Abstract
The prognosis of Philadelphia positive (Ph+) chronic myeloid leukemia (CML) has been revolutionized since the discovery of the pathogenetic role of BCR-ABL and the invention of tyrosine kinase inhibitors (TKIs). With a follow-up of 8 years, patients had an OS of 85 % and, with second generation TKIs, dasatinib and nilotinib, almost 50 % of the resistant patients gained a remission with an OS over 90 % at 2 years. Currently the challenge is preventing resistance leading to progression to advance phases that have still few chances of effective treatment. Another objective, derived from the needs of our patients, beside the pride of the scientist, is the discontinuation of the treatment. Second generations TKIs applied to the first line setting seem to be a good option either to avoid progression and to achieve deeper rates of molecular response, necessary for the cure.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
• Deininger M, O'Brien SG, Guilhot F, et al. 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. ASH Annual Meeting Abstracts. 2009;114:1126.
• Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51.
Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20.
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Sci. 2004;305:399–401.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.
Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303–9.
Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leuk. 2008;22:1200–6.
Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. Am J Clin Oncol. 2008;26:3204–12.
Shah N, Bahceci E, Lambert A, Ploughman L, Radich J. Resistance, outcome and the development of mutations with dasatinib in patients with chronic-phase chronic myeloid leukemia (CML-CP). ASH Annu Meet Abstr. 2009;114:1122.
Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114:4944–53.
• Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95:232–40.
Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–41.
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;11:4941–7.
Kantarjian HM, Giles F, Gattermann N, et al. 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. Blood. 2007;110:3540–6.
Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204–10.
• Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:1141–5.
• Cortes JE, Jones D, O'Brien S, et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol. 2010;28:398–404.
Pemmaraju N, Kantarjian HM, Luthra R, et al. Results of a phase II trial of dasatinib as frontline therapy for chronic myeloid leukemia (CML) in chronic phase (CP). ASH AnnuMeet Abstr. 2011;118:1700.
•• Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123–9.
Marin D, Hedgley C, Clark RE, et al. The predictive value of early molecular response in chronic phase CML patients treated with dasatinib first line therapy. ASH Annu Meet Abstr. 2011;118:785.
Radich JP, Kopecky KJ, Kamel-Reid S, et al. A randomized phase II trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): The S0325 Intergroup Trial. ASH Annu Meet Abstr. 2010;116:LBA-6.
• Cortes JE, Jones D, O'Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 28:392–7.
Quintas-Cardama A, Kantarjian HM, Luthra R, et al. Efficacy of frontline nilotinib therapy in patients (Pts) with newly diagnosed Philadelphia chromosome (Ph)-positive chronic myeloid leukemia in early chronic phase (CML-CP). ASH Annu Meet Abstr. 2011;118:454.
• Rosti G, Palandri F, Castagnetti F, et al. Nilotinib for the frontline treatment of Ph + chronic myeloid leukemia. Blood. 2009;114:4933–8.
Gugliotta G, Castagnetti F, Breccia M, et al. Early CP CML, Nilotinib 400 mg twice daily frontline: beyond 3 years, results remain excellent and stable (A GIMEMA CML Working Party Trial). ASH Annu Meet Abstr. 2011;118:2756.
Castagnetti F, Rosti G, Breccia M, et al. Alternating nilotinib 400 mg twice daily and imatinib 400 mg once daily as frontline treatment of Ph + chronic myeloid leukemia. A Phase 2 Multicentric Study of the GIMEMA CML Working Party. ASH Annu Meet Abstr. 2011;118:453.
•• Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib vs imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12:841–51.
Saglio G, LeCoutre PD, Pasquini R, et al. Nilotinib versus imatinib in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 36-month (mo) Follow-up. ASH Annu Meet Abstr. 2011;118:452.
de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358–63.
Hochhaus A, O'Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leuk. 2009;23:1054–61.
Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.
• Quintas-Cardama A, Kantarjian H, Jones D, et al. 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. Blood. 2009;113:6315–21.
• Alvarado Y, Kantarjian H, O'Brien S, et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer. 2009;115:3709–18.
• Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437–44.
• Jabbour E, Kantarjian H, O'Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011;118:4541–6.
Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116:3758–65.
Palandri F, Iacobucci I, Soverini S, et al. Treatment of Philadelphia-positive chronic myeloid leukemia with imatinib: importance of a stable molecular response. Clin Cancer Res. 2009;15:1059–63.
•• Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232–8.
•• Hanfstein B, Muller MC, Erben P, et al. Molecular and cytogenetic response after 3 months of imatinib treatment is predictive for the risk of disease progression and death in newly diagnosed chronic myeloid leukemia patients–a follow-up analysis of the German CML Study IV. ASH Annual Meeting Abstracts. 2011;118:783.
•• Hochhaus A, Saglio G, Chuah C, et al. Dasatinib and imatinib-induced reductions in BCR-ABL transcript levels below 10% at 3 months are associated with improved responses in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): analysis of molecular response kinetics in the DASISION Trial. ASH Annual Meeting Abstracts. 2011;118:2767.
Branford S, Lawrence R, Grigg A, et al. Long-term follow-up of patients with CML in chronic phase treated with first-line imatinib suggests that earlier achievement of a major molecular response leads to greater stability of response. ASH Annu Meet Abstr. 2008;112:2113.
• Cross NCP, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 2012.
Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109:58–60.
•• Mahon F-X, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.
Mahon F-X, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: update results of the STIM Study. ASH Annu Meet Abstr. 2011;118:603.
Rea D, Rousselot P, Nicolini FE, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia (CML) patients (pts) with stable undetectable Bcr-Abl transcripts: results from the French CML Group (FILMC). ASH Annu Meet Abstr. 2011;118:604.
Goldman J, Gordon M. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter? Leuk Lymphoma. 2006;47:1–7.
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C. Fava: none; G. Rege-Cambrin: none; G. Saglio: consultancy and speakers’ bureaus (Novartis and BMS).
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Fava, C., Rege-Cambrin, G. & Saglio, G. Chronic Myeloid Leukemia: State of the Art in 2012. Curr Oncol Rep 14, 379–386 (2012). https://doi.org/10.1007/s11912-012-0253-9
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DOI: https://doi.org/10.1007/s11912-012-0253-9