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

• Published in: Blood 2003-03, Vol.101 (5), p.1941-1949
• Main Authors: Bumm, Thomas, Müller, Christel, Al-Ali, Haifa-Kathrin, Krohn, Knut, Shepherd, Patricia, Schmidt, Erika, Leiblein, Sabine, Franke, Christina, Hennig, Evelin, Friedrich, Thomas, Krahl, Reiner, Niederwieser, Dietger, Deininger, Michael W.N.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B-Lymphocytes - pathology; Benzamides; Biological and medical sciences; Blood Cells - pathology; Bone Marrow Cells - pathology; Clone Cells - pathology; Cohort Studies; Cytarabine - administration & dosage; Cytarabine - adverse effects; Dosage Compensation, Genetic; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Fusion Proteins, bcr-abl - antagonists & inhibitors; Hematologic and hematopoietic diseases; Hematopoiesis; Humans; Idarubicin - administration & dosage; Idarubicin - adverse effects; Imatinib Mesylate; Immunotherapy; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Middle Aged; Myelodysplastic Syndromes - pathology; Pharmacology. Drug treatments; Philadelphia Chromosome; Piperazines - pharmacology; Piperazines - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Receptors, Androgen - analysis; Remission Induction
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-07-2053

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 ofBcr-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.