OHSU Scientists Begin Human Trials Of A Drug Aimed At The Underlying Cause Of Chronic Myelogenous Leukemia

June 25, 1998

For the first time, patients with a specific form of leukemia will receive an investigational drug therapy aimed precisely at the molecules causing their cancer. The first patient, 68-year-old Bud Romine from Tillamook, Ore., will take his first dose of the experimental drug on Thursday, June 25, 1998, at Oregon Health Sciences University.

The often fatal blood disease is called chronic myelogenous leukemia and strikes about 6,000 Americans annually. "The highly targeted drug eliminates leukemia cells in mice, and will be used for the first time in humans this summer," explained Brian Druker, M.D., principal investigator of the trial and associate professor of hematology and medical oncology at Oregon Health Sciences University.

Until now, patients with chronic myelogenous leukemia have been treated with chemotherapy aimed at killing rapidly dividing cells or they have undergone bone marrow transplantation aimed at replacing their diseased marrow.

"This experimental therapy is different than chemotherapy because it targets leukemia cells and leaves normal cells alone," explained Druker.

"When I was diagnosed with leukemia four years ago I began chemotherapy," said Romine. "But I never went into remission. Then I read about Brian Druker's work in The Oregonian and I wrote him a letter."

Romine will be the first of about 50 patients to enter the clinical trial. Within a year, physicians expect to determine the success of the therapy. All patients in the trial will receive the drug, and dosages will be escalated until either significant benefits or side effects appear.

The multicenter trial was designed by the Oregon Cancer Center based at OHSU and will also be conducted at UCLA and M.D. Anderson Medical Center in Texas.

"The commitment of the Oregon Cancer Center to controlling cancer and leukemia is based upon two fundamental premises. First, you can't prevent or cure cancer or leukemia unless you understand what makes these mutant cells behave in the way they do," explained Grover Bagby, M.D., director of the Oregon Cancer Center. "Second, cancer and leukemia cells behave in an abnormal way because the structure of cellular proteins has been altered by mutations. Although this new agent needs to be validated in large numbers of patients, Dr. Druker's work is the perfect example of the power of molecular biology to bring new, more effective and potentially less toxic treatments to patients with serious illnesses. We need such highly targeted approaches for all patients with malignant diseases."

Hitting its victims in mid-life, CML arises when chromosomes 9 and 22 exchange segments and form a faulty gene that produces an abnormal protein called BCR-ABL. BCR-ABL is a protein belonging to a family of enzymes called tyrosine kinases that influence the control of cell growth. The abnormal BCR-ABL protein increases the enzymatic activity that drives the white cells to proliferate uncontrollably, inducing leukemia. Essentially, there are no brakes to stop the proliferation.

The investigational drug inhibits the enzymatic activity of the renegade BCR-ABL protein. Called a tyrosine kinase inhibitor, the drug has succeeded in destroying BCR-ABL cells in cell culture studies and animal trials in mice, but it does not kill normal cells. "We will treat CML patients with this compound in the form of a pill," said Druker. "We hope the compound will seek out the faulty cells with the BCR-ABL protein and destroy them."

"The highly specific drug therapy is a direct extension of our lab work on CML," said Druker. "Our studies have revealed that the BCR-ABL protein is the obvious abnormality to attack in CML."

Druker stressed that the development of this new cancer- fighting drug represents an example of the fundamental importance of determining the molecular mechanisms that drive cell growth in specific diseases. Once that is understood, drugs can be designed to zero in precisely on the abnormal cells and leave healthy cells intact.

"The community of leukemia doctors is very interested in this trial because the drug is so unique and we have reason to believe it will be very specific for CML cells," said James D. Griffin, M.D., professor of medicine at Harvard University and specialist in CML at the Dana-Farber Cancer Institute. "The design of the study is very good and we expect results soon."

Druker explains that within the first year of the trial, physicians will hope to see preliminary results concerning the safety and efficacy of the drug. However, Druker is cautious, so as not to raise expectations too much at this stage. "As with all potential medications, the first clinical trials will be done with a small number of patients for whom there is no other effective therapy, with the objective of finding a safe dose for larger trials," said Druker.

Druker's research is supported by grants from the National Institutes of Health and the Leukemia Society of America.

More Details

Bud Romine is a retired conductor from the Southern Pacific Railroad. He was diagnosed with chronic myelogenous leukemia in September, 1994, after seeing his doctor for a routine checkup. A blood test revealed that Bud was in the beginning stages of CML. He underwent chemotherapy for the next four years, but never went into remission.

"For the past four years, leukemia has been the first thing on Bud's mind when he wakes up in the morning and the last thing on his mind when he goes to bed," said Yvonne Romine, his wife. "But we still have a lot of laughs together. "We cry together, too, and somehow this keeps us going."

Bud and his wife read about Dr. Druker in an Oregonian article on April 30, 1996, and contacted him at OHSU. The Romines will remain in the Portland area during most of the clinical trial for close monitoring of Bud's blood and bone marrow.

The Romines have three children, five grandchildren and 1 great-grandchild.

Oregon Health & Science University

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