Therapies Reduce Resistance to Gleevec®

Patients With Different Leukemia Types Benefit

Certain leukemia patients resistant to the drug imatinib mesylate (Gleevec) can overcome the setback with two more potent targeted therapies, according to new study results.

The therapies, known as BMS-354825 and AMN107, appear to be promising for patients with relapsed chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) associated with the "Philadelphia chromosome."

The findings, presented in December during the annual American Society of Hematology (ASH) meeting, involve two independent Phase I clinical trials (small studies that determine drug dosage) conducted by M. D. Anderson and two other institutions.

BMS-354825 shows remarkable activity

In the BMS-354825 trial, the drug was tested in all three phases of CML. Investigators found that of 29 patients in the chronic phase of CML, 89% experienced a complete "hematologic response" (control of white blood cell counts). The same response occurred in about one-third of the patients with advanced disease (accelerated phase and blastic crisis).

Researchers also found the drug capable of overcoming Gleevec resistance in the vast majority of cases with a mutation within the BCR-ABL gene, which causes CML. These mutations are the major cause for resistance to Gleevec, says Moshe Talpaz, M.D., a professor in the Department of Experimental Therapeutics at M. D. Anderson.

"This is a remarkably high response rate," says Talpaz, who is co-principal investigator on the trial with Charles Sawyers, M.D., professor of medicine at the University of California, Los Angeles School of Medicine. "The results suggest that we may be able to 'tailor' therapy according to the molecular profile of the disease."

Side effects of BMS-354825, which included reduced red and white blood cells and platelets, have been well tolerated.

AMN107 targets CML and Philadelphia-positive ALL

The second study showed that the oral targeted therapy, AMN107, can produce responses in patients with advanced Gleevec-resistant CML and Philadelphia-positive ALL.

The study has accrued 65 patients since opening last May. Even though an optimal dose has yet to be established as no significant toxicities have been encountered, more than 50% of patients with Gleevec-resistant CML have responded so far, says Francis Giles, M.D., professor of medicine in the Department of Leukemia at M. D. Anderson, who presented results of the study, conducted with the University of Frankfurt in Germany.

"While more study needs to be done to define a reasonable regimen for this drug, it has, so far, produced very important responses in patients who were desperately ill," Giles says.

Both drugs more potent than Gleevec

CML and Philadelphia-positive ALL are caused by the fusing of a piece of chromosome 9 containing part of the ABL gene with a piece of chromosome 22 containing part of the BCR gene. Together they form the cancer-causing gene BCR-ABL. Gleevec binds to this abnormal enzyme and shuts down its activity, often leading to the death of the leukemia cell.

AMN107 is up to 30 times more potent than Gleevec because it was designed to bind to the enzyme more efficiently, Giles says.

BMS-354825 has a dual action, which gives it a 300-fold greater potency to inhibit BCR-ABL, based on preclinical tests that compared it to Gleevec, Talpaz says.