Therapie der chronischen myeloischen Leukämie 2004

Zusammenfassung

Die chronische myeloische Leukämie (CML) stellt eine Modellerkrankung für Diagnostik und Therapie neoplastischer Erkrankungen dar. Die zugrundeliegende zytogenetische Aberration, das Philadelphia-Chromosom, mit der BCR-ABL-Genfusion sowie der mehrstufige Verlauf mit der stabilen, therapeutisch gut zu beeinflussenden chronischen Phase, der Akzelerations- und der Blastenphase ermöglichen die Übertragung molekularzytogenetischer Erkenntnisse in die klinisch-therapeutische Anwendung. Auf der Grundlage der molekularen Aufklärung der Pathogenese der CML erfolgte die Entwicklung des selektiven Inhibitors der BCR-ABL-Tyrosinkinase Imatinib. Vielversprechende präklinische Daten wurden in Phase-I- bis III-Studien bestätigt. Imatinib ist bezüglich der hämatologischen und zytogenetischen Remissionsraten und der Nebenwirkungen der Therapie mit Interferon α überlegen. Offene Fragen der Imatinib-Therapie sind die Therapiedauer bei Patienten mit gutem Ansprechen, Langzeitnebenwirkungen, Persistenz einer minimalen Resterkrankung bei den meisten Patienten, die Gefahr der Resistenzentwicklung bei Langzeit-Monotherapie sowie der Stellenwert von Kombinationstherapien. Prospektive klinische Studien, bespielsweise die CML-IV-Studie der deutschen CML-Studiengruppe, sollen diese Fragen beantworten. Insbesondere soll der Stellenwert der einzelnen Therapiebausteine (Imatinib, Interferon α, Ara-C, allogene Stammzelltransplantation) geprüft werden. Der Einschluss neudiagnostizierter CML-Patienten in die CML-IV-Studie wird empfohlen.

Summary

Chronic myelogenous leukemia consitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosom with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon α. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon α, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

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