Velcade combinations in mantle cell lymphoma: are we learning anything?

In the March edition of the journal, Kouroukis et al. [1] describe a phase II study of the combination of bortezomib (Velcade) with gemcitabine in relapsed mantle cell lymphoma (MCL). The study was primarily designed to determine the efficacy of this combination in patients having received up to three prior lines of therapy. Both bortezomib and gemcitabine have demonstrable single-agent activity in this disease [2,3], and the authors adopted a dosing regimen that had previously been established in a solid tumor phase I study [4]. This involved bortezomib given at 1.0 mg/m² IV on days 1, 4, 8, and 11 with gemcitabine at 1000 mg/m² IV on days 1 and 8 of a 21-day schedule. In total, 26 patients were eligible for assessment. The observed overall response rate was 60% (15 patients) with an additional nine patients having stable disease, which meant that only one patient had initial progression. The median progression-free survival was 11.4 months. The major toxicity observed was hematological with virtually all patients experiencing some cytopenia, and in almost half of the patients this was severe (grade III/IV). Significant neurological toxicity occurred in only two (8%) patients, although ‘pain’ was seen in an additional four (15%). In common with many bortezomib studies fatigue was a common non-hematological side effect, with 11% experiencing grade III/IV toxicity. As a consequence of the hematological toxicity just over 50% of cycles were given at the intended dose intensity, and in patients who had previously received high-dose therapy this fell to 25%.

This is a relatively small study that has combined two drugs with proven single-agent activity in MCL. The combination is clearly active with most patients achieving some degree of disease response, but how does this compare to other published regimens? Bortezomib as a single agent produces response rates of up to 46% [5–8] in small phase II settings, and 33% when evaluated in a multicenter international registration study [3]. In all of these studies the patient populations examined were more heavily pretreated than in the current study. In the study of Kouroukis et al. 58% of the patients had low-risk disease according to the Mantle Cell Lymphoma International Prognostic Index (MIPI), and 73% had received only one prior chemotherapy regimen. This is therefore a relatively lightly treated population who you might expect to have a good response to second-line chemotherapy. A suitable comparison would be two multicenter studies evaluating fludarabine combinations with rituximab [9,10], where the majority of patients were at first relapse. In both of these studies the observed response rates were over 70%, and were maintained for approximately 1 year. The observed response rate in the study from Kouroukis et al. would probably be higher if rituximab had been added to their combination, and so all these results are probably broadly similar.

The stated attraction of this regimen is that it is a non-anthracycline containing combination. However, the hematological toxicity described would appear to limit its applicability to those patient groups where you might wish to avoid this class of drug, namely more elderly patients with limited bone marrow reserve. In addition, this would also appear to limit its use in patients following high-dose procedures. The hematological toxicity would also probably limit the incorporation of other agents into this regimen, with the possible exception of anti-CD20 monoclonal antibodies. Dose modifications to this combination may be required before it can be taken further.

Whilst there have been clear recent improvements in the management of mantle cell lymphoma the disease remains largely incurable, and following relapse it can be difficult to obtain meaningful remissions. Bortezomib and temsirolimus are the only two licensed drugs in this disease. Both are active [3,11] and warrant exploration in combination trials. To date there are no reported randomized trials with bortezomib in MCL, as the drug received a license in the USA based on a single-arm phase II study [3]. A frontline randomized study is being run by the drug company with the intention of obtaining a European license, and a randomized relapse study is currently ongoing in the UK.

Bortezomib is currently being explored in combination with regimens with proven efficacy in MCL as well as in other lymphoma subgroups. Trials combining it with fludarabine [12], bendamustine [13], rituximab [14], high-dose AraC [15], Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) [16], and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) [17,18], amongst others, are reported, and more are ongoing. Most of these studies incorporate rituximab, and most involve patients with relapsed and refractory disease. All of them include small numbers of patients and none of them are randomized. As a consequence it is virtually impossible to form any kind of judgement as to which combination is more efficacious than any other based on the patient population being treated.

There are a plethora of new agents at various stages of development that are going to be explored in MCL [19] as well as other lymphoma subtypes. Unless we have standard templates in place for studies in rare hematological malignancies it will be impossible to know which drugs and combinations of drugs are the most useful to incorporate into clinical practice. In response to this, the European Mantle Cell Lymphoma Network is currently developing such a template for trials in MCL. This will become increasingly important, as the costs involved in combining newer agents are significant. Unless we can prove the comparative superiority of newer regimens it is possible that the single most important factor in determining whether they are adopted widely or not will be financial toxicity.

Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at www.informahealthcare.com/lal.