Rationale for Clinical Development
Follicular Lymphoma
Lenalidomide exerts direct effects on FL tumors and their microenvironment in vitro.5,9,24,25 In preclinical studies, these effects on FL, T, and natural killer (NK) cells contribute to immune synapse repair and alter expression of costimulatory molecules.9,24 Immunomodulatory effects in vitro include enhanced T-cell proliferation and function and NK-cell function, including NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) in conjunction with rituximab.5,10,25
Proposed Mechanism of Action of Lenalidomide Plus Rituximab (R2) in Follicular Lymphoma
R2 has demonstrated increased activity in preclinical studies of follicular lymphoma.
Diffuse Large B-Cell Lymphoma
Lenalidomide has direct effects in vitro on both DLBCL cells and the tumor microenvironment.5,10,25-28 In preclinical studies, direct effects using non–germinal center B cell-like (GCB) tumor cells are mediated by binding to the cereblon-containing E3 ubiquitin ligase and include inhibition of interferon regulatory factor 4 expression and nuclear factor κB activity, increased interferon-β production, inhibition of proliferation, and induction of apoptosis.26-28
Proposed Mechanism of Action of R2-CHOP in Diffuse Large B-Cell Lymphoma
The increased immunomodulatory activity of R2 compared with either agent alone combined with the cytotoxic activity of CHOP represent the rationale for investigating R2-CHOP in activated B-cell DLBCL.
Mantle Cell Lymphoma
In preclinical studies, lenalidomide increases mitochondrial release of cytochrome c and activates caspases, resulting in direct MCL tumor cell killing.11,29 In lymphoma cells, the combination of lenalidomide and rituximab increases both direct anti-tumor killing activities of lenalidomide and NK-cell–mediated killing observed with rituximab.10,11 Lenalidomide also increases rituximab-mediated activation of caspases 3, 8, and 911 and increases NK-cell killing capacity through ADCC in these cells.10