Should There Be a Standard Therapy for Mantle Cell Lymphoma?

Mitchell R Smith


Future Oncol. 2011;7(2):227-237. 

In This Article

Future Perspective

The key to improving therapy for MCL is a more complete understanding of the biology of this disease. While cyclin D1 dysregulation is pathognomonic, it is not sufficient to cause MCL. What molecular events cooperate with cyclin D1 to drive proliferation, which is, at present, the best prognostic marker of MCL behavior? Does the answer lie in regulators of cyclin D1, such as CDKs, in downstream effectors of cyclin D1, such as the Rb pathway, or in the controls of parallel proliferation pathways, such as BCR signaling through syk, btk, PI3K, AKT and mTOR? What is the role of defects in cell-death pathways, such as in TNF-related pathways and the mitochondrial apoptotic pathways regulated by BCL2 family members and inhibitors of apoptosis? Each of these are potential 'druggable' targets, with agents already in clinical development. Animal models and/or cell lines more typical of MCL than the currently available blastoid variants would be very helpful in elucidating the efficacy of the many potential novel therapeutics and combinations. The ultimate solution to prolonged survival, if not cure, of MCL will come from such targeted therapies.

In the shorter term, we will need to empirically establish a backbone of therapy to serve as a platform to add newer agents. In the young, fit patient, we will determine the role of high-dose cytarabine and high-dose therapy with stem cell support, and then add other active agents with nonoverlapping toxicities. In the older, less fit patient, we will build on R–B and then investigate additions to induction and, since there is residual disease, consolidation. Early detection of molecular relapse will trigger treatment with well-tolerated biological agents to prolong remission. Progress will be incremental, turning MCL into a more chronic disease, until we solve the biologic complexity to develop an effective cocktail of targeted agents.


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