Resolving Confusion: The New Realities of Mantle Cell Lymphoma

In their Areas of Confusion article, “Management of Relapsed Mantle Cell Lymphoma: Still a Treatment Challenge,” Ruan et al attempt to make the case that the relative merits of different upfront approaches for mantle cell lymphoma (MCL) are difficult to appreciate due to the differences in eligible patient populations and limited randomized data. They assert that the “improvements” we have seen in many patients with mantle cell lymphoma are largely attributed to improvements in second-line therapy over the past decade or so. The “areas of confusion” stem largely from the plethora of new approaches and therapies now available to patients with relapsed disease, and the limited guidance regarding the optimal use of these agents in the relapsed setting. Indeed, Ruan et al are absolutely accurate.

The agents with demonstrated activity in MCL include proteasome inhibitors such as bortezomib (Velcade), the first drug ever approved for the disease; new/old agents such as bendamustine; new-generation immunomodulaotry agents such as lenolidomide (Revlimid); mTOR inhibitors such as temsirolimus (Torisel), and a host of other drugs targeting the PI3-kinase-AKT-mTOR pathway; cyclin dependent kinase inhibitors; histone deacetylase inhibitors that may be able to turn off pathognomonic cyclin D1 expression; and even metronomic based chemotherapy options.

While Ruan et al present only a brief review of these options, the article nearly completely circumnavigates any discussion regarding the new reality in mantle cell lymphoma. The new reality is that, at the biologic level, we may now understand as much about mantle cell lymphoma as any cancer, certainly, as much as any lymphoproliferative malignancy.

Disease Features

Recent insights into MCL have revealed a multitude of molecular lesions that collectively appear unique to MCL. These include overexpression of cyclin D1 due to the (11:14) translocation; loss of cyclin-dependent kinase inhibitiors such as p27 and p21; and dysregulation of BH3-only mimetics such as BIM and NOXA, which may directly or indirectly be attributed to the dysregulation of the PI3-kinase-AKT-mTOR signaling pathway. Our understanding of the molecular pharmacology of the many new agents active in MCL makes nearly complete sense when taken in the context of our understanding of the disease biology. In fact, the constellation of these dysregulated pathways has led to the identification of some of the most important prognostic factors in MCL, namely those revolving around the proliferation rate (Ki-67) and proliferation signature associated with various subpopulations of patients with MCL. We now know that like so many other types of cancer and lymphoma, MCL is not one disease.

The reality is that we are witness to an unprecedented change in the history of MCL. Changes in outcome are likely a product of new developments in both the upfront and relapsed settings. In fact, two very recent articles[1,2] suggest that the survival of patients with MCL has likely doubled in the recent past, a finding related to a multititude of advancements in both upfront care (transplant, monoclonal antibodies, integration of new agents) and the relapse setting. Our upfront experiences with simple CHOP-based therapy (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone) have thankfully evolved, and now include immunochemotherapy combinations, be it with CHOP or CHOP-ICE (ifosfamide, carboplatin, etoposide) combinations, and hyperCVAD-R (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone, rituximab) alternating with methotrexate and cytarabine. The compelling differences between these upfront regimens is underscored by the observation that hyperCVAD-R/methotrexate/cytarabine appears to even overcome the prognostic significance of the mantle cell prognostic index (MIPI) developed from patients treated with largely CHOP-based treatment programs.

While the role of peripheral blood stem cell transplantation (PBSCT) is certainly being actively investigated, it is clear that the preponderance of evidence suggests that upfront PBSCT produces meaningful progression-free survival intervals never before seen with CHOP or even simple R-CHOP–based programs. Even more encouraging are recent experiences from the allogeneic stem cell transplant literature. These data have compelled some to suggest that the graft-vs-lymphoma effect seen in MCL has the potential to be “curative” even in a heavily treated and refractory patient population. The diversity of new agents active in MCL-which differ mechanistically from our more traditional cytotoxic agents-offers a chance to cycle likely non–cross-resistant therapies in the relapsed setting, or to supplement upfront treatment programs, hoping to exploit synergistic combinations. More importantly, these new agents offer an opportunity to innovatively develop new rationally constructed platforms specific for the disease.

Tailored Therapy and Clinical Assumptions

The concept of tailoring treatment to the patient, as noted by Ruan et al., is certainly the goal of every practicing oncologist. But rather than tailoring the trial to the patient, it makes intuitively more sense to tailor the drug to the biology. Making assumptions regarding the clinical aggressiveness of the disease and the need to direct a patient to a chemotherapy-containing regimen defies consideration of the underlying biology, and precludes the more realistic assessment of a compound’s therapeutic potential. These assumptions may lead to the wrong conclusions about the activity of the drug under study. In fact, the development and rational integration of novel agents in multiple myeloma, chronic myelogenous leukemia, and T-cell lymphoma have clearly demonstrated that new drug platforms can change the natural history of previously challenging cancers irrespective of clinical assumptions. As we move forward in MCL, it will be imperative, in my estimation, to integrate a biologic understanding into our conduct of new clinical trials, and to begin to think about how we can use new and old agents alike in a rational manner.

Perhaps our treatment paradigms in MCL should follow the success used in the treatment of acute lymphoblastic leukemia, where we identify the optimal induction chemotherapy (hyperCVAD-R vs R-CHOP-ICE vs R-EPOCH [etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, doxorubicin HCl] vs R-CHOP), followed by consolidation (PBSCT, non–cross-resistant chemotherapy program), followed by a maintenance program (monoclonal antibodies, immunomodulatory agents, mTOR inhibitors). This type of algorithm, appropriately stratified based on biologically relevant prognostic factors, could be the next step forward as we continue to change the natural history of this challenging disease.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Tam CS, Bassett R, Ledesma C, et al: Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood 113:4144-52, 2009.
2. Herrmann A, Hoster E, Zwingers T, et al: Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27:511-8, 2009.