Campath-1H Safe and Effective in Refractory B-CLL

ORLANDO—About one third of "bad prognosis" refractory B-cell chronic lymphocytic leukemia (B-CLL) patients are salvageable with alemtuzumab (Campath-1H), according to a compassionate use study presented at the 43rd Annual Meeting of the American Society of Hematology (abstract 1538).

Alemtuzumab is a humanized monoclonal antibody, specifically targeted at the CD52 antigen, the most abundant antigen on normal and malignant lymphocytes, said Kanti R. Rai, MD, of the Long Island Jewish Medical Center, New Hyde Park, NY, and Albert Einstein College of Medicine, Bronx, NY. Alemtuzumab activates the complement system and antibody-dependent cellular cytotoxicity, causing cell lysis.

In the prior pivotal clinical trial (Keating MJ et al: Blood 94[suppl 1]:705a, 1999) among 93 patients with CLL who had failed therapy with fludarabine (Fludara), the alemtuzumab response rate had been 33%, Dr. Rai said. "After that pivotal clinical trial, because alemtuzumab is not an antibody that is simple to use, many oncologists wanted to have their own experience with it before it became commercially available," he said.

All patients in the compassionate use study had failed fludarabine treatment or had relapsed within 6 months after prior alemtuzumab treatment.

Patients were in WHO performance status 2 or less and had failed a median of 5 (range, 1 to 11) prior chemotherapy regimens. Median age was 62, and mean time from initial CLL diagnosis was 5.7 years. Twenty-two patients had discontinued prior regimens because of adverse events, and 26 because of disease progression.

Patients (n = 136; 74% male) received alemtuzumab 3 mg by slow intravenous infusion on day 1, followed by dose escalation (on days 2 through 5) to 10 mg and eventually to 30 mg when tolerated. Following this, all patients received alemtuzumab maintenance therapy at 30 mg, three times a week for a maximum of 12 weeks.

Anti-infection prophylaxis with trimethoprim/sulfamethoxazole and famciclovir (Famvir) was mandatory from day 8 to at least 2 months after the last dose of alemtuzumab.

Response rates were evaluated according to 1996 NCI criteria, and adverse event grading was on a 1 to 4 scale according to NCI toxicity criteria.

Study Results

The researchers noted complete responses in 8% of patients and partial responses in 32%, for an overall response rate of 40%. At a median follow-up of 5 months, median progression-free survival was 7.3 months in the 54 responders and 3.9 months in the overall population. Overall median survival was 13.4 months among responders and 7.6 months in the group as a whole, Dr. Rai reported.

There were eight deaths, four attributed to progressive disease, two to infections, one to a ruptured spleen, and one unknown.

Infusion-related events were almost universally grade 1 or 2 (fever 65%, rigors 71%, nausea 45%) and occurred mostly in the first 2 weeks of treatment. Grade 3-4 hematologic toxicity (neutropenia 22%, thrombocytopenia 23%, anemia 11%) also occurred mainly in the first 2 weeks.

Infections occurred in 44 patients (32%). The most common infections were candida (7 cases, one grade 3), pneumonia (7 cases, four grade 3-4), herpes simplex (6 cases, one grade 3), herpes zoster (2 cases), cytomegalovirus reactivation (2 cases, both grade 3-4), and one case of grade 4 Pseudomonas septicemia.

Dr. Rai concluded that this experience with compassionate-use alemtuzumab shows that the agent is safe and
effective in these heavily pretreated, high-risk B-CLL patients.

"The bottom line is that we confirmed the pivotal trial findings of Keating et al that about one third of bad prognosis patients with B-CLL are salvageable with Campath—and that among responders, the duration of response and survival rates are very good," Dr. Rai said.

He added, "This is encouraging. Now we are bringing Campath into other trials as front-line therapy in CLL patients whose immune status is reasonably intact. We give fludarabine to reduce the tumor burden and achieve a partial response and then bring in Campath, hoping to convert those partial responses to complete responses."