By Rabiya S. Tuma, PhD

For Doug Jensen, Gleevec® [imatinib] came around none too soon. In September 1997, he thought he had a cold. By the time the new year rolled around, he was coughing so much his family had to cut short a visit with friends. “After about six months of this, I finally told the doctor I wasn’t leaving his office until he figured out what was wrong.” Having ruled out various other possibilities, the doctor did a blood test and found that Jensen’s white cell count was 30 times higher than normal.

Although an estimated 4,600 adults in the United States will be diagnosed with chronic myelogenous leukemia (CML) this year, targeted therapies, including Gleevec, are changing the face of the disease, improving patients’ quality of life and prolonging survival. “The transition is, quite frankly, the most dramatic and significant progress that has been seen in any tumor in the last 30 or 40 years,” says Frank Giles, MD, a leukemia specialist at M. D. Anderson Cancer Center in Houston.

Patients with CML have an overgrowth of white blood cells in their bone marrow and peripheral blood, which crowd out the red blood cells and platelets. Coupled with no known risk factors, the absence of symptoms early in the disease means most patients are diagnosed through routine blood tests. When patients do have symptoms, they often include fatigue, unexplained weight loss, fever, night sweats or pain on their left side under the ribs caused by the swelling of the spleen.

Once a clinician identifies the excess of white cells, CML is relatively easy to diagnose because the vast majority of CML cases are characterized by a genetic mutation called the Philadelphia chromosome. This chromosome is created when the long arms of chromosomes 9 and 22 break off and switch places (translocation). The Philadelphia chromosome produces the bcr-abl protein, which is an enzyme—a tyrosine kinase—that tells the white cells to continue growing even when too many already exist. This fusion protein is almost never seen outside leukemia cells and is thus the target of Gleevec and other new therapies.

Growing Treatment Options

At the time of Jensen’s diagnosis in March 1998, the two standard treatments for CML were bone marrow transplant or interferon. Transplantation—then and now—is the only curative therapy for CML, but the procedure may cause treatment-related complications and death in 20 to 40 percent of patients. Additionally, only about 10 percent of patients meet the eligibility criteria for a transplant, including good general health and health history, young age (the median age of patients with Philadelphia chromosome-type CML is 67) and a matched donor (usually a sibling).

Jensen’s doctor opted for interferon, a treatment that induces cytogenetic remission in about 15 percent of patients, meaning that doctors no longer find evidence of the Philadelphia chromosome in the patient’s marrow. For other CML patients, interferon may control blood cell counts to varying degrees but fail to alter the underlying pathology that caused the disease.

Many people find interferon a tough medicine to take because it causes flu-like symptoms. “When you have a cold, your body naturally secretes a lot of interferon,” says Brian Druker, MD, a leukemia specialist at Oregon Health and Sciences University in Portland. “Many of the things like fevers, muscle and joint aches, difficulty concentrating, and feeling a bit depressed are all due to interferon. Imagine having to put up with that every day of your life.”

For Jensen, it was worse than any flu he ever had. It started the night of his first injection and didn’t stop. “I was so sick I couldn’t get out of my chair,” he says. In September 1998, six months after his initial diagnosis, his doctor took him off interferon—“they decided the interferon was killing me faster than leukemia would”—and sent him to Dr. Druker to discuss a new drug he planned to test.
The new drug was Gleevec—the first molecularly targeted drug designed to interfere with the bcr-abl kinase in CML cells. Gleevec works by binding to the bcr-abl protein and turning off this abnormal protein’s activity. The leukemia cells die without the enzyme’s activity. And because healthy cells don’t have the abnormal bcr-abl protein, they are unaffected by Gleevec.

Jensen was the 13th patient to receive Gleevec after joining the drug’s first clinical trial in April 1999. Once on Gleevec, Dr. Druker’s team saw temporary drops in Jensen’s white cell count, but the cell count would continually climb back up. The other patients in the trial were doing well, so the researchers increased Jensen’s dose of Gleevec in an attempt to control his cell counts. It worked.

For the past two years, Jensen’s marrow has shown no signs of CML. “It is undetectable,” says Jensen. “I’m so fortunate I have to pinch myself sometimes. You get that phone call with the diagnosis and you think ‘OK, that’s it.’ But here I am seven years later and I’m doing great.”

Thanks to the remarkable response of Jensen and many others like him, Gleevec received accelerated approval from the Food and Drug Administration in May 2001 for the treatment of advanced-stage CML patients or chronic phase patients who didn’t respond to or relapsed after interferon. Approval for the treatment of newly diagnosed patients followed in December 2002.

Gleevec: Four Years Later

Dr. Druker and colleagues are conducting a long-term trial of newly diagnosed patients with chronic phase CML who were treated with either Gleevec or a combination of interferon and a chemotherapy drug called Cytosar® (cytarabine). In December 2004, after half the patients had been followed for almost four years, 75 percent of the 553 patients treated with Gleevec are still on the drug, compared with only 4 percent of those taking a combination of interferon and Cytosar. (Many of the interferon/Cytosar-treated patients subsequently switched over and responded to Gleevec.)

Of the patients in the Gleevec trial arm, 98 percent had their blood counts return to normal and 84 percent show no evidence of disease after nearly four years of therapy. These results are very encouraging as they suggest patients can benefit from Gleevec for long periods of time. Only about 4 percent of patients appear to progress while on Gleevec every year (about a 16 percent progression rate over four years). Side effects of Gleevec are typically minor, with skin rash, diarrhea and water retention being the most common.

“Gleevec exceeded my expectations,” says Dr. Druker. “I was worried initially about serious toxicity, so perhaps the biggest surprise is how well tolerated it is. There was a part of me that thought we might be able to cure a disease like CML with Gleevec—and yet we haven’t been able to do that. Our biggest effort in the lab right now is to figure out why we can ’t.”

Despite the dramatic responses, Gleevec isn’t a perfect drug. Patients whose blood counts normalize but still show evidence of the Philadelphia chromosome in the marrow may relapse. Drs. Druker and Giles suggest these patients either consider bone marrow transplantation or enrolling in a clinical trial testing the newer generation of molecularly targeted drugs.

Is More Gleevec Better?

Some researchers think increasing the dose of Gleevec from 400 mg per day to 800 mg may increase the proportion of CML patients who achieve both a clinical and a molecular remission. Some institutions, like M. D. Anderson Cancer Center in Houston, are conducting studies of higher doses of Gleevec, and formal randomized trials to determine the right dose of Gleevec (400, 600 or 800 mg per day) are currently ongoing.

At present, the starting dose is a matter of debate in the field because the side effects frequently become worse, with an increase in fatigue, muscle cramps and myelosuppression. Patients who do not respond to 400 mg of Gleevec are usually treated with 600 or 800 mg, as many of them will respond to a higher dose.

Newer Targeted Agents

A routine blood test in March 1999 led to the CML diagnosis for Cheryl Iantorno. Because the 44-year-old was in the very early stages of the disease, doctors considered a bone marrow transplant but concluded that past health problems might cause complications.

Like Jensen, she tried interferon, but she too had a bad response to the drug. She started taking Gleevec when it became available and had a partial response, but her white cell count wasn’t completely stable. Last year, after about two years on Gleevec, her white cell count started to climb. Her doctor advised her to go to the University of California at Los Angeles, where Charles Sawyers, MD, was planning to test a new drug called dasatinib (BMS-354825). When patients become resistant to Gleevec, it is often because a group of CML cells have a mutation in the bcr-abl gene. Once a mutation is present, the drug cannot bind to the protein and CML cells grow unchecked.

Dasatinib and another drug called AMN107 are the newest generation of molecularly targeted drugs for CML. Studies show that dasatinib and AMN107 are better able to control the mutant proteins compared with Gleevec (see illustration). Like Gleevec, both turn off the bcr-abl protein, but each work at a slightly different site on the protein. And while the drugs are similar, these differences may affect how well they work in patients. Active phase II clinical trials for both drugs will provide a more complete picture of how and when these drugs work.

One hundred to 300 times stronger than Gleevec at shutting down the bcr-abl protein, dasatinib turns off the bcr-abl enzymes in leukemia cells that have become resistant to Gleevec. This specificity is possibly the reason for successful control of Gleevec-resistant CML.

Dr. Sawyers and his colleagues at UCLA together with researchers from M. D. Anderson Cancer Center completed a phase I trial with dasatinib in 39 CML patients who either did not respond or relapsed on Gleevec therapy. Phase I trials look at the safety of the drug in question rather than its effectiveness, but researchers can already see that dasatinib works. Thirty-four patients (87 percent) had a complete hematologic response, meaning their white blood cell counts returned to normal, and 13 (33 percent) had a complete cytogenetic response, meaning no cells contained the Philadelphia chromosome. Dasatinib was well tolerated and did not have a significantly different side effect profile than Gleevec.

“In a phase I setting, the drug has remarkable activity,” says Dr. Sawyers. “It is extremely promising for these patients for whom Gleevec didn’t work. The phase II studies are now in progress, and we are hoping for accelerated approval from the FDA in much the same way that Gleevec was approved.” Trials with dasatinib are open at a number of sites throughout the United States (see clinical trials).

Furthermore, Dr. Sawyers and colleagues have found that some patients with advanced disease, either accelerated phase or blast crisis, also respond to the drug, although the duration of this response is not yet known. This discovery is important because patients with advanced disease sometimes respond to Gleevec, but often relapse after several months.

AMN107, developed by the manufacturer of Gleevec, provides another option for Gleevec-resistant patients. Like Gleevec, it blocks the bcr-abl protein, but with 30 times the strength.

Dr. Giles enrolled 98 CML patients, who either did not respond to or progressed on Gleevec, in an ongoing phase I trial. AMN107 was active in patients with all stages of disease, with more than half achieving a response despite not having responded to Gleevec.

Still unclear is how the new drugs will be incorporated into therapy for CML patients. Doctors say the new targeted agents might be given in combination with Gleevec or they might be used sequentially, with Gleevec used as a front-line therapy followed by dasatinib or AMN107 if and when patients relapse.

On the Horizon

Additionally, researchers have identified other compounds, including Zarnestra™ (tipifarnib), a drug being developed for acute leukemia that may have activity in CML and strengthen the effectiveness of Gleevec when used in combinations. Other drugs like Ceflatonin® (homoharringtonine) and SAHA (suberoylanilide hydroxamic acid) are being combined with Gleevec to improve its response rates. Because these new medicines are targeted therapies designed to block one or more cellular proteins, scientists hope they can combine the drugs without greatly increasing side effects.

Given the effectiveness of Gleevec and the two new drugs, Dr. Druker sees a different scenario than he did just a couple of years ago. “I can paint a very optimistic picture for newly diagnosed CML patients. Gleevec may get them five to 10 years of response and if they relapse, they might be able to get five years out of the next drug.” He points out that Gleevec didn’t exist just seven years ago, and two second-generation drugs are already available. “We are taking CML from a controllable disease with long-term survival and moving it into a potential cure.”