Skip to main content

Advertisement

SpringerLink
Log in

Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose homoharringtonine as well as standard-dose imatinib, which we called the G-CSF + homoharringtonine + imatinib (GHI) regimen, in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib. Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day−1 until remission, together with homoharringtonine (1 mg/m2 s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily). Patients who failed to obtain at least a partial hematologic response (PHR) after three courses were taken off study. Patients who responded to induction treatment and who had a matched donor received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The results demonstrates that the GHI regimen re-induce hematologic responses or improve the cytogenetic responses in all evaluable patients. Furthermore, eligible patients have benefited from allo-HSCT after response to this induction treatment. We conclude that the GHI regimen may overcome disease-poor response to conventional doses of imatinib and this approach deserves further evaluation as frontline therapy for newly diagnosed CML.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sacchi S, Kantarjian HM, O'Brien S et al (1999) Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 86:2632–2641

    Article  CAS  PubMed  Google Scholar 

  2. Gratwohl A, Brand R, Apperley J et al (2006) Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 91:513–521

    PubMed  Google Scholar 

  3. Druker BJ, Sawyers CL, Kantarjian H et al (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042

    Article  CAS  PubMed  Google Scholar 

  4. Branford S, Rudzki Z, Walsh S et al (2003) Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102:276–283

    Article  CAS  PubMed  Google Scholar 

  5. Soverini S, Martinelli G, Rosti G et al (2005) ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and horter survival: a study by the GIMEMA working party on chronic myeloid leukemia. J Clin Oncol 23:4100–4109

    Article  CAS  PubMed  Google Scholar 

  6. Quintás-Cardama A, Kantarjian H, Garcia-Manero G et al (2007) Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer 109:248–255

    Article  PubMed  Google Scholar 

  7. Marin D, Kaeda JS, Andreasson C et al (2005) Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 103:1850–18555

    Article  CAS  PubMed  Google Scholar 

  8. Graham SM, Jørgensen HG, Allan E et al (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99:319–325

    Article  CAS  PubMed  Google Scholar 

  9. Jørgensen HG, Copland M, Allan EK et al (2006) Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 12:626–633

    Article  PubMed  Google Scholar 

  10. Zhang WG, Wang FX, Chen YX et al (2008) Combination chemotherapy with low-dose cytarabine, homoharringtonine, and granulocyte colony-stimulating factor priming in patients with relapsed or refractory acute myeloid leukemia. Am J Hematol 83:185–188

    Article  CAS  PubMed  Google Scholar 

  11. Fruehauf S, Topaly J, Buss EC et al (2007) Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109:1543–1549

    Article  CAS  PubMed  Google Scholar 

  12. Bene MC, Castoldi G, Knapp W et al (1995) Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9:1783–1786

    CAS  PubMed  Google Scholar 

  13. Jabbour E, Kantarjian HM, Jones D (2009) Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113:2154–2160

    Article  CAS  PubMed  Google Scholar 

  14. Shah NP, Nicoll JM, Nagar B et al (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–223

    Article  CAS  PubMed  Google Scholar 

  15. Kantarjian HM, Talpaz M, O'Brien S et al (2003) Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101:473–475

    Article  CAS  PubMed  Google Scholar 

  16. Zonder JA, Pemberton P, Brandt H, Mohamad AN, Schiffer CA (2002) The effect of dose increase to imatinib mesylate in patients with chronic or accelerated phase chronic myeloid leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res 9:2092–2097

    Google Scholar 

  17. Marin D, Goldman JM, Olavarria E, Apperley J (2003) Transient benefit only from increasing the imatinib dose in CML patients who do not acheive cytogenetic remissions on conventional doses. Blood 102:2702–2703

    Article  CAS  PubMed  Google Scholar 

  18. O'Brien S, Kantarjian H, Keating M (1995) Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 86:3322–3326

    PubMed  Google Scholar 

  19. O'Brien S, Talpaz M, Cortes J et al (2002) Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Cancer 94:2024–2032

    Article  PubMed  Google Scholar 

  20. Tipping AJ, Mahon FX, Zafirides G, Lagarde V, Goldman JM, Melo JV (2002) Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia 16:2349–2357

    Article  CAS  PubMed  Google Scholar 

  21. Scappini B, Onida F, Kantarjian HM et al (2002) In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Cancer 94:2653–2662

    Article  CAS  PubMed  Google Scholar 

  22. O'Brien SG, Guilhot F, Larson RA et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004

    Article  PubMed  Google Scholar 

  23. Bhatia R, Holtz M, Niu N et al (2003) Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101:4701–4707

    Article  CAS  PubMed  Google Scholar 

  24. Gorre ME, Mohammed M, Ellwood K (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880

    Article  CAS  PubMed  Google Scholar 

  25. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R (2002) Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99:3792–3800

    Article  CAS  PubMed  Google Scholar 

  26. Mauro MJ, Druker BJ, Maziarz RT (2004) Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 28(Suppl 1):71–73

    Article  Google Scholar 

  27. Cortes J, O'Brien S, Kantarjian H (2004) Discontinuation of imatinib therapy after achieving a molecular response. Blood 104:2204–2205

    Article  CAS  PubMed  Google Scholar 

  28. Hui CH, Goh KY, White D et al (2003) Successful peripheral blood stem cell mobilization with filgrastim in patients with chronic myeloid leukaemia achieving complete cytogenetic response with imatinib, without increasing disease burden as measured by quantitative real-time PCR. Leukemia 17:821–828

    Article  CAS  PubMed  Google Scholar 

  29. Drummond MW, Marin D, Clark RE et al (2003) Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission. Br J Haematol 123:479–483

    Article  PubMed  Google Scholar 

  30. Marin D, Marktel S, Bua M et al (2003) Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon α. Leukemia 17:1448–1453

    Article  CAS  PubMed  Google Scholar 

  31. Sneed TB, Kantarjian HM, Talpaz M et al (2004) The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer 100:116–121

    Article  CAS  PubMed  Google Scholar 

  32. Marin D, Marktel S, Foot N, Bua M, Goldman JM, Apperley JF (2003) Granulocyte colony-stimulating factor reverses cytopenia and may permit cytogenetic responses in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica 88:227–279

    CAS  PubMed  Google Scholar 

  33. Heim D, Ebnöther M, Meyer-Monard S et al (2003) G-CSF for imatinib-induced neutropenia. Leukemia 17:805–807

    Article  CAS  PubMed  Google Scholar 

  34. Quintas-Cardama A, Kantarjian H, O'Brien S et al (2004) Granulocyte colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 100:2592–2597

    Article  CAS  PubMed  Google Scholar 

  35. Jorgensen HG, Copland M, Holyoake TL (2005) Granulocyte colony-stimulating factor (Filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase myelogenous leukemia. Cancer 103:210–211

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all patients for their cooperation.

Author information

Authors and Affiliations

  1. Henan Key Lab of Experimental Haematology, Henan Institute of Haematology, Henan Tumor Hospital, Zhengzhou Medical School, Zhengzhou University, 127 Dongming Road, Zhengzhou, 450008, People’s Republic of China

    Baijun Fang, Ning Li & Yongping Song

  2. Institute of Haematology and Blood Diseases Hospital, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Qin Han & Robert Chunhua Zhao

Authors
  1. Baijun Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yongping Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qin Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Chunhua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yongping Song.

Additional information

Baijun Fang and Ning Li contributed equally to this work.

This work has been supported by grants from the “863 Projects” of Ministry of Science and Technology of P.R. China (No 2002AA205061) and the National Natural Science Foundation of China (No. 30900637).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fang, B., Li, N., Song, Y. et al. Standard-dose imatinib plus low-dose homoharringtonine and granulocyte colony-stimulating factor is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis who have failed prior single-agent therapy with imatinib. Ann Hematol 89, 1099–1105 (2010). https://doi.org/10.1007/s00277-010-0991-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-010-0991-4

Keywords

Search

Navigation