Bendamustine-Rituximab as First-line Treatment for NHL Patients Over the Age of 80 Years

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Fourteen elderly patients (median age 85 years) who were considered non-candidates for R-CHOP were treated first-line with a combination of bendamustine and rituximab. Of these, 7 achieved a complete response and 2 achieved a partial response. Toxicity was minimal. Although promising, these results need to be confirmed in larger studies.

Source: Weidmann E, et al. Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. Ann Oncol 2011;22:1839-1844.

Although R-CHOP (rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone) is considered highly effective chemotherapy for patients with aggressive non-Hodgkin's lymphoma (NHL) even in older patients,1 its use among very old patients is often withheld because of existing comorbidities or organ dysfunction. Acknowledging that lymphoma occurs with increasing frequency with each advancing decade, there is a need to develop other, potentially less toxic chemotherapy combinations for this population. In this regard, bendamustine is an excellent candidate. This drug, initially synthesized five decades ago has reemerged over the past decade2 and is now approved for use in the United States for patients with NHL. The authors were among the first to use the drug in patients with aggressive NHL. In a Phase 2 study they demonstrated an overall response rate of 44% in 18 patients with refractory disease, a few of whom had long-lasting remissions.3 Subsequently, when used in combination with rituximab, it was shown to be both highly effective and well tolerated in patients with relapsed or refractory disease.4,5 Because of the toxicity profile, the combination was considered particularly suitable for lymphoma treatment in frail, elderly patients. The current report reflects the first trial of rituximab with bendamustine for initial treatment of aggressive NHL and it was focused on patients older than age 80 years who were not considered candidates for R-CHOP.

This Phase 2 trial was conducted in Frankfurt, Germany. Enrollment was slow and although projected to include 30 patients, only 14 were entered onto study during the 26-month enrollment period (April 2004-June 2006). The median patient age was 85 years (range 80-95 years) and the age-adjusted international prognostic index was 0 in five patients, 1 in three patients, and 2 in six patients. Thirteen patients were assessable for response. Seven patients (54%) had a complete response, two (15%) a partial response, and four (31%) progressive disease. The median overall survival was 7.7 months, and the median progression-free survival 7.7 months. Six patients (43%) were alive without disease at 20–72 months from the start of treatment. Major toxicity was neutropenia (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11%. There were no life-threatening infections. G-CSF was not used as primary prophylaxis and only two patients received G-CSF as secondary prophylaxis. There was no grade 4 non-hematologic toxicity and minimal grade 3 non-hematologic toxicity observed. Two patients exhibited grade 3 renal toxicity and three patients experienced fatigue. One patient had what is described as a psychotic episode and he was withdrawn from study, although his data were included in the survival analysis. Alopecia was not observed. There was no treatment-related mortality. Although there were no dose reductions, treatment was delayed (6 to 33 days) in approximately one-third of all treatment cycles.

Commentary

Bendamustine is an interesting drug. Considered an alkylating agent because of its nitrogen mustard moiety, the drug also contains a purine-like ring,2 perhaps explaining some of its more protean effects. In vitro studies have demonstrated rapid DNA cross-linking and strand breaks6 as well as inhibition of mitotic check points.7 By virtue of these effects, the drug appears not to be cross-resistant with other alkylators.7 Furthermore, the low toxicity and its demonstrable synergy with rituximab are appealing, particularly for elderly patients, or for those who are otherwise not candidates for R-CHOP.

The current study is an important advance, but certainly insufficient for general recommendation. First, it is a single institution's experience and with disappointingly low enrollment. This, no doubt, reflects the difficulty with recruiting elderly patients for study, a phenomenon that the community of clinical investigators needs to overcome in light of the increasing numbers of older patients for which trial-derived treatment standards are sorely needed. Second, randomized studies in which this combination is compared with alternatives, such as CVP (cyclophosphamide, vincristine, and prednisone) for patients who are not candidates for R-CHOP is called for. In this light, Italian investigators are exploring a novel combination of mitoxantrone, etoposide, prednisone, bleomycin, and vincristine with preliminary results among patients over the age of 80 years comparable to that observed with bendamustine-rituximab, although perhaps with somewhat greater toxicity. A comparison of these two regimens in a randomized trial would seem a logical next step to address this important question of how to treat aggressive NHL in patients over the age of 80 years.

References

1. Coiffier B, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242.

2. Cheson BD, Rummel MJ. Bendamustine: Rebirth of an old drug. J Clin Oncol 2009;27:1492-1501.

3. Weidmann E, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol 2002;13:1285-1289.

4. 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.

5. 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.

6. Strumberg D, et al. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 1996;7: 415-421.

7. Leoni LM, et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 2008;14:309-317.