Investigational Drug Shows Promise in Gleevec?-Resistent CML

Posted by rob on December 29, 2005 under Uncategorized | Be the First to Comment

The investigational drug AMN107 has produced treatment responses in some patients with chronic myeloid leukemia (CML) that does not respond to Gleevec? (imatinib mesylate), as well as in some patients with acute lymphoblastic leukemia (ALL) that is positive for the Philadelphia chromosome. These results were presented at the 47th annual meeting of the American Society of Hematology (ASH).

Chronic myeloid leukemia (CML), also called chronic granulocytic leukemia, is a cancer that originates in the immune cells. It affects approximately 4,600 people annually in the U.S. In the case of CML, large numbers of young immune cells 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 properly, leaving patients susceptible to infection.

Chronic myeloid leukemia begins with a chronic phase, during which few clinical problems, if any, occur. However, when left untreated, the chronic phase progresses into acute phases; these phases, called the accelerated and blastic phases, are characterized by fast-growing and aggressive cancer. 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 and side effects can both be substantial in patients undergoing an allogeneic stem cell transplant; researchers have thus 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 the constantly activated growth of cancer cells. Roughly 30% of adult patients with ALL also have this genetic abnormality.

Gleevec is a biological agent that binds to and slows or stops the uncontrolled growth of cancer cells with this genetic mutation. Unfortunately, a small number of patients who are treated with Gleevec do not achieve anticancer responses; researchers are evaluating novel agents for this group of patients.

AMN107 is an investigational drug that targets the same protein as Gleevec, but through a different mechanism. AMN107 is reported to be significantly more potent than Gleevec. To evaluate AMN107 in the treatment of Gleevec-resistant leukemia, researchers from the MD Anderson Cancer Center in Texas conducted a phase I clinical trial among 119 patients with Gleevec-resistant CML in chronic, accelerated, or blastic phases or Philadelphia chromosome-positive ALL.

Treatment with AMN107 was generally well tolerated and produced notable anticancer activity. Among patients with CML, the rate of cytogenetic response (reduction of genetically abnormal cells) ranged from 22% to 100%, and the rate of hematologic response (normalization of blood cell counts) ranged from 44% to 100%. Among patients with ALL, rate of hematologic response ranged from 10% to 33%.

The researchers concluded that AMN107 has significant activity in patients with Gleevec-resistant CML and possibly in some patients with ALL.

Reference: Kantarjian HM, Ottman O, Cortes J, et al. AMN107, a novel aminopyrine inhibitor of Bcr-Abl, has significant activity in imatinib-resistant chronic myeloid leukemia (CML) or Philadelphia-chromosome positive acute lymphoid leukemia (Ph+ALL). Blood . 2005;106:15a. Abstract # 37.

Investigational Drug Shows Promise in Gleevec?-Resistent CML