According to results recently presented at the 2005 annual meeting of the American Association of Cancer Research (AACR), the targeted agent AMN107 provides anti-cancer responses in patients with chronic myeloid leukemia (CML) who do not respond to Gleevec® (imatinib mesylate).
Chronic myeloid leukemia (CML), also called chronic granulocytic leukemia, is a cancer of the white blood cells. It affects approximately 4,600 people annually in the United States. The bone marrow contains early blood-forming cells called stem cells, which grow and mature into 3 blood cell types: red blood cells, which provide oxygen to tissues; platelets, which aid in blood clotting; and white blood cells, which fight infection. In the case of CML, large numbers of young granulocytes (a type of white blood cell) do not mature, resulting in an excess accumulation of these cells. These leukemia cells then crowd the bone marrow and blood, suppressing formation and function of other blood cells normally present in these areas. In addition, the leukemia cells cannot perform their function in the body properly, leaving patients susceptible to infection.
Chronic myeloid leukemia begins with a chronic phase, during which few clinical problems, if any, occur. However, if left untreated, the chronic phase progresses into acute phases characterized by fast-growing and aggressive cancer. These phases are called the accelerated and blastic phases. Patients reaching these acute phases have a poor prognosis for long-term survival. Historically, the only curative option for patients with CML was an allogeneic stem cell transplant. However, treatment-related mortality, as well as side effects, can be substantial in patients undergoing an allogeneic stem cell transplant, so researchers have focused efforts on curative treatment options that are more easily tolerated.
Philadelphia chromosome-positive CML refers to the majority of cases of CML in which a genetic abnormality, referred to as the Philadelphia chromosome, results in constantly activated growth of cancer cells. Gleevec® is a biological agent that binds to and slows or stops the uncontrolled growth of the cancer cells with this genetic mutation. In addition, Gleevec® has activity in several biological pathways implicated in the development and/or expression of cancer. Gleevec® is approved by the FDA for the treatment of adult and pediatric patients with CML and has become a standard treatment option. Unfortunately, a small number of patients who are treated with Gleevec® do not achieve anti-cancer responses, and researchers are evaluating novel agents for this group of patients.
AMN107 is an agent that targets the same mutation in Philadelphia-chromosome positive patients; however, the way in which AMN107 binds to its target differs from Gleevec®. Researchers from the MD Anderson Cancer Center recently initiated a clinical trial evaluating AMN107 in patients with CML. This trial is ongoing, but interim results have been presented. This trial included 100 patients who did not respond to Gleevec® and were treated with AMN107. Over 90% of patients with chronic-phase CML achieved a hematologic response, meaning their blood cell levels have returned to normal, and over 70% of patients with accelerated or blast-phase CML have achieved a hematologic response.
The researchers concluded that AMN107 may provide significant anti-cancer activity in patients with CML who do not respond to Gleevec®. However, longer follow-up is needed to determine how hematologic response rates translate into survival data, and future clinical trials are necessary to determine the potential role of AMN107 in the clinical setting. Patients with CML that is not responding to Gleevec® may wish to speak with their physician regarding their individual risks and benefits of participating in a clinical trial evaluating AMN107 or other novel therapeutic approaches. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (cancer.gov) and www.cancerconsultants.com.
Reference: Giles F, et al. AMN107 Rescues Gleevec-Resistant Patients in Clinical Trial Conducted by Researchers at UT M. D. Anderson. Proceedings from the 2005 annual meeting of the American Association of Cancer Research. Anaheim, CA. Presented Tuesday, April 19, 2005. Abstract #3971.