CLL Responds to Monoclonal Antibodies Against Both CD20 and CF52 Antigens

NEW ORLEANS—Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) may benefit from treatment with monoclonal antibody treatments directed against the CD20 and/or CD52 antigens, according to data presented at the ASH meeting. Increasing dosing frequency of rituximab (Rituxan) to three times per week produced responses in half of CLL/SLL patients treated in a phase I/II trial reported by John C. Byrd, MD, of the Hematology-Oncology Service at Walter Reed Army Medical Center, Washington, DC. In a separate study at M.D. Anderson Cancer Center in Houston, one-third of patients with CLL refractory to fludarabine (Fludara) responded to the anti-CD52 monoclonal antibody Campath-1H.

Thrice Weekly Rituximab

Giving rituximab at an accelerated, three-times-per-week schedule produces responses in half of patients with CLL or SLL, including some complete responses, Dr. Byrd reported (see Table 1). Although rituximab had demonstrated significant activity in low-grade non-Hodgkin’s lymphoma (NHL), it was less effective in SLL, a nodal variant of CLL. The SLL patients had relatively low serum rituximab trough levels on the standard weekly dosing regimen. To address the possibility that the lower response rate was due to inadequate rituximab dose levels, Dr. Byrd initiated the thrice-weekly schedule.

The study included 33 patients, 26 with CLL and 7 with SLL. Patients had a median of two prior therapies. According to Rai criteria, 8 patients had intermediate-risk disease, and 25 had high-risk disease. All had CD20 expression.

Rituximab was given on day 1 at a 100 mg dose over 4 hours to minimize infusion-related events. Patients then received rituximab at 250 mg/m² or 375 mg/m² on day 3 and then three times per week at that dose for 4 weeks for a total of 12 treatments. Patients also received diphenhydramine HCl (Benadryl), acetaminophen (Tylenol), and allopurinol (Allopurinol, Oxipurinol, and others) to minimize infusion-related side effects. If infusion-related events occurred, the infusion was stopped, symptoms treated, and the infusion resumed after symptoms had resolved.

One patient had treatment discontinued due to infusion effects. Twenty had infusion reactions on day 1, and 12 had infusion events on day 3. Six patients had platelet levels of 20,000-50,000 cells/mm³. Half of these patients had platelets drop to under 20,000 cells/mm³ after the first rituximab infusion, but these later returned to baseline levels. Dr. Byrd reported that there was no correlation between lymphocyte counts and infusion-related events.

Six patients had serious adverse events. One died of pulmonary hemorrhage, which Dr. Byrd said was possibly drug-related, and five developed infections.

Response Rates

“The overall response rate was 44%,” Dr. Byrd reported. “Response was 100% in patients who had not been previously treated.”

“Rituximab has significant clinical activity in CLL,” Dr. Byrd commented. Patients who responded to rituximab had hematologic improvement and a decrease in lymphadenopathy. The durability of these responses is uncertain, since median follow-up was only 6 months at the time of this report.

Based on these results, Dr. Byrd advised using the three-times-weekly schedule for rituximab in CLL/SLL and using the stepped-up dosing schedule to minimize infusion reactions.

Anti-CD52 Antibody Michael J. Keating, MD, on behalf of the International Campath study group, reported preliminary data from a phase II study of the anti-CD52 antibody Campath-1H. In previous trials, Campath-1H produced high response rates in patients with B-cell CLL who were treatment-naïve, but was less effective in previously treated patients. The new study looked at 93 patients with B-cell CLL previously treated with alkylating agents and refractory to fludarabine.

“This is a group with an extremely poor prognosis,” Dr. Keating pointed out. All patients either had no response to previous chemotherapy or had relapsed within 6 months or less after a fludarabine regimen.

In 93 patients evaluable for response, Dr. Keating reported:

2 (2%) achieved complete response (CR).

29 (31%) had partial response (PR).

55 (59%) had stable disease.

4 (4%) had progressive disease.

3 (3%) with uncertain responses, which were assumed to be treatment failures.

Toxicity a Problem

“Even though many patients had stable disease by the study criteria, most had cleared peripheral blood and reduction of lymphadenopathy,” Dr. Keating said. “They were classified as stable disease because of insufficient recovery of platelets or shrinkage of lymph nodes.”

Patients who were Rai stage IV did less well and patients over age 70 had a low response rate which was not statistically significant, Dr. Keating added. Response rates were associated with the size of involved nodes (see Table 2). At a median follow-up of more than 5 months, the two patients in CR were still in remission and estimated median survival was 12+ months.

Toxicity was a problem, however. Mortality due to infection was 5%, including 3% fatal sepsis and 2% fatal pneumonia. “Almost all patients have some sort of side effects during the first 3 infusions,” Dr. Keating said. These included grade 3-4 rigors, fever, dyspnea, or fatigue in 10% to 20%.

The risk of infection decreased with time, and Dr. Keating speculated that it may be correlated with CD4 cell counts. “Campath-1H is very active in advanced refractory patients with CLL. The toxicity profile is acceptable in such a patient population,” Dr. Keating concluded.