"Use It Again!"

Retherapy With Bendamustine in Indolent B-Cell Lymphoproliferative Disorders

Marco Montillo; Alessandra Tedeschi


Expert Rev Hematol. 2013;6(3):247-250. 

In This Article

Abstract and Introduction


Evaluation of: Weide R, Feiten S, Friesenhahn V et al. Retreatment with bendamustine-containing regimens in patients with relapsed/refractory chronic lymphocytic leukemia and indolent B-cell lymphomas achieves high response rates and some long lasting remissions. Leuk. Lymphoma doi:10.3109/10428194.2012.747679 (2012) (Epub ahead of print).
A pattern of relapse followed by further therapy is prevalent in patients with indolent lymphoid malignancies indicating the need for additional effective salvage therapies. Previous therapy, response and duration of response to that therapy are among the most important factors in determining the next therapy. Bendamustine, a bifunctional alkylating agent, has been tested alone or in combination in patients with chronic lymphocytic leukemia and indolent non-Hodgkin's lymphomas. In this article, the authors reported data, collected retrospectively, regarding repeatedly treating patients affected by indolent lymphoid malignancies with bendamustine-including regimens at the moment of relapse. Their experience showed that this drug is effective and manageable even when reused in both settings: chronic lymphocytic leukemia and non-Hodgkin's lymphomas combined with rituximab and/or mitoxantrone. The slow evolution in the treatment of patients with lymphoid malignancies has recently given way to a major revolution. Over the past decade, the availability of novel and active targeted agents, particularly monoclonal antibodies, has engendered major progress in the treatment of both aggressive and indolent lymphoid malignancies. Despite the fact that new therapeutic strategies are relying less on nonspecific cytotoxic drugs and more on targeted agents, a pattern of relapse followed by further therapy is prevalent in patients with indolent lymphoid malignancies, indicating the need for additional effective salvage therapies.


Bendamustine is neither a new drug, nor a biologically targeted agent.[1] The drug was originally designed to have both alkylating and antimetabolite properties. Given the incomplete crossreactivity between bendamustine and other alkylating agents, bendamustine was initially tested in the relapsed/refractory setting. On the basis of the results of a Phase III randomized trial comparing bendamustine with chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL), bendamustine obtained approval by the US FDA.[2] In this trial, the overall response rate (ORR) obtained in the bendamustine arm was 68% compared with 39% in the chlorambucil arm, similarly, the complete remission (CR) rate with bendamustine was higher compared with chlorambucil; 29 and 4%, respectively. Moreover, the median progression-free survival (PFS) was significantly longer with 21 months recorded in the bendamustine arm compared with 9 months observed in the chlorambucil arm.

While the role of rituximab in the management of indolent non-Hodgkin's lymphomas (NHL) has become increasingly important in the last decade, the development of resistance to this anti-CD20 monoclonal antibody may occur.

A Phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell NHL refractory to rituximab.[3] An ORR of 77% (15% CR, 19% unconfirmed CR and 43% partial) was observed with an acceptable toxicity.

Despite the significant activity shown using bendamustine, the era of single-agent treatment in indolent lymphoproliferative disorders is essentially over. Several combinations incorporating bendamustine have been evaluated. Results of the combination bendamustine plus mitoxantrone (BM) have been reported to be effective in CLL even after fludarabine treatment.[4,5]

Bendamustine has been successfully combined with rituximab (BR) in pretreated and previously untreated indolent lymphoid malignancies. A study from Germany accrued 63 patients with relapsed or refractory low-grade NHL for treatment with BR. The responses to BR observed in this trial were an ORR of 90% with 60% having CR. In the group of relapsed mantle cell lymphoma (MCL), the ORR and CR obtained were 75 and 50%, respectively. The duration of response was relatively long with a median PFS of 24 months. In patients with MCL, the median PFS was 18 months.[6] A confirmatory trial, using the identical treatment regimen, enrolled 69 patients with relapsed or refractory low-grade NHL and 66 patients were treated with BR.[7]

More recently, in a randomized, multicenter, Phase III study after a median follow-up of 45 months, BR was found to be significantly more effective than rituximab plus CHOP in prolonging PFS in patients previously untreated with indolent and MCL (69.5 vs 31.2 months).[8] Finally, BR was better tolerated.

The same group who developed the combination BM demonstrated the efficacy of BM with the addition of rituximab in relapsed/refractory CLL and NHL. They observed a high response rate, even obtaining a number of long-lasting remissions.[9] Grade 3 and 4 hematological toxicity was not mild but manageable, then they administered this combination in the elderly population with B-cell lymphoid malignancies.[10]

Bortezomib has demonstrated excellent single-agent activity in patients with relapsed/refractory MCL.[11,12] These data provide a solid rationale for combining bendamustine with bortezomib for the treatment of indolent lymphomas. The majority of ongoing studies are looking at a triple combination of bendamustine, bortezomib and rituximab in the relapsed/refractory setting.[13]

Encouraged by the results with fludarabine, cyclophosphamide and rituximab, the German CLL Study Group (GCLLSG) initiated CLL2M, testing the safety and efficacy of bendamustine combined with rituximab in patients with relapsed and/or refractory CLL.[14]

Pretreatment characteristics of the 78 patients enrolled in this prospective, multicenter, nonrandomized Phase II study were unfavorable in a high percentage of them. In the intention-to-treat population analysis, the ORR was 59.0% with 9% for CR and 47.4% for nodular partial response or PR. After a median follow-up of 24 months, the median event-free survival was 14.7 months, while PFS was 15.2 months. Recently, the GCLLSG tested this combination in previously untreated CLL.[15] Results on the 117 patients enrolled showed an ORR of 88% with a CR rate of 23.1%. After a median observation time of 27 months, 90.5% of the patients were alive. The event-free survival was 33.9 months. Severe infections of grade 3 or 4 occurred in 7.7% of the patients. Regarding myelotoxicity, grade 3 or 4 neutropenia was observed in 19.7% of the cases while thrombocytopenia and anemia were documented in 22.2 and 19.7% of the patients, respectively. Comparative studies are needed, but at the moment there are no Phase III studies on patients relapsing after fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and rituximab, while a randomized study for BR versus FCR as initial therapy in CLL is still ongoing.