Drug prolongs lives of chronic lymphocytic leukemia patients

The drug rituximab significantly prolonged the lives of some people with chronic lymphocytic leukemia (CLL), the most common form of leukemia in adult Americans.

The findings come from a comparative analysis of two completed national phase II and phase III clinical trials that will be presented Dec. 8, 8:00 a.m. PT, at the 45th annual meeting of the American Society of Hematology (ASH) in San Diego, Calif.

The two multicenter clinical trials compare the antibody rituximab plus fludarabine, a chemotherapeutic drug, to fludarabine alone. Rituximab is an antibody-based drug approved for lymphoma. Physicians now use fludarabine alone as the current standard therapy for CLL.

The findings of the two studies show that after an average of 43 months, rituximab plus the drug fludarabine increases progression-free survival by 22 percent and overall survival by 12 percent compared to fludarabine alone.

“The findings are the first of any tested modern therapy to show a significant improvement in overall survival for people with CLL,” says study leader John C. Byrd, a medical oncologist with The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Byrd will present the findings at ASH.

“The results suggest that rituximab is going to be an extremely important drug in the treatment of this disease.”

An estimated 7,300 Americans will be diagnosed with CLL in 2003, and 4,400 people are expected to die of the disease. The disease causes no symptoms initially. Doctors usually diagnose it through routine blood tests; average age at diagnosis is 62. Early stage patients can live 10 years or more, but patients with more advanced disease may live only 18 months to three years.

Rituximab is a monoclonal antibody that targets a protein known as CD20 found on immune cells known as B lymphocytes. Scientists believe rituximab kills malignant CLL cells by causing programmed cell death, or apoptosis.

This randomized phase 2 study included 104 previously untreated CLL patients. The outcomes of these patients were compared to those of 179 similar patients who received fludarabine alone as part of an earlier randomized trial.

The earlier trial, known as Cancer and Leukemia Group B (CALGB) 9011, compared fludarabine alone to the drug chlorambucil, the former standard of care for CLL. The results of that study (published in the Dec. 14, 2000, New England Journal of Medicine) established fludarabine alone as the standard of care in CLL patients.

Of patients receiving fludarabine alone in that study, 81 percent had survived after two years, 20 percent experienced a complete remission and 45 percent showed no progression of their disease.

Of patients receiving rituximab plus fludarabine in this new study (known as CALGB 9712), 93 percent had survived after two years, 38 percent experienced a complete remission and 67 percent showed no disease progression.

“That’s a significant improvement,” says Byrd, the D. Warren Brown Professor in Leukemia Research, and a Leukemia and Lymphoma Society of America Clinical Scholar.

The findings also may cause investigators to re-think the best time to begin therapy for CLL in patients with a high likelihood of developing progressive disease. Older studies showed that giving patients chlorambucil early did not improve survival, so doctors don’t usually begin therapy until symptoms appear.

“This study may cause us to re-evaluate that approach,” Byrd says. “Future clinical trials may test whether giving rituximab alone or in combination when the disease is just diagnosed is beneficial.”

Funds from the National Cancer Institute, Kimmel Cancer Research Foundation, the Leukemia and Lymphoma Society of America and D. Warren Brown Foundation supported this research

The CALGB is a national clinical research group sponsored by the National Cancer Institute and founded in 1955 to improve cancer treatment, prevention and detection. The group consists of nearly 30 university medical centers, over 185 community hospitals and almost 3000 collaborating physicians and focuses on leukemia, lymphoma, melanoma and cancers of the breast, lung, gastrointestinal tract and genito-urinary tract.

Contact: Darrell E. Ward, (614) 293-3737; Ward-15@medctr.osu.edu