Annals of Hematology

, Volume 92, Issue 8, pp 1049–1056

High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group

  • Noortje Thielen
  • Bronno van der Holt
  • Gregor E. G. Verhoef
  • Rianne A. H. M. Ammerlaan
  • Pieter Sonneveld
  • Jeroen J. W. M. Janssen
  • Wendy Deenik
  • J. H. Frederik Falkenburg
  • Marie José Kersten
  • Harm A. M. Sinnige
  • Martin Schipperus
  • Anton Schattenberg
  • Rien van Marwijk Kooy
  • Willem M. Smit
  • Isabel W. T. Chu
  • Peter J. M. Valk
  • Gert J. Ossenkoppele
  • Jan J. Cornelissen
Original Article
  • 364 Downloads

Abstract

Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18–65 years were randomly assigned to either imatinib 800 mg (n = 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m2 for 7 days (n = 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).

Keywords

Chronic myeloid leukemia Imatinib Cytarabine Major molecular response 

Supplementary material

277_2013_1730_MOESM1_ESM.doc (618 kb)
ESM 1(DOC 617 kb)

References

  1. 1.
    Deininger M, O'Brien S, Guilhot F, Goldman JM, Hochhaus A, Hughes 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. Blood 114 (Abstract 1126)Google Scholar
  2. 2.
    Kantarjian H, Shah NP, 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 Med 362:2260–2270PubMedCrossRefGoogle Scholar
  3. 3.
    Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259PubMedCrossRefGoogle Scholar
  4. 4.
    de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M et al (2008) Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26:3358–3363PubMedCrossRefGoogle Scholar
  5. 5.
    Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ (2000) Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood 96:3195–3199PubMedGoogle Scholar
  6. 6.
    Topaly J, Zeller WJ, Fruehauf S (2001) Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15:342–347PubMedCrossRefGoogle Scholar
  7. 7.
    Talpaz M, Silver R, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937PubMedCrossRefGoogle Scholar
  8. 8.
    Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539PubMedCrossRefGoogle Scholar
  9. 9.
    Kantarjian HM, Larson RA, Guilhot F, O'Brien SG, Mone M, Rudoltz M et al (2009) Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 115:551–560PubMedCrossRefGoogle Scholar
  10. 10.
    Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S et al (2009) The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML working party experience after a 7-year follow-up. Haematologica 94:205–212PubMedCrossRefGoogle Scholar
  11. 11.
    Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S et al (2003) Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101:473–475PubMedCrossRefGoogle Scholar
  12. 12.
    Kantarjian H, Talpaz M, O'Brien 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. Blood 103:2873–2878PubMedCrossRefGoogle Scholar
  13. 13.
    Cortes JE, Kantarjian HM, Goldberg SL, Powell BL, Giles FJ, Wetzler M et al (2009) High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27:4754–4759PubMedCrossRefGoogle Scholar
  14. 14.
    Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N et al (2011) 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 29:1634–1642PubMedCrossRefGoogle Scholar
  15. 15.
    Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E et al (2009) Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet study. Blood 113:4497–4504PubMedCrossRefGoogle Scholar
  16. 16.
    Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim DW et al (2010) Phase III, randomized, open-label 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 28:424–430PubMedCrossRefGoogle Scholar
  17. 17.
    Deenik W, van der Holt B, Verhoef GE, Smit WM, Kersten MJ, Kluin-Nelemans HC et al (2008) Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood 111:2581–2588PubMedCrossRefGoogle Scholar
  18. 18.
    Deenik W, Janssen JJ, van der Holt B, Verhoef GE, Smit WM, Kersten MJ et al (2010) Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia. Haematologica 95:914–921PubMedCrossRefGoogle Scholar
  19. 19.
    Ross DM, Branford S, Moore S, Hughes TP (2006) Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL. Leukemia 20:664–670PubMedCrossRefGoogle Scholar
  20. 20.
    Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al (2009) Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 23:1054–1061PubMedCrossRefGoogle Scholar
  21. 21.
    Hughes TP, Hochhaus A, Branford S, Muller MC, Kaeda JS, Foroni L et al (2010) 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 116:3758–3765PubMedCrossRefGoogle Scholar
  22. 22.
    Kantarjian H, O'Brien S, Garcia-Manero G, Faderl S, Ravandi F, Jabbour E (2012) Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy. Cancer 118:3116–3122PubMedCrossRefGoogle Scholar
  23. 23.
    Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF et al (2008) 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 112:3965–3973PubMedCrossRefGoogle Scholar
  24. 24.
    Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, Rigal-Huguet F et al (2003) Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 102:4298–4305PubMedCrossRefGoogle Scholar
  25. 25.
    Hurtado-Monroy R, Vargas-Viveros P, Candelaria M, Cervera E, Cruz J, Gutierrez O et al (2008) Imatinib compared with imatinib/cytarabine for the first-line treatment of early Philadelphia chromosome-positive chronic myeloid leukemia: results of a randomized clinical trial of the Mexican Collaborative Leukemia Group. Clin Leuk 2:128–132CrossRefGoogle Scholar
  26. 26.
    Preudhomme C, Guilhot J, Nicolini FE, Guerci-Bresler A, Rigal-Huguet F, Maloisel F et al (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363:2511–2521PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Noortje Thielen
    • 1
  • Bronno van der Holt
    • 2
  • Gregor E. G. Verhoef
    • 3
  • Rianne A. H. M. Ammerlaan
    • 2
  • Pieter Sonneveld
    • 4
  • Jeroen J. W. M. Janssen
    • 1
  • Wendy Deenik
    • 5
  • J. H. Frederik Falkenburg
    • 6
  • Marie José Kersten
    • 7
  • Harm A. M. Sinnige
    • 8
  • Martin Schipperus
    • 9
  • Anton Schattenberg
    • 10
  • Rien van Marwijk Kooy
    • 11
  • Willem M. Smit
    • 12
  • Isabel W. T. Chu
    • 4
  • Peter J. M. Valk
    • 4
  • Gert J. Ossenkoppele
    • 1
  • Jan J. Cornelissen
    • 4
  1. 1.Department of HematologyVU University Medical CenterAmsterdamthe Netherlands
  2. 2.HOVON Data CenterErasmus University Medical Center-Daniel den HoedRotterdamthe Netherlands
  3. 3.Department of HematologyUniversity Hospital GasthuisbergLeuvenBelgium
  4. 4.Department of HematologyErasmus University Medical CenterRotterdamthe Netherlands
  5. 5.Department of Internal MedicineTergooiziekenhuizenHilversumthe Netherlands
  6. 6.Department of HematologyLeiden University Medical CenterLeidenthe Netherlands
  7. 7.Department of HematologyAcademic Medical CenterAmsterdamthe Netherlands
  8. 8.Department of HematologyJeroen Bosch Hospital‘s-Hertogenboschthe Netherlands
  9. 9.Department of HematologyHaga Hospitalthe Haguethe Netherlands
  10. 10.Department of HematologyRadboud University Nijmegen Medical CenterNijmegenthe Netherlands
  11. 11.Department of Internal MedicineIsala KliniekenZwollethe Netherlands
  12. 12.Department of Internal MedicineMedisch Spectrum TwenteEnschedethe Netherlands

Personalised recommendations