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
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
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.
Nov 6, 2013 - Ponatinib is active in chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, according to a study published online Nov. 1 in the New England Journal of Medicine.