New agents in follicular lymphoma.

The follicular lymphomas are indolent diseases that are highly responsive to various combinations of standard chemotherapy drugs. Nevertheless, until recently, no regimen had improved patient outcome. The incorporation of effective and well-tolerated monoclonal antibodies, such as rituximab, into chemoimmunotherapeutic strategies provided the first evidence that survival of these patients could be prolonged. Nevertheless, follicular lymphoma remains incurable and characterized by recurrent relapses requiring additional treatment. An increasing number of effective drugs are now being evaluated either alone or in combinations including the chemotherapy drugs bendamustine and bortezomib. More targeted agents include monoclonal antibodies and their derivatives such as drug-antibody conjugates and small modular immunopharmaceuticals. Other agents inhibit various cellular pathways including those triggered by the B-cell receptor, including spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase, and other intracellular pathways such as the mammalian target of rapamycin (mTOR), PI3-kinase, and apoptosis, and drugs that target the tumor microenvironment, notably the immunomodulatory agent lenalidomide. The development of combinations of these agents should be based on scientific rationale with correlative studies to enhance our understanding of the mechanisms of action and resistance of the drugs and the biology of the tumor to further improve the outcome of patients with follicular lymphoma.