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 BcrAbl 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

Insights into the stem cells of chronic myeloid leukemia

“…6,7 At the same time, direct assessment of more primitive populations typically reveals the presence of a persistent, even predominant, normal (polyclonal) stem cell compartment. 67,68 On the other hand, if the bulk of the leukemic cells are killed by treatments that are either non-specific (for example, intensive chemotherapy 69 ) or specific (for example, tyrosine kinase inhibitors that target the BCR-ABL oncoprotein 70,71 ), the residual normal HSCs, being the more numerous, are stimulated to reinitiate normal hematopoiesis. This can then produce a full cytogenetic, as well as a hematologic remission, the duration of which will depend on the effectiveness and duration of the anti-leukemic treatment applied.…”

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

“…30 In detail, CEP 8 SO, LSI 5q EGR 1SO/D5S23 SG, LSI D7S522 SO/CEP 7SG, LSI MLL Dual Color, LSI CBFB, inv 16 DualColor, LSI D20S108 SO, LSI D13S319 SO and LSI p53SO were used to detect abnormalities. The cutoffs for positivity, determined in the background of healthy individuals, range between 1 and 4.5%.…”

Chronic Myeloid Leukemia

“…22 In addition, clonal chromosomal abnormalities have also been detected in Ph -cells. 23 The prognostic significance of this finding is currently unknown, but progression to acute myeloid leukemia has been seen in patients with dysplastic morphology. Quantitative PCR.…”