Bendamustine/Rituximab (Treanda/Rituxan)

In B-Cell and Mantle-Cell Non-Hodgkin’s Lymphoma Presenter: Richard H. van der Jagt, Ottawa Hospital, Ottawa, Ontario, Canada Bendamustine HCl (Treanda, Cephalon) is an alkylating agent with singular activity in multiple hematological and solid tumors. It induces cell death via apoptosis and via the apoptosis-independent pathway of mitotic catastrophe. The combination of bendamustine and rituximab produces a syn-ergistic antitumor effect on NHL cells.

The objective of the phase 2, multicenter clinical study was to evaluate the efficacy and safety of bendamustine plus rituximab in patients with relapsed NHL. This study enrolled adults with relapsed, indolent (slowly growing) B-cell or mantle-cell NHL whose was not refractory to rituximab. Relapse was defined as disease progression of six months or less since the last rituximab dose. generic cialis 20mg

Patients received intravenous (IV) rituximab 375 mg/m2 on day one and IV bendamustine 90 mg/m2 on days two and three of a 28-day cycle for four to six cycles. An additional dose of IV rituximab 375 mg/m2 was given one week before the first cycle of bendamustine and four weeks after the last cycle.

The primary analysis population included 66 patients (59% were men) with a median age of 60 years (range, 40 to 84 years). The indolent histological phenotype was seen in 54 patients with the following histological subtypes: follicular (center cell) lymphoma (in 61%), small lymphocytic lymphoma (in 15%), lymphoplasmacytic lymphoma (in 3%), and marginal zone lymphoma (in 3%); 18% had mantle-cell lymphoma. A total of 82% of patients had stage III or IV disease. These patients experienced relapse from a median of one previous cycle of chemotherapy (ranging from one to four cycles); 56% had received previous treatment with rituximab.

For the 12 patients with mantle-cell lymphoma, the overall objective response rate was 92%. The median duration of response for all patients was 21 months (95% confidence interval [CI], 18.3, 24.5). In patients with mantle-cell lymphoma, the median duration of response was 19.2 months (95% CI, 12.2, 24.4).

After a median follow-up period of 20.3 months, median progression-free survival was equivalent: 23 months for patients with indolent NHL and 22.9 months for those with mantle-cell NHL.

Grade 3 and 4 neutropenia was observed in 36% of patients. Common nonhematological toxicities (grades 1 and 2, grade 3, and grade 4) included nausea (68%, 0%, and 0%) and fatigue (47%, 3%, and 0%), respectively. One patient had grade 3 sepsis, which was considered to be unrelated to bendamustine.

The investigators concluded that bendamustine, when given with rituximab, produced a high objective response rate and was generally well tolerated in patients with relapsed indolent and mantle-cell NHL whose disease was not refractory to rit-uximab. These results suggest that bendamustine/rituximab might be comparable in activity to chemotherapy with cy-clophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone (CHOP) plus rituximab. Further studies of this combination are warranted.

Other Rituximab (Rituxan) Combinations For Non-Hodgkin’s Lymphoma

Presenter: John P. Leonard, Weill Cornell Medical College and New York Presbyterian Hospital, New York, N.Y.

The widespread use of rituximab has demonstrated the effectiveness of unlabeled monoclonal antibody treatment of NHL. As a single agent, rituximab is useful in indolent lym-phoma, particularly the follicular subtype, and it has clinical activity in virtually all other B-cell malignancies. The optimal role of rituximab in various treatment settings is still being defined, both alone and in combination with other therapies.
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Several important studies of this agent are also relevant to those of other antibodies under development, such as the need to clarify the dominant mechanisms of action in NHL and the pathways of resistance to antibody therapy; to understand the importance of complement resistance antigens and Fc receptor polymorphisms; and to modify doses and schedules.

Other unlabeled antibodies are under evaluation in NHL, such as alemtuzumab (Campath-1H, Berlex), a humanized antibody with activity against CD52. Although alemtuzumab has been investigated primarily in chronic lymphocytic leukemia (CLL), it is also active in nodal disease and in both T-cell and B-cell lymphomas. The full role of this agent in NHL remains to be defined.

Other agents include epratuzumab (Immunomedics), which targets CD22, and galiximab (Biogen Idec), which reacts with CD80. Epratuzumab is active in both follicular NHL and diffuse large B-cell NHL; it is being studied in trials of autoimmune disorders and B-cell malignancies. Galiximab also shows activity as a single agent in follicular lymphoma.

Given the tolerability of rituximab and the desire of patients to avoid the toxicities of chemotherapy, much emphasis is being placed on combinations of antibodies with each other and with other biologics. One clinical study investigated the combination of rituximab and cytokines plus other immune adjuvant therapies such as interleukin-2 and cytosine- guanosine (CpG) oligonucleotides.

Bortezomib (Velcade, Millennium), a proteasome inhibitor with efficacy in relapsed mantle-cell lymphoma, is also being combined with rituximab, and initial results are promising.

Preliminary results have shown that a combination of epratuzumab and rituximab is well tolerated and has notable clinical activity.

A galiximab/rituximab combination appears to have a favorable action in preliminary studies (see page 675). The im-munomodulatory agent lenalidomide (Revlimid, Celgene) is being combined with rituximab to treat relapsing NHL in a study now in progress. eriacta

The combination of rituximab with other promising agents seems to be effective in preliminary trials, but randomized trials are needed to determine whether to make rituximab-sen-sitive patients more sensitive to new agents or whether to make rituximab-resistant patients sensitive to a combination of agents.