According to results presented at the 2005 International World Congress on chronic lymphocytic leukemia (CLL), the addition of Genasense® (oblimersen sodium) to chemotherapy reduces the risk of cancer progression in patients with relapsed or refractory CLL more than chemotherapy alone.
CLL is a cancer involving the lymph (immune) system, which includes lymph nodes, blood and blood vessels found throughout the body, the spleen, thymus, and tonsils. High quantities of this cancer are present throughout circulating blood and in bone marrow (spongy material inside large bones that produces blood-forming cells). CLL is the most common form of adult leukemia, and the American Cancer Society estimates that approximately 8,000 people will be diagnosed with CLL this year. Currently, there are approximately 60,000 people in the US living with CLL.
CLL is characterized by the production of atypical lymphocytes. Lymphocytes are specialized immune cells that exist in two forms: B- and T-cells. These cells are produced in the bone marrow and each serves a specific function in fighting infection. The large majority of CLL cases involve mature B-lymphocytes that tend to live much longer than normal, accumulating in the blood, bone marrow, lymph nodes, and spleen. This results in overcrowding of these areas and suppression of the formation and function of blood and immune cells. Additionally, the cancerous lymphocytes themselves do not function normally, leading to a further decrease in the body’s ability to fight infection.
CLL is considered a slow-growing or low-grade cancer. Treatment for CLL may include chemotherapy (often including the agent Fludara), radiation therapy, biological therapy, and/or stem cell transplantation. Treatment options are limited for patients who have received several prior therapies (a condition referred to as “relapsed”) or have stopped responding to standard therapies (a condition referred to as “refractory”).
One mechanism that makes cancer cells resistant to chemotherapy is Bcl2 expression. This occurs in refractory patients. Bcl2 is a protein that exists in delicate balance with other related proteins. Its function is to prevent cells from apoptosis (death). It is not entirely understood how Bcl2 proteins protect cancer cells from the lethal effects of chemotherapy. It is known, however, that various types of cancer, including CLL, are associated with high levels of Bcl2 proteins.
Genasense inhibits the production of Bcl2 protein by binding to the specific molecules that are responsible its production. This binding action stops production of Bcl2 proteins within a cell, making the cell sensitive to chemotherapy agents again. Previous studies have demonstrated that Genasense amplifies the cytotoxicity (ability to kill cancer cells) of many chemotherapy agents for a variety of different blood cancers.
A recent phase III trial was conducted to evaluate the addition of Genasense to chemotherapy in the treatment of CLL. This trial included 241 patients with relapsed or refractory CLL; approximately half was treated with the chemotherapy agents Fludara® (fludarabine) and Cytoxan® (Cyclophosphamide), while the other half was treated with the same chemotherapy combination plus Genasense.
Regression of cancer occurred in 17% of patients treated with Genasense compared with only 7% of patients treated with chemotherapy alone. Anticancer responses lasted for an average of approximately 22 months in the group of patients treated with chemotherapy only; this duration has not yet been reached in the group of patients treated with Genasense. To date, only 25% of the patients treated with Genasense who achieved anti-cancer responses have experienced a cancer relapse, compared with three-times that amount (75%) of the patients who had anticancer responses with only chemotherapy. Genasense was generally well tolerated. The most common severe side effects were low levels of platelets, nausea, and complications at the site of catheter insertion.
The researchers concluded that, by re-sensitizing the cancer cells to the killing effects of chemotherapy, the addition of Genasense to the chemotherapy combination Fludara plus Cytoxan appears promising in the treatment of relapsed or refractory CLL. Since these results are from the last phase of clinical trials prior to FDA review, a New Drug Application for accelerated approval has recently been initiated for Genasense.
Reference: Genta Incorporated. Data from Phase 3 Trial of Genasense® Confirm Extended Durability of Remission and Benefit in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Available at: http://www.genta.com/Genta/InvestorRelation/2005/press_20050919.html. Accessed September 2005.