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.

Abstract

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.

• Authors: Thomas Bumm, Christel Müller, Haifa-Kathrin Al-Ali, Knut Krohn, Patricia Shepherd, Erika Schmidt, Sabine Leiblein, Christina Franke, Evelin Hennig, Thomas Friedrich, Reiner Krahl, Dietger Niederwieser, Michael W N Deininger
• Journal: Blood (Blood) Vol. 101 Issue 5 Pg. 1941-9 (Mar 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12411298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Piperazines
• Pyrimidines
• Receptors, Androgen
• Cytarabine
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• Idarubicin

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• B-Lymphocytes (pathology)
• Benzamides
• Blood Cells (pathology)
• Bone Marrow Cells (pathology)
• Clone Cells (pathology)
• Cohort Studies
• Cytarabine (administration & dosage, adverse effects)
• Dosage Compensation, Genetic
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Hematopoiesis
• Humans
• Idarubicin (administration & dosage, adverse effects)
• Imatinib Mesylate
• Karyotyping
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Middle Aged
• Myelodysplastic Syndromes (pathology)
• Philadelphia Chromosome
• Piperazines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Receptors, Androgen (analysis)
• Remission Induction