NEW ORLEANSSTI 571, an investigational drug for the treatment
of chronic myelogenous leukemia (CML), produced complete hematologic
responses in all patients receiving higher doses, according to
preliminary analysis of phase I data presented at the 41st Annual
Meeting of the American Society of Hematology (ASH) (see illustration
). All participants had failed interferon-alfa therapy.
In CML, a chromosomal translocation (the Philadelphia chromosome)
results in an oncogene that produces the abnormal protein bcr-abl.
This fusion protein has enhanced tyrosine kinase activity, resulting
in the excessive proliferation of white blood cells characteristic of
Thus, an inhibitor of the abl protein tyrosine kinase would be
predicted to be an effective and targeted therapeutic agent,
said Brian J. Druker, MD, associate professor of medicine, Oregon
Health Sciences University, Portland.
Preclinical studies initiated at Dr. Drukers laboratory and
confirmed in numerous other labs have shown that STI 571, a signal
transduction inhibitor, is a potent and selective inhibitor of the
abl and bcr-abl tyrosine kinases, and that the agent
selectively kills bcr-abl expressing cells in vitro and
In addition, as an oral formulation, it is highly bioavailable. Dr.
Druker noted that the agent has been shown to have a half-life of
between 13 and 18 hours, suggesting that once-daily administration is appropriate.
Dr. Druker conducted the study in conjunction with Moshe Talpaz, MD,
of M.D. Anderson Cancer Center, and Charles Sawyers, MD, of the
Jonsson Cancer Center at UCLA, as well as scientists at Novartis
Pharmaceuticals, which is developing the agent.
Inclusion criteria for the study were diagnosis with
Ph-chromosome-positive CML in the chronic phase of the disease with
blast percentages in peripheral blood or bone less than 15%.
Interferon failure was defined as 3 months of therapy without a
hematologic response, or 1 year on interferon therapy without a
cytogenic response, or acquired hematologic or cytogenic response
that has been lost. In addition, some (less than 10%) interferon
intolerant patients were enrolled.
A total of 61 patients (36 male, median age 57) participated in the
study. The median duration of disease in the cohort was 3.7 years.
Participants received once-daily oral doses of STI 571 at 11 dose
levels ranging from 25 mg to 600 mg. No other cytoreductive agents
were allowed. At the time of this report, the median duration of
treatment was 190 days, with some patients on therapy for well over a
year (up to 439 days).
New Trials of STI 571
Novartis Pharmaceuticals has initiated a phase II clinical trial of
Additional trials evaluating STI 571 in combination with chemotherapy
For more information about these studies, contact the Novartis
Hematologic responses (defined as a 50% decrease in white blood cell
count from baseline maintained for a least 1 month) were seen among
all 51 patients receiving doses of 140 mg or greater. Complete
hematologic responses (defined as normal white blood cell and
platelet counts maintained for at least 4 weeks), however, were not
observed until doses of 200 mg or greater were reached, Dr. Druker said.
All patients receiving 300 mg or more (31/31) had a complete
hematologic response. The white blood cell counts fell into the
normal range within 3 to 4 weeks and were maintained throughout the
duration of therapy, Dr. Druker said.
Cytogenic responses have been observed in 35% of patients on the
higher dose (greater than 300 mg). Dr. Druker noted that cytogenic
responses have been observed among 45% (9/20) of those with at least
5 months of treatment.
It is noteworthy that, first, it is possible to have a minimal
response at 5 months with a major response at 8 months; second, in
general, cytogenic responses have improved over time; and third, at 5
months, the majority of cytogenic responses are major responses,
Dr. Druker said. He observed that three patients at 5 months
follow-up were 100% Ph-chromosome negative.
Dr. Druker said that a maximally tolerated dose has not yet been
defined. He noted that the majority of patients at doses of 140 mg
and greater have had decreases in hemoglobin of 1 to 2 g/dL.
With continuing therapy, levels typically return to baseline or
above baseline levels, he said.
Among the 31 patients being treated at a dose of 300 mg or higher,
grade 2 myelosuppression has been seen in six patients and grade 3 in
three patients. However, myelosuppression may be an indication
of therapeutic benefit rather than toxicity in this patient
population, Dr. Druker pointed out.
Adverse events have included grade 1 nausea (when taken on an empty
stomach) in 40% of patients, and muscle cramps, arthralgia, and
periorbital edema, each in 10% of patients.
Dr. Druker concluded that STI 571 has been well tolerated as an oral
agent among CML patients refractory to other therapies. He emphasized
that at least one third of the cohort had several disease criteria
that would meet accelerated phase definitions. He cautioned, however:
Despite these exciting results, I will be the very first to
admit that we still have a lot to learn about this agent. We clearly
dont know how durable the responses will be, if we will see the
emergence of resistance, or if there will be any long-term
unanticipated side effects.