From OncoLog, Feburary/March 2005, Vol. 50, No. 2/3

Novel Drugs Address Gleevec Resistance

In ongoing phase I clinical trials at M. D. Anderson Cancer Center, two different molecularly targeted therapies are showing promise as the “next-generation” agents for treating imatinib (Gleevec)-resistant chronic myeloid leukemia. Five years ago, Gleevec ushered in the age of the smart drug—drugs targeted to fight specific cancer cells while leaving normal cells unharmed. Relatively nontoxic and easy to administer, Gleevec led to a marked improvement in survival for a majority of patients with chronic myeloid leukemia (CML), producing unprecedented clinical remissions and becoming the new standard of care. Still, some patients were unaffected by the drug and others eventually developed resistance to it.

Now, two new targeted therapies in early clinical trials show significant promise for treating Gleevec-resistant CML. After testing the novel compounds in laboratory studies, M. D. Anderson undertook two independent phase I clinical trials, one of BMS-354825 in conjunction with the University of California, Los Angeles, and the other of AMN107 with the University of Frankfurt in Germany.

Encouraging response in phase I trials

BMS-354825 has shown an impressive response rate, said Moshe Talpaz, M.D., a professor in the Department of Experimental Therapeutics at M. D. Anderson. “The majority of patients with advanced, Gleevec-resistant CML responded to the drug.”

Of 22 patients with advanced, blast phase or accelerated phase CML, five had complete hematologic responses, while three additional patients showed no evidence of leukemia. Furthermore, of 29 patients with early-stage CML who were either resistant to Gleevec or could not tolerate the drug’s side effects, 73% experienced a complete hematologic response.

Dr. Talpaz expects the response rates to rise as the study progresses. “We haven’t reached anything close to the maximum tolerated dose, yet we still are seeing very encouraging responses,” he said.

“Also exciting is the fact that clinical responses matched very well to preclinical testing in animal models. A specific mutation that was resistant to BMS-354825 in the test tube and animal model was also associated with resistance in patients. This suggests that we may be on the road toward developing treatment tailored to the molecular profile of the disease in different patient subsets.”

Another new agent, AMN107, has shown promise not only in CML but also in patients with acute lymphocytic leukemia (ALL) associated with the Philadelphia chromosome.

More than half of 65 patients with Gleevec-resistant CML who have joined the study since it began in May 2004 have had responses—including cytogenetic and molecular responses in some patients, said Francis Giles, M.D., a professor in the Department of Leukemia. “And we have not yet seen any consistent severe side effects.

“Gleevec changed everything in CML. It has led to marked improvement in survival in all three phases of the disease, and it also has shown benefit in treating the 20% of ALL that shares the same genetic abnormality as CML, the Philadelphia chromosome,” Dr. Giles said. “But a drug that can cope with resistance to Gleevec might do even better across the board, although it must be remembered that we are still learning how to optimally use Gleevec itself, a drug which we have only had available for a few years.”

Engineering “better-fitting” drugs

Like Gleevec, BMS-354825 and AMN107 reduce the activity of an abnormal tyrosine kinase enzyme (Bcr-Abl) that leads to uncontrolled cell growth in CML. However, these new, next-generation drugs are more potent than Gleevec because they were designed to more efficiently bind to the enzyme.

“Through molecular, chemical, and crystallography studies, we now know the detailed structure of the enzyme, which allowed the development of better-fitting drugs,” Dr. Giles said. “This increases the effectiveness of the agents and perhaps reduces the potential of developing resistance by treating more of the mutations that arise.

“These are engineered drugs, so we know exactly how they work, but we cannot yet say whether there are clinically meaningful differences between them,” he continued. “More studies are needed to see how the drugs will ultimately perform.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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