Leukemia May Build Resistance to Drug

W A S H I N G T O N, June 22, 2001 -- Two factors — a geneticmutation and the excessive production of a key enzyme — havecaused some patients with very advanced leukemia to developresistance to the new anti-cancer drug Gleevec, scientists saidThursday.

Dr. Charles Sawyers, a cancer doctor at the Jonsson CancerCenter at the University of California at Los Angeles who led theresearch, said this discovery of why Gleevec failed to beat thedisease in very ill patients could point the way towardstrategies to combat resistance to the drug.

He emphasized the findings, published in the journal Science,do not diminish the value of Gleevec as a weapon against chronicmyeloid leukemia (CML). The drug, made by Swiss drug manufacturerNovartis AG (NOVZn.S), is known as Glivec outside the UnitedStates.

"In no way does this discredit or dampen enthusiasm for thedrug," Sawyers said in a telephone interview.

"This is an amazingly good drug. There are now thousands ofpatients being treated with the drug, and resistance is a veryrare phenomenon in patients who are still in the chronicphase," before the cancer turns more vicious.

The U.S. Food and Drug Administration on May 10 approvedGleevec for use against CML. It also is being studied for use intreating other cancers.

CML, which generally strikes middle-aged people, is amalignant cancer of the bone marrow that causes rampant growth ofblood-forming cells. After about five years of a chronic phase,the disease develops into an end-stage "blast crisis" thatusually kills patients in two to six months.

Gleevec, formerly known as STI-571, can cause remission ofthe cancer by inhibiting an enzyme produced by an abnormal genecalled BCR-ABL that generates cancer cell growth.

In patients in the chronic stage of this type of leukemia,remissions brought about by treatment with Gleevec appeared to bedurable, the researchers said. But they also noticed that whilepatients in the final stage initially went into remission usingGleevec, a relapse often followed.

'The Cancer Cell Wins'

In seeking the mechanism behind the relapses, the UCLAresearchers studied 11 patients in the blast crisis phase whoinitially had responded to Gleevec and then relapsed.

In three of them, the researchers found the BCR-ABL gene had"amplified" — meaning extra copies of the gene had produced moreof the harmful enzyme than the drug could control.

"It's just a competition and the cancer cell wins," Sawyerssaid.

In six other patients, a mutation that substituted a singleamino acid in the enzyme's active site thwarted the drug'sefforts to inhibit the damaging enzyme.

There was not sufficient DNA to provide answers about theother two patients, according to the study.

Sawyers said it was encouraging to learn it was the ingenuityof BCR-ABL that caused the relapses and not some mystery factorthat could take some time to unmask.

"We know who the bad guy is still," Sawyers said. "Theenemy has identified himself."

Dr. David Parkinson, vice president for clinical research forNovartis, noted the resistance is seen only in the sickestpatients, while the large majority of patients still respond wellto the drug. Parkinson added the UCLA team's findings provideclues as to how to prevent remissions.

"The importance of this is that it really begins to givemore insight into the molecular basis of the resistance, sothat actually makes our clinical strategies much more targetedand much more likely to be successful," Parkinson added.

Sawyers, one of three oncologists to conduct the firsttests of Gleevec on humans, said researchers need to developanother drug that targets the BCR-ABL gene and could be used incombination with Gleevec to prevent resistance.help people learn how to help their communities.