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 each day.
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. Druker said.
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 would relapse.
Side effects of treatment included grade 3 and 4 neutropenia and grade 2 and 3 hepatotoxicity.