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Bendamustine for the Treatment of Indolent Non-Hodgkins Lymphoma and Chronic Lymphocytic Leukemia
Guest Discussant: Robert G. Fenton, MD, PhD, Clinical Associate Professor, Clinical Research Committee Member, University of Maryland, Marlene and Stewart Greenbaum Cancer Center. Dr. Fenton reports no financial relationships relevant to this field of study.
Bendamustine was first synthesized in 1963 in East Germany, but its clinical development as an anti-neoplastic agent really began after the fall of the Iron Curtain. Bendamustine combines a mechlorethamine group, similar to other alkylating agents such as cytoxan and chlorambucil, with a benzimidazole ring, similar to some purine analogs such as 2-chlorodeoxyadenosine (although no evidence for an anti-metabolite function has been demonstrated). In-vitro experiments suggest that bendamustine induces more DNA adducts and strand breaks than other alkylating agents, and that DNA lesions are repaired with slower kinetics.1 In early clinical studies, non-cross resistance to bendamustine was observed in chlorambucil-resistant CLL and chemotherapy-refractory NHL2 and, during the past decade, bendamustine has demonstrated potent activity as a single agent, and in combination, for low-grade B-cell neoplasms. Some of the most relevant studies will be reviewed here.
Bendamustine in NHL
Single-agent bendamustine was tested in 100 heavily pretreated (median of two previous regimens), rituximab-refractory indolent NHL patients.3 The patients (ages 31-84) received bendamustine 120 mg/m2 day 1 and day 2 every 21 days for 6-8 cycles. The overall response rate (ORR) was 84%, with 29% CR and a progression-free survival (PFS) of 9.7 months. Toxicities were mainly myelosuppression, but also included fatigue, nausea, and xerostomia. This study led to FDA approval of bendamustine for second-line treatment of indolent NHL.
The striking activity of bendamustine as a single agent led to investigations of its activity in combination with rituximab. The German group treated 63 patients with relapsed or refractory low-grade NHL (58% with high risk FLIPI scores) with rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 day 2 and day 3 on a 28-day schedule.4 The median age was 63, and toxicities included 16% grade 3-4 neutropenia and grade 1 nausea in 102 or 136 cycles. The ORR to the BR regimen was 90%, with 60% CR. The subgroup of patients with mantle-cell lymphoma (MCL) had an ORR of 75%, with 50% CR. The median PFS for all patients was 24 months, and 18 months for the MCL group. These results prompted an identical confirmatory study in the United States. Sixty-six patients with a median age of 60 were treated with BR.5 The results were amazingly concordant with the German study, with an ORR of 92%, 55% CR, and a PFS of 23 months. Outcomes were similar for the indolent NHL and mantle-cell histologies. Toxicity was mainly hematologic (36% grade 3-4 neutropenia). The overall survival has not been reported for either study.
In a phase-II study of 54 patients with relapsed/refractory NHL and CLL (ages 40-83), mitoxantrone (10 mg/m2 day 2) was added to bendamustine (90 mg/m2 day 1 and day 2) and rituximab (375 mg/m2 on days 8, 15, 22, 29), followed by BM without rituximab for an additional five cycles.6 The ORR was 96%, with 41% CR and a PFS of 17 months in CLL and > 27 months in NHL (follicular lymphoma, mantle-cell lymphoma, and marginal zone lymphoma). While this BMR regimen is active, a randomized study would be required to determine if mitoxantrone adds anything to the BR regimen.
Unpublished data for bendamustine treatment of NHL
A German cooperative group study recently performed a randomized study of 513 patients randomized to R-CHOP or BR for the first-line treatment of MCL and follicular lymphoma (FL). The data strongly favor the BR regimen in PFS (55 months vs. 35 months), CR (40% vs. 30%). In FL, the PFS was 47 months for R-CHOP and has not yet been reached for BR. The BR regimen was associated with less alopecia, neupogen requirement, stomatitis, and sepsis, and was felt to potentially be an excellent treatment option for elderly patients with MCL.
Bortezomib has significant single-agent activity in MCL and some activity in FL. ECOG performed a phase-II study of bendamustine (90 mg/m2 days 1 and 2) with standard doses of bortezomib and rituximab (BVR regimen). The ORR was 80% and PFS at one year was 74%. The Vertical study treated 65 FL patients with BVR in which the bortezomib was administered once a week for four weeks (instead of the usual days 1, 4, 8, and 11 every 21-day schedule), on a 35-day treatment cycle. The ORR of evaluable patients is 85%. Note that as in MM, there appears to be significantly less peripheral neuropathy when bortezomib is used on a once-a-week schedule.
Important future trials will include a planned phase-III comparison of the very active FCR (fludarabine, cyclophosphamide, rituximab) regimen with BR in the first-line treatment of NHL patients. It will also be of great interest to determine the activity of BVR in MCL as compared to HyperCVAD +R with or without bortezomib. For elderly patients, the Ara-C/MTX cycles of HyperCVAD may be replaced with bortezomib to generate a regimen that can be tolerated by patients with co-morbid medical conditions. The ability to mobilize adequate stem cells for auto-transplant after bendamustine treatment, and the incidence of drug-induced myelodysplastic syndrome (MDS), remain to be fully explored.
Bendamustine in CLL
Two phase-I/II studies from Europe demonstrated promising activity of single-agent bendamustine in heavily pretreated and refractory CLL.7,8 The MTD was either 70 or 100 mg/m2 days 1 and 2, when given on a 3-4 week cycle. Response rates were approximately 50% with some CRs. Dose-limiting toxicities were myelosuppression and infection. Based on these data, the German CLL Study Group performed a prospective, multicenter, randomized trial of bendamustine (100 mg/m2 days 1 and 2) vs. oral chlorambucil (0.8 mg/kg on days 1 and 15, every 28 days) in 319 previously untreated CLL patients < 75 years of age.9 Bendamustine was more active, with a RR of 68% vs. 31% for chlorambucil (p = 0.0001) and improved PFS (21.6 vs. 8.3 months; p = 0.0001). Bendamustine induced more grade 3-4 neutropenia (23 vs. 10%) but was otherwise well tolerated. This study led to FDA approval of bendamustine for the first-line treatment of CLL. However, the choice of chlorambucil as the control arm does not conform to the modern use of fludarabine as the standard first-line therapy, which is also known to be significantly more active than chlorambucil.
The German CLL Study Group then added rituximab (375 mg/m2 cycle 1, increased to 500 mg/m2 on subsequent cycles) to bendamustine (70 mg/m2 days 1 and 2) given every 28 days for up to six cycles. One hundred seventeen patients were treated in this phase-II study, with a 90% RR that included 33% CRs. Seventy-five percent of patients were still in remission at 18 months.10 This group is now recruiting patients to a phase-III study (CLL10) comparing FCR with BR as a primary therapy for CLL.
In conclusion, bendamustine has demonstrated significant activity for the treatment of low-grade B-cell malignancies. Its future role in the treatment of FL, MCL, and CLL will await the results of ongoing phase-III studies comparing BR and BVR to more standard regimens in each disease. It appears likely that given its predictable toxicity profile and induction of durable remissions will render it an important agent for treating frail, elderly patients who are not candidates for more aggressive therapies.
1. Strumberg D, et al. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs. 1996;7: 415-421.
2. Rummel MJ, Mitrou PS, Hoelzer D. Bendamustine in the treatment of non-Hodgkin's lymphoma: Results and future perspectives. Semin Oncol. 2002;29:27-32.
3. Kahl BS, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010;116:106-114.
4. Rummel MJ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:3383-3389.
5. Robinson KS, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008;26:4473-4479.
6. Weide R, et al. High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group. Leuk Lymphoma. 2004;48:1299-1306.
7. Bergmann MA, et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica. 2005;90:1357-1364.
8. Lissitchkov T, et al. Phase I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukemia (Binet stages B and C) requiring therapy. J Cancer Res Clin Oncol. 2006;132:99-104.
9. Knauf WU, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously un