Since the introduction of imatinib just over a decade ago, there has been a dramatic change in the treatment and prognosis of early chronic phase chronic myeloid leukaemia (CML). This review article focuses on recent advances, culminating in the approval of nilotinib by the US Food and Drug Administration for the treatment of adult patients with newly diagnosed CML in the chronic phase.
Baccarani, M. , Cortes, J. , Pane, F. , Niederwieser, D. , Saglio, G. , Apperley, J. et al. (2009a) Chronic myeloid leukemia: an update of concepts and management recommendations ofEuropean Leukemianet. J Clin Oncol27: 6041-6051.
2.
Baccarani, M. , Druker, B.J. , Cortes-Franco, J. , Hughes, T.P. , Kim, D.W. , Pane, F. et al. (2009b) 24 months update of the TOPS study: a phase III, randomized, open-label study of 400mg/d (SD-IM) versus 800 mg/d (HD-IM) of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) . Blood114, abstract 337 .
3.
Burke, B.A. and Carroll, M.(2010) BCR-ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia . Leukemia24: 1105-1112.
4.
Cortes, J. , Baccarani, M. , Guilhot, F. , Druker, B.J. , Branford, S. , Kim, D.W. et al. (2008) A phase III, randomized. open-label study of 400 mg versus 800 mg of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints: 1-year results of TOPS (tyrosine kinase inhibitor optimization and selectivity) study . Blood112: 130-131.
5.
Cortes, J. , Borthakur, G. , O’Brien, S. , Jones, D. , Jabbour, E. , Ravandi, F. et al. (2009b) Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP) . Blood114, abstract 338 .
6.
Cortes, J. , O’Brien, S. , Jones, D. , Jabbour, E. , Konopleva, M. , Ferrajoli, A. et al. (2009a) Efficacy of nilotinib in patients (pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP) . Blood114, abstract 341 .
7.
Deininger, M. , O’Brien, S.G. , Guilhot, F. , Goldman, J.M. , Hochhaus, A. , Hughes, T.P. et al. (2009) International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib . Blood114, abstract 1126 .
8.
Essers, M.A. , Offner, S. , Blanco-Bose, W.E. , Waibler, Z. , Kalinke, U. , Duchosal, M.A. et al. (2009) IFNalpha activates dormant haematopoietic stem cells in vivo . Nature458: 904-908.
9.
Giles, F.J. ( 2009) New directions in the treatment of imatinib failure and/or resistance . Semin Hematol46: S27-S33.
10.
Gregory, M.A. , Phang, T.L. , Neviani, P. , Alvarez-Calderon, F. , Eide, C.A. , O’Hare, T. et al. (2010) Wnt/ Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of BCR-ABL . Cancer Cell18: 74-87.
11.
Guilhot, F. , Preudhomme, C. , Guilhot, J. , Mahon, F.X. , Nicolini, F.E. , Rigual-Huguet, F. et al. (2009) Significant higher rates of undetectable molecular residual disease and molecular responses with pegylated form of interferon A2a in combination with imatinib (Im) for the treatment of newly diagnosed chronic phase (CP) chronic myeloid leukaemia (CML) patients (pts): confirmatory results at 18 months of part 1 of the SPIRIT phase III randomized trial of the French CML Group (FI LMC) . Blood114, abstract 340 .
12.
Hehlmann, R. , Jung-Munkwitz, S. , Lauseker, M. , Leitner, A. , Pletsch, N. , Shazi, S. et al. (2009)Random ized comparison of imatinib 800 mg vs. imatinib 400 mg +/- IFN in newly diagnosed Bcr/Abl positive chronic phase CML: analysis of molecular remission at 12 months; the German CML-Study IV. Blood 114, abstract 339.
13.
Hochhaus, A. , Baccarani, M. , Deininger, M. , Apperley, J.F. , Lipton, J.H. , Goldberg, S.L. et al. (2008) Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib . Leukemia22: 1200-1206.
14.
Hughes, T. and Branford, S. ( 2006) Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia . Blood Rev20: 29-41.
15.
Kantarjian, H. , Shah, N.P. , Hochhaus, A. , Cortes, J. , Shah, S. , Ayala, M. et al. (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia . N Engl J Med362: 2260-2270.
16.
Kantarjian, H. , Talpaz, M. , O’Brien, S.S. , Garcia-Manero, G. , Verstovsek, S. , Giles, F. et al. (2004) High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia . Blood103: 2873-2878.
17.
Kantarjian, H.M. , Giles, F. , Gattermann, N. , Bhalla, K. , Alimena, G. , Palandri, F. et al. (2007) Nilotinib (formerly AMN107), a Highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance . Blood110: 3540-3546.
18.
Mahon, F.X. , Rea, D. , Guilhot, F. , Huguet, F. , Nicolini, F.E. , Legros, L. et al. (2009) Discontinuation of imatinib therapy after achieving a molecular response in chronic myeloid leukemia patients . Blood114: 353-353.
19.
O’Dwyer, E. , Swords, R. , Giles, F. , Lecoutre, P. , McMullin, M. , Langabeer, S. et al. (2010) Nilotinib 300 mg twice daily is effective and well tolerated as first line treatment of Ph-positive chronic myeloid leukemia in chronic phase: updated results of the ICORG 0802 phase 2 study . Haematologica95: 340-340.
20.
Quintas-Cardama, A. , Kantarjian, H. , Jones, D. , Shan, J.Q. , Borthakur, G. , Thomas, D. et al. (2009) Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy . Blood113: 6315-6321.
21.
Rosti, G. , Palandri, F. , Castagnetti, F. , Breccia, M. , Levato, L. , Gugliotta, G. et al. (2009) Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia . Blood114: 4933-4938.
22.
Saglio, G. , Kim, D.W. , Issaragrisil, S. , Le Coutre, P. , Etienne, G. , Lobo, C. et al. (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia . N Engl J Med362: 2251-2259.
23.
Silver, R.T. , Woolf, S.H. , Hehlmann, R. , Appelbaum, F.R. , Anderson, J. , Bennett, C. et al. (1999) An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology . Blood94: 1517-1536.
24.
Thiesing, J.T. , Ohno-Jones, S. , Kolibaba, K.S. and Druker, B.J. ( 2000) Efficacy of STI571, an ABL tyrosine kinase inhibitor, in conjunction with other antileukemic agents against BCR-ABL-positive cells . Blood96: 3195-3199.
25.
US Food and Drug Administration (2010) Nilotinib (Tasigna), www.fda.gov/AboutFDA/CentersOffices/CDER/ucm216218.htm.