During the last two years, several hundred leukemia patients, including some at the Hutch and Seattle Cancer Care Alliance, have received an experimental treatment that seemed too good to be true.
It's a capsule taken daily, and it dramatically reduced or eliminated symptoms, inducing remission with virtually no side effects.
The drug, known by STI-571 or its brand name Gleevec, has been hailed as a breakthrough in cancer biology, one of the first of its kind in a new era of anti-cancer therapeutic agents.
But whether or when drugs like Gleevec will replace hematopoietic (blood) stem-cell transplantation - a technique pioneered and perfected at the Hutch and the only known cure for leukemia - is an open question, said Dr. Fred Appelbaum, head of the Clinical Research Division.
"The availability of Gleevec has redefined the therapeutic dilemma patients face," he said. "With more treatment options, in some ways it's made counseling patients more difficult. In other cases, it makes it easier.
"There is no question that Gleevec represents a milestone in cancer-drug development, but as of now, we don't know of any patients who have been cured by Gleevec. So far, the longest time period any patient has been on Gleevec is about two years, so questions about the drug's long-term effects remain to be answered."
For patients under age 50 with chronic myelogenous leukemia (CML) and an appropriate stem-cell donor, transplantation remains the preferred treatment option, said Appelbaum, also the director of the Seattle Cancer Care Alliance.
"When counseling a young patient with CML with a matched sibling who can serve as a donor, we recommend stem-cell transplant as the first treatment," he said. "We have an 80-percent success rate for such patients treated here.
"For younger patients with unrelated donors, the success rate for transplantation is still good, although not quite as high as with a matched sibling. But Gleevec can be a good therapy until a matched donor is found."
Despite potential limitations, there is no doubt that Gleevec, which the FDA approved as a novel drug in May, offers significant benefits for a number of leukemia patients treated at the Alliance and elsewhere and is a milder form of therapy than bone-marrow transplantation.
"Doctors at the Hutchinson Center and the Alliance rejoice in any therapeutic advance," Appelbaum said. "We'd love to see transplants put out of business. But until other cures have been developed, we are continually working to make transplants as nontoxic as possible."
Gleevec, manufactured by Novartis Pharmaceuticals Corp., was shown by Dr. Brian Druker and colleagues at Oregon Health Sciences University in Portland, Ore., to inhibit the protein gone awry in blood cells from patients with CML.
Unlike all other cancers, CML owes its origin to a single molecular defect: the breakage and swapping of portions of chromosomes 9 and 22, a genetic rearrangement that produces a truncated chromosome 22 known as the Philadelphia chromosome.
The rearrangement results in the formation of a new gene, bcr-abl, that consists of DNA from each intact chromosome - bcr on chromosome 22 and abl on chromosome 9 - juxtaposed at the breakpoint fusion on the Philadelphia chromosome.
Under normal circumstances, the abl gene specifies formation of a protein involved in cell communication. But in its mutant conformation as bcr-abl, the gene dramatically overproduces the protein, leading to the uncontrolled cell division that is the hallmark of cancer.
The protein abl is one of a family of cell-signaling proteins called tyrosine kinases. Druker reasoned that the identification of an inhibitor of the overproduced abl protein might result in an effective therapy for CML and began screening of compounds in the lab for such inhibitory activity.
Gleevec emerged as a molecule that inhibits abl as well as a related tyrosine kinase that is overproduced in a form of gastrointestinal cancer. Studies of the drug's efficacy are ongoing for both forms of cancer.
A concern for any new therapy is whether diseased cells will find ways to escape the drugs' toxic effects, and already, for patients with late-stage CML, known as blast crisis, resistance to Gleevec has been reported.
CML progresses through a predictable series of stages, initially presenting as a relatively benign condition, called the "chronic phase," during which there is uncontrolled expansion of myeloid (white precursor) cells. Over time, the chronic phase can develop into a blast crisis, an aggressive phase that is characterized by excessive proliferation of blasts, which are abnormal immature blood cells. Blast crisis is commonly fatal, as patients suffer from bleeding and infections.
Resistance has not developed in patients treated with Gleevec who are in the chronic phase of CML, although some doctors, including Appelbaum, caution that only long-term studies can address this issue.
"Relapse has definitely been seen for patients treated in the acute phase of the disease and assuredly will happen in the chronic phase," he said. "The question is after how long a time period," he said.
The possibility of resistance is not the only potential problem for long-term use.
"We do know that delay of the transplantation procedure worsens outcome, even if the patient is in remission," Appelbaum said. "But while we recommend proceeding immediately to transplant when a favorable outcome is likely, we understand that there are patients who want to try the drug for a period of time."
Other treatments for CML include the drugs hydroxyurea and alpha-interferon. Neither acts as a cure, and alpha-interferon causes a number of potentially severe side effects that cause patients to discontinue its use.
Cells from a small percentage of patients with two other blood malignancies, acute lymphocytic leukemia and acute myelogenous leukemia, also harbor the Philadelphia chromosome, and Gleevec has been used to treat those patients as well.
Speaking at the University of Washington earlier this month, Druker reported that while these patients had significant initial responses to the therapy, virtually all patients relapsed.
One of Gleevec's biggest strengths may be its use in conjunction with hematopoietic stem-cell transplantation, Appelbaum said.
"Treatment with Gleevec prior to transplantation may significantly reduce the tumor burden, putting the patient in a better position for a favorable outcome," he said."We're conducting trials right now combining Gleevec with the nonmyeloblative (mini) transplant that has been so successful with older patients."
The Hutch is engaged in clinical trials involving Gleevec, some in collaboration with Druker, and Center scientists are working to develop novel, targeted therapies for leukemia and other malignancies.
With every promising new development, Appelbaum said, doctors - and their job of counseling patients - must evolve.
"Patient care is constantly changing," he said. "Although it won't be as easy for cancers other than CML, the identification of Gleevec represents what we'd like to do with any disease: development of targets and drugs."