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Expanding the Scope of Bendamustine

Victorian, Brande

doi: 10.1097/01.COT.0000387943.77995.29

Approved by the FDA in 2008, bendamustine is still a relatively new therapy for patients with chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphoma (B-NHL). Given the positive results seen in patients receiving the agent, researchers have been looking at bendamustine’s applicability in other types of cancer and in combined regimens as well.

At the ASCO Annual Meeting, a number of publication-only abstracts looked at the use of bendamustine in B-cell lymphoproliferative disorders, relapsed or refractory B-cell non-Hodgkin lymphoma, and in combination with ionizing radiation. Although these studies are in their early stages, mostly Phase I with small numbers of patients, they provide a good glimpse into the potential indications for this drug in the future.

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B-Cell Lymphoproliferative Disorders

In lieu of the positive data that has been reported, researchers at the University of Virginia Health System wanted to compare outcomes at their institution with those reported by the medical community at large, said Jeanna Knoble, MD, a former fellow at the Division of Hematology-Oncology there, who coauthored the study with John Densmore, MD, of the University of Virginia, and Michael E. Williams of the University of Virginia Medical Center.

“We have a reasonable amount of experience at the University of Virginia and it really seems like bendamustine is gaining a lot of favor in oncology practice, so we thought it might be helpful for people to know a little bit more about the toxicity and about our experiences, given that it’s a new drug and a lot of people haven’t used it much before,” Dr. Knoble said in a telephone interview after the meeting.



A retrospective chart review was conducted on patients who received bendamustine for the treatment of a lymphoproliferative disorder, both on or off clinical trials (Abstract e18542). From September 2004 through July 2009, 30 patients, median age 68.5, received one to seven cycles of therapy. Four types of lymphoproliferative disorders were present: follicular lymphoma (14 patients) mantle cell lymphoma (MCL) (6), CLL/small lymphocytic lymphoma (SLL) (8), and diffuse large B-cell lymphoma (DLBCL) (2).

Bendamustine was used as a single agent in 11 patients and in combination with rituximab in the remaining 19 patients. All had received prior therapy, 28 with at least one rituximab-containing regimen. Dosing ranged from 60 to 120 mg/m2 on Days 1 and 2 of each three- or four-week cycle.

Patients’ overall response rate was 73%, with a complete response rate of 37%, and a partial response of 37% as well. By condition, overall response was 13% in patients with follicular lymphoma, 3% in MCL patients, 6% in CLL/SLL, and 2% in diffuse large B-cell. Median progression-free survival was 17 months.

The most commonly reported toxicity was nausea, and there were no treatment-related deaths. Despite a poorer response rate seen in patients with MCL, the results of the study correlated with previously reported findings, the authors concluded.

The inclusion of several different lymphoproliferative disorders is helpful for oncologists to see how patients with different diseases respond, Dr. Knoble said, although she acknowledged that the study didn’t include a very large number of patients.

“Bendamustine is a good drug to think about in terms of patients tolerating it well and having a meaningful response. Often in patients who are difficult to treat in the refractory setting, you have limited options that don’t have a lot of toxicity, so this is a good drug in that situation and this study showed that in a variety of clinical settings.”

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What About Relapsed/Refractory B-NHL?

Although good data exist concerning the use of bendamustine with or without rituximab in indolent B-cell NHL, there is a lag of evidence in relapsed or refractory aggressive B-NHL, according to the authors of a multicenter Phase I study assessing toxicity in this population (Abstract e18540).

Included in the study led by Masafumi Taniwaki, MD, of Kyoto Prefectural University of Medicine, were nine patients with relapsed or refractory diffuse large B-cell lymphoma (5 patients), mantle cell lymphoma (2), and transformed lymphoma (2) after one or two prior regimens, excluding high-dose therapy.

JEANNA KNOBLE, MD: “Often in patients who are difficult to treat in the refractory setting, you have limited options that don’t have a lot of toxicity, so bendamustine is a good drug in that situation, and this study showed that in a variety of clinical settings

JEANNA KNOBLE, MD: “Often in patients who are difficult to treat in the refractory setting, you have limited options that don’t have a lot of toxicity, so bendamustine is a good drug in that situation, and this study showed that in a variety of clinical settings

All patients (median age 65) received rituximab (375 mg/m2) and bendamustine on Days 1, 2, and 3, of each 21-day cycle for up to six cycles. Three DLBCL patients received bendamustine at a dose of 90 mg/m2, while the remaining six patients received a dose of 120 mg/m2. The median age of the patients was 65.

Bendamustine was well tolerated. No dose-limiting toxicity was observed with either treatment dose, and the most frequent toxicities were Grade 3/4 lymphopenia, which all patients experienced, and Grade 1-3 leukopenia (89%).

The overall response rate was 78% (seven of nine patients), and the complete response was 49% (four out of nine patients). Based on these results, the authors are planning to continue their research with a Phase II study.

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Newly Diagnosed CLL Patients

To look at current treatment patters among patients with newly diagnosed CLL, Gregory P. Hess, MD, MBA, and fellow colleagues at SDI Health in Plymouth Meeting, PA, assessed health care claims from their patients who were diagnosed with CLL between 2004 and 2007 and who were age 18 or older with two years of follow-up data (Abstract e16561).

“America is aging and there’s an increase in the prevalence of many cancers and there’s been a lot of advances in cancer therapy, which is great, but we’re also seeing rapid changes in practice patterns, so we wanted to use recent data to, again, see what those patterns were for this disease,” Dr. Hess said in a telephone interview.

A total of 9,136 patients were included in the descriptive study. The majority of patients were older than 70 (54%); male (52%); Caucasian (85%); Medicare insured (51.3%); had a median income of $62,500; and had a non-cancer Charlson Comorbidity Index less than one (93.5%).

Patients were classified into four groups: no treatment, chemotherapy only, rituximab only, and rituximab plus chemotherapy.

Among those treated, 66.7% received chemotherapy, 13.4% rituximab only, and 19% rituximab plus chemotherapy. The rituximab-only group had the highest percentage of patients over age 70 (49% vs 27% for rituximab plus chemotherapy, and 40% for chemotherapy alone). Patients over 65 were less likely to receive oncologic treatment in the first year (70%).

The median time from prognosis to frontline treatment was 153 days for the chemotherapy-only group, and 102 days for the rituximab group. Compared with the situation for frontline CLL, those who relapsed and received second-line treatment (120 patients) received relatively more rituximab and rituximab plus chemotherapy than chemotherapy alone (52.5% vs 46%).

“This study confirms that a large proportion of patients still have watchful waiting, meaning that they don’t necessarily need or receive active therapy. In the second case, it shows some interesting results for the combination of chemotherapy plus monoclonal antibodies, in this case rituximab,” Dr. Hess said.

In a two-year retrospective cohort analysis of CLL patients, approximately 6.7% received systemic therapy. Among them, chemotherapy was the most common frontline regimen, and rituximab and rituximab combined with chemotherapy were the most common regimens for patients with relapsed disease.

“We saw some early signals where there may be improved outcomes for those patients receiving chemotherapy plus monoclonal antibody therapy, so the next step would be to test and confirm those outcomes once we’ve adjusted for potential confounders,” Dr. Hess said.

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Potential in Fractionated Stereotactic Radiotherapy

Charting unmarked territory, an abstract (TPS146) from the Trials in Progress poster session (OT 7/10/10) shared details of a planned study looking at bendamustine and fractionated stereotactic radiotherapy in patients with one to three untreated brain metastases.

Because bendamustine is a multifunctional alkylating agent, its mechanisms of action make it likely to function as a radiosensitizer, making it potentially useful in combination with ionizing radiation, noted the authors, led by John C. Grecula, MD, Associate Professor in the College of Medicine at Ohio State University Comprehensive Cancer Center. The single-arm Phase I study funded by the National Comprehensive Cancer Network will determine the toxicity of combination therapy with the two agents with the primary endpoint of establishing a recommended Phase II dose of bendamustine.

Eligible patients will undergo treatment with bendamustine (40 mg/m2) on Days 1, 2, and 3, and surgical resection of brain metastases on Day 3 as well. In patients undergoing surgery, plasma for bendamustine pharmacokinetics will be obtained on either Day 1 or 2 prior to, during, and up to two hours after bendamustine infusion.

Fractionated stereotactic radiotherapy will start within four weeks after surgery and on Day 1 if patients are not undergoing surgery. Bendamustine will be administered 90 minutes prior to daily fractionated stereotactic radiotherapy. Patients will be escalated utilizing a Phase I design, starting at 40 mg/m2 for five days, with six to 18 patients expected to be studied.

Although contacted for an interview, Dr. Grecula was unable to release details of the forthcoming trial. At the time the abstract was accepted, two patients had been accrued.

© 2010 Lippincott Williams & Wilkins, Inc.
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