The evidence that Tregs are reduced after therapy with fludarabine, agrees with the hypothesis that these cells play a critical role in protecting CLL cells from getting killed by the immune system.47 The same happens when patients with CLL were treated with thalidomide.52 This drug and its analogues, such as lenalidomide, acts as immunomodulatory agents targeting the microenvironment and both are shown to be effective in the treatment of CLL patients, probably by means of TNF modulation.53–55. Here, TNF is linked to B-cell chronic lymphocytic leukemia.