Nilotinib ( AMN107 ) appears to offer striking benefits in patients with chronic myelogenous leukemia ( CML ) who are resistant to Imatinib ( Gleevec/Glivec ), the standard therapy for this cancer, according to researchers at The University of Texas M. D. Anderson Cancer Center.

Results of a 119-patient, phase I dose-escalation study, published in The New England Journal of Medicine ( NEJM ), show that Nilotinib offers a relatively favorable safety profile and obvious activity, researchers say, even though the study was not designed to measure the agent's effectiveness.

Nilotinib is a tyrosine kinase inhibitor like Imatinib, both of which were developed by Novartis.
Preclinical studies have shown that Nilotinib, which is administered in pill form, is up to 50 times more potent than Imatinib because it was designed to more efficiently bind to, and shut down, the protein enzyme responsible for the disease.

While Kantarjian notes that Nilotinib seems to have fewer side effects than Imatinib, which is considered a safe drug, some patients in this trial were found to have abnormal electrical activity in their hearts, and one patient experienced two cardiac events. " We believe this issue is manageable with the right dose of Nilotinib and with careful monitoring, but of course we want to test the agent further to make sure it is 100 percent safe," he says.

" Imatinib should remain the standard of care," Kantarjian says. " For chronic myelogenous leukemia patients who respond to Imatinib, and most of them do, 93 percent are doing well five years after treatment."

The study, which included researchers and patients from M. D. Anderson, the University of Frankfurt and Heidelberg University in Germany, and the H. Lee Moffitt Cancer Center, tested Nilotinib in Imatinib-resistant patients who had little or no other treatment options available to them.

The participants had either chronic myelogenous leukemia or Philadelphia-positive acute lymphocytic leukemia ( ALL ). These diseases are caused by the swapping of genetic material in bone marrow stem cells, which results in an abnormality called the Philadelphia chromosome, and creation of a new gene. This gene produces the fusion protein, BCR-ABL, which leads to development of leukemia.
Imatinib and Nilotinib both bind to, and inactivate, BCR-ABL.

In the trial, researchers continually increased the dose of Nilotinib from a low of 50 mg. to as much as 1,200 mg. daily in some patients.

Nilotinib improved outcomes in all three forms of chronic myelogenous leukemia, and was most effective in treating chronic phase chronic myelogenous leukemia, Kantarjian says. Of the 12 patients in this category, 11 had a complete hematological remission of their cancer, meaning a disappearance of all findings consistent with advanced stage chronic myelogenous leukemia, and return of blood counts to normal.

A total of 13 of 33 patients in the blastic phase of the disease disease – the most advanced stage – had a hematological response ( defined as control of white blood cell counts ), and 9 had a cytogenetic response ( elimination of cells with the cancer-causing defect ). Of 46 patients in the accelerated phase, 33 had a hematological response and 22 had a cytogenetic response.

The drug had less activity than expected in patients with acute lymphocytic leukemia. Only 2 of 13 patients responded, and that may be because the cancer was too advanced to be affected by a single drug, Kantarjian said.

The researchers also found that Nilotinib's side effects were quite tolerable, and different than those seen with Imatinib. They included myelosuppression, transient increases in bilirubin due to breakdown of red blood cells, and skin rashes.

Kantarjian adds that occasional patients experienced an abnormally long QTcF interval, a measurement of the time between the onset and the end of electrical activity in the heart's ventricular chamber. Prolongation of this interval is considered a marker of a cardiac arrhythmia. One patient had two adverse cardiac events that were associated with use of Nilotinib, and one sudden death was reported in a patient beyond the follow-up time analysis, he says, but the cause of that death is unknown.

" This finding indicates the need for careful monitoring for cardiac events and arrhythmias in all patients who are receiving Nilotinib, and a strict avoidance of medications that may prolong the QTcF interval," the researchers write.

" We would like to see, in the long run, if there are any unusual side effects to Nilotinib, and then directly compare it with Imatinib in newly diagnosed chronic myelogenous leukemia patients," Kantarjian says.

Source: University of Texas M. D. Anderson Cancer Center, 2006


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