According to results presented at the 2004 annual meeting of the American Society of Hematology, the targeted agent tipifarnib (Zarnestra™) produces anti-cancer responses and may improve survival in elderly patients who cannot tolerate standard treatment for acute myeloid leukemia.
Acute myeloid leukemia (AML) is a cancer of the bone marrow and blood characterized by the uncontrolled growth of immature white blood cells (immune cells), which never develop into functioning cells. Besides not being able to carry out the functions of mature immune cells, AML cells may also crowd out normal blood cells in the bone marrow and blood. AML is considered to be an aggressive cancer and patients are often at a high risk of developing a cancer recurrence following therapy, particularly if they are not able to undergo high doses of therapy. Chromosomal variables of AML cells, as well as levels of cancer cells in the blood, further distinguish patients into being at a high-risk, standard-risk or low-risk of developing a cancer recurrence, and treatment may be altered according to these stratifications. Patients with AML that has stopped responding to standard therapies (refractory) or elderly patients who are not able to tolerate standard chemotherapeutic approaches are left with limited treatment options.
Tipifarnib is an agent that is classified as a farnesyl transferase inhibitor and is still in clinical trials. It is estimated that approximately 30% of leukemias have a mutated ras gene. The ras gene is a part of a biological pathway that transmits growth signals from the surface of a cell to within a cell. Normally, this growth pathway is under strict control. However, a mutation (alteration) within the ras gene can stimulate a cell to grow and replicate in an uncontrolled manner. Additionally, ras mutations have been implicated in suppressing another important growth regulatory pathway controlled by the p53 gene. The p53 gene is responsible for the suppression of cellular replication when a cell perceives a genetic mutation, such as in the development of cancer. Tipifarnib has been designed to block a key enzyme (protein), called farnesyl transferase, which is involved in the mutated ras pathway. This slows down or stops the excessive replication of cancer cells caused by the mutated ras pathway. It is speculated that tipifarnib may create anti-cancer effects through other biological pathways as well.
A multi-institutional clinical trial was recently conducted to evaluate tipifarnib in the treatment of elderly patients with AML. This trial included 170 elderly patients, with an average age of approximately 73 years, who had not received prior therapy. The patients either could not tolerate standard chemotherapy or refused treatment with chemotherapy and were treated with tipifarnib orally, on an outpatient basis. Anti-cancer responses following tipifarnib were achieved in 34% of patients and 18% of patients achieved a complete disappearance of cancer (complete response). The average duration of a complete response was 6.4 months. Patients who achieved a complete response had an average duration of survival of 14.4 months, with 63% of these patients alive at 12 months. The average duration of survival for patients who did not achieve an anti-cancer response with tipifarnib was 3.1 months. Tipifarnib was generally well tolerated, with the most common serious non-hematologic (blood) related side effects being infection and gastrointestinal complications. Eighteen percent of patients were hospitalized due to side effects caused by tipifarnib and the death rate associated with treatment with tipifarnib was 5%.
The researchers concluded that tipifarnib produces anti-cancer responses and improves survival in patients who achieve a response to treatment in elderly patients with AML who are not eligible for treatment with chemotherapy. Future clinical trials are planned to evaluate tipifarnib in order to help define the potential clinical role of tipifarnib in this patient population, as well as other patients with AML. Patients who have been diagnosed with AML and are not candidates for chemotherapy may wish to speak with their physician about the risks and benefits of participation in a clinical trial further evaluating tipifarnib or other novel therapeutic strategies. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (cancer.gov) and www.cancerconsultants.com. Personalized clinical trial searches are also performed on behalf of patients at cancerconsultants.com.
Reference: Lancet J, Gotlib J, Gojo I, et al. Tipifarnib (ZARNESTRA™) in Previously Untreated Poor-Risk AML of the Elderly: Updated Results of a Multicenter Phase 2 Trial. Proceedings from the 2004 annual meeting of the American Society of Hematology. December, 2004. Abstract # 874.
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