A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma

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BlankClinical Cancer Research Vol. 12, 7046-7053, December 1, 2006

© 2006 American Association for Cancer Research

A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for

Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma

Khuda D. Khan1, Christos Emmanouilides2, Don M. Benson, Jr.3, Deborah Hurst6,

Pablo 6, Glenn Michelson6, Milan6, Amy K. Ferketich4, Lawrence

Piro7, P. Leonard8, Pierluigi Porcu3,5, F. Eisenbeis3,5, Amy L.

Banks3, Lei Chen3, C. Byrd3,5 and A. Caligiuri3,5

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 , California; and 8 Weill Medical

College of Cornell University, New York, New York

Requests for reprints: 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: .caligiuri@... .

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 gamma 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.