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Brand name(s): TREANDA®

• Approved for B-cell non-Hodgkin lymphoma
• Approved for chronic lymphocytic leukemia

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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Glossary Terms

A type of drug that is used in the treatment of cancer. It interferes with the cell's DNA and inhibits cancer cell growth.

A condition in which the number of red blood cells is below normal.

An anticancer drug that belongs to the family of drugs called alkylating agents.

An indolent (slow-growing) cancer in which too many immature lymphocytes (white blood cells) are found mostly in the blood and bone marrow. Sometimes, in later stages of the disease, cancer cells are found in the lymph nodes and the disease is called small lymphocytic lymphoma. Also called CLL.

The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.

A virus that may be carried in an inactive state for life by healthy individuals. It is a cause of severe pneumonia in people with a suppressed immune system, such as those undergoing bone marrow transplantation or those with leukemia or lymphoma. Also called CMV.

In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

A condition marked by fever and a lower-than-normal number of neutrophils in the blood. A neutrophil is a type of white blood cell that helps fight infection. Having too few neutrophils increases the risk of infection.

Tissue in which new blood cells are formed.

In medicine, loss of blood from damaged blood vessels. A hemorrhage may be internal or external, and usually involves a lot of bleeding in a short time.

An exaggerated response by the immune system to a drug or other substance.

A type of cancer that grows slowly.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called IV.

A condition in which there is a lower-than-normal number of leukocytes (white blood cells) in the blood.

Disease or swelling of the lymph nodes.

A statistics term. The middle value in a set of measurements.

A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. When myelosuppression is severe, it is called myeloablation.

A condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell).

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

Cancer that is growing, spreading, or getting worse.

A type of chronic lymphocytic leukemia (CLL), in which too many immature white blood cells (prolymphocytes) are found in the blood and bone marrow. Prolymphocytic leukemia usually progresses more rapidly than classic CLL. Also called PLL.

A cell that carries oxygen to all parts of the body. Also called erythrocyte and RBC.

A monoclonal antibody used to treat certain types of B-cell non-Hodgkin lymphoma and symptoms of rheumatoid arthritis. Monoclonal antibodies are made in the laboratory and can bind to substances in the body, including cancer cells. Rituximab binds to the protein called CD20, which is found on B-cells, and may kill cancer cells. Also called Rituxan.

The presence of bacteria or their toxins in the blood or tissues.

A condition in which there is a lower-than-normal number of platelets in the blood. It may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues.

The infusion of components of blood or whole blood into the bloodstream. The blood may be donated from another person, or it may have been taken from the person earlier and stored until needed.