title: 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.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: Cancer Center of the Carolinas, Greenville, South Carolina, USA.
authors.forename: William Larry
authors.initials: WL
authors.lastname: Gluck
authors.forename: Deborah
authors.initials: D
authors.lastname: Hurst
authors.forename: Alan
authors.initials: A
authors.lastname: Yuen
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Levine
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dayton
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lucas
authors.forename: Kimberly
authors.initials: K
authors.lastname: Denis-Mize
authors.forename: Barbara
authors.initials: B
authors.lastname: Tong
authors.forename: Dawn
authors.initials: D
authors.lastname: Navis
authors.forename: Anita
authors.initials: A
authors.lastname: Difrancesco
authors.forename: Sandra
authors.initials: S
authors.lastname: Milan
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wilson
authors.forename: Maurice
authors.initials: M
authors.lastname: Wolin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000069283:Rituximab; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007376:Interleukin-2; D000069283:Rituximab