ASCOSTI-571, an investigational drug that has high activity in
benign-phase chronic myelogenous leukemia (CML), also produces
significant hematologic responses in patients with advanced-stage CML
or acute forms of leukemia, Moshe Talpaz, MD, said at the 36th
annual meeting of the American Society of Clinical Oncology (ASCO) in
New Orleans.
The phase I trial was conducted by Dr. Talpaz, of M.D. Anderson
Cancer Center, in conjunction with Charles Sawyer, MD, of UCLA
Jonsson Cancer Center, and Brian Druker, MD, of Oregon Health
Sciences University.
STI is very active in inducing hematologic remissions in
chronic-phase patients. I cant say that we expected to find
responses of the same nature in very advanced disease, Dr.
Talpaz said in an interview with ONI. Many of these
patients are heavily pretreated with several different doses, so the
true value of the drug in these situation has to be assessed.
STI-571, which was developed by Dr. Druker in conjunction with
Novartis Pharmaceuticals, inhibits the enzymatic activity of the
Bcr-Abl protein, and is known as a signal transduction inhibitor
(STI). The abnormal Bcr-Abl protein is found in virtually all CML
patients, and is vital to the survival and proliferation of leukemia
cells. When the protein is blocked, the result is a halt to the
progression of the disease.
The current study included 51 patients (48 evaluable), 33 CML
patients in myeloid blast crisis and 15 patients with CML in lymphoid
blast crisis or Bcr-Abl-positive acute lymphocytic leukemia (ALL).
Patients received STI-571 orally once a day. Equal numbers of
patients were treated with six treatment-dose cohorts, ranging from
300 mg to 800 mg, as these doses had previously shown significant
therapeutic benefit in interferon-refractory, stable-phase CML
patients.
Study Results
Among the 33 patients in myeloid blast crisis treated with STI-571, 9
(27%) achieved a complete remission, defined as the decline of bone
marrow blasts to less than 5%. Another 15 had a partial response
(45%) for a total response rate of more than 70%.
Of the 15 patients with lymphoid acute phase CML or Bcr-Abl-positive
ALL, 9 were complete responders and 2 were partial responders for a
total response rate of 70%. Partial response was defined as
suppression of bone marrow blasts to less than 50%.
The responses are very surprising, because there is a 70%
response rate for each of the situations. Dr. Talpaz said.
It is surprising to us that STI-571 worked at all at that
stage. There are so many genetic evolutions between onset and blast
crisis. At this very advanced stage, the disease can move quickly to
change its genetic presentation and develop resistance, so we thought
that at this stage, the disease would be driven by factors other than treatment.
Nevertheless, he said, STI-571 inhibited Bcr-Abl, and it
was active, even at this very advanced stage.
Patients had some overall moderate toxicity (nausea and vomiting), he
said. Significant periorbital, facial, and leg edema occurred at
doses of 600 mg or more.
Of the 33 patients with CML in myeloid blast crisis, 6 (20%) achieved
ongoing remissions for a period of 5 months to more than a year. Two
of these patients also achieved a complete cytogenetic remission,
with complete disappearance of the Philadelphia chromosome.
In the lymphoid blast crisis group, regretfully, 8 of the 9
patients who were complete responders suffered a relapse within 1 to
4 months, Dr. Talpaz reported. The response was not
durable, and the results for these patients are somewhat
disappointing.
The one patient with lymphoid blast crisis who had a sustained
response has been in remission for more than 7 months. She had
an extramedullary relapse, and ultrasound showed tumors in 5 or 6
sites, he said. When she started STI-571, the whole
visible measure of disease disappeared within 1 to 2 weeks.
Dr. Talpaz commented that blast crisis CML and advanced acute
leukemias are aggressive diseases, and it shouldnt
surprise us that, at this particular stage, remissions are
short-lived.
He pointed out that the short remissions seen in this study do
not change the STI-571 treatment paradigm, because in the chronic
disease phase, the remissions are very durable. We started work on
this drug in 1998 in chronic-phase patients, and remissions are
ongoing.
