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FDA Approval for Bendamustine Hydrochloride

Brand name(s): TREANDA®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

 

B-Cell Non-Hodgkin Lymphoma

On October 31, 2008, the U.S. Food and Drug Administration (FDA) approved bendamustine hydrochloride (TREANDA®, Cephalon, Inc.), an intravenously administered alkylating agent, for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Bendamustine hydrochloride was evaluated in a single arm trial of 100 patients with indolent B-cell NHL. All patients had disease progression during or within six months of treatment with rituximab or a rituximab-containing regimen. Bendamustine hydrochloride was administered intravenously at a dose of 120 mg/m2 infused over 60 minutes on days 1 and 2 of a 21-day treatment cycle for up to eight cycles.

Efficacy was assessed by a blinded independent review committee using the modified International Working Group response criteria for NHL. The efficacy endpoints included overall response rate (complete responses, complete responses unconfirmed, or partial responses) and durations of response (DR).

ORR and median DR were 74 percent (95 percent CI 64.3, 82.3) and 9.2 months (95 percent CI 7.1, 10.8), respectively. Complete responses were reported in 13 percent, complete responses unconfirmed in 4 percent, and partial responses in 57 percent of patients treated.

The safety of bendamustine hydrochloride was evaluated in the above study and an additional study. A total of 176 patients with B-cell NHL who had received prior rituximab (161 patients with indolent lymphoma and 15 with transformed NHL) were evaluated for safety.

The most frequently reported non-hematologic adverse reactions reported were nausea (75 percent), fatigue (57 percent), vomiting (40 percent), diarrhea (37 percent) and pyrexia (34 percent). The most frequently reported abnormal hematologic laboratory values were lymphopenia (99 percent), leukopenia (94 percent), anemia (88 percent), neutropenia (86 percent), and thrombocytopenia (86 percent).

Grade 3 or 4 adverse reactions were reported in 71 percent of the combined safety population. The most frequently reported non-hematologic grade 3 or 4 adverse reactions were fatigue (11 percent), febrile neutropenia (6 percent), and pneumonia, hypokalemia and dehydration (each reported in 5 percent of patients).

The most frequently reported grade 3 or 4 hematologic laboratory abnormalities were lymphocytopenia (94 percent), neutropenia (60 percent), leukopenia (56 percent), thrombocytopenia (25 percent), and anemia (11 percent). Three patients died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with grade 3 thrombocytopenia, and pneumonia from a cytomegalovirus infection.

For patients with indolent NHL, bendamustine hydrochloride is administered as a 60 minute IV infusion on days 1 and 2 of a 21-day cycle for up to eight cycles. The recommended dose is 120 mg/m2.

This dose, infusion duration, and cycle length of bendamustine hydrochloride is different from that approved dosing regimen for the chronic lymphocytic leukemia (CLL) indication (see below). For patients with CLL, bendamustine hydrochloride is administered as a 30 minute IV infusion on days 1 and 2 of a 28-day cycle for up to six cycles. The recommended dose for the CLL indication is 100 mg/m2.

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Chronic Lymphocytic Leukemia

On March 20, 2008, the FDA approved bendamustine hydrochloride (TREANDA, Cephalon, Inc.), an intravenously administered alkylating agent, for the treatment of patients with chronic lymphocytic leukemia (CLL).

The safety and efficacy of bendamustine were evaluated in a randomized, controlled, multicenter trial comparing bendamustine to chlorambucil as first-line treatment for CLL patients. The trial was conducted in 301 patients (153 on bendamustine and 148 on chlorambucil) with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms (such as weight loss of 10 percent or more, drenching night sweats, extreme fatigue, or unexplained fever of 100.5 degrees Farenheit or higher), rapidly progressive disease, or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukemia were excluded. Patients were randomly assigned to receive either bendamustine, 100 mg/m2 intravenously on days 1 and 2 every 28 days, or to receive chlorambucil, 0.8mg/kg/day orally on days 1 and 15 every 28 days. Up to 6 cycles were administered to each patient.

The efficacy analyses were based on National Cancer Institute-Sponsored Working Group criteria. The overall response rate was 59 percent for bendamustine versus 26 percent for chlorambucil (p < 0.0001) with 8 percent versus < 1 percent complete responses on the bendamustine and chlorambucil arms, respectively. The median progression-free survival was 18 months for bendamustine versus 6 months for chlorambucil (hazard ratio = 0.27: 95 percent Confidence Interval = 0.17 - 0.43; p < 0.0001). Survival data are not mature.

Patients treated with bendamustine had a higher incidence of adverse reactions (89 percent) than those treated with chlorambucil (79 percent). The most common adverse reactions (approximately 15 percent) were neutropenia, pyrexia, thrombocytopenia, nausea, anemia, leucopenia, and vomiting. Neutropenic fever was more common in the bendamustine group compared to the chlorambucil group. Red blood cell transfusions were administered to 20 percent of the bendamustine-treated patients compared to 6 percent of those receiving chlorambucil. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine were hypersensitivity and pyrexia. The number of deaths during the treatment period was similar in both treatment arms.

The recommended dose of bendamustine is 100 mg/m2 administered intravenously over 30 minutes on days 1 and 2 of a 28-day cycle, up to six cycles.

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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 1, 2013