Novel agents in follicular lymphoma: choosing the best target.

Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment. Given the large number of candidate drugs and potential combinations, it will be crucial to prioritize evaluation based on sound preclinical and early clinical studies. Combinations that exploit driver mechanisms within tumor cells and target parallel pathways to minimize the development of drug resistance, as well as harness the potential of the immune system would seem most logical. In order to expedite progress, future studies will need to use innovative trial designs and employ surrogate end points. The development of validated prognostic tools to identify higher risk patients and reliable predictive markers to select subgroups most likely to benefit from targeted agents will be paramount. The potential for unexpected toxicity with novel combinations must be recognized, necessitating both short- and long-term vigilance. Finally, as a greater number of treatment options become available, optimal sequencing must be determined in order to both prolong life and maintain its quality.