title: A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/m(2) (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 FcgammaR 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.
authors.affiliation: American Health Network Oncology/Hematology, Indianapolis, Indiana, USA.
authors.forename: Khuda D
authors.initials: KD
authors.lastname: Khan
authors.forename: Christos
authors.initials: C
authors.lastname: Emmanouilides
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Deborah
authors.initials: D
authors.lastname: Hurst
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia
authors.forename: Glenn
authors.initials: G
authors.lastname: Michelson
authors.forename: Sandra
authors.initials: S
authors.lastname: Milan
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Lawrence
authors.initials: L
authors.lastname: Piro
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Porcu
authors.forename: Charles F
authors.initials: CF
authors.lastname: Eisenbeis
authors.forename: Amy L
authors.initials: AL
authors.lastname: Banks
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D000069283:Rituximab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D007376:Interleukin-2; D017452:Receptors, IgG; D011994:Recombinant Proteins; D000069283:Rituximab