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Cancer Therapy: Clinical |
Authors' Affiliations: 1 American Health Network Oncology/Hematology, Indianapolis, Indiana; 2 Division of Hematology/Oncology, University of California Los Angeles Medical Center, Los Angeles, California; 3 Division of Hematology and Oncology, Department of Internal Medicine; 4 Department of Epidemiology; 5 The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 6 Chiron Corp., Emeryville, California; 7 Cancer Institute Medical Group, Santa Monica, California; and 8 Weill Medical College of Cornell University, New York, New York
Requests for reprints: Michael A. Caligiuri, The Ohio State University Comprehensive Cancer Center, Division of Hematology/Oncology, The Ohio State University, 458A Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-7521; Fax: 614-293-7522; E-mail: Michael.caligiuri{at}osumc.edu.
Purpose: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)–bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted.
Experimental Design: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m2 (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9).
Results: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as Fc
R polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy.
Conclusions: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.
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