Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia

Abstract

Bendamustine, an alkylating agent without cross-resistance to cyclophosphamide is active in a variety of lymphoproliferative and other malignancies. In an open phase-II study we treated 23 patients with a median age of 62 years at study entry (43-86 years) with advanced, refractory or relapsed (Rai stage III n = 9, Rai stage IV n = 14) chronic lymphocytic leukemia (CLL) with bendamustine. At study entry, only 13 patients were chemotherapy-naive. The treatment schedule with bendamustine was as follows: for patients up to 70 years 60 mg/m2 for 5 days, for patients over 70 years 50 mg/m2 for 5 days, repetition at day 29. Remission criteria were used according to Cheson et al. (1996). All patients were evaluable for toxicity and 20 for response. An objective remission was achieved in 15/20 patients (75%), including six patients with complete remission (CR). Three of the complete responders had no chemotherapy prior to bendamustine. No change (NC) occurred in 5/20 patients (25%). Median overall survival after bendamustine treatment is 13.6 months (1-46 months) and 16.6 months (1-46 months) in patients responding to bendamustine. In total, 74 courses of bendamustine were applied. Therapy-related anemia and thrombocytopenia were rare. However, WHO grade III/IV leukocytopenia occurred in 38/74 cycles (51%), resulting in treatment-related mortality in 3/23 patients (13%). These patients were severely immunocompromised due to pretreatment or the underlying disease. As a corollary of the study, a general prophylactic antibiotic treatment (trimethoprim/ sulfamerazine) was instituted. A general feature was the decline of the CD4/CD8 ratio: mean before therapy: 1.36; after two courses: 0.98; after four courses: 0.6, as documented in all patients who received at least two courses of bendamustine (n = 12). All evaluable patients showed a decline in the CD4/8 ratio. However, this decline was not clearly related to an increased risk of infectious episodes. We observed mainly cutaneous allergic reactions (three WHO grade I; one WHO grade II) leading to a cessation of bendamustine treatment in 4/23 patients (18%). Bendamustine is highly effective in advanced or refractory CLL. In multiple pretreated or otherwise severely immunocompromised patients bendamustine might lead to additional immunosuppression with subsequent infectious complications.

Synthesis and Characterization of Some New Phase Ii Metabolites of the Alkylator Bendamustine and Their Identification in Human Bile, Urine, and Plasma From Patients With Cholangiocarcinoma

“…1) is a promising bifunctional alkylating agent containing a heterocyclic nucleus that induces more long-lasting DNA double-strand breaks than other alkylating drugs (Strumberg et al, 1996). The compound was first synthesized in 1963 with anticipated purine-based antimetabolic activity and has shown preferentially cytotoxic activity in the treatment of hematological malignancies, including non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and multiple myeloma, as well as breast cancer (Höffken et al, 1998;Heider and Niederle, 2001;Kath et al, 2001;Aivado et al, 2002;Bremer, 2002;Konstantinov et al, 2002;Pönisch and Niederwieser, 2002;Weidmann et al, 2002). Moreover, anticancer activity was reported in advanced small cell lung cancer and head or neck tumors (Reck et al, 1998;Rahn et al, 2001).…”

In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia

“…[23][24][25][26][27][28][29] Bendamustine belongs to the group of bifunctional alkylating agents. The nitrogen mustard group in position 5 is linked to a benzimidazol nucleus, showing a methyl-group in position 1 and a butanoic acid residue in position 2 ( Figure 1).…”

What Is New in Lymphoma?

“…Bendamustine has demonstrated activity in indolent and aggressive NHL, HL, chronic lymphocytic leukemia, and multiple myeloma. [61][62][63][64] In vitro and clinical data also support a beneficial interaction with rituximab. In a study of 63 patients with relapsed or refractory indolent NHL or mantle cell lymphoma (MCL), the response rate to this combination was 94% with 71% complete remissions.…”