Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia

N Engl J Med. 1991 Dec 12;325(24):1682-7. doi: 10.1056/NEJM199112123252402.


Background and methods: Treatment of cancer with the epipodophyllotoxins (etoposide and teniposide) has been linked to the development of acute myeloid leukemia (AML) in children and adults, but the factors that might influence the risk of this complication of therapy are poorly defined. We therefore assessed the importance of potential risk factors for secondary AML in 734 consecutive children with acute lymphoblastic leukemia who attained complete remission and received continuation (maintenance) treatment according to different schedules of epipodophyllotoxin administration.

Results: Secondary AML was diagnosed in 21 of the 734 patients, in 17 of whom this complication was the initial adverse event. Prolonged administration of epipodophyllotoxin (teniposide with or without etoposide) twice weekly or weekly was independently associated with the development of secondary AML (P less than 0.01 by Cox regression analysis). The overall cumulative risk of AML at six years was 3.8 percent (95 percent confidence interval, 2.3 percent to 6.1 percent); but within the subgroups treated twice weekly or weekly, the risks were 12.3 percent (95 percent confidence interval, 5.7 percent to 25.4 percent) and 12.4 percent (95 percent confidence interval, 6.1 percent to 24.4 percent), respectively. In the subgroups not treated with epipodophyllotoxins or treated with them only during remission induction or every two weeks during continuation treatment, the highest cumulative risk was 1.6 percent (95 percent confidence interval, 0.4 percent to 6.1 percent). After adjustment for treatment frequency, there was no apparent relation between the total dose of epipodophyllotoxins and the development of secondary AML. The relative hazard of etoposide as compared with teniposide could not be determined.

Conclusions: The risk of epipodophyllotoxin-related AML depends largely on the schedule of drug administration. Other factors, including the cumulative dose of epipodophyllotoxin, radiotherapy, and the initial biologic features of the leukemic blast cells, do not appear to have critical roles.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Disease
  • Adolescent
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Etoposide / administration & dosage
  • Humans
  • Leukemia, Myeloid / chemically induced*
  • Neoplasms, Second Primary / chemically induced
  • Podophyllotoxin / administration & dosage
  • Podophyllotoxin / adverse effects*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Remission Induction
  • Risk Factors
  • Teniposide / administration & dosage


  • Etoposide
  • Teniposide
  • Podophyllotoxin