Clonal aberrations in Philadelphia chromosome negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha

Induction of centrosome and chromosome aberrations by imatinib in vitro

“…32,33 Impaired T-cell-mediated immunosurveillance could explain the increasing number of reports dealing with the incidence of secondary hematologic malignancies and infections in patients under imatinib. 14,15,32,34 The mechanisms by which imatinib affects genetic stability in normal cells are unknown, as no uniform influence of the drug on gene expression patterns in PhÀ CD34 þ cells has been detectable in vivo. 24 However, they are likely due to its function as a potent kinase inhibitor by stereochemically mimicking ATP.…”

“…10 After imatinib therapy, the emergence of Ph-negative clones distinctly different in their karyotypes from the Ph-positive clone is reported with variable frequency. [10][11][12][14][15][16] Preliminary data suggest that 3% up to 17% of patients treated with imatinib display such clonal evolution. 14,17 Common changes are trisomy 8 and monosomy 7.…”

“…14,17 Common changes are trisomy 8 and monosomy 7. 10,12,14 Since most patients receive conventional cytostatic therapy before imatinib treatment and results from long-term follow-up studies under first-line imatinib therapy are not available yet, the role of imatinib in the origin of Ph-negative clones is still unclear.…”

Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure

“…The incidence is comparable to that after IFN or imatinib therapies (2-17%). 5 Since clonal chromosome aberrations in Ph negative cells are mainly numerical, at least after imatinib treatment, 17 these findings suggest a causative role of imatinib or dasatinib or prior chemotherapy in the emergence of clonal evolution or reflect genomic instability of the hematopoietic cells of CML patients. Ph negative evolution could also be due to selective pressure by imatinib or dasatinib on Ph positive clones, allowing pre-existing Ph negative clones to predominate.…”

“…Pre-treatment for the 71 patients consisted of imatinib, HU (n=48), IFN (n=49), cytosine arabinoside (AraC, n=11) and nilotinib (n=2) alone or in combination. Median duration of dasatinib therapy was nine months (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Dasatinib was stopped due to progressive disease in four, and because of hematologic toxicity in three patients.…”