The monoclonal anti-CD20 antibody rituximab (Rituxan) induces the death of chronic lymphocytic leukemia (CLL) cells in part through apoptosis. Tumor necrosis factor (TNF)-α and other cytokines up-regulate bcl-2 and other anti-apoptotic proteins, thereby inhibiting apoptosis. In addition, TNF-α may play a role in the cytokine release syndrome and infusion toxicity associated with monoclonal antibody therapy. Therefore, antagonists of TNF-α represent potential therapeutic agents that may be able to decrease infusion toxicity and enhance rituximab-induced apoptosis. We initiated a phase II trial of etanercept in combination with rituximab in patients (pts) with relapsed CLL or small lymphocytic lymphoma (SLL), with the goals of increasing clinical activity of rituximab and reducing infusion toxicity through neutralization of TNF-α. Pts received etanercept 25 mg subcutaneously (SC) twice weekly during weeks 1–5 and rituximab 375 mg/m2 intravenously (IV) three times weekly during weeks 2–5. Stepped up dosing of rituximab was used with the first two rituximab treatments. From 12/02 to 10/03, 19 pts (14 male) with a median of 2 prior therapies (range 1–8) were enrolled. Therapy was generally well tolerated, although 5 pts developed grade 4 neutropenia and 5 pts developed grade 3–4 infection or neutropenic fever. Four of 19 pts achieved an NCI 96 partial response, with no responses in 8 pts with del(17p13.1), corresponding to loss of the p53 gene. In contrast, 4 of 11 pts without del(17p13.1) achieved a PR, including 1 pt with a complex karyotype. This study was stopped for interim analysis and has reopened, with the exclusion of patients with a del(17p13.1) based upon the response outcome above and a previous preliminary report by our group demonstrating that rituximab was ineffective for del(17p13.1) CLL (

Cancer Res 63:36, 2003
). We conclude that the combination of rituximab and etanercept has clinical activity in heavily treated, relapsed CLL pts without del(17p13.1), irrespective of prior rituximab treatment. Accrual to this study continues, and the results will be updated at the 2004 ASH meeting.

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