Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review

Elias Jabbour, Jorge Cortes, Hagop Kantarjian, Elias Jabbour, Jorge Cortes, Hagop Kantarjian

Abstract

Introduction: Chronic myelogenous leukemia (CML) is a progressive and often fatal hematopoietic neoplasm. The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate represented a major therapeutic advance over conventional CML therapy, with more than 90% of patients obtaining complete hematologic response, and 70%-80% of patients achieving a complete cytogenetic response. Despite the high efficacy of imatinib, a minority of patients in chronic phase CML and more patients in advanced phases are resistant to imatinib, or develop resistance during treatment. This is attributed, in 40% to 50% of cases, to the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Attempts to circumvent resistance led to the discovery of nilotinib (Tasigna), a novel, potent and selective oral Bcr-Abl kinase inhibitor.

Aims: To review the evidence for the use of nilotinib in the management of CML.

Evidence review: Preclinical and clinical investigations demonstrate that nilotinib effectively overcomes imatinib resistance, and has further improved the treatment of CML.

Place in therapy: Nilotinib is currently indicated for patients with CML in chronic and accelerated phases following imatinib failure. Randomized studies are ongoing to assess the efficacy of nilotinib in patients with newly diagnosed CML.

Keywords: CML; imatinib-intolerance; imatinib-resistance; nilotinib; tyrosine kinase inhibitors.

Figures

Figure 1
Figure 1
Structural formulae of imatinib and nilotinib.
Figure 2
Figure 2
Comparison of imatinib and nilotinib (AMN107) iC50 values for blocking proliferation of Ba/F3 cells expressing non-mutated Bcr-Abl or kinase domain mutated Bcr-Abl. Copyright © 2005, Elsevier. Reproduced with permission from Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–141. Notes: Solid gray bars indicate imatinib iC 50 values, and solid red bars indicate nilotinib (AMN107) IC50 values. Dotted black line indicates the mean trough plasma level of imatinib reported in patients 24 hours following treatment with a once-daily dose of 400 mg.

References

    1. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164–172.
    1. Goldman JM, Melo JV. Chronic myeloid leukemia – advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464.
    1. Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-{alpha} Blood. 2004;104:1979–1988.
    1. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652.
    1. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.
    1. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–2878.
    1. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res. 2005;11:3425–3432.
    1. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423–1432.
    1. Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta. 2005;1754:3–13.
    1. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1–11.
    1. Cowan-Jacob SW, Guez V, Griffin JD, et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem. 2004;4:285–299.
    1. Nicolini FE, Corm S, Le QH, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(varphi)-LMC GROUP) Leukemia. 2006;20:1061–1066.
    1. Corbin AS, Buchdunger E, Pascal F, Druker BJ. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem. 2002;277:32214–32219.
    1. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11:4941–4947.
    1. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–141.
    1. Talpaz M, Shah N, Kantarjian HM, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–2541.
    1. Grafone T, Mancini M, Ottaqviani E, et al. A novel 4-anilino-3-quinolinecarbonitile dual SRC and ABL kinase inhibitor (SKI-606) has in vitro pro-apoptotic activity on CML Ph blast cells resistant to imatinib. Available at: .
    1. Kimura S, Naito H, Segawa H, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood. 2005;106:3948–3954.
    1. O’Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: tightening the grip of imatinib. Cancer Cell. 2005;7:117–119.
    1. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500–4505.
    1. Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): A novel and selective inhibitor Bcr-Abl. Br J Cancer. 2006;7:129–141.
    1. von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107) Blood. 2006;108:1328–1333.
    1. Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD. Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood. 2007;109:5011–5015.
    1. Weisberg E, Catley L, Wright RD, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood. 2007;109:2112–2120.
    1. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–2551.
    1. Kantarjian H, Hochhaus A, Bhalla K, et al. Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): Updated phase II results [abstract] J Clin Oncol. 2008;26:7010.
    1. le Coutre P, Apperley J, Ottmann OG, et al. Nilotinib in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib-resistance or -intolerance: Update of a phase II study [abstract] J Clin Oncol. 2008;26:7050.
    1. Giles F, Kantarjian H, le Coutre P, et al. Nilotinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to imatinib [abstract] J Clin Oncol. 2008;26:7017.
    1. Ottmann OG, Larson RA, Kantarjian HM, et al. Nilotinib in patients (pts) with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to imatinib [abstract] Blood. 2007;2815
    1. Jabbour E, le Coutre P, Rosti G, et al. Minimal cross-intolerance between nilotinib and imatinib in patients with imatinib-intolerant chronic myelogenous leukemia (CML) in chronic phase (CP) or accelerated phase (AP) [abstract] J Clin Oncol. 2008;26:7063.
    1. Cortes J, Ferrajoli A, Borthakur G, et al. Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia chromosome (Ph)- positive chronic myelogenous leukemia in early chronic phase (CML-CP) [abstract] J Clin Oncol. 2008;26:7016.
    1. Shah N, Nicoll J, Branford S, et al. Molecular analysis of dasatinib resistance mechanisms in CML patients identifies novel BCR-ABL mutations predicted to retain sensitivity to imatinib: rationale for combination tyrosine kinase inhibitor therapy [abstract] Blood. 2005;106:318a.
    1. Brendel C, Scharenberg C, Dohse M, et al. Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia. 2007;21:1267–1275.
    1. White DL, Saunders VA, Dang P, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. i. 2006;108:697–704.
    1. Jabbour E, Cortes J, Kantarjian H. Dasatinib for the treatment of Philadelphia chromosome-positive leukaemias. Expert Opin Investig Drugs. 2007;16(5):679–687.
    1. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–2541.
    1. O’Hare T, Eide CA, Tyner JW, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilo-tinib or dasatinib. Proc Natl Acad Sci U S A. 2008;105:5507–5512.
    1. Fiskus W, Pranpat M, Bali P, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006;108:645–652.

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