By Monica Zangwill, MD

James Gibson, a 55-year-old from Philadelphia, was caught off guard when his doctor found an enlarged spleen at his checkup. “I had bleeding and felt tired, but I kept saying, ‘Well, you’re 50.’”

VBW remembers when her doctor called and said her white blood cells were elevated on a routine blood count. “I said, ‘Can we wait until after Christmas for another blood test?’” the 58-year-old from Connecticut recalls now. She felt well, and during the holiday season she was understandably busy.

A few tests later both Gibson and BW were diagnosed with chronic lymphocytic leukemia (CLL), the most common form of leukemia in adults in North America.

Unlike the acute leukemias, acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL), which are more well publicized because of their sudden onset and immediate life-threatening nature, the chronic leukemias, CLL and its less common cousin, chronic myelogenous leukemia (CML), progress slowly in most patients and are long lasting. Currently, CLL is not curable, but some patients with CLL may live from seven to more than 15 years, depending upon the aggressiveness of their disease.

In CLL, which mostly affects people over age 50, the B lymphocytes, a type of white blood cell, do not mature correctly and can’t function properly. Over time these abnormal B lymphocytes, also called B cells, can accumulate until they crowd out normal blood cells in the blood, bone marrow, and lymph nodes. When there are so many abnormal B cells in the body that the normal blood cells can’t reach a proper functioning level, patients become susceptible to problems like bleeding and infection. Fortunately for Gibson, BW, and the approximately 7,000 other people diagnosed with CLL each year in the United States, new approaches and new options are rapidly emerging to better control this disease.

Staging CLL and Starting Treatment
Five years ago, BW was diagnosed with stage 0, or low-risk, CLL. Her white blood cell count was abnormally high, but she had no swollen lymph nodes or enlarged organs. For this stage, treatment may not be needed, but physicians take a “wait and watch” approach with careful monitoring for symptoms and repeated blood testing. BW is grateful not to have to undergo chemotherapy, but the thought of it looms overhead. “You just always wonder when it will happen,” she says.

Because many cases of CLL progress slowly, there are a number of CLL patients who may share BW concern. Alan Kinniburgh, PhD, vice president of research administration at The Leukemia & Lymphoma Society, says the issue with CLL is deciding when to treat a patient. Careful staging and evaluation of the disease helps patients and physicians better consider the pros and cons of treatment.

For intermediate-risk CLL—considered stage I when the lymph nodes become enlarged, or stage II when the liver or spleen is also enlarged—deciding when to start therapy depends on the presence of symptoms. Patients with stage III or IV disease usually do have symptoms such as anemia and reduced clotting ability from low platelet counts as a result of the neoplastic cells crowding out normal functioning bone marrow cells. Doctors often treat these high-risk CLL patients immediately and aggressively.

Traditionally, frontline treatments for advanced CLL included chemotherapy with Leukeran® (chlorambucil) or cyclophosphamide with or without steroids such as prednisone. More recently, doctors are using chemotherapy drugs called purine analogues such as fludarabine, particularly in younger patients. While these treatments are often initially effective, none of them are curative and most patients will eventually relapse. So, scientists continue to search for new ways to attack CLL.

New Options in Treatment
Monoclonal antibodies are emerging as promising drugs to fight advanced CLL. In general, making monoclonal antibody therapy work is like finding the right key to fit into a lock. Scientists find a lock, or a specific target on the cancer cell, and then they chemically manufacture many copies of the key, which is the particular antibody that fits it. Once the key (the antibody) and lock (the target) match up, the cancer cells die.

The exact way monoclonal antibodies work to kill B cells in CLL is not clear, but Susan O’Brien, MD, professor of medicine at M. D. Anderson Cancer Center, Houston, says monoclonal antibodies rely on a patient’s own immune system.

“The monoclonal antibodies bind to the target cell,” she says, “which triggers the immune system to kill that cell.” In addition, monoclonal antibodies may directly kill some leukemia cells.

The monoclonal antibodies’ targeted approach also makes them more tolerable to patients. Traditional chemotherapy drugs kill cancer cells and some healthy cells, but the monoclonal antibodies can zero in on the problem cell type and leave other cell types alone. Leaving healthy cells alone reduces side effects such as nausea and hair loss.

The U.S. Food and Drug Administration approved Rituxan® (rituximab), a monoclonal antibody directed at a specific protein of the B cell, for use in lymphoma patients. Since lymphoma and CLL are both cancers of white blood cells, doctors began to use Rituxan in CLL patients, and clinical trials done with CLL patients who were resistant to fludarabine showed Rituxan could fight the malignant cells of CLL as well.

Gibson currently takes Rituxan as treatment for his CLL. Gibson started on fludarabine and had few side effects, but his B lymphocyte count rose again after a couple of years. His doctor then suggested Rituxan.

“It’s been quite effective,” he says. “It’s kept me at normal levels for about two-and-a-half years.”

Kanti Rai, MD, chief of the division of hematology and oncology, Long Island Jewish Medical Center, New York, studies the use of another potent monoclonal antibody called Campath® (alemtuzumab) in CLL patients. Dr. Rai and his colleagues gave Campath to patients with advanced CLL who had failed all other traditional treatments, and more than one-third of these patients had a positive response. Currently, other researchers are taking Campath one step further.

“Many people are now conducting other trials to see if Campath will be useful in patients with earlier-stage CLL, rather than [just in] advanced and highly resistant patients,” says Dr. Rai.

A drawback to using monoclonal antibodies is that they can cause flu-like symptoms during infusion. Also, some monoclonal antibodies, Campath in particular, can reduce white blood cells so much that patients become susceptible to opportunistic infections they would usually be able to fight off. Dr. Rai notes that current research studies are working to curtail these problems. There’s a lot of activity going on, he says, to make these drugs safer and more user-friendly.

Combination Therapies—The Next Frontier
Hematologists and oncologists are excited about the prospects of combining monoclonal antibodies with traditional chemotherapy drugs to treat patients with CLL.

“When you add Rituxan to fludarabine-based chemotherapy,” says Dr. O’Brien, “you markedly increase your complete response rate.” The monoclonal antibody and the chemotherapy seem to work synergistically to make each other more powerful.

Stefan Faderl, MD, assistant professor, M. D. Anderson Cancer Center, Houston, agrees. “There are a lot of potential options and possibilities to integrate monoclonal antibodies into existing chemotherapy combinations or more newer chemotherapy combinations in CLL,” he says.

His research looks at the effect of combining the two monoclonal antibodies, Campath and Rituxan. About 50% of the patients with relapsed and refractory chronic lymphoid malignancies in his phase II trial who received both Campath and Rituxan responded with a reduction of their disease.

There are other types of drugs, besides the monoclonal antibodies, that can also specifically target the B-cell lymphocytes of CLL. Donald R. Fleming, MD, director of oncology and hematology, Medical Center of Vincennes, Indiana, studies the drug Ontak® (denileukin diftitox), which is made by fusing a fragment of diptheria toxin to interleukin-2 (IL-2). Ontak works by targeting IL-2 receptors on the surface of malignant cells and some normal lymphocytes, which leads to the death of these cells. Patients in an initial phase II trial run by Dr. Fleming showed only modest improvement, but he expects Ontak will still find a place in the fight against CLL. “We’re thinking about combining it with a drug like Rituxan to increase the response,” he says.

Combining two or more drug therapies is clearly the next frontier of CLL treatment. Dr. Faderl even describes the possibility of giving chemotherapy and antibody combinations as preparation for bone marrow or stem cell transplants. Most physicians consider transplants too risky in CLL patients who are almost always over 50 years old. Discovering a more effective preparation regimen could make bone marrow transplant an option for some people with CLL.
New discoveries to treat CLL are arising quickly, but like most new cancer therapies, it will take time to sort out which are the most beneficial and the safest. Fortunately, most patients with CLL have time to learn about their disease and make informed decisions about their treatments.

“You do tend to get up on what’s going on and learn the function of your blood cells far more than you ever did before,” says Gibson.

Both Gibson and BW are knowledgeable about their disease and have surrounded themselves with strong support systems. “I’m still hoping that they’ll find a targeted treatment that will be even more effective for me,” says Gibson. “But, I’ve been very fortunate and active and continuing to do everything I’ve normally done.”