By Cathy Dunn

The first years of the 21st century have been a roller coaster ride for Jason McEntire.

Since the new millennium‚ the 26–year–old Stockton‚ California‚ resident has battled testicular cancer‚ married the love of his life‚ and found a profession he enjoys. Just when everything seemed to be getting better‚ McEntire’s world turned topsy–turvy.

“In January 2001‚ I got the good news that my testicular cancer was in remission‚” says McEntire. “But that same day‚ I learned I’d developed chronic myelogenous leukemia [CML].”

Leukemia‚ malignancy that originates in a cell in the bone marrow‚ is characterized by the uncontrolled growth of developing marrow cells. The two major classifications of leukemia‚ myelogenous and lymphocytic‚ denote the cell type involved‚ and each of these can be either acute (rapidly progressing) or chronic (slowly progressing). Thus there are four common types of leukemia: chronic myelogenous leukemia (CML)‚ acute myelogenous leukemia (AML)‚ chronic lymphocytic leukemia (CLL)‚ and acute lymphocytic leukemia (ALL).
CML patient Jason McEntire (right) ran his first marathon after successful treatment with Gleevec. His running partner was Brian Druker‚ MD (left)‚ the physician who treated him.

“The disease is characterized by an overproduction of white blood cells [the body’s chief infection fighters] in the blood and bone marrow‚” says Brian Druker‚ MD‚ director of the Leukemia Center‚ Oregon Health & Science University Cancer Institute. “A normal white blood count ranges from 5‚000 to 10‚000 cells. Patients with CML may have between 50‚000 and 500‚000 white cells.” More than 4‚000 new cases of CML are diagnosed annually.

Scientists don’t yet know exactly what causes CML‚ but they understand the chain of events that leads to the overproduction of white cells. First‚ a change occurs in the DNA inside a white blood cell‚ which leads to the development of the Philadelphia chromosome (Ph). This chromosome creates an abnormal protein that repeatedly orders the body’s bone marrow to mass–produce white cells. The three phases of the disease—chronic‚ accelerated‚ and blast (acute)—refer to stages of leukemia progression.

Dr. Druker says the most common treatment for CML is bone marrow transplant‚ which is risky for some patients‚ or interferon injections‚ which can have severe side effects.

“The good news about CML is that it can be treated and the odds of survival are getting better‚” says McEntire. “I knew if I chose to have a bone marrow transplant‚ I’d have a 75–80% chance of survival. My other option was to participate in a clinical trial‚ taking an experimental drug called Gleevec™.”
McEntire chose Gleevec (imatinib mesylate) because he was intrigued by the positive results he read about this new medication‚ which was approved by the U.S. Food and Drug Administration (FDA) in May 2001. His quest for treatment led to Oregon Health & Science University‚ where he met Dr. Druker.

“Gleevec represents a new class of treatments called targeted therapies‚” says Dr. Druker‚ who developed the drug in collaboration with Novartis
Pharmaceuticals US. “These medications are designed to seek and destroy cancerous cells while leaving healthy cells intact.

“In CML patients‚” he adds‚ “Gleevec locks onto an errant protein known as Bcr–Abl manufactured by the Philadelphia chromosome. The drug then switches off the protein’s haywire signaling mechanism so white cell counts return to normal levels in most patients.”

In early clinical trials‚ a majority of patients taking Gleevec showed a return to normal white cell counts in a matter of weeks and had only mild side effects. These positive results led to FDA approval of Gleevec for use in CML patients in: 1) the chronic phase and no longer responding to interferon; 2) the accelerated phase; and 3) the myeloid blast crisis phase. As with any disease‚ the earlier treatment begins‚ the better the chances for success.

More good news for patients: Gleevec is in pill form‚ eliminating side effects such as infections that may accompany chemotherapy infusions. When side effects do occur‚ they’re usually mild. Queasiness‚ puffiness around the eyes‚ and diarrhea are most common.

After a year of taking Gleevec‚ McEntire’s condition has stabilized. Although there’s no evidence of leukemia in his blood‚ some cancerous cells remain in his bone marrow. But that hasn’t stopped him from resuming an active lifestyle.
Earlier this year‚ the athletic McEntire was chosen as a torchbearer for the 2002 Winter Olympics‚ running in Sacramento‚ California‚ exactly one year to the day after his CML diagnosis.

In June‚ McEntire ran his first marathon in San Diego to raise funds for The Leukemia & Lymphoma Society‚ an organization that he says has played a significant role in his life. Besides friends and family members‚ McEntire raced with someone who has made a special difference in his life—Dr. Druker.
Although Gleevec continues to show promise‚ it is by no means a cure‚ Dr. Druker notes. “We’ve been very impressed with the results so far‚ but we still have a long way to go. We hope to use this paradigm to produce even more effective treatments for different types of cancer‚” he says.

In fact‚ at the May 2002 American Society of Clinical Oncology (ASCO) meeting‚ a large trial was reported that found Gleevec to be better than interferon in newly diagnosed patients with CML‚ and Gleevec has now become the preferred drug for this type of leukemia.

Battling AML with Antibody Therapy
While Gleevec makes inroads into CML treatment‚ another targeted therapy‚ Mylotarg™ (gemtuzumab ozogamicin)‚ is showing impressive results combating acute myelogenous leukemia (AML)‚ the most common type of acute leukemia in adults. Each year‚ more than 10‚000 Americans are diagnosed with AML. The disease is characterized by rapid‚ uncontrolled growth of immature white blood cells called myeloblasts. As a result‚ the body cannot produce enough normal red and white blood cells and platelets.

Sara Chalmers knows firsthand how devastating AML can be. The 53–year–old from Perkasie‚ Pennsylvania‚ thought her fatigue might be caused by anemia. She asked her doctor to order a blood test. “I’m usually a very upbeat‚ energetic person‚” she says‚ “so I knew something was wrong when I couldn’t get rid of my tiredness.”

Chalmers‚ who also has a heart condition‚ was diagnosed with AML in January 2002 and was immediately hospitalized for an intense regimen of chemotherapy. During her first week of treatment‚ she began having side effects: she retained fluid‚ started to lose her hair‚ and lost some of her sense of taste. During her second week in the hospital‚ Chalmers developed fungal pneumonia‚ an illness that nearly took her life. Although there was still evidence of cancer in her bone marrow‚ her chemotherapy treatments had to be delayed while she recuperated.

Chalmers’ doctor then offered her a new treatment option‚ Mylotarg. The drug has shown great promise in treating AML.

“Mylotarg consists of two parts: a humanized monoclonal antibody and a potent cytotoxic agent called calicheamicin‚” says Martin Tallman‚ MD‚ Northwestern University Medical School‚ Chicago‚ and a leading AML researcher. “Each part has a specific function. Mylotarg’s antibody portion recognizes the CD33 antigen present on the surface of myeloid leukemic cells and attaches to it. Then calicheamicin is released directly into cancer cells‚ destroying them and bypassing healthy cells.

“Calicheamicin is so toxic it cannot be injected directly into the body‚ so it must be paired with a carrier‚ an antibody that will deliver it to cancer cells‚” he adds.
Mylotarg has the distinction of being first in a new class of antibody–targeted therapy treatments. The drug received FDA approval in 2000 to treat relapsed AML patients age 60 or older who were not candidates for other types of chemotherapy. Relapsed patients typically require prolonged hospitalization and less than 20% survive more than five years.

Two doses of the medication are given intravenously‚ usually two weeks apart. Some patients are hospitalized overnight after their first treatment so they can be monitored for side effects. In many cases‚ patients who achieve remission with Mylotarg become healthy enough to undergo stem cell transplantation‚ increasing their odds for survival.

“I didn’t have any side effects with Mylotarg‚” says Chalmers‚ who received her first treatment in May. “My condition is stable and I feel better than I’ve felt in a year.”

Treating APL: Where East Meets West
When Chinese researchers began using a deadly poison in 1996 to successfully treat acute promyelocytic leukemia (APL)‚ the Western world took notice. APL‚ a rare subtype of AML‚ causes anemia‚ susceptibility to infections‚ and bleeding. The disease strikes about 1‚500 people a year. The Chinese success with arsenic trioxide—now approved under the name Trisenox™—garnered the attention of researchers at Memorial Sloan–Kettering Cancer Center‚ who started their own pilot study.

As a result‚ the New York–based cancer researchers became the first American investigators to show that arsenic does indeed induce remission in APL patients who have relapsed.

Results of the pilot study were impressive. Eleven of the 12 patients who had relapsed after conventional therapy achieved remission within several weeks when treated with Trisenox. Repeat treatments were given every three to six weeks for two therapy cycles. After retesting‚ eight patients did not show molecular evidence of APL; the other three tested positive and eventually relapsed.

“Based on these highly sensitive molecular results‚ treatment with arsenic trioxide appears to exceed the effectiveness of any single drug to treat APL‚” reports Steven Soignet‚ MD‚ lead author of the study published in The New England Journal of Medicine. “Still‚ this is not a cure. More studies will tell us how truly effective arsenic trioxide will be over the long term.‚
Exactly how the drug works is still a mystery. Researchers suspect that it forces immature APL cells to partially mature‚ then self–destruct. Other studies will test the effectiveness of Trisenox against lymphoma and cancers of the cervix‚ bladder‚ and kidney.

A Paradigm for Cancer Treatment
Gleevec‚ Mylotarg‚ and Trisenox are ushering in a new generation of leukemia–fighting medicines‚ raising the bar in the search for effective treatments. Researchers face an ongoing battle against an elusive enemy‚ but they’re making inroads.

“Perhaps one day we’ll discover a cure for leukemia‚” says Dr. Druker. “Meanwhile‚ finding new uses for targeted therapies will bring us one step closer to that goal.”