Current best options for first line treatment of chronic phase chronic myeloid leukemia

CURRENT INTERNATIONAL EXPERIENCE

Hehlmann and S. Saußele

III Medizinische Klinik, Medizinische Fakultät Mannheim Universität Heidelberg, Mannheim, Germany

e-mail: sekretariat.hehlmann@medma.uni-heidelberg.de

Accepted September 16, 2013.

ABSTRACT

Treatment with tyrosine kinase inhibitors (TKI) has remarkably improved prognosis of chronic myeloid leukemia (CML). The 2013 ELN management recommendations recommend imatinib, dasatinib and nilotinib equally for first line treatment of CML and define new response levels.

Nilotinib and dasatinib induce responses faster than imatinib 400 mg. Faster responses are also observed with dose optimized imatinib 800 mg. Off-target effects of 2nd generation TKI are of concern. No serious long term side effects have been reported with imatinib. The impact of early response on survival has led to new definitions of optimal response and failure. More than 10 % residual BCR-ABL transcripts according to the international scale (IS) or more than 35 % Ph positive metaphases at 6 months are defined as failure and an indication for a change of treatment. The limitations of this definition are discussed. Optimization of TKI treatment to achieve deep and durable molecular responses provides a perspective for treatment discontinuation and cure of CML.

Read in PDF (RUS)pdficon

REFERENCES

  1. Baccarani M., Deininger M.W., Rosti G. et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872–884
  2. Experts in Chronic Myeloid L. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013; 121(22): 4439–42.
  3. Hehlmann R., Heimpel H., Hasford J. et al. Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: Prolongation of survival by hydroxyurea. Blood 1993; 82: 398–407.
  4. Chronic Myeloid Leukemia Trialists’ Collaborative G. Hydroxyurea versus busulphan for chronic myeloid leukaemia: an individual patient data metaanalysis of three randomized trials. Br. J. Haematol. 2000; 110: 573–6.
  5. Italian Cooperative Study Group On Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N. Engl. J. Med. 1994; 330(12): 820–5.
  6. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists’ Collaborative Group. J. Natl. Cancer Inst. 1997; 89(21): 1616–20.
  7. Thomas D.E., Clift R.A., Fefer A. et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann. Intern. Med. 1986; 104: 155–63.
  8. Hansen J.A., Gooley T.A., Martin P.J. et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N. Engl. J. Med. 1998; 338: 962–8.
  9. Hehlmann R. A chance of cure for every patient with chronic myeloid leukemia? N. Engl. J. Med. 1998; 338(14): 980–2.
  10. Druker B.J., Guilhot F., O’Brien S.G. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 2006; 355(23): 2408–17.
  11. Donohue B. Investigator’s Broschure: Clinical Development — STI571 (formerly CGP 57148B) — Imatinib mesylate. Novartis Edition 15; 2013.
  12. Hehlmann R., Lauseker M., Jung-Munkwitz S. et al. Tolerability-Adapted Imatinib 800 mg/d Versus 400 mg/d Versus 400 mg/d Plus Interferon-alpha in Newly Diagnosed Chronic Myeloid Leukemia. J. Clin. Oncol. 2011; 29(12): 1634–42.
  13. Gambacorti-Passerini C., Antolini L., Mahon F.X. et al. Multicenter Independent Assessment of Outcomes in Chronic Myeloid Leukemia Patients Treated With Imatinib. J. Natl. Cancer Inst. 2011; 103(7): 553–61.
  14. Deininger M., O’Brien S.G., 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(22): 1126.
  15. Soverini S., Hochhaus A., Nicolini F.E. et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011; 118(5): 1208–15.
  16. Kantarjian H.M., Shah N.P., Cortes J.E. 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(5): 1123–9.
  17. Larson R.A., Hochhaus A., Hughes T.P. et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012; 26(10): 2197–203.
  18. Cortes J.E., 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. 2010; 28(3): 392–7.
  19. Rosti G., Palandri F., Castagnetti F. et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 2009; 114(24): 4933–8.
  20. Cortes J.E., Kim D.W., Kantarjian H.M. et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J. Clin. Oncol. 2012; 30(28): 3486–92.
  21. Cortes J.E., 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(3): 398–404.
  22. Hochhaus A., Saglio G., Larson R.A. et al. Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 2013; 121(18): 3703–8.
  23. Cortes J., Giles F., O’Brien S. et al. Results of high-dose imatinib mesylate in patients with Philadelphia chromosome positive chronic myeloid leukemia after failure of interferon-alfa. Blood 2003; 102: 83–6.
  24. 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: 2873–8.
  25. Cortes J.E., Kantarjian H.M., Goldberg S.L. et al. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J. Clin. Oncol. 2009; 27(28): 4754–9.
  26. Hughes T.P., Branford S., White D.L. et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008; 112(10): 3965–73.
  27. Cortes J.E., Baccarani M., Guilhot F. et al. Phase III, randomized, openlabel study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J. Clin. Oncol. 2010; 28(3): 424–30.
  28. Montani D., Bergot E., Guenther S. et al. Pulmonary Arterial Hypertension in Patients Treated by Dasatinib. Circulation 2012; 125(17): 2128–37.
  29. Giles F.J., Mauro M.J., Hong F. et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 2013; 27: 1310–5.
  30. Kim T.D., Rea D., Schwarz M. et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 2013; 27(6): 1316–21.
  31. Sokal J.E., Cox E.B., Baccarani M. et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984; 63(4): 789–99.
  32. Hasford J., Pfirrmann M., Hehlmann R. et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J. Natl. Cancer Inst. 1998; 90(11): 850–8.
  33. Hasford J., Baccarani M., Hoffmann V. et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011; 118(3): 686–92.
  34. Fabarius A., Leitner A., Hochhaus A. et al. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011; 118(26): 6760–8.
  35. Hanfstein B., Müller M.C., Hehlmann R. et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 2012; 26(9): 2096–102.
  36. Marin D., Ibrahim A.R., 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(3): 232–8.
  37. Hehlmann R., Müller M.C., Lauseker M. et al. Deep Molecular Response (MR4.5) is reached by the majority of imatinib-treated patients, predicts survival, and is achieved faster by optimized high-dose imatinib — results from the randomized CML-Study IV. J. Clin. Oncol. 2014; 32: 415–423.
  38. Saussele S., Lauseker M., Gratwohl A. et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 2010; 115(10): 1880–5.
  39. Saglio G., Kim D.W., Issaragrisil S. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 2010; 362(24): 2251–9.
  40. Kantarjian H., Shah N.P., Hochhaus A. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 2010; 362(24): 2260–70.
  41. Hehlmann R. How I treat CML blast crisis. Blood 2012; 120(4): 737–47.
  42. Saglio G., Kantarjian H.M., Shah N. et al. Early Response (Molecular and Cytogenetic) and Long-Term Outcomes in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Exploratory Analysis of DASISION 3-Year Data. ASH Annual Meeting Abstracts 2012; 120(21): 1675.
  43. Hochhaus A., Hughes T.P., Saglio G. et al. Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients). ASH Annual Meeting Abstracts 2012; 120(21): 167.
  44. Mahon F.X., Rea 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(11): 1029–35.
  45. Ross D.M., Branford S., Seymour J.F. et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 2013; 122(4): 515–22.
  46. Branford S., Yeung D.T., Ross D.M. et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood 2013; 121(19): 3818–24.