International Journal of Hematology

, Volume 108, Issue 6, pp 640–646 | Cite as

Chronic myelogenous leukemia presenting with central nervous system infiltration, successfully treated with central nervous system-directed chemotherapy followed by allogeneic stem cell transplantation

  • Akira Chiba
  • Takashi Toya
  • Hideaki Mizuno
  • Junji Tokushige
  • Fumihiko Nakamura
  • Kumi Nakazaki
  • Mineo KurokawaEmail author
Case Report


With the introduction of tyrosine kinase inhibitors (TKIs), prognosis of chronic myelogenous leukemia (CML) has improved dramatically. However, treatment for blast phase (BP) CML remains a challenge. CML infiltration of the central nervous system (CNS) is particularly rare and no effective treatment strategy has been established. The present case reports a 30-year-old man presenting with sensory deafness. Marked leukocytosis with p210 BCR-ABL1 mRNA positivity and Philadelphia chromosome detected by bone marrow biopsy confirmed the diagnosis of CML. Dura thickening in brain MRI and immature cells with Philadelphia chromosome in spinal fluid confirmed CNS invasion of CML and he was diagnosed with BP-CML. Two cycles of hyper-CVAD/MA (cyclophosphamide, vincristine, doxorubicin and dexamethasone/ high-dose methotrexate and cytarabine) therapy with dasatinib and concomitant intrathecal chemotherapy induced complete cytogenetic response and remission of CNS involvement. Bone marrow transplantation from an unrelated HLA-mismatched donor was performed and complete molecular response in bone marrow and complete remission in CNS disease was achieved. To our knowledge, this the first report of BP-CML with CNS infiltration at initial diagnosis, and shows that CNS-directed chemotherapy with dasatinib followed by allogeneic hematopoietic stem cell transplantation is useful in the treatment for BP-CML with CNS invasion in the TKI era.


Chronic myelogenous leukemia Tyrosine kinase inhibitor Central nervous system Blast phase Allogeneic hematopoietic stem cell transplantation 


Compliance with ethical standards

Conflict of interest

M.K. received lecture fee and research grants from Bristol-Myers Squibb. M.K. received lecture fee and research grants and F.N. received lecture fee from Novartis Pharma K.K.


  1. 1.
    Usui N. JSH guideline for tumors of hematopoietic and lymphoid tissues-leukemia: 4. Chronic myelogenous leukemia (CML) /myeloproliferative neoplasms (MPN). Int J Hematol. 2017;106(5):591–611.CrossRefGoogle Scholar
  2. 2.
    Saussele S, Silver RT. Management of chronic myeloid leukemia in blast crisis. Ann Hematol. 2015;94(Suppl 2):159–65.CrossRefGoogle Scholar
  3. 3.
    Wang Y, Wu D, Sun A, Jin Z, Qiu H, Miao M, et al. Allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in second chronic phase attained by imatinib after onset of blast crisis. Int J Hematol. 2008;87(2):167–71.CrossRefGoogle Scholar
  4. 4.
    Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14–22.CrossRefGoogle Scholar
  5. 5.
    Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–99.PubMedGoogle Scholar
  6. 6.
    Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, 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;90:850–8.CrossRefGoogle Scholar
  7. 7.
    Benjamini O, Dumlao TL, Kantarjian H, O’Brien S, Garcia-Manero G, Faderl S, et al. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol. 2014;89:282–7.CrossRefGoogle Scholar
  8. 8.
    Ravandi F, O’Brien S, Thomas D, Faderl S, Jones D, Garris R, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116:2070–7.CrossRefGoogle Scholar
  9. 9.
    Pfeifer H, Wassmann B, Hofmann WK, Komor M, Scheuring U, Bruck P, et al. Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate. Clin Cancer Res. 2003;9(13):4674–81.PubMedGoogle Scholar
  10. 10.
    Rajappa S, Uppin SG, Raghunadharao D, Rao IS, Surath A. Isolated central nervous system blast crisis in chronic myeloid leukaemia. Haematol Oncol. 2004;22:179–81.CrossRefGoogle Scholar
  11. 11.
    Rytting ME, Wierda WG. Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy. Leuk Lymphoma. 2004;45(8):1623–6.CrossRefGoogle Scholar
  12. 12.
    Johnson NA, Fetni R, Caplan SN. Isolated central nervous system relapse in patients with chronic myeloid leukemia on imatinib mesylate. Leuk Lymphoma. 2005;46(4):629–30.CrossRefGoogle Scholar
  13. 13.
    Beyazit Y, Aksu S, Kekilli M, Haznedaroglu IC, Kilickap S, Goker H. Unusual extramedullary relapses under imatinib mesylate treatment in chronic myeloid leukemia. Am J Hematol. 2005;79(1):79–80.CrossRefGoogle Scholar
  14. 14.
    Matsuda M, Morita Y, Shimada T, Miyake J, Hirase C, Tanaka M, et al. Extramedullary blast crisis derived from 2 different clones in the central nervous system and neck during complete cytogenetic response of chronic myelogenous leukemia treated with imatinib mesylate. Int J Hematol. 2005;81:307–9.CrossRefGoogle Scholar
  15. 15.
    Kim HJ, Jung CW, Kim K, Ahn JS, Kim WS, Park K, et al. Isolated blast crisis in XNS in a patient with chronic myelogenous leukaemia maintaining major cytogenetic response after imatinib. J Clin Oncol. 2006;24:4028–9.CrossRefGoogle Scholar
  16. 16.
    Oshima K, Kanda Y, Yamashita T, Takahashi S, Mori T, Nakaseko C, et al. Central Nervous System Relapse of Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2008;14(10):1100–7.CrossRefGoogle Scholar
  17. 17.
    Isobe Y, Sugimoto K, Masuda A, Hamano Y, Oshimi K. Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate. Intern Med J. 2009;39(6):408–11.CrossRefGoogle Scholar
  18. 18.
    Thomas A, Stein CK, Gentile TC, Shah CM. Isolated CNS relapse of CML after bone marrow transplantation. Leuk Res. 2010;34(4):113–4.CrossRefGoogle Scholar
  19. 19.
    Barlow A, Robertson M, Doig A, Stewart W, Drummond MW. Isolated central nervous system lymphoid blast crisis in chronic myeloid leukaemia in major molecular remission. Br J Haematol. 2008;142(3):327.CrossRefGoogle Scholar
  20. 20.
    Neumann M, Blau IW, Burmeister T, Tiwtze-Buerger C, Blau O, Gerbitz A, et al. Intrathecal application of donor lymphocytes in leukemic meningeosis after allogeneic stem cell transplantation. Ann Hematol. 2011;90(8):911–6.CrossRefGoogle Scholar
  21. 21.
    Radhika N, Minakshi M, Rajesh M, Manas BR, Deepak Kumar M. Central nervous system blast crisis in chronic myeloid leukemia on imatinib mesylate therapy: report of two cases. Indian J Hematol Blood Transfus. 2011;27(1):51–4.CrossRefGoogle Scholar
  22. 22.
    Fuchs M, Reinhöfer M, Ragoschke-Schumm A, Sayer HG, Boer K, Witte OW, et al. Isolated central nervous system relapse of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation. BMC Blood Disord. 2012;12:2–5.CrossRefGoogle Scholar
  23. 23.
    Lindhorst SM, Lopez RD, Sanders RD. An unusual presentation of chronic myelogenous leukemia: a review of isolated central nervous system relapse. J Natl Compr Cancer Netw. 2013;11(11):745–50.CrossRefGoogle Scholar
  24. 24.
    Nishimoto M, Nakamae H, Koh KR, Kosaka S, Matsumoto K, Morita K, et al. Dasatinib maintenance therapy after allogeneic hematopoietic stem cell transplantation for an isolated central nervous system blast crisis in chronic myelogenous leukemia. Acta Haematol. 2013;130:111–4.CrossRefGoogle Scholar
  25. 25.
    Gaur S, Torabi AR, Corral J. Isolated central nervous system relapse in two patients with BCR-ABL-positive acute leukemia while receiving a next-generation tyrosine kinase inhibitor. In Vivo. 2014;28:1149–53.PubMedGoogle Scholar
  26. 26.
    Park MJ, Park PW, Seo YH, Kim KH, Seo JY, Jeong JH, et al. A case of isolated lymphoblastic relapse of the central nervous system in a patient with chronic myelogenous leukemia treated with imatinib. Ann Lab Med. 2014;34:247–51.CrossRefGoogle Scholar
  27. 27.
    Lai SW, Huang TC, Chen JH, Wu YY, Chang PY. Dasatinib as the salvage therapy for chronic myeloid leukemia with blast crisis and central nervous system involvement: a case report. Oncol Lett. 2015;9:1957–61.CrossRefGoogle Scholar
  28. 28.
    Xu Z, Zheng M, Wu C, Ma Y, Meng L, Zhou J, et al. The overwhelmingly positive response to Dasatinib of a patient with multiple blast crisis of chronic myeloid leukemia. Int J Clin Exp Med. 2015;8:1460–6.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Gomez J, Duenas V. Isolated central nervous system relapse in chronic myeloid leukemia. Case Rep Med. 2015;2015:232915.CrossRefGoogle Scholar
  30. 30.
    Jain A, Gupta N. Isolated CNS blast crises in chronic myeloid leukaemia presenting as hypertrophic pachymeningitis and bilateral optic neuritis: a case report. J Clin Diagn Res. 2016;10:OE01–5.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S, et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma. 2004;45(4):695–8.CrossRefGoogle Scholar
  32. 32.
    Cordon-Cargo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA. 1989;86(2):695–8.CrossRefGoogle Scholar
  33. 33.
    Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein mediated efflux. J Pharmacol Exp Ther. 2003;304:1085–92.CrossRefGoogle Scholar
  34. 34.
    O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65(11):4500–5.CrossRefGoogle Scholar
  35. 35.
    Porkka K, Koskenvesa P, Lundán T, Rimpilainen J, Mustjoki S, Smykla R, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112(4):1005–12.CrossRefGoogle Scholar
  36. 36.
    Strari P, Kantarjian H, Thomas D, O’Brien S, Konoplev S, Jorgensen JL, et al. HCVAD plus imatinib or dasatinib in lymphoid blastic phase chronic myeloid leukemia. Cancer. 2014;120:373–80.CrossRefGoogle Scholar
  37. 37.
    Jain N, van Besign K. Chronic myelogenous leukemia: role of stem cell transplant in the imatinib era. Hematol Oncol Clin N Am. 2011;25:1025–48.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2018

Authors and Affiliations

  • Akira Chiba
    • 1
  • Takashi Toya
    • 1
  • Hideaki Mizuno
    • 1
  • Junji Tokushige
    • 1
  • Fumihiko Nakamura
    • 1
  • Kumi Nakazaki
    • 1
  • Mineo Kurokawa
    • 1
    • 2
    Email author
  1. 1.Department of Hematology and Oncology, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Department of Cell Therapy and Transplantation MedicineThe University of Tokyo HospitalTokyoJapan

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