Researchers involved in an international study have reported that the toxicity profile for nilotinib (AMN 107) is different than for Gleevec (imatinib). The details of this study were presented at the 2007 meeting of the American Society of Clinical Oncology in June.

Gleevec is the standard initial treatment of newly diagnosed patients with CML. Gleevec produces a high rate of cytogenetic remissions and major molecular responses and has improved progression-free and overall survival. However, Gleevec does not eradicate the Bcr-Abl clone as detected by PCR.  Furthermore, a small but significant fraction of patients will develop Gleevec resistance or are intolerant to the drug. Patients who fail or are intolerant to Gleevec now have alternatives other than allogeneic stem cell transplantation for treatment.

There are two new agents that have been developed for the treatment of patients with Bcr-Abl-positive CML and acute lymphoblastic leukemia (ALL): nilotinib (AMN107) and Sprycel (dasatinib). These agents appear to have great promise for the treatment of patients who fail Gleevec. Sprycel has been approved by the US Food and Drug Administration and nilotinib will probably be approved in the near future. Two new other second generation kinase inhibitors were introduced at the 2007 ASCO meeting; bosutinib and INNO-406, both of which show promise as active agents in patients resistant to Gleevec and other kinases. Both nilotinib and Sprycel have also been evaluated in newly diagnosed patients with CML and the evaluation of combination of tyrosine kinase inhibitors is likely in the near future.

At ASCO 2007, researchers involved in an international study presented data on 95 patients with CML in chronic phase who were intolerant to Gleevec and treated with nilotinib. Gleevec intolerance was defined as no major cyotogenetic response and discontinuation of Gleevec due to grade 3/4 toxicities or persistent or recurrent grade 2 toxicities. The incidence of Gleevec intolerance by these definitions was 30%. These authors reported that only 2/80 patients who had non-hematologic toxicities while receiving Gleevec had similar toxicities while receiving nilotinib. However, hematologic toxicities appeared to be similar for the two drugs. After 6 months of therapy 55% of patients treated with nilotinib had achieved a major cytogenetic response. These data suggest that nilotinib is well tolerated in patients with Gleevec intolerance.

Comments: The 30% incidence of Gleevec intolerance is much higher than previously reported and the reasons for this are unclear. However, nilotinib does not appear to share the non-hematologic toxicities associated with Gleevec.

References: Jabbour E, Le Coutre M, Baccarani M, et al. Nilotinib is associated with minimal cross intolerance to imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP). Proceedings from the American Society of Clinical Oncology Conference. Chicago/IL. 2007. Abstract # 7039

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