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AMN107 May Benefit Leukemia Patients Resistant to Gleevec: Presented at ASH

By Mike Fillon

ATLANTA, GA -- December 12, 2005 -- The targeted agent AMN107 may be beneficial for some leukemia patients who are resistant to Gleevec (imatinib mesylate), according to a study presented here at the 47^th Annual Meeting of the American Society of Hematology (ASH).

Specifically, the researchers found significant improvement in outcome in all 3 phases of chronic myeloid leukemia (CML) in addition to a form of acute lymphocytic leukemia (ALL) that has the same genetic abnormality as CML, known as the Philadelphia chromosome.

AMN107 is an investigational oral compound that inhibits the activity of specific proteins, including BCR-ABL and 32 of 33 mutant forms of protein responsible for the development of CML. It is 10- to 50-fold more potent than imatinib against BCR-ABL-expressing cell lines, including most imatinib-resistant BCR-ABL mutants, according to Hagop M. Kantarjian, MD, chairman of the leukemia department and professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, Texas.

Most cases of CML have leukemic cells that share a chromosome abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body, Dr. Kantarjian said. This abnormality is a reciprocal translocation between 1 chromosome 9 and 1 chromosome 22 that is designated t(9;22). It results in 1 chromosome 9 longer than normal and 1 chromosome 22 shorter than normal. The latter is called the Philadelphia chromosome and designated Ph1.

Dr. Kantarjian and colleagues at the University of Texas MD Anderson Cancer Center and the University of Frankfurt, Frankfurt, Germany, conducted at study of 119 patients with imatinib-resistant CML in blast crisis (BC), AP, CP, or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were treated with AMN107. He presented the results in a presentation on December 10^th.

Initial daily doses of AMN107 ranged from 50 mg QD to 1200 mg QD, and 400 mg BID to 600 mg BID. Dose escalations occurred in 48 of the 69 patients in the once-daily groups, and one patient in the 400 mg BID group escalated to 600 mg BID.

As of June 15, 2005, patients had been treated for a median of 120 days. AMN107 was well tolerated, and the most common drug-related adverse events were constipation, nausea, and vomiting.

Among CML patients who harbored a BCR-ABL mutation prior to treatment, 60% achieved a hematologic response and 41% achieved a cytogenetic response. In addition, 72% of CML patients who had no BCR-ABL mutation prior to taking AMN107 achieved a hematologic response, and 59% achieved a cytogenetic response. Ph+ ALL patients who harbored a mutation prior to treatment with AMN107 achieved a 33% response rate.

"AMN107 was shown to have significant activity in patients with advanced imatinib-resistant CML and Philadelphia chromosome-positive acute lymphoblastic leukemia," Dr. Kantarjian said.

While some patients fared better than others when treated with AMN107, those patients had few if any treatment options available, he said. "Current therapies, though effective, still have many limitations, and new treatment options with proven safety and efficacy can only benefit this patient population."

Study funding was provided by Novartis. Dr. Kantarjian has received funding support from Novartis.


[Presentation title: AMN107, a Novel Aminopyrimidine Inhibitor of BCR-ABL, Has Significant Activity in Imatinib-Resistant Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoid Leukemia (Ph + ALL). Abstract 37]

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