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Chronic myeloid leukemia: Pathophysiology, diagnostic parameters, and current treatment concepts

Chronische myeloische Leukämie: Pathophysiologie, Diagnostik und aktuelle Therapiekonzepte

Wiener Klinische Wochenschrift volume 115, pages 485–504 (2003)Cite this article

Zusammenfassung

Die chronisch myeloische Leukämie (CML) ist eine Stammzellerkrankung, die durch eine exzessive Akkumulation myeloischer Zellen gekennzeichnet ist. In den CML Zellen findet sich die spezifische Translokation t(9;22), welche dasbcr/abl Onkogen generiert. Das entsprechende Onkoprotein (=BCR/ABL) weist eine konstitutive Tyrosinkinaseaktivität auf und fördert Wachstum und Überleben der CML Zellen. Aus klinischer Sicht unterscheidet man drei Krankheitsphasen: die chronische Phase (CP), die akzelerierte Phase (AP) und die Blastenphase (BP), welche einer akuten Leukämie entspricht. Die Progression zur AP und BP ist durch das Auftreten zusätzlicher genetischer Defekte gekennzeichnet, welche mitbcr/abl kooperieren und zur Therapieresistenz führen. Die Prognose der CML ist variabel und hängt von der Krankheitsphase, dem Alter und dem Therapieresponse ab. Die einzige derzeit verfügbare kurative Therapie ist die Stammzelltransplantation. Für Patienten, welche nicht transplantiert werden können, stehen potente anti-leukämische Substanzen, wie der BCR/ABL Tyrosinkinase-Inhibitor STI571 (Glivec, Imatinib), Interferon alpha (mit und ohne ARA-C) oder andere zytoreduktive Medikamente zur Verfügung. Dabei übertrifft STI571 offensichtlich alle anderen Medikamente in Bezug auf den zytogenetischen und molekularen Response. Langzeitergebnisse mit STI571 liegen derzeit allerdings noch nicht vor, und vor kurzem wurde auch über STI571 Resistenzen berichtet. Zukünftige Strategien werden daher das Ziel verfolgen, diesen Resistenzen durch Applikation von zusätzlichen antileukämischen Substanzen entgegenzuwirken. Ob diese Strategien zu einer kurativen medikamentösen Therapie der CML führen werden, bleibt abzuwarten.

Summary

Chronic myeloid leukemia (CML) is a stem cell disease characterized by excessive accumulation of clonal myeloid (precursor) cells in hematopoietic tissues. CML cells display the translocation t(9; 22) that creates thebcr/abl oncogene. The respective oncoprotein (=BCR/ABL) exhibits constitutive tyrosine kinase activity and promotes growth and survival in CML cells. Clinically, CML can be divided into three phases: the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP) that resembles acute leukemia. Progression to AP and BP is associated with occurrence of additional genetic defects that cooperate withbcr/abl in leukemogenesis and lead to resistance against antileukemic drugs. The prognosis in CML is variable depending on the phase of disease, age, and response to therapy. The only curative approach available to date is stem cell transplantation. For those who cannot be transplanted, the BCR/ABL tyrosine kinase inhibitor STI571 (Glivec, Imatinib), interferon-alpha (with or without ARAC), or other cytoreductive drugs are prescribed. Currently available data show that STI571 is a superior compound compared to other drugs in producing complete cytogenetic and molecular responses. However, despite superior initial data and high expectations for an effect on survival, long term results are not available so far, and resistance against STI571 has been reported. Forthcoming strategies are therefore attempting to prevent or counteract STI571 resistance by co-administration of other antileukemic drugs. Whether these strategies will lead to curative drug therapy in CML in the future remains at present unknown.

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Affiliations

  1. Abteilung Hämatologie und Hämostaseologie, Universitätsklinik für Innere Medizin I, AKH-Wien, Währinger, Gürtel 18-20, A-1097, Wien, Austria

    Christian Sillaber M.D., Matthias Mayerhofer, Hermine Agis, Verena Sagaster, Wolfgang R. Sperr & Peter Valent

  2. Klinisches Institut für medizinische und chemische Laboratoriumsdiagnostik, AKH-Wien, Vienna, Austria

    Christine Mannhalter

  3. 5. Medizinische Abteilung mit Onkologie, Krankenhaus Lainz, Vienna, Austria

    Klaus Geissler

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  1. Christian Sillaber M.D.
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  2. Matthias Mayerhofer
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  3. Hermine Agis
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  4. Verena Sagaster
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  5. Christine Mannhalter
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  6. Wolfgang R. Sperr
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  7. Klaus Geissler
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  8. Peter Valent
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Correspondence to Christian Sillaber M.D..

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Supported by: Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich, grant #P 15487 and #P16412.

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Sillaber, C., Mayerhofer, M., Agis, H. et al. Chronic myeloid leukemia: Pathophysiology, diagnostic parameters, and current treatment concepts. Wien Klin Wochenschr 115, 485–504 (2003). https://doi.org/10.1007/BF03041033

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Schlüsselwörter

  • CML
  • BCR/ABL
  • Targeted Therapy
  • STI571
  • Glivec
  • Imatinib

Key words

  • CML
  • BCR/ABL
  • targeted therapy
  • STI571
  • Glivec
  • Imatinib