Effect Of Bendamustine Research Articles

Effect of bendamustine plus rituximab on relapsed extragastric mucosa-associated lymphoid tissue lymphoma

Objective To investigate the rituximab plus bendamustine (R-Benda) therapeutic effect for relapsed extragastric mucosa-associated lymphoid tissue (MALT) lymphoma. Methods Ten patients (three females and seven males) with relapsed extragastric MALT lymphoma undergoing therapy with R-Benda were defined. Bendamustine was given at a dose of 90 mg/m2 on days 2 and 3 in nine patients and at 70 mg/m2 in one patient, while all received 375 mg/m2 rituximab on day 1. Results Nine patients received six courses of therapy,while one patient discontinued therapy after five courses for personal reasons, while one elderly patient had progressive disease after three courses. Tolerance of therapy was excellent, and all except one patient responded. Eight patients achieved the complete remission, one achieved the partial remission, and one patient progressed. Toxicities were mild and mainly hematological.After a median follow-up of 24 months (range, 5-43 months), 9 patients were alive. Conclusion R-Benda regime has high activity and good tolerance for patients with relapsed extragastric MALT lymphoma. Key words: Lymphoma, mucosa-associated lymphoid tissue; Recurrence; Rituximab; Bendamustine

Multiple Myeloma and the Bone Marrow Niche

e4 fusion of bendamustine with vorinostat that aims to increase the efficacy of the alkylator through the HDACi-mediated chromatin relaxation to make DNA more accessible to the damaging effect of bendamustine. It induced a high rate of response in Vk*MYC MM that was sustained for more than three months in mice receiving only two doses, one week apart. The IAP antagonist LCL161 results in rapid degradation of cIAP1/2 with stabilization of NIK and constitutive activation of NFkB. In vivo this results in activation of the innate immune system, with a cytokine release syndrome the dose limiting toxicity. In Vk*MYC mice with MM LCL161 results in a phagocytic-cell dependent, NK and T-cell independent anti-tumor response that is augmented with the addition of cyclophosphamide. Inhibition of coinhibitory receptors CTLA4, PD1 or PDL1 was ineffective, however activation of the costimulatory receptor CD137 with agonist antibody resulted in NK and CD8 T-cell dependent anti-tumor responses. These preclinical studies suggest that the Vk*MYC model can be successfully used to rationally develop novel targeted and immunotherapies for the treatment of MM.

Activity of the alkylating histone-deacetylase inhibition fusion molecule EDO-S-101 in preclinical models of human glioblastoma independent from MGMT expression.

e13031 Background: EDO-S101 combines the DNA damaging effect of bendamustine with the pan-histone deacetylase inhibitor vorinostat. The molecule was tested in models of human MGMT negative and posi...

Bendamustine and melphalan kill myeloma cells similarly through reactive oxygen species production and activation of the p53 pathway and do not overcome resistance to each other

Because the old alkylating drug bendamustine (BDM) is currently under evaluation in patients with multiple myeloma, we compared its efficacy to that of melphalan in 29 human myeloma cell lines (HMCLs). The concentrations of BDM and melphalan that killed 50% of cells (LD50) in HMCLs were linearly correlated (p < 0.001), and reactive oxygen (ROS) scavengers similarly inhibited cell death induced by both drugs. Sensitivity of HMCLs to both drugs was correlated to p53: the BDM and melphalan median LD50 values of TP53wild-type HMCLs were more than two-fold lower than those of TP53abnormal HMCLs (p < 0.001), and p53 silencing in TP53wt NCI-H929 cells inhibited BDM- and melphalan-induced cell death. Both drugs induced expression of p53 targets, p21, Puma and DR5, only in TP53wt HMCLs. In primary cells, both drugs induced an increase in DR5 expression in cells without del(17p). Finally, we demonstrated that the combined effect of BDM and melphalan was additive, and that BDM did not overcome melphalan resistance and vice versa.

One Size Does Not Fit All in Follicular Lymphoma

One Size Does Not Fit All in Follicular Lymphoma

Lack of effect of bendamustine on Fridericia corrected QT interval (QTcF) in a phase III study of bendamustine-rituximab in advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL).

e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTcF intervals, pharmacokinetic/pharmacodynamic (PK/PD) analysis, and changes in ECG morphology. The ECG analysis included patients with ≥1 ECG at baseline and on treatment. Results: There were 53 enrolled patients (92% white; 60% male; mean age 63.0 y, range 37-84 y; mean body surface area 2.0 m2, range 1.4-2.6 m2). No clinically relevant signal of any bendamustine effect on cardiac repolarization was detected based on the mean change in QTcF from baseline and outlier analyses (Table). In the PK/PD analyses, predicted change in QTcF for bendamustine and its metabolites, M3 and M4, were not significant: 5.4 ms (upper CI 7.6 ms), 6.0 ms (8.8 ms), and 7.1 ms (10.1 ms), respectively, but there were few data. No new ECG morphologic changes were seen. Conclusions: In this small population with previously untreated advanced NHL or MCL, bendamustine was associated with a small increase in mean QTcF that was not clinically meaningful. Support: Teva BPP R&amp;D, Inc. Clinical trial information: NCT01073163. [Table: see text]

Cytosine arabinoside potentiates the apoptotic effect of bendamustine on several B- and T-cell leukemia/lymphoma cells and cell lines

Bendamustine and cytosine arabinoside (ara-c) are commonly used cytotoxic agents with unique mechanisms of action. We have previously reported a striking additive cytotoxic effect of the consecutive combination of bendamustine and ara-c in mantle cell lymphoma (MCL) cell lines. In the present study, cell lines of follicular lymphoma (DOHH-2), chronic lymphocytic leukemia/lymphoma (EHEB), diffuse large B-cell lymphoma (SU-DHL-4), T-cell leukemia/lymphoma (JURKAT and KARPAS-299) and MCL (JEKO-1 and GRANTA-519) were exposed to the two single drugs or the drugs combined, given simultaneously and consecutively. Peripheral blood chronic lymphocytic leukemia (CLL) B-cells from five patients were also analyzed. Apoptosis, cell proliferation/metabolic activity and mitochondrial damage were evaluated. The combination index (CI) was used to assess synergy between the drugs. Bendamustine exhibited a relevant cytotoxic effect that was dose- and time-dependent, except for SU-DHL-4 and T-cell lymphoma cells. The addition of ara-c after bendamustine significantly potentiated the single-drug cytotoxic effect of bendamustine on all cell lines, including 17p − CLL B-cells, JURKAT and SU-DHL-4, the latter presenting the highest synergism (CI < 0.01). Bendamustine and ara-c are highly synergistic on T- and B-cell lymphoma cells and cell lines, similar to MCL, overcoming resistance to the single agents.

Effect of bendamustine on apoptosis and colony-initiating precursors in Hodgkin lymphoma cells.

e18559 Background: Hodgkin lymphoma (HL) recurring after stem cell transplantation is incurable and active agents are needed in this setting. Bendamustine is a bi-functional alkylator active in non-Hodgkin lymphoma. Activity of bendamustine towards tumor cells of HL has never been previously described. Methods: A panel of human cell lines (L1236, L428, KMH2, HDLM2, L540), validated models for HL, was studied. Cells were exposed to increasing concentrations of bendamustine (12.5 to 100 µmol/L) and analyzed for proliferation, apoptosis and cell cycle changes. Effect of bendamustine on HL clonogenic precursors was assessed by primary/secondary methylcellulose assays and colony cells characterization (CD30, aldehyde dehydrogenase [ALDH] or Hoechst [Hcst]-33342). Results: Bendamustine displayed a significant time- and dose-dependent antiproliferative effect on all HL cell lines, with an observed IC50 between 25-50 µmol/L at 48 hrs. In all lines, at least 50% of cells showed Annexin-V binding following 24 hrs of exposure to concentrations lower than 100 µmol/L, with 70% to 90% of apoptotic cells at longer times (48-72 hrs). Sensitivity to Bendamustine of HL cells was independent from the presence of p53 mutations. In all HL lines, exposure to a concentration as low as 25 µmol/L induced >50% of cells to accumulate in the G2/M phase of the cell cycle with presence of tetraploid nuclei witnessing mitotic defects. Finally, a 24 hr-exposure to very low concentrations (IC50: 17-38 µmol/L) of bendamustine was able to inhibit primary colony formation in all HL cell lines irrespective of p53 status. Intriguingly, a significantly lower concentration of the agent (IC50: 3.1-15.0 µmol/L) was able to suppress formation of secondary colonies, which were sustained, in L428 and KMH2 cells, by CD30+/ALDH)hi or Hcsthi precursor cells. Conclusions: Bendamustine displays marked antiproliferative and pro-apototic effects on cultured HL cells, irrespective of p53 status, by promoting G2/M arrest and changes compatible with mitotic catastrophe. HL colony-initiating precursors are highly sensitive to extremely low concentrations of the agent. Clinical testing of bendamustine in HL both as single agent and in combination is warranted.