ASH: Nilotinib Effective Against Most Gleevec-Resistant Mutations

ORLANDO, Dec. 11 -- For chromic myeloid leukemia patients who develop resistance or are refractory to Gleevec (imatinib), nilotinib is waiting in the wings, according to an international evaluation.

In a study of peripheral blood samples from patients enrolled in a phase II study of nilotinib (AMN107) who experienced Gleevec failure, the investigational agent induced hematologic and/or cytogenetic responses in patients with 23 of 24 Gleevec-resistant mutations, said Andreas Hochhaus, M.D., of the University of Heidelberg faculty in Mannheim, Germany.

Hematologic responses occurred in 78% of patients with chronic phase CML, 75% of those in accelerated phase, and in 25% of those in blast crisis, Dr. Hochhaus and colleagues said at the American Society of Hematology meeting here.

"These preliminary data suggest that nilotinib may help patients for whom imatinib has stopped working by overcoming the gene mutation that cause imatinib resistance," said Dr. Hochhaus. "It also shows the importance of determining each patient's specific gene mutation, to apply individualized dosage of nilotinib according to the mutation pattern."

Nilotinib is an orally active amino-pyrimidine-derivative which selectively inhibits the BCR-ABL tyrosine kinase with greater potency in vitro compared with Gleevec.

In preclinical studies, nilotinib was 20 to 50 times more potent than Gleevec in cells that were sensitive to Gleevec, and three to seven times more potent in Gleevec-resistant cells lines.

In in vitro studies, 32 of 33 BCR-ABL mutations have been shown to be sensitive to nilotinib. The lone holdout was the threonine 315 isoleucine (T315I) which is notoriously resistant to all tyrosine kinase inhibitors, Dr. Hochaus said.

Dr. Hochhaus and colleagues conducted a study of the spectrum of BCR-ABL mutation in peripheral blood samples from patients with Gleevec-resistant Philadelphia-chromosome positive CML. In all, 101 of the patients were in chronic phase, and 41 were in accelerated phase.

The authors detected a total of 24 different mutation affecting 20 amino acids. All but the T315I mutation showed some sensitivity to Gleevec, Dr. Hochhaus reported. Mutations occurred in 44% of all patients whose disease was in chronic phase, and in 61% of those in accelerated phase. In addition, 7% of patients in chronic phase and 15% in accelerated phase had multiple mutations.

"We have observed efficacy of nilotinib in patients with mutations but also in patients without mutations, and this clearly demonstrates that BCR-ABL is still the driving force of the proliferation in CML patients with resistance, even in patients without specific mutations," Dr. Hochhaus said.

Nilotinib was also effective in patients with mutations in the phosphate-binding loop of tyrosine kinase, which are highly resistant to Gleevec, although the time to hematologic and cytogenetic responses was prolonged in patients with this type of mutation he noted.

"We should focus on the very close and intensive monitoring of CML patients on imatinib treatment to find the right time point to switch the treatment from the first line treatment to an alternative tyrosine kinase inhibitor," Dr. Hochhaus said.

The study was supported by Novartis, makers of Gleevec and nilotinib. Two of Dr. Hochhaus co-investigators are employees of the company.

The FDA last June approved Sprycel (dasatinib) for adults in all phases of chronic myeloid resistance or intolerance to prior therapy with Gleevec.