Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL

TLDR

Imatinib resistance can develop in chronic myelogenous leukemia, and preclinical studies show nilotinib is 20–50 times more potent against CML cells. A phase‑1 dose‑escalation trial enrolled 119 patients with imatinib‑resistant CML or ALL, administering nilotinib orally at 50–1200 mg once daily or 400–600 mg twice daily, with myelosuppression, hyperbilirubinemia, and rashes as common adverse events. Nilotinib produced hematologic responses in 13/33 blastic, 33/46 accelerated, and 11/12 chronic phase patients, with cytogenetic responses in 9, 22, and 11 respectively, and a favorable safety profile. ClinicalTrials.gov identifier NCT00109707.

Abstract

Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50.In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily.Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission.Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov]. .