http://www.curetoday.com/publications/cure/2010/summer2010/progress-thats-worth-the-wait
Progress That's Worth the Wait

Karen Patterson

Bruce Lantry is not a typical CLL patient.

People with chronic lymphocytic leukemia—a cancer that occurs when abnormal white blood cells accumulate in the blood and bone marrow—commonly have no symptoms at diagnosis. But in early 2009, Lantry, a piano tuner, was exhausted, short of breath, and felt like his ears were plugged. The first doctor he’d seen in a long time took one look, saw enlarged lymph glands, and ordered blood work.

When results showed a perilously low red blood cell count and a soaring white count, Lantry recalls saying, “‘I guess I’m still alive.’ And she said, ‘Just barely.’” 

For Lantry, who lives in rural southwest Nebraska, the urgent treatment he needed was 100 miles away in North Platte, where he was sent by ambulance for immediate blood transfusions and bone marrow testing.

The next week he returned to North Platte and learned, at age 62, that he had stage 4 CLL, which had shut down his bone marrow’s ability to produce healthy blood and immune cells. In mid-March he started his six months of treatment, which he took for three days every 28 days.  

Lantry’s treatment combination was called FCR, for the chemotherapy drugs Fludara (fludarabine) and Cytoxan (cyclophosphamide), plus an antibody called Rituxan (rituximab). “Everyone I talked to was given those,” Lantry says of his fellow CLL patients.

Ultimately his lymph glands shrank and his cancer, once rampant, was virtually gone from his bone marrow.

CLL is the most common form of adult leukemia in the Western Hemisphere, with some 15,000 U.S. patients diagnosed each year. Its effects on white cells can impair the immune system and leave patients more vulnerable to infections and even secondary cancers. Research has found about a third of patients never need treatment and have a long survival time with the disease, while another third have disease that eventually progresses. The remaining third have an aggressive disease at onset and need treatment quickly, like Lantry.

On diagnosis, early-stage patients do not yet need treatment, says Kenneth Foon, MD, chair of hematological malignancies at the Nevada Cancer Institute in Las Vegas, and can be followed for years with a “watch and wait” approach. 

Symptoms may include unexplained fever, chills, night sweats, or weight loss (fatigue by itself is a vague symptom, Foon says); “bulky” lymph nodes or organs, meaning they are dramatically enlarged; or bone marrow failure has left a patient anemic or with a low platelet count. Rapidly escalating lymphocyte counts might also be a sign treatment is necessary. Treatment usually involves chemotherapy or other medicines.

Widely used risk categories can help guide treatment decisions. Patients at low risk for needing immediate treatment have a high lymphocyte count in the blood or marrow but usually lack symptoms. Intermediate-risk patients likewise have a high lymphocyte count and might lack symptoms, but they also have enlarged lymph nodes, spleen, or liver—which may or may not warrant treatment. High-risk patients, like Lantry, have the elevated lymphocyte count plus anemia or a low platelet count, and usually need immediate treatment.

Patients who don’t yet require treatment of the leukemia itself might still need medicine. Typically steroids or Rituxan are prescribed for side effects resulting from the abnormal activity of lymphocytes—such as autoimmune hemolytic anemia, where the immune system destroys red blood cells, or autoimmune thrombocytopenia, where it destroys platelets.

John Byrd, MD, professor of medicine and medicinal chemistry and associate director for translational research at The Ohio State University Comprehensive Cancer Center, says one significant CLL complication he sees is diagnosis anxiety. Patients, often feeling healthy, abruptly learn they have cancer but that instead of treating it, the plan is to watch and wait.

We have very effective treatments that may not cure patients but will prolong their life and their quality of life.

Although CLL is rarely cured, newly available treatments—often combining drugs and immune-based medicines called monoclonal antibodies—are making the disease more manageable. Even for patients whose condition is advanced, “there’s absolutely reason to be optimistic,” Foon says. “We have very effective treatments that may not cure patients but will prolong their life and their quality of life.”

Progress has been marked in the last quarter century, since the advent of Fludara to treat CLL, says Michael J. Keating, MB, professor of medicine in hematology at M.D. Anderson Cancer Center in Houston, whose research helped lead to widespread use of that drug.

Few other options were available until about 15 years ago, when studies showed better outcomes by combining Fludara and Cytoxan. More recently, the monoclonal antibody Rituxan proved a worthy addition, and the FCR regimen that Keating and colleagues developed was approved in February for front-line treatment and for patients whose previous therapies failed.

Recent data show the addition of Rituxan to chemotherapy is not only improving many patients’ condition but extending their lives. After six months of FCR, patients who responded achieved longer remissions, Keating says. “On average, the time to relapse of patients that achieve a response is of the order of five years or so. During that time the patients are on no treatment and only have to go see their local doctors.”

The new medicines are allowing oncologists to increasingly adapt therapy to a patient’s risks. For instance, FCR is an aggressive approach that can be hard on people who are over 65 (the majority of CLL patients are 65 or older at diagnosis) or have other illnesses.

An alternative, called “FCR-Lite,” uses lower doses of the FCR drugs. Another option is replacing the Fludara in FCR with a similar drug, Pentostatin (deoxycoformycin), which may suppress immunity less. Other alternatives include using Treanda or Campath alone.

Doctors can also tailor treatment by looking for a chromosomal variation called the 11q23 deletion. That variation makes CLL vulnerable to Cytoxan, Byrd says; patients lacking the deletion may be able to receive just Fludara and Rituxan (FR).

The goal is to avoid long-term complications. For instance, patients who receive FCR have about a 3 percent risk of developing a secondary leukemia, acute myeloid leukemia (see sidebar), compared with virtually no risk on FR, Byrd says. While neither strategy is wrong, “Our approach is when we don’t have clear evidence that more is better, generally we do less.”

Patients can undergo testing called FISH, or fluorescence in situ hybridization, which can detect 11q as well as other chromosomal deletions, such as 17p13. The 17p deletion indicates more aggressive disease, while patients with an 11q deletion tend to respond well to treatment but have shorter remissions, Keating says. A study of CLL patients, most of whom had not received any treatment, found about 18 percent had an 11q deletion and 7 percent had a 17p deletion.

Another test identifies patients who have a mutation in a gene called IgVH (about half have it). Without the mutation, patients often need treatment sooner and have shorter remissions. Patients should discuss these tests with their physicians.

Keating says along with FISH results and mutation status, he focuses on a patient’s age and levels of a protein on CLL cells called beta-2 microglobulin (younger patients and those with lower levels of the protein usually fare better). “With those four things you can get a very good idea of how likely people are to respond and how likely a response is to last,” he says.

Meanwhile, as thousands of Americans with CLL watch and wait, and thousands more are in treatment or remission, drug development marches on.

One medicine that might help soon is Revlimid (lenalidomide)—a pill already available for multiple myeloma and in phase 3 testing for CLL. Rather than suppressing the immune system, as many chemotherapy drugs do, Revlimid activates it to seek and destroy CLL cells.

Medical Illustration: Deciding on Treatment

“Patients refer to it as ‘watch and worry,’” Byrd says. “You know there’s something in you that’s not right, so when is it going to hit?”

He encourages patients to do everything they can, including consulting a physician who frequently treats CLL, to fully understand the disease’s course. “By getting information early, patients can become comfortable with how the disease is managed, and get on with their lives.”

Lantry agrees information is a lifeline. Despite his rural residence, he has learned about CLL from connections he made through the Leukemia & Lymphoma Society (www.leukemia-lymphoma.org; 800-955-4572)—including ongoing online support, a telephone group on blood cancers, and the society’s First Connections program that has linked him to “phone buddies” in New Jersey and Nebraska.

“I got more support and comfort from them than through anything else at the beginning,” he says. “When you’re first diagnosed … you don’t know what on earth is going to happen.”

Meanwhile, other medicines have emerged to fight CLL, including additional monoclonal antibodies, which target specific proteins on the cancer cell. One such antibody is Campath (alemtuzumab), which received accelerated approval in 2001 and regular approval in 2007. Campath is typically used alone, sometimes for initial treatment but often in patients who experience relapse, Keating says. Another monoclonal antibody, Arzerra (ofatumumab), approved last October, has been promising in patients whose CLL doesn’t respond to Fludara and Campath. 

Another medicine is Treanda (bendamustine), a chemotherapy drug used for decades in Eastern Europe but not approved in the U.S. until 2008. Treanda is more potent than Cytoxan and is being used alone and with Rituxan.

There are many, many patients now staying in remission for more than 10 years. And it’s likely in the next five years we will develop immune therapy approaches which will hopefully control the disease over the long term.

An alphanumeric soup of other possible treatments is mostly in early stages of development. Among them are CAL-101 and PCI-32765, both oral medications that Byrd says don’t suppress bone marrow activity or cause common chemo side effects. ABT-263, meanwhile, is being tested alone for patients whose previous treatment failed and will be tested with Rituxan as first-line therapy. The monoclonal antibody lumiliximab has shown promise when added to FCR, and the monoclonal antibody GA101 likewise may complement existing antibodies. Two drugs in development, Flavopiridol (alvocidib) and SCH 727965, may especially help patients who have the troublesome 17p deletion, Byrd says.

Patients who relapse shortly after therapy, or don’t respond as well, are particularly challenging. Relatively few—those who are young and healthy—might qualify for allogeneic stem cell transplantation, designed to permanently restore the bone marrow. Transplant recipients, usually in a clinical trial, first receive high-dose chemotherapy and/or radiation, then donor stem cells are introduced into the blood. 

Foon notes the procedure is very high-risk, with complications including graft-versus-host disease, where the newly transplanted immune system can attack the organs or cause a chronic skin condition. Rarely do CLL patients reach the point where they need to take this path, he says.

However, recent development of a “reduced-intensity transplant,” which uses lower doses of chemotherapy, has made the therapy more tolerable (though somewhat less effective) and broadened the list of potential recipients to people in their mid-70s, Keating says.

Overall, Keating tells patients with CLL to remain hopeful. “There are many, many patients now staying in remission for more than 10 years,” he says. “And it’s likely in the next five years we will develop immune therapy approaches which will hopefully control the disease over the long term.” 

Print | cure Printing...