June 22, 2001
Leukemia Wonder Drug Suffers Setback
As Half of Patients Report Disease Relapse
By David P. Hamilton and Vanessa Fuhrmans
Staff Reporters of The Wall Street Journal
Gleevec, the cancer therapy hailed as a wonder drug against certain types of tumors, turns out to have an Achilles' heel after all: More than half of late-stage patients with chronic myeloid leukemia who initially benefited from the drug have seen their cancer return within six months, an often-fatal relapse.
Scientists first reported signs of resistance to Gleevec, a drug developed by Switzerland's Novartis AG, last year. But those effects were largely overshadowed by Gleevec's surprisingly effective ability to precisely attack CML, a notoriously difficult-to-treat cancer, at the molecular level. Its more than 90% success rate in clinical trials sparked hopes that the cancer might soon become a chronic disease that could be controlled with regular drug treatments, prompting the U.S. Food and Drug Administration to approve Gleevec in record time last month.
Novartis and cancer researchers are quick to note that Gleevec remains an effective treatment for patients with less-advanced forms of CML, a rare form of leukemia estimated to strike roughly 9,000 people in the U.S. and Europe every year. Indeed, in one clinical trial, more than 90% of 532 people in earlier phases of CML saw their blood counts return to normal, and 28% showed no evidence of cancer left in their bone marrow.
Still, the pronounced drug resistance among the sickest patients provides a sobering reminder of what a wily opponent cancer can be, even when confronted with the most powerful cancer treatments modern science can produce.
Many scientists, in fact, argue that drug resistance is all but inevitable in cases in which a drug like Gleevec is used alone. That is particularly true in acute CML, in which certain blood cells multiply uncontrollably in a process dubbed "blast crisis." Such rapid growth, which can also lead to a higher rate of cellular mutation, appears to aid tumor cells in developing ways to nullify even precisely targeted treatments such as Gleevec.
"Resistance to single agents is the rule," says Brian Druker, a researcher at the Oregon Health Sciences University in Portland who helped pioneer Gleevec treatment. Still, he notes, "If we see resistance in blast-crisis patients, it might be only a matter of time before we see it in chronic disease as well."
The late-stage resistance has steered Novartis and outside researchers to focus on Gleevec as an earlier, even initial, form of leukemia treatment. Currently the drug is approved as a second-line therapy for patients in which interferon treatment has failed. Clinical trials of Gleevec are under way with early-stage CML patients who have had little or no experience with chemotherapy, bone-marrow and other treatments. Novartis hopes to use data from these trials to push for eventual approval of the drug as a front-line treatment.
"The more we learn about the disease and forms of resistance, the better we can devise clinical strategies to treat patients more effectively," says David Parkinson, head of global oncology clinical research at Novartis.
At the University of California at Los Angeles, a team led by cancer specialist Charles Sawyers has taken an important first step toward understanding exactly how CML can work its way around Gleevec's laserlike attack on cancerous cells. The work may suggest ways to design more effective treatments.
The team, which studied 11 patients who had developed resistance to Gleevec, found two types of alterations in the genetic machinery of cancerous cells that help explain their ability to counteract the drug. The group reports its findings Friday in the journal Science.
In six of the 11 patients, Dr. Sawyers's group found that cancerous blood cells exhibited a single mutation in the abnormal gene responsible for CML. That gene, known as BCR-ABL, produces a protein called Bcr-Abl, which plays a key role in encouraging cancer cells to multiply wildly. Gleevec works by gumming up a crucial "socket" in that protein, much the way someone might disable a lock by breaking off a key inside it. The mutant BCR-ABL gene, however, slightly alters the shape of the resulting protein in such a way that Gleevec can no longer bind to it.
In a second group of three patients, the researchers found that the cancer cells had somehow each produced multiple copies of the aberrant BCR-ABL gene. While it isn't entirely clear how such "amplified" genes counteract Gleevec, Dr. Sawyers suggests they may simply produce so much additional Bcr-Abl protein that Gleevec is unable to block it all.
The new research is encouraging to scientists such as Oregon Health Sciences University's Dr. Druker, who originally feared that Gleevec-resistant cells might have developed a way of reproducing that doesn't rely on BCR-ABL. Were that the case, researchers would be forced to spend months or years figuring out that new mechanism before they could counteract it. Now, however, Drs. Sawyers and Druker believe that it should be relatively straightforward to produce new drugs that can block the mutant form of the Bcr-Abl protein.
Dealing with amplified BCR-ABL genes may be much trickier, although the scientists suggest higher doses of Gleevec, possibly administered intravenously instead of by pill as it is now, may do the trick.
Novartis and outside researchers are also looking at ways to combine the drug with traditional chemotherapies, since Gleevec should render even drug-resistant cells more vulnerable to chemical attack. One clinical trial launched late last year will explore the effectiveness of Gleevec in combination with the chemotherapy agent cytosine arabinoside.
"My hope is that if in a year or two we see relapses in chronic patients because of these mutations, we'll have new drugs to treat those patients," Dr. Druker says.
Write to David P. Hamilton at david.hamilton@wsj.com and Vanessa Fuhrmans at vanessa.fuhrmans@wsj.com |
