Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group.
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.
Bhatia
Smita
S
Division of Pediatric Oncology, City of Hope National Medical Center, Duarte, CA, USA. sbhatia@coh.org
Krailo
Mark D
MD
Chen
Zhengjia
Z
Burden
Laura
L
Askin
Frederic B
FB
Dickman
Paul S
PS
Grier
Holcombe E
HE
Link
Michael P
MP
Meyers
Paul A
PA
Perlman
Elizabeth J
EJ
Rausen
Aaron R
AR
Robison
Leslie L
LL
Vietti
Teresa J
TJ
Miser
James S
JS
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D003609:Dactinomycin / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000009:adverse effects; D015994:Incidence; D007223:Infant; D007951:Leukemia, Myeloid / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000453:epidemiology; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000453:epidemiology; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy*; D016016:Proportional Hazards Models; D012306:Risk; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide