Skip to main content
SpringerLink
Log in

Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia

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

Abstract

During imatinib therapy, many patients with chronic myeloid leukemia (CML) develop severe neutropenia, leading to treatment interruptions, and potentially compromising response to imatinib. Berbamine (a bisbenzylisoquinoline alkaloid) has been widely used in Asian countries for managing leukopenia associated with chemotherapy. To investigate whether berbamine shows clinical benefit in reversing imatinib-associated neutropenia, we analyzed 63 chronic-phase CML patients who had developed grade ≥2 neutropenia and were treated with (n = 34, berbamine group) or without (n = 29, control group) berbamine. Among those patients with grade 2 neutropenia, five of 13 (38.5%) progressed to grade 3 neutropenia without berbamine support, while in the berbamine group, the rate decreased to 3/20 (15%) (p = 0.213). Although the rate of recovery from grade ≥3 neutropenia was similar in the two groups (94.1 vs. 90.5%, p = 0.559), berbamine markedly shortened the recovery time (median, 11 vs. 24 days, p = 0.006), and prevented recurrence of grade ≥3 neutropenia (18.8 vs. 52.6%, p = 0.039). Moreover, with berbamine support, the time to achieve complete cytogenetic response was significantly shorter (median, 6.5 vs. 10 months, p = 0.007). There were no severe adverse events associated with berbamine treatment. In conclusion, the present study reveals the potential clinical value of berbamine in the treatment of CML with imatinib-induced neutropenia. The use of berbamine may improve response to imatinib by stimulating normal hematopoiesis and faster neutropenia recovery.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007;109:4686–92.

    Article  CAS  PubMed  Google Scholar 

  2. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  PubMed  Google Scholar 

  3. Au WY, Caguioa PB, Chuah C, Hsu SC, Jootar S, Kim DW, et al. Chronic myeloid leukemia in Asia. Int J Hematol. 2009;89:14–23.

    Article  PubMed  Google Scholar 

  4. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–52.

    Article  CAS  PubMed  Google Scholar 

  5. Nagai T, Takeuchi J, Dobashi N, Kanakura Y, Taniguchi S, Ezaki K, et al. Imatinib for newly diagnosed chronic-phase chronic myeloid leukemia: results of a prospective study in Japan. Int J Hematol. 2008;92:111–7.

    Article  Google Scholar 

  6. Sneed TB, Kantarjian HM, Talpaz M, O’Brien S, Rios MB, Bekele BN, et al. The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer. 2004;100:116–21.

    Article  CAS  PubMed  Google Scholar 

  7. Quintas-Cardama A, Kantarjian H, O’Brien S, Garcia-Manero G, Rios MB, Talpaz M, et al. Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer. 2004;100:2592–7.

    Article  CAS  PubMed  Google Scholar 

  8. Marin D, Marktel S, Foot N, Bua M, Goldman JM, Apperley JF. Granulocyte colony-stimulating factor reverses cytopenia and may permit cytogenetic responses in patients with chronic myeloid leukemia treated with imatinib mesylate. Haematologica. 2003;88:227–9.

    CAS  PubMed  Google Scholar 

  9. Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood. 2007;109:93–9.

    Article  CAS  PubMed  Google Scholar 

  10. Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B, et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood. 2006;107:4628–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shimoda K, Okamura S, Harada N, Ikematsu W, Kondo S, Kawasaki C, et al. Granulocyte colony-stimulating factor receptors on human acute leukemia: biphenotypic leukemic cells possess granulocyte colony-stimulating factor receptors. Cancer Res. 1992;52:3052–5.

    CAS  PubMed  Google Scholar 

  12. Kumazawa Y, Kaneko M, Inagaki K, Matsuzaki N, Nomoto K. Accelerated recovery from gamma-irradiation-induced leukopenia in mice by the biscoclaurine alkaloid, Cepharanthin—comparison with recombinant human granulocyte colony-stimulating factor. Int J Immunopharmacol. 1990;12:523–30.

    Article  CAS  PubMed  Google Scholar 

  13. Li SY, Jei W, Seow WK, Thong YH. Effect of berbamine on blood and bone-marrow stem cells of cyclophosphamide-treated mice. Int J Immunopharmacol. 1994;16:245–9.

    Article  CAS  PubMed  Google Scholar 

  14. O’Brien S, Berman E, Borghaei H, Deangelo DJ, Devetten MP, Devine S, et al. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. J Natl Compr Canc Netw. 2009;7:984–1023.

    Article  PubMed  Google Scholar 

  15. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, 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.

    Article  CAS  PubMed  Google Scholar 

  16. Marin D, Marktel S, Bua M, Szydlo RM, Franceschino A, Nathan I, et al. Prognostic factors for patients with chronic myeloid leukaemia in chronic phase treated with imatinib mesylate after failure of interferon alfa. Leukemia. 2003;17:1448–53.

    Article  CAS  PubMed  Google Scholar 

  17. Zhao Y, Liu L, Wang Y, Wu G, Lai X, Cao W, et al. Efficacy and prognosis of chronic myeloid leukemia treated with imatinib mesylate in a Chinese population. Int J Hematol. 2009;89:445–51.

    Article  CAS  PubMed  Google Scholar 

  18. Zaucha JM, Wyrowinska E, Prejzner W, Calbecka M, Hellmann A. Imatinib-associated neutropenia may not be overcome by filgrastim treatment in patients with blastic phase of chronic myeloid leukaemia. Clin Lab Haematol. 2006;28:208–10.

    Article  CAS  PubMed  Google Scholar 

  19. Jorgensen HG, Copland M, Holyoake TL. Granulocyte colony-stimulating factor (Filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase myelogenous leukemia. Cancer. 2005;103:210–1.

    Article  PubMed  Google Scholar 

  20. Heim D, Ebnother M, Meyer-Monard S, Tsakiris D, Linn M, Tichelli A, et al. G-CSF for imatinib-induced neutropenia. Leukemia. 2003;17:805–7.

    Article  CAS  PubMed  Google Scholar 

  21. Liu X, Zhou ZR. The effect of berbamine on the immunoregulation of BALB/c mice. J Chin Med Univ. 1996;25:229–31.

    Google Scholar 

  22. Yang K, Zhao X, Xiao P, Liu G. Clinical trial of berbamine in 405 leukopenia patients. Yao Hsueh Tung Pao. 1982;17:21–2.

    Google Scholar 

  23. Sugita J, Tanaka J, Kurosawa M, Fukuhara T, Hashino S, Torimoto E, et al. Effects of the mean daily doses of imatinib during the first year on survival of patients with chronic myeloid leukemia in Japan: a study of the Hokkaido Hematology Study Group. Eur J Haematol. 2008;80:160–3.

    CAS  PubMed  Google Scholar 

  24. Nannya Y, Yokota H, Sato Y, Yamamoto G, Asai T, Ichikawa M, et al. Molecular and cytogenetic response of chronic myelogenous leukemia treated with imatinib mesylate: one institutional experience in Japan. Int J Hematol. 2008;88:159–64.

    Article  CAS  PubMed  Google Scholar 

  25. Kim DH, Sriharsha L, Jung CW, Kamel-Reid S, Radich JP, Lipton JH, et al. Comprehensive evaluation of time-to-response parameter as a predictor of treatment failure following imatinib therapy in chronic phase chronic myeloid leukemia: which parameter at which time-point does matter. Am J Hematol. 2010;85:856–62.

    Article  CAS  PubMed  Google Scholar 

  26. Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009;15:4750–8.

    Article  CAS  PubMed  Google Scholar 

  27. Xu R, Dong Q, Yu Y, Zhao X, Gan X, Wu D, et al. Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. Leuk Res. 2006;30:17–23.

    Article  CAS  PubMed  Google Scholar 

  28. Wei YL, Xu L, Liang Y, Xu XH, Zhao XY. Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo. Acta Pharmacol Sin. 2009;30:451–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The work was funded by National Natural Science Funds (81000193).

Author information

Authors and Affiliations

  1. Bone Marrow Transplant Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China

    Yanmin Zhao, Yamin Tan, Gongqiang Wu, Lizhen Liu, Yingjia Wang, Yi Luo, Jimin Shi & He Huang

Authors
  1. Yanmin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yamin Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gongqiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lizhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingjia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jimin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. He Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to He Huang.

Additional information

Y. Zhao and Y. Tan contributed equally to this study.

About this article

Cite this article

Zhao, Y., Tan, Y., Wu, G. et al. Berbamine overcomes imatinib-induced neutropenia and permits cytogenetic responses in Chinese patients with chronic-phase chronic myeloid leukemia. Int J Hematol 94, 156–162 (2011). https://doi.org/10.1007/s12185-011-0887-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0887-7

Keywords

Search

Navigation