Should There Be a Standard Therapy for Mantle Cell Lymphoma?

Mitchell R Smith


Future Oncol. 2011;7(2):227-237. 

In This Article

Heterogeneity of Mantle Cell Lymphoma: Biologic Determinants

As in CLL, immunoglobulin heavy chain genes are mutated in a subset of MCL patients, but, in contrast to CLL, this does not seem to correlate with outcome. Recent data, however, suggest that using a cut-off for mutation of 5% in MCL (vs 2% in CLL) may identify a better prognostic subgroup.[7] Preferential use of certain heavy chain variable region genes suggests that antigenic drive may play a role.

Mantle cell lymphoma is characterized by dysregulated expression of cyclin D1 caused by the cytogenetic translocation t(11;14) (q13;q32).[8] Rare cyclin D1-negative cases overexpress cyclin D2 or D3, but have gene signature profiles similar to the cyclin D1-positive cases.[9,10] Cyclin D1 interacts with cyclin-dependent kinases (CDKs) to phosphorylate Rb, which then drives the cell through the G1-S checkpoint. Nonetheless, cyclin D1 overexpression in mouse B cells is not sufficient to induce lymphoma and cyclin D apparently is necessary, but not sufficient, to produce MCL. Ongoing investigations in patients are revealing a range of secondary genetic and, in some data, epigenetic alterations that seem to be associated with MCL pathogenesis and variable clinical behavior. Post-transcriptional downregulation of the CDK inhibitor p27 appears to be a frequent factor cooperating with cyclin D1, and low p27 protein levels correlate with poor prognosis.[8] This p27 regulation appears, at least in some cases, to reflect enhanced proteasomal degradation. Therefore, based on the aforementioned biologic insights, CDK and proteasome inhibition are rational therapeutic approaches being investigated in MCL. Another critical cell cycle checkpoint component is p53, which, in turn, is controlled by ATM and by CDKN2A. The CDKN2A gene locus contains both the CDK inhibitor p16INK4A and p14ARF, which, through MDM2, controls p53. Therefore, these pathways are also rational targets for MCL therapeutics.[9]

Mantle cell lymphoma has shorter survival than other indolent lymphomas; perhaps a reflection of the previously noted biologic determinants that lead to loss of cell cycle checkpoints and thus enhanced proliferation. Similar to other indolent lymphomas, MCL is also not curable, perhaps reflecting aberrant apoptotic pathways. The two major apoptotic pathways are direct triggering of apoptosis via death receptor signaling of caspase 8 activation and the indirect pathway, through mitochondria, leading to activation of caspase 9. Abnormalities at multiple levels of each of these apoptotic pathways (beyond the scope of this article), described in MCL, may account for some biologic heterogeneity and provide therapeutic targets.[11] Examples of such agents in clinical trials are antisense oligonucleotides that downregulate BCL2,[12] small-molecule inhibitors of dimerization of BCL2 family proteins[13,14] and TNF-related apoptosis-inducing ligand (TRAIL) receptor agonist antibodies.[15]

Along with dysregulation of the cell cycle and apoptotic threshold, the complex cell signaling pathways that coordinately regulate growth and survival signals are altered in MCL and other B-cell malignancies. Signaling through the B-cell receptor (BCR) provides survival signals for B cells. BCR signaling includes downstream activation of syk, btk, PI3K (in particular, the δ-isoform seems specific for lymphoid cells), AKT and mTOR. Variability in the components of this pathway in different MCL patients needs further exploration, but may account for some variability in clinical behavior. Small-molecule inhibitors of each of these enzymes are in clinical development and are candidates for MCL-targeted therapy.

The role of epigenetic modulation in MCL is in its early stages of exploration. A curious effect of the translocated cyclin D1 allele has been defined and offered as support for use of cladribine in MCL therapy,[16] although the clinical efficacy of cladribine appears modest.[17,18] Recent genome-wide methylation analysis has identified potential specific therapeutic targets, as well as raised the possibility of DNA methylation as a more general target.[19]

Nuclear expression of the transcription factor SOX11 appears to be a marker for MCL, along with lymphoblastic lymphoma and approximately 50% of Burkitt lymphoma. In one study, lack of nuclear SOX11 characterized indolent MCL[11] and was associated with less complex cytogenetics and more than 5% of mutated immunoglobin genes.[7] A study suggesting that lack of nuclear SOX11 was a poor prognostic feature involved only five such patients and their prognostic features were not fully described, though they appeared to be older than the rest of the population.[20]

To date, no individual clinicopathologic feature, perhaps other than blastoid variant, has allowed the prediction of clinical behavior. The best biologic predictor appears to be proliferative rate. While this has been assessed in clinical trials by a panel of proliferation-related genes, via either microarray gene signatures[9] or a limited panel of genes,[21] clinically, it is usually measured by Ki-67.[22,23] It is likely that quantitation rather than estimation will enhance its predictive value.[24]

Thus, although an optimal prognostic scoring system for MCL is not yet precisely defined, the common lymphoma prognostic indicators of age, stage, LDH and performance status, as well as proliferation indices, can predict outcome. There is a subgroup of patients with very indolent MCL, originally described clinically as patients with splenomegaly and a CLL-like blood picture. More recently, 13 genes that are underexpressed in indolent MCL have been described but require validation.[7] Our ability to identify the group of patients with MCL who will have an indolent course and longer survival needs to be improved, although a period of observation in the asymptomatic patient remains a reasonable approach in selected cases. Similarly, patients with asymptomatic relapse may also be candidates for a period of observation in the absence of curative therapeutic options, although this should be the subject of clinical investigation. The use of retrospective data analyses to develop prognostic scoring systems must be viewed with caution as these analyses are confounded by the continuing evolution of staging and treatment options.


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