According to results presented at the 2004 annual meeting of the American Society of Hematology (ASH), an agent still in clinical trials referred to as BMS-354825 may help patients to overcome resistance to Gleevec® (imatinib) for the treatment of chronic myeloid leukemia (CML).
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, patients can develop a resistance to Gleevec®, a state in which their disease no longer responds to the drug. Researchers are evaluating ways in which to overcome this resistance and/or newer agents that may target the disease in a different way in efforts to improve survival for this group of patients.
Researchers from the University of California Los Angeles (UCLA) and the MD Anderson Cancer Center in Houston, Texas recently conducted an early clinical trial evaluating the agent BMS-354825 in patients with CML who were resistant to Gleevec®. BMS-354825 binds to the same target as Gleevec®, but physically in a different place. This trial included 36 patients with CML who had become resistant to Gleevec®. Following treatment with BMS-354825, disappearances of detectable cancer in the blood (hematologic remissions) occurred in 86% of patients. In addition, 45% of these patients experienced anti-cancer responses noticeable in chromosomes (cytogenetic resmission).
The researchers concluded that BMS-354825 produces significant anti-cancer responses in patients with CML who are resistant to Gleevec®. The researchers have begun enrollment in the next phase of clinical trials evaluating GMS-354825 and anticipate its use for patients resistant to Gleevec® or in addition to Gleevec® as initial therapy. Patients with CML who have become resistant to Gleevec® may wish to speak with their physician regarding participation in clinical trials further evaluating BMS-354825 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: Sawyers C, et al. Hematologic and cytogenetic responses in imatinib-resistance chronic myeloid leukemia patients treated with the dual kinase inhibitor BMS-354825: results from a phase I dose escalation study. Proceedings from the 2004 annual meeting of the American Society of Hematology. December 2004. Abstract#1.