Emergence of clonal cytogenetic abnormalities in Ph−cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority

作者：Thomas G.P. Bumm, Christel Müller, Haifa Kathrin Al‐Ali, Knut Krohn, Patricia C. A. Shepherd, Erika Schmidt, Sabine Leiblein, Christina Franke, Evelin Hennig, Thomas Friedrich, Rainer Krahl, Dietger W. Niederwieser, Michael W. Deininger · 发表于：Blood · 年份：2003 · DOI：10.1182/blood-2002-07-2053 · 被引用次数：222 · 研究领域：Chronic Myeloid Leukemia Treatments、Chronic Lymphocytic Leukemia Research、Eosinophilic Disorders and Syndromes

Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.