Should There Be a Standard Therapy for Mantle Cell Lymphoma?

Mitchell R Smith

Disclosures

Future Oncol. 2011;7(2):227-237. 

In This Article

New Agents

Classes of drugs with activity in MCL include the mTOR inhibitors, nucleoside analogs and immune modulating agents thalidomide[60] and lenalidomide.[54] Other agents currently in earlier stages of development for B-cell lymphoma/leukemia are, in general, likely to have an impact in MCL as well. Monoclonal antibodies requiring additional studies in MCL include those targeting anti-CD20 but are molecularly engineered in various ways to be humanized, those that have different affinity for Fc receptors or those that have altered effects on direct cytotoxicity, complement activation or ADCC. In addition, some antibodies bind to different epitopes of CD20, which may yield different effects, particularly if they do not induce translocation of CD20 into lipid rafts. Antibodies or antibody-related molecules, unlabelled or attached to toxins, drugs or radioactive particles, that target other B-cell surface molecules, such as CD19, CD22 and CD37, are also of interest.

The mTOR inhibitor temsirolimus is active in refractory MCL, with a 38% response rate lasting, on average, 7 months.[61] The oral mTOR inhibitor everolimus is under investigation in a similar population.[62] These may be attractive candidates for use in initial therapeutic combinations. In earlier stages of development are small-molecule inhibitors of the BCR signaling pathway that target syk, btk, PI3K-δ and AKT.

Nucleoside analogs are active in relapsed MCL.[18,63] As initial therapy, cladribine was found in a Phase II study to have modest activity, apparently improved with the addition of rituximab.[17] This combination is a well-tolerated potential option that could be considered as initial therapy in selected patients. Some data suggest that cladribine may work partly as an epigenetic modulating agent,[16] and this opens the way for other rational combinations that are worth further study.

Since cyclin D1 is required to make a diagnosis of MCL, the cyclin pathway is a logical therapeutic target. Cyclins are controlled by CDK and specific CDK inhibitors have been identified. The CDK inhibitor flavopiridol had disappointing initial results, but newer pharmacokinetically based dosing regimens of a bolus followed by infusion have significant activity in CLL and are being investigated in MCL. An oral CDK inhibitor has demonstrated cell cycle inhibition in patients with relapsed MCL.[64]

Agents that promote apoptosis are also worth investigation. Inhibition of BCL2 family protein interactions through blocking of the BH3 domain common to these proteins is the attractive target of obatoclax and navitoclax (ABT263). Molecules that target other post-mitochondrial events in apoptosis such as second mitochondria-derived activator of caspase mimetics, are in earlier development. The TRAIL pathway that directly signals apoptosis is the target of TRAIL itself, as well as TRAIL-receptor agonist antibodies.

Investigation of biologically targeted agents must include both clinical and biologic end points. Furthermore, improved preclinical understanding of MCL, in terms of biology, drug sensitivity and resistance mechanism,s will be critical to selecting the most rational combinations to test in the clinic. Biologically targeted agents with activity in MCL present a multitude of opportunities for combination approaches to enhance both induction and consolidation. Given the wide range of potential combinations of these active agents, defining optimal use will require better clinical trial accrual.

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