Campath Effective in Highly Refractory CLL Population

FORT LAUDERDALE, Fla—Studies show that chronic lymphocytic leukemia (CLL) responds to therapy with alemtuzumab (Campath). However, the monoclonal antibody is immunosuppressive, and patients who receive it should be on prophylactic antibiotics, Susan O’Brien, MD, said at the 6^th Annual Conference of the National Comprehensive Cancer Network (NCCN).

Binds to CD52 Antigen

Dr. O’Brien, of M.D. Anderson Cancer Center, said that Campath-1H is a humanized monoclonal antibody that binds to the CD52 antigen, a small glycoprotein on the surface of all lymphocytes and a small fraction of monocytes. "CD52 is not present on cells where you would not want it to be if you’re going to use it to treat lymphoid malignancies, namely granulocytes, platelets, and erythroid or myeloid precursors," she said.

Essentially all CLL cells will bind with alemtuzumab. "CD52 is highly expressed on CLL cells. With flow cytometry, the percentage of positive cells is 95% to 99%, and the number of molecules per cell is also very high," Dr. O’Brien said.

Most of the original experience with alemtuzumab is from Europe. Osterborg published the largest series in 29 patients with CLL—all had been previously treated, and 21 had refractory, advanced-stage disease. The schedule used in this study is now the standard: a flat dose of 30 mg, given intravenously over 2 hours, three times a week for 4 to 12 weeks. Antibiotic prophylaxis was not routine in these initial trials, Dr. O’Brien said.

The overall response rate from this study was 42%, with a median response duration of 1 year.

"Interestingly, there was a marked difference in response by site," Dr. O’Brien said. "Campath universally will clear out lymphocytes from the bloodstream and is fairly good at getting rid of disease in the marrow and spleen, but, in these initial trials, it was not particularly effective in bulky lymph node sites."

This finding led researchers to drop the antibody in lymphoma and focus more on developing it for the treatment of CLL, she said.

Side effects were typical monoclonal antibody type reactions, including fever and chills with the initial doses. These are usually mild to moderate, although occasionally severe.

With the initial doses, the biggest problem was infection, Dr. O’Brien said. More than 40% of patients had reactivation of herpes. Other infections included Candida and Pneumocystis carinii pneumonia (PCP). This led to the recommendation that all patients treated with alemtuzumab should receive prophylaxis for herpes and PCP.

A pivotal phase II study by Keating et al, presented at the American Society of Hematology meeting in 1999, led to the start of the FDA approval process for the antibody. This multicenter trial enrolled 93 patients with CLL who had failed alkylating agents and fludarabine (Fludara)—either on initial or subsequent therapy.

To minimize toxicity, the antibody was titrated upward over the first 3 days to the 30-mg target dose. All the patients received premedication to minimize infusion-related side effects, as well as PCP and herpes prophylaxis during the therapy and for 2 months afterward.

Overall Response Rate of 33%

The response data, reviewed by an independent panel, showed an overall response rate of 33%, Dr. O’Brien said. The median time to progression was about 9 months.

The main side effects in this study were related to initial infusion. While severe reactions were uncommon, an occasional severe reaction did occur. "The main complication in this trial is infection, with grade 3-4 infection seen in 19% of patients," she said.

Based on these findings, Dr. O’Brien concluded that "Campath is a very active agent." About one third of the extremely refractory patients participating in the pivotal study responded to the antibody. "The toxicity profile is acceptable, but you do have to monitor the initial infusion-related side effects as well as the risk of infection," she noted.

Campath received a favorable recommendation from the Food and Drug Administration’s Oncologic Drugs Advisory Committee, and is currently being considered for accelerated approval by the FDA. Dr. O’Brien predicted that the agent will be commercially available as early as May 2001.

"In the long run, I think the real role for this antibody might not be in heavily pretreated patients," she said. "It is also important to remember that the response rate with bulky adenopathy is not very acceptable, so the initial patients should not be those with bulky adenopathy."