PORTLAND, OregonA rationally designed drug now known as STI 571
is both effective and well tolerated in treating certain leukemia
patients that have not responded to other therapies. The results of
two phase I clinical trials using STI 571 for chronic myelogenous
leukemia (CML) and acute lymphoblastic leukemia (ALL) were reported
by Brian Druker, MD, of the Oregon Health Sciences University in
Portland, at the ASH meeting. The trials were conducted in
collaboration with M.D. Anderson Cancer Center in Houston, Novartis
Pharmaceuticals in East Hanover, New Jersey, and the University of
California at Los Angeles.
Formerly known as CGP 57418B, STI 571 works by inhibiting the Abl
protein tyrosine kinase (see Figure 1).
Almost all cases of CML are caused by a chromosomal translocation in
a hematopoietic stem cell. This translocation creates an altered
chromosome 22, the Philadelphia chromosome, containing a new gene
called bc-abl. Some patients with acute lymphoblastic leukemia also
have the Philadelphia chromosome. The bc-abl genes product, a
tyrosine kinase, causes white blood cells to proliferate out of
control. STI 571 inhibits the kinase activity of the aberrant Abl
protein. As a result, STI 571 theoretically should stop further
abnormal proliferation of white blood cells caused by the bc-abl
tyrosine kinase while not interfering with the normal activities of
the hundreds of other tyrosine kinases.
The first phase I study started in June 1998 and included 61 adults
who had both the Philadelphia chromosome and CML, were in the chronic
phase (less than 15% blasts), and did not respond to interferon. Each
received one oral dose daily of STI 571. Eleven dose levels were
tested, ranging from 25 mg to 600 mg per day.
All patients receiving at least 140 mg per day had a hematological
response to STI 571 (defined as at least a 50% drop in white blood
cell count for at least 2 weeks). Everyone who received at least 300
mg per day made a complete hematological responses (normal white
blood cell and platelet counts for at least 4 weeks) within 3 to 4
weeks. This complete response has lasted throughout therapy. In
addition, 45% of patients on 300 mg or more per day had a cytogenetic
response (decrease in the number of cells containing the Philadelphia
chromosome) within 5 months.
STI 571 did not cause dose-limiting toxicity at any of the doses used
in this trial. The most common side effects were nausea (40%), cramps
(10%), arthralgias (10%), and periorbital edema (10%). In addition,
among the 31 patients taking at least 300 mg, 9 experienced
myelosuppression, 6 with grade 2 and 3 patients with grade 3.
Dr. Druker concluded that STI 571 was both effective and safe in the
short term as a treatment for CML, even in patients who did not
respond to other treatments. He cautioned, however, that it was not
yet clear how durable the responses would be or whether longer use
would reveal long-term side effects.
Following the encouraging results with CML, the research team began a
phase I study of STI 571 for treating acute leukemias. That study
enrolled 33 patients who had either ALL or CML in myeloid blast
crisis. Patients received 300, 400, 500, or 600 mg of STI 571 orally
Four patients died (two of infections, and two of progression of
their leukemias), leaving 29 evaluable patients with a median
treatment duration of 68 days. Of the 18 myeloid blast crisis, 6 had
a complete response (marrow blasts less than 5%), and 4 had a partial
response (marrow blasts less than 15%). Three of 11 ALL patients had
a complete response and 6 had a partial response. In general,
responding patients tend to respond relatively early, Dr.
Responses Not Durable
All but one ALL patient, however, relapsed between days 45 and 81.
The problem in treating acute leukemias has not been
response, Dr. Druker said, but relapse. STI has
significant activity in BCR-ABL acute leukemias, Dr. Druker
concluded. However, responses are rarely durable.
The results for myeloid blast crisis patients were a little more
promising. One patient had not yet relapsed after 200 days, and
another had not yet relapsed after 150 days. Some other patients were
too early in their therapy for researchers to know yet whether they
Side effects of treatment included grade 3 and 4 neutropenia and
grade 2 and 3 hepatotoxicity.