ESMO Guideline for Mantle Cell Lymphoma

An Expert Interview With Martin Dreyling, MD, PhD

Martin H. Dreyling, MD, PhD; Linda Brookes, MSc


September 25, 2014

In This Article

Treatment Guideline: Emphasis on Targeted Therapies

Medscape: What are the guideline's main recommendations about treatment?

Prof Dreyling: I think it is established worldwide that in fit younger patients (up to 65 years of age), dose-intensified therapy including high-dose cytarabine is standard of care. In the United States, one approach is rituximab in combination with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HyperCVAD), whereas in Europe we prefer a sequential dose intensification regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) alternating with rituximab, dexamethasone, cytarabine, cisplatin (R-DHAP), followed by autologous stem cell transplantation.[8]

Medscape: What about treatment for elderly patients?

Prof Dreyling: For the elderly, who are the majority of MCL patients, we again agreed on two standard regimens of induction: R-CHOP and bendamustine-rituximab (BR)[9] and rituximab maintenance as standard of care, at least after R-CHOP, on the basis of our own randomized trial.[10] When it comes to relapsed disease, the situation is a little more challenging. We recommend either BR or R-DHAP with or without targeted approaches as salvage induction, because most patients will have initially received R-CHOP. In younger patients who did not initially receive autologous stem cell transplantation, you might have to reconsider this approach. Alternatively, you also have to discuss allogeneic stem cell transplantation. However, for the majority of patients, who are over age 65, this consolidation is not possible.

Medscape: What about targeted approaches to treatment?

Prof Dreyling: Probably the most important part of this new guideline is the evaluation of molecular targeted therapies. It is almost certainly the most interesting area, because so far there has been no direct comparison between molecular approaches. We deliberately focused on the drugs that have already been approved somewhere in the world, namely bortezomib, ibrutinib, lenalidomide, and temsirolimus. Temsirolimus is the only one of these registered in Europe for the treatment of patients with relapsed and/or refractory MCL.[11]

There was a consensus that we would recommend these targeted approaches in combination with immunochemotherapy, but we stress that this approach is still investigational; it has not yet been explored in phase 3 trials, which are currently ongoing. But we strongly feel that a combined approach will be the future strategy of treatment.

The question of how to rank these molecular approaches remains open, and to be honest, no one definitely knows, although there are some strong opinions. Specifically, for bortezomib, lenalidomide, and temsirolimus, we have seen response rates of 30%-50%,[11,12,13,14,15,16,17,18] so it is rational to prefer a combination with chemotherapy, whereas ibrutinib achieved a higher response rate,[19] but longer follow-up is warranted.

New Bortezomib Data Not Included

Medscape: New phase 3 data on bortezomib in newly diagnosed MCL were presented at this year's American Society of Clinical Oncology (ASCO) meeting.[20] Did this affect the recommendation in the new guideline?

Prof Dreyling: This was the big news at ASCO, a randomized trial in favor of bortezomib in combination with R-CHOP[20]; that is the first randomized trial evaluating a molecular agent in first-line treatment of MCL. In light of the results, one has to discuss whether bortezomib should be part of the standard of care in first line, but these data were not evaluable at the time of our consensus. In that study, the bortezomib-containing regimen led to a significant 59% prolongation of progression-free survival, from 14 to 26 months, compared with R-CHOP. On the other hand, there was a pronounced increase in grade ≥ 3 thrombocytopenia in the bortezomib group (57% vs 6%), and around 23% of patients on bortezomib required platelet transfusions, which is unusually high for conventional treatment. However, I really would support the conclusion of the presentation at ASCO, a cautious but balanced comment on the consequence of the study, saying that "bortezomib in combination with a CHOP-like regimen [in the study, bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone; VR-CAP] could be considered a new standard of care for newly diagnosed MCL patients not considered for intensive treatment and bone marrow transplantation." I think we need to look more thoroughly at the final results, including overall survival, to see whether the VR-CAP regimen is worthwhile.

Medscape: Does the new guideline say anything about the tolerability of these molecular targeted approaches?

Prof Dreyling: All of these molecular approaches are rather well tolerated. Because of their tolerability, targeted approaches might be appropriate for compromised patients, but again, this hypothesis has to be proven in prospective trials.[5]

Radiation Insufficient as Monotherapy

Medscape: Do the new guidelines mention radiotherapy or radioimmunotherapy? This would be different from the United States, where radiotherapy is not used much.

Prof Dreyling: On the basis of what is published, it has been suggested that radiation is very efficient in early-stage disease, which is very rare.[21] On the other hand, we have some data that are only partially published which essentially indicate that radiotherapy alone achieves only short remissions, of one year or less. Therefore we recommend a shortened conventional chemotherapy followed by consolidation radiation in these very few cases of early-stage disease, but this conclusion is based on only one study.[22] We are convinced that radiation is not sufficient alone, but the strength of our recommendation is level B only, strong or moderate evidence.


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