Gleevec available to treat chronic myeloid leukemia
But mutation may result in resistance to drug
In less than three months, the Food and Drug Administration (FDA) approved a promising oral treatment for patients with chronic myeloid leukemia (CML). At the time, researchers still wondered about the long-term effects of the drug, imatinib mesylate (Gleevec), also known as STI-571. Now some researchers have found that the gene responsible for CML can adapt to avoid the inhibitory effects of the drug.
Gleevec, developed by East Hanover, NJ-based Novartis, became available in mid-May. Gleevec is a new type of cancer drug that has a "rational" drug design. It is a protein-tyrosine kinase inhibitor that blocks the constitutive kinase, BCR-ABL, which is created by the Philadelphia chromosome, a genetic defect common among patients with CML.
The FDA put the drug under its accelerated approval program of drugs for serious or life-threatening diseases based on results from three international, open-label, single-arm Phase II studies that included 1,027 patients diagnosed with Philadelphia-chromosome CML. Patients in the chronic phase of the disease showed a hematologic response of 88%; 63% of those were in the accelerated phase and 26% were in the myeloid blast crisis phase. Side effects reported in the trials include nausea, vomiting, edema, muscle cramps, skin rash, diarrhea, heartburn, and headache. Severe fluid retention occurred in up to 2% of patients. (For complete prescribing information and clinical trial results, visit www.pharma.us.novartis.com/product/pi/pdf/gleevec.pdf.)
Charles Sawyers, MD, a researcher and oncologist at the Jonsson Cancer Center at the University of California-Los Angeles, was the lead researcher in Gleevec trials for all three phases of the disease. The initial results were incredible to see, he says. "It’s absolutely amazing that just a pill with minimal side effects could be so dramatic."
But Sawyers did find that some patients developed resistance. "If patients have the advanced forms like blast crisis, they can develop resistance within about three months."
A recent study, published in the June 22 issue of Science (292:2231-2233) examined the relapse of advanced-stage CML patients who initially had responded to Gleevec. In all cases examined, the researchers found that the drug resistance was associated with reactivation of BCR-ABL signal transduction. "These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance," the researchers say.
Combination therapy key
In patients who show resistance, the drug needs to be used in combination therapy, says Sawyers. Jonsson Cancer Center is actively trying to enroll patients in combination studies that combine Gleevec with different types of chemotherapy, depending upon the patient’s stage of disease. The Center now is holding two or three combination trials, in addition to continuing to follow the patients who are on Gleevec alone.
For the patients using only Gleevec, the question is how long do the responses to the drug last, Sawyers says. "Are they permanent, or will patients develop resistance even when they have the early stage? We don’t know the answer because the drug is too new. It’s important that we continue to collect the information on these patients."
Gleevec, which Novartis says will cost $2,000-$2,400 per month for the average patient (the company does offer a patient assistance program for the drug), also was shown to be helpful in the treatment of gastrointestinal stromal tumor, Sawyers says. "That’s because those patients have a key mutation in an enzyme that is related to ABL, called KIT."
According to the June 2001 issue of The Oncologist, trials are under way in prostate cancer, lung cancer, glioma, and in other tumors overexpressing platelet-derived growth factor receptor (PDGF) receptor or c-KIT. "It should and will be tested against other tumors expressing c-KIT and PDGF receptor, and is likely to work against chronic monomyelocytic leukemia, in which the c-KIT receptor is overexpressed," says Bruce A. Chabner, MD, editor-in-chief of the journal, in an editorial.
The Oncologist contains an article by researchers at Oregon Health Sciences in Portland that presents previously unpublished information regarding the drug’s pharmacokinetics: its reliable absorption, long half-life, and limited acute and chromic toxicity (6:244-238). Although Chabner acknowledges that researchers still do not know if the drug’s CML control is permanent or temporary, his editorial brims with excitement about the drug.
"In conclusion, ST1571, or Gleevec, represents a monumental leap forward in cancer chemotherapy," Chabner writes. "It proves a principle. It justifies an approach. It demonstrates that highly specific, non-toxic therapy is possible."
[Editor’s note: Look for more detailed information on Gleevec in an upcoming issue of Drug Criteria and Outcomes.]
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