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.
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.
Bumm
Thomas
T
Department of Hematology, University of Leipzig, Germany.
Müller
Christel
C
Al-Ali
Haifa-Kathrin
HK
Krohn
Knut
K
Shepherd
Patricia
P
Schmidt
Erika
E
Leiblein
Sabine
S
Franke
Christina
C
Hennig
Evelin
E
Friedrich
Thomas
T
Krahl
Reiner
R
Niederwieser
Dietger
D
Deininger
Michael W N
MW
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000473:pathology*; D001549:Benzamides; D001773:Blood Cells / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002999:Clone Cells / Q000473:pathology*; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D004303:Dosage Compensation, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006410:Hematopoiesis; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage / Q000009:adverse effects; D000068877:Imatinib Mesylate; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000473:pathology; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000032:analysis; D012074:Remission Induction
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D011944:Receptors, Androgen; D003561:Cytarabine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D015255:Idarubicin