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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/m IV on days 1, 4, 8, and 11 with gemcitabine at 1000 mg/m 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 nonhematological 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 secondline 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