Two recent developments increase the likelihood that Gleevec will soon have a pharmacogenomic successor in chronic myeloid leukemia and some forms of amyotrophic lateral leukemia.
The Bristol-Myers Squibb drug Sprycel and the Novartis drug Tasigna each appeared in research suggesting they have the potential to be favorable therapies for patients who test positive for Gleevec-resistance mutations. The arrival of drugs to replace Gleevec in resistant patients will finally create a market to help clinicians choose between therapies for CML and ALL. Genzyme and Quest Diagnostics each offer assays for detecting Gleevec-resistant leukemia cells, and there may still be some room for more diagnostics in that developing market.
"The laboratory understanding of how certain mutations should or shouldn't respond to dasatinib [Sprycel] was borne out exactly in the trial, which argues for genotype-based assessment of patients being part of making treatment decisions," said Charles Sawyers, an investigator at the Howard Hughes Medical Institute and a professor of medicine in the University of California, Los Angeles' department of hematology and oncology. Sawyers was a co-author on the study.
Both Sprycel and Tasigna were developed to circumvent tumor-cell mutations that can render CML and Philadelphia chromosome-positive ALL resistant to Gleevec. Only the T315I mutation in the Bcr/Abl drug-target protein is known to confer resistance to all three drugs, but research on Sprycel and Tasigna may continue to reveal new mutations associated with resistance or intolerance.
"The laboratory understanding of how certain mutations should or shouldn't respond to dasatinib [Sprycel] was borne out exactly in the trial, which argues for genotype-based assessment of patients being part of making treatment decisions."
With Tasigna, "you have to use different doses, depending on what the mutation is, whereas with [Sprycel], you don't," said Sawyers.
UCLA holds the patents for diagnostic use of most of the approximately 50 or so mutations known to cause Gleevec resistance, and in October, it granted Genzyme an exclusive license. It was not clear from Genzyme statements whether UCLA and the company have agreements in place covering future mutational discoveries, and the UCLA intellectual property office did not respond before deadline.
Celeste Chenet-Monte, marketing director at Genzyme Genetics, said she could add no more detail regarding the license agreement other than to confirm that it covers mutations conferring Gleevec resistance.
Genzyme began selling its Gleevec-resistance mutation assay in February. The company recommends testing for patients who show clinical signs of resistance, or when total Bcr/Abl levels begin to rise, as determined by a separate Genzyme test.
Chenet-Monte said she could not yet provide a gauge of demand for the mutational assay, but said it had probably been suppressed by the lack of a Gleevec replacement for resistant patients. "Up to this point there was nothing that clinicians could do because there was not a replacement therapy, other than alter the dose of Gleevec," she said. "I think that until there is something out there that they can use, they tend to not do tests, quite frankly."
Both Genzyme's and Quest's Gleevec-resistance mutation assays use DNA sequencing on a span of the Bcr/Abl fusion gene that runs from exon 4 through exon 9, according to Chenet-Monte and Quest's website, respectively. The intellectual property position of the two tests was not immediately clear, and Chenet-Monte said she could add no further detail. Genzyme has not sublicensed the UCLA intellectual property to Quest, she said. Quest did not respond to calls for comment.
Although new mutations may join T315I in conferring complete resistance to Sprycel and Tasigna, none are known yet, and Chenet-Monte said she did not know of researchers looking for them. "That won't happen until those drugs are licensed and in use for a while — that's what usually happens, anyway," she said.
"There are others that may have some other resistance, but I don't know all the data for [Sprycel] as yet," said Bob Wassman, Genzyme Genetics' medical director. "It's reasonable to assume that there may be other ones, but it's so much stronger a drug design, as I understand it, that there are probably different effects," he said. Investigators are looking at the Bcr/Abl protein and gene to find additional resistance mechanisms, he added.
Asked whether Genzyme had considered a test for the T315I mutation to complement upcoming therapies, Wassman said the company had considered it, but that it made more sense to use a sequencing assay to capture all Bcr/Abl changes.
In the first peer-reviewed study of Sprycel, which appears in the June 15 issue of the New England Journal of Medicine, a majority of patients experienced a significant hematologic response, with 37 of 40 chronic-phase CML patients showing no Ph+ cells in blood samples. Thirty-one of 44 patients with accelerated-phase CML or blast-crisis CML showed major hematologic responses. About 45 percent of chronic-phase CML patients showed a major cytogenetic response, as did about 25 percent of CML patients in accelerated phase or blast crisis.
A major cytogenetic response is a large decline in the number of bone marrow cells harboring the Ph+ chromosome that produces the abnormal fusion protein Bcr/Abl.
Responding patients maintained their status in 95 percent of chronic-phase CML cases and in 82 percent of accelerated-phase cases, with a median follow-up of more than 12 months and 5 months, respectively. Unpublished phase II studies that the group has presented to the FDA and that it showed at the April American Association for Cancer Research meeting in Washington, DC, appear to confirm the genetics of Sprycel response.
For a drug that inhibits multiple tyrosine kinases, Sprycel was also tolerated "surprisingly well" by its human subjects, said Sawyers. "The expectation is that it should have more side effects, but it doesn't look like it does," he said.
The phase I Tasigna data, which also appear in the June 15 issue of the New England Journal of Medicine, report that 11 of 12 chronic-phase CML patients had a complete hematologic remission. Thirteen of 33 blast-phase patients had a hematologic response and 9 had a cytogenic response. Thirty-three of 46 patients with accelerated CML had a hematologic response and 22 had a cytogenic response.
Other possible replacements for Gleevec include Wyeth's SKI-606, Nippon Shinyaku's NS-187, and ChemGenex Pharmaceuticals' Ceflatonin. ChemGenex, an Australian company, presented data this week at the European Hematology Association meeting showing 11 of 15 patients receiving Ceflatonin as monotherapy or combination therapy experienced a complete hematologic response, the company said in a statement. Among the responders were six patients carrying mutations conferring resistance to Gleevec, the company said.
— Chris Womack ([email protected])