Alemtuzumab/Rituximab Feasible, Active in Lymphoid Malignancies

LUGANO, Switzerland—Combination monoclonal antibody treatment of lymphoid malignancies may be as safe as single-antibody therapy, and produces a better overall response rate, new data suggest. The data come from a recent study of 48 heavily pretreated, poor-prognosis patients treated with the combination of alemtuzumab (Campath-1H) and rituximab (Rituxan), presented at the 8th International Conference on Malignant Lymphoma (ICML).

Responses were seen "in all anatomic compartments, indicating activity of this combination," said Stefan Faderl, MD, assistant professor, Department of Leukemia, University of Texas M.D. Anderson Cancer Center.

Single-agent monoclonal antibody therapy can achieve high response rates in patients with chronic lymphocytic leukemia (CLL) and various histologies of non-Hodgkin’s lymphoma. However, these agents are not curative by themselves. The rationale for combining alemtuzumab and rituximab, both of which have proven single-agent activity in these disorders, is that the two together may achieve a synergistic treatment effect, Dr. Faderl explained.

Rituximab targets the CD20 antigen, ubiquitously expressed in B-cell lympho-proliferative disorders, while alemtuzu-mab targets CD52, which is the most abundantly expressed glycoprotein on CLL cells, he said. Synergism may come from the suboptimal activity of either monoclonal antibody in a specific disease site (ie, bone marrow) or from complementary modes of cell clearance.

To test the combination, Dr. Faderl and his colleagues enrolled CD20- and CD52-positive patients with relapsed or refractory lymphoid malignancies. Previous exposure to either antibody was allowed.

Median patient age was 61 years, and 77% were Rai stage 3 or greater. About half were refractory to fludarabine (Fludara). Most (33 of 48) patients had CLL, while 8 had CLL/PLL (prolympho-cytic leukemia). The rest had PLL (1), mantle cell lymphoma (4), and Richter’s transformation of CLL (2).

The 4-week treatment included rituxi-mab 375 mg/m² once weekly plus alem-tuzumab on an escalating dose schedule (3, 10, and 30 mg during week 1, and 30 mg on days 3 and 5 for the next 3 weeks).

Of 36 patients evaluable for response, 18 (50%) had a response; this included 3 complete responders, 1 patient with a nodular partial response, and 14 with a partial response. The remaining 18 patients had no response (either stable disease or progression on therapy).

All but one of the responses were seen among the patients with CLL or CLL/PLL (response rates of 59% and 50%, respectively); the one patient with PLL had a response. "Although the numbers are relatively small, of patients with the Richter’s transformation or diagnosis of mantle cell leukemia, none responded, and actually all progressed during therapy," Dr. Faderl reported.

About two thirds of patients developed myelosuppression, although it was usually grade 1-2. Episodes of grade 3-4 myelosuppression were rare, usually transient, and could be helped with hematopoietic growth factor support, Dr. Faderl noted. Most nonhematologic toxicities were infusion-related and included rigors, fevers, and skin reactions, mostly grade 1-2. The infection rate was no different than what might be expected with single-antibody therapy.

Six-month follow-up on responders showed a median time to progression of 6 months, with a median survival of 12.5 months, Dr. Faderl said.

In future trials, investigators will probably want to more narrowly define the population of patients that will benefit most from this combination, Dr. Faderl said. In addition, "we want to explore other routes of administration besides IV, especially with alemtuzumab," he said.