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Hämatologische Nebenwirkungen der Tyrosinkinaseinhibition mit Imatinib

Hematological side effects of tyrosine kinase inhibition using imatinib

  • Schwerpunkt: Iatrogene Pathologie
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Zusammenfassung

Imatinib (STI571, Gleevec™/Glivec®) und neuere kleinmolekulare Tyrosinkinaseinhibitoren erzielen hohe Ansprechraten bei der Behandlung von chronischer myeloischer Leukämie (CML), gastrointestinalen Stromatumoren (GIST) und seltenen chronischen myeloproliferativen Erkrankungen. Es werden Tyrosinkinase-abhängige Signalwege unterbrochen und Optionen für Neoplasien mit aktivierenden Mutationen im Abelson-, Abl-related-, Kit- oder PDGF-RA- und PDGF-RB-Gen geboten. Allerdings können sekundär therapieresistente mutierte Tumorzellklone auftreten.

Meist wird Imatinib bei nur geringen Nebenwirkungen gut vertragen. Es werden jedoch Toxizitäten (Ödeme, Hautrötungen, Übelkeit oder Myelosuppression) beobachtet. Einige CML-Patienten entwickeln sekundäre Philadelphia- (Ph-)/Bcr-Abl-negative klonale chromosomale Anomalien. Beckenkammbiopsien von CML-Patienten, bei denen in kompletter Remission eine prolongierte Panzytopenie nach Imatinib besteht, zeigen meist eine Markhypoplasie. Morphologisch liegen dann entweder Merkmale einer aplastischen Anämie oder eines myelodysplastischen Syndroms vor, das sich in der Ph-negativen Hämatopoese manifestiert. Vereinzelt kann eine uni- oder multilineäre Dysplasie von einem Blastenexzess begleitet sein und in eine akute Leukämie übergehen. Schwerwiegende hämatologische Nebenwirkungen von Imatinib sind jedoch extrem selten.

Aktuelle Fragen beziehen sich auf die zugrunde liegenden molekularen Mechanismen, besonders auf das Auftreten distinkter Ph-negativer aberranter Klone unter Tyrosinkinaseinhibition.

Abstract

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones.

Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare.

Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.

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Authors and Affiliations

  1. Pathologisches Institut, Universität Freiburg

    A. Schmitt-Graeff

  2. Medizinische Klinik, Klinikum Mannheim der Universität Heidelberg

    A. Hochhaus

  3. Pathologisches Institut, Universität Freiburg, Postfach 214, 79002, Freiburg

    A. Schmitt-Graeff

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  2. A. Hochhaus
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Correspondence to A. Schmitt-Graeff.

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Schmitt-Graeff, A., Hochhaus, A. Hämatologische Nebenwirkungen der Tyrosinkinaseinhibition mit Imatinib. Pathologe 27, 40–46 (2006). https://doi.org/10.1007/s00292-005-0806-x

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  • DOI: https://doi.org/10.1007/s00292-005-0806-x

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