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Imatinib-resistant leukemia: AMN107 offers benefits in some forms

Researchers at The University of Texas M. D. Anderson Cancer Center found that AMN107 can produce dramatic benefits in patients with some forms of leukemia that are resistant to Imatinib ( Gleevec/Glivec).

At the 47th Annual Meeting of the American Society of Hematology ( ASH ), the investigators reported marked improvement in outcome in all three phases of chronic myeloid leukemia ( CML ) as well as benefit in treating a form of acute lymphocytic leukemia ( ALL ) that shares the same genetic abnormality as CML, the Philadelphia chromosome.

" This drug is very promising and appears at this point to offer an effective option for patients who do not achieve an optimal response to Gleevec therapy," says Hagop Kantarjian.

. If additional studies continue to show such results, Kantarjian says, he believes AMN107, which is taken in pill form, "will either replace Gleevec as the standard of care in the future or will be used in combination with it."

Both chronic myeloid leukemia and Philadelphia-positive acute lymphocytic leukemia is caused by the swapping of genetic material in bone marrow stem cells between two chromosomes, which produces an abnormality called the Philadelphia chromosome. This new gene then produces a novel tyrosine kinase ( Bcr-Abl ) that signals the abnormal cell growth that leads to development of leukemia.

While both Gleevec and AMN107 shut down the activity of Bcr-Abl, laboratory experiments with AMN107 show it is up to 50 times more potent because it binds more efficiently to the enzyme than does Gleevec.

In the phase I clinical trial being reported, 119 patients who were resistant to Gleevec were given AMN107, and in some cases the dose was increased up to twelve fold. The researchers found that the range of response varied, depending on the form of the cancer and the presence of genetic mutations.
For example, hematologic response from the drug ( defined as control of white blood cell counts ) ranged from 44 percent to 100 percent in different subgroups of chronic myeloid leukemia patients, and the more enduring cytogenetic response ( elimination of cells with the cancer-causing defect ) ranged from 22 percent to 100 percent.
There was less overall response in acute lymphocytic leukemia patients ( ranging from 10 percent to 33 percent, depending on extent of disease ).

Kantarjian notes that while some patients fared better than others with AMN107, these patients had little or no other treatment options available.

Source: University of Texas M. D. Anderson Cancer Center, 2005