STI-571 in the Treatment of Children with Philadelphia (Ph+) Chromosome-Positive Leukemia: Results from a Children's Oncology Group (COG) Phase I Study.

Reviewer: M. Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 8, 2001

Presenter: Martin A. Champagne


STI-571 is a novel chemotherapeutic agent that selectively inhibits the abnormal tyrosine kinase that results from the translocation of the c-abl gene on chromosome 9 to one of two breakpoint regions on chromosome 22 (t 9;22). This translocation, known as the Philadelphia Chromosome, results in the continuous tyrosine kinase activity that leads to malignancy in many leukemias. In children, Ph + leukemias include 2-3% of acute lymphoblastic leukemia (ALL) and the adult type chronic myeloid leukemia (CML). STI571 has been shown to be safe and effective in adults, but had not yet been studied in children. This Phase I study was designed to establish the maximum tolerated dose (MTD), determine the dose-limiting toxicity (DLT), and characterize the pharmacokinetic activity of STI571 in children.

Materials and Methods

  • 30 patients under the age of 22 with either CML refractory to interferon alpha, CML relapsing after stem cell transplant, or refractory or relapsing Ph+ leukemia were treated with escalating doses of STI571.
  • patient (pt) characteristics:
    • median age 15, range 3-20
    • diagnosis of CML (n=19), ALL (n=9), and AML (n=2).
    • 23 males, 7 females
  • doses used (all doses given orally, once a day):
    • 260 mg/m2 (n=6)
    • 340 mg/m2 (n=11)
    • 440 mg/m2 (n=7)
    • 570 mg/m2 (n=6)
  • toxicities were graded according to NIH criteria


  • Grade 3 or 4 hematological toxicities for all 142 courses of treatment
  • were as following:
    • leukocytes < 2K, 18 pts (10% of all courses)
    • neutrophils < 1K, 41 pts (22%)
    • hemoglobin < 8 g/dl, 15 pts (8%)
    • platelets < 50 K, 23 pts (13%)
  • Grade 3 or 4 GI toxicities for all courses: 4 cases of AST/ALT elevations
  • Most common toxicities were grade 1 or 2 nausea (n=8) and vomiting (n=10).
  • No dose limiting toxicity was seen
  • No maximum tolerated dose has been determined
  • No clear dose-toxicity correlation was seen
  • 5 patients had a complete cytogenic response (4 ALL, 1 blast phase CML), and 1 pt had a major response

Author's conclusions:

  • STI571 has a safe profile in children at the doses studied, with no MTD or DLT seen.
  • Main toxicities were hematological and mild nausea and vomiting.
  • There is no apparent dose/toxicity relationship at the doses studied.
  • STI571 has a safety profile in children similar to that seen in adults, with a possibly decreased incidence of fluid retention.
  • Doses of 260-340 mg/m2 in children were similar to doses of 400 - 600 mg/m2 in adults (recommended dose) in terms of drug exposure Anti-leukemia activity was seen at all dose levels.
  • The current, on-going Phase II study will further assess the efficacy of STI571 in chronic phase CML and in combination with chemotherapy.

Clinical and Scientific Implications:

STI571 is a safe anti-neoplastic agent for use in children. This study may herald its use in the pediatric population. While STI571 appears effective in this Phase I study, its efficacy will be further defined in an on-going Phase II study.