Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

J Clin Oncol. 2015 Sep 1;33(25):2803-11. doi: 10.1200/JCO.2014.59.5363. Epub 2015 Jul 20.


Lenalidomide is an orally active immunomodulatory drug that has direct antineoplastic activity and indirect effects mediated through multiple types of immune cells found in the tumor microenvironment, including B, T, natural killer (NK), and dendritic cells. Recently, the E3 ubiquitin ligase cereblon was identified as a molecular target that may underlie the effects of lenalidomide on tumor cells, as well as on cells in the tumor microenvironment. Decreases in cereblon attenuate these effects and also confer resistance to lenalidomide. Tumoricidal effects of lenalidomide are associated with reduced interferon regulatory factor 4, a downstream target of cereblon. Lenalidomide stimulates proliferation and activation of NK cells, thereby enhancing NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. These effects appear to be secondary to cytokine production from T cells. Lenalidomide has been shown to produce synergistic effects in experimental models when evaluated in combination with rituximab, dexamethasone, bortezomib, and B-cell receptor signaling inhibitors, consistent with mechanisms complementary to these agents. These experimental findings have translated to the clinic, where single-agent use displays durable responses in relapsed/refractory non-Hodgkin lymphoma, and combination with rituximab and other agents leads to improved responses at first line and in relapsed/refractory disease. The activity of lenalidomide is evident across multiple lymphoma subtypes, including indolent and aggressive forms. The interaction among cell types in the immune microenvironment is increasingly recognized as important to tumor cell recognition and destruction, as well as to protection of normal immune cells, as reflected by lenalidomide studies across multiple types of B-cell lymphomas.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • B-Lymphocytes / drug effects*
  • Bortezomib / pharmacology
  • Cytokines / drug effects
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dexamethasone / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Hematopoiesis / drug effects
  • Humans
  • Killer Cells, Natural / drug effects
  • Lenalidomide
  • Lymphoma, B-Cell / drug therapy*
  • Molecular Targeted Therapy*
  • Peptide Hydrolases / drug effects
  • Peptide Hydrolases / metabolism
  • Rituximab / pharmacology
  • T-Lymphocytes / drug effects
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology
  • Thalidomide / therapeutic use
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Ubiquitin-Protein Ligases / drug effects
  • Ubiquitin-Protein Ligases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CRBN protein, human
  • Cytokines
  • Rituximab
  • Thalidomide
  • Bortezomib
  • Dexamethasone
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • Lenalidomide