Rituximab has been combined with a number of biological agents, including alpha-interferon (Davis et al: Clin Cancer Res 6:2644-2652, 2000; Kimby et al: Blood 96:577a[abstract 2479], 2000) and interleukin (IL)-12 (Ansell et al: Blood 99:67-74, 2002). The current design of combination trials is often based more on the availability of active agents than on any scientific rationale. The bcl-2 protein is overproduced in 60% to 80% or more of follicular NHL patients and in more than 80% of patients with CLL. A result is decreased apoptosis related to the prevention or slowing of activation of caspases. A resulting effect is a form of multidrug resistance. bcl-2 knockout mice have severe immunodeficiency and lymphocytopenia, suggesting that bcl-2 may be required for the viability of these cells. G3139 is an antisense bcl-2 oligonucleotide currently in clinical trials for a variety of solid tumors and hematologic malignancies.
O’Brien et al (abstract #3213) reported the first US phase I trial of the antisense molecule in patients with CLL. Surprisingly, the dose of 7 mg/kg as a continuous infusion, which has been routinely well tolerated by patients with solid tumors, resulted in life-threatening hypotension and hypoglycemia requiring monitoring in an intensive care unit setting. Other adverse events included hemolysis and high fever. As a result, subsequent patients have been treated at a dose of 3 mg/kg, which has been well tolerated. A reduction in the lymphocytosis was noted in all treated patients. An important randomized phase III trial is ongoing in patients with CLL who relapsed after or were refractory to fludarabine therapy. They are randomized to fludarabine combined with cyclophosphamide with or without G3139.
Previous data using a human lymphoma xenograft model (Smith et al: Blood 96:338a [abstract 1458], 2000) suggested at least additive benefit when a bcl-2 oligonucleotide antisense molecule was combined with rituximab. At the 2001 ASH meeting, Auer et al (abstract #3358) incubated fresh human CLL cells in culture with G3139 as well as dexamethasone, fludarabine, or rituximab. Down-regulation of bcl-2 and apoptosis was observed with antisense alone, and the effect was enhanced in the presence of rituximab or fludarabine. These observations support the combination of these agents in clinical trials, which will be activated in the near future.
Epratuzumab (hLL2 [LymphoCide]) is an anti-CD22 monoclonal antibody with activity against indolent and aggressive NHL and with a good safety profile (Leonard et al: Blood 94:92a[abstract 404], 1999; Leonard et al: Blood 96:578a[abstract 2482], 2000). As a result, Leonard et al (abstract #3506) conducted a phase II trial in which this antibody was combined with rituximab to treat a variety of histologies of indolent and aggressive NHL. The combination appeared to be well tolerated and the limited efficacy data showed five complete remissions of the first 18 patients on study.