Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response.

Published

Journal Article

PURPOSE: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Thirty-four patients with advanced NHL received rituximab (375 mg/m(2) i.v. weekly, weeks 1-4) and escalating doses of s.c. IL-2 [2-7.5 MIU daily (n = 19) or 4.5-14 million international units three times weekly (n = 15), weeks 2-5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated. RESULTS: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients. CONCLUSIONS: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.

Full Text

Duke Authors

Cited Authors

  • Gluck, WL; Hurst, D; Yuen, A; Levine, AM; Dayton, MA; Gockerman, JP; Lucas, J; Denis-Mize, K; Tong, B; Navis, D; Difrancesco, A; Milan, S; Wilson, SE; Wolin, M

Published Date

  • April 1, 2004

Published In

Volume / Issue

  • 10 / 7

Start / End Page

  • 2253 - 2264

PubMed ID

  • 15073100

Pubmed Central ID

  • 15073100

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.ccr-1087-3

Language

  • eng

Conference Location

  • United States