Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy.
New England Journal of Medicine (Impact Factor: 55.87). 06/2010; 362(24):2251-9. DOI: 10.1056/NEJMoa0912614
Source: PubMed


Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome-positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months.
At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups.
Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. ( number, NCT00471497.)

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    • "Phase III studies with second-generation TKIs like Nilotinib and Dasatinib have also shown superior efficacy to Imatinib in newly diagnosed CML, inducing faster and higher rates of CCRs and molecular responses. Therefore, both drugs are approved by the Food and Drug Administration to be used in patients with newly diagnosed CML in chronic phase (CML-CP) [21, 22]. "
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    ABSTRACT: Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
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    • "Resistance to imatinib as related to BCR-ABL point mutations has been largely overcome by using the 2nd generation TKIs dasatinib and nilotinib [10,11]. Although data on long-term treatment results are not yet available, 2nd generation TKIs, especially nilotinib, have been shown to be more effective than imatinib in first line therapy in attaining important endpoints as a complete cytogenetic response (CCyR), i.e. the absence of Ph+ cells in blood and bone marrow and a major molecular response (MMR), i.e. the near absence of BCR-ABL fusion mRNA transcripts (a reduction to ≤0.1% on the international scale) [12,13]. The latter endpoint is strongly predictive for long-term event-free survival [14]. "
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    ABSTRACT: The antitumor drug nilotinib has a large inter- and intra individual variability in pharmacokinetics. Adherence to treatment may substantially influence plasma levels and has been recognized as the most important determinant of treatment failure in chronic myeloid leukemia (CML). A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize the treatment of chronic phase CML (CP-CML) with a protein kinase inhibitor like nilotinib.Methods/design: In this multicenter prospective observational cohort study 70 adult patients with CP-CML starting treatment with nilotinib will be followed up for at least 12 months. Response to treatment is evaluated after 3, 6 and 12 months. Adherence is primarily assessed by counting the daily intake of nilotinib capsules by means of a medication event monitoring system (MEMS). Before the start of nilotinib treatment and after 3, 6 and 12 months, patients are asked to fill in a comprehensive questionnaire including topics on quality of life, side effects, attitude towards disease and medication, the patients' appreciation of information received about the medication, and discontinuation, and trough plasma levels of nilotinib are measured. The present study aims to get more insight into the efficacy of treatment with nilotinib and the various aspects that govern optimal response, of which adherence is a primary endpoint. We hypothesize that patients who experience inadequate response levels to nilotinib are less adherent. In addition, their plasma levels of nilotinib may be lower. We expect that our findings will be useful for health care professionals to support patients with the use of nilotinib in order to derive optimal benefit from their medication.Trial registration: Netherlands Trial Registry NTR3992.
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    • "Second-generation TKIs show slight, but significant, increases in the proportion of patients achieving early CCyR on nilotinib (Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients [ENESTnd])71 and dasatinib (DASatinib versus Imatinib Study In treatment-Naive CML patients [DASISION])72 compared with patients receiving imatinib. Furthermore, both studies showed that nilotinib and dasatinib induced deep MMR, such as MMR3 and MMR4, in a larger proportion of patients than did imatinib. "
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    ABSTRACT: Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukemia (CML) and functions by targeting BCR-ABL tyrosine kinases. Imatinib has substantially changed the clinical management and improved the prognosis of CML and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph(+) ALL). Here, we review the pharmacology, mode of action, and pharmacokinetics of imatinib; Chinese efficacy studies in CML and Ph(+) ALL; safety and tolerability; patient-focused perspectives, such as quality of life, patient satisfaction, acceptability, and adherence; and uptake of imatinib.
    Full-text · Article · Mar 2014 · OncoTargets and Therapy
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