifosfamide / administration & dosage
  • Ifosfamide / adverse effects
  • Incidence
  • Infant
  • Leukemia, Myeloid / chemically induced*
  • Leukemia, Myeloid / epidemiology
  • Male
  • Neoplasms, Second Primary / chemically induced*
  • Neoplasms, Second Primary / epidemiology
  • Neural Tube Defects / chemically induced*
  • Neural Tube Defects / epidemiology
  • Neuroectodermal Tumors, Primitive / drug therapy*
  • Proportional Hazards Models
  • Risk
  • Sarcoma, Ewing / drug therapy*
  • Vincristine / administration & dosage
  • Vincristine / adverse effects

Substances

  • Dactinomycin
  • Vincristine
  • Etoposide
  • Doxorubicin
  • Cyclophosphamide
  • Ifosfamide