Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia

Abstract

Imatinib mesylate (Gleevec s ), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.

Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

“…So far, clinical observations do not support a direct mutagenic effect of imatinib. The increase of chromosomal aberrations in Philadelphia-negative cells reported during early clinical studies of imatinib (Andersen et al, 2002;Terre et al, 2004) is not observed in patients treated upfront with imatinib. However, agents with mutagenic capacity such as cigarette smoking cause malignant disease not before decades of exposure.…”

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

“…The incidence of Philadelphia independent clonal evolution during imatinib was in the range of the literature (2-17%). 1,4,5 The lower incidence of Philadelphia independent clonal evolution in patients with interferon corresponds to the small number of anecdotal reports in the literature. 1,6 Imatinib was started in 14/15 patients in chronic phase of CML.…”

“…In previous studies, the proportion of patients who had received pretreatment was higher. 1,4 The median interval from the start of therapy with imatinib or IFN to the first observation of the Ph independent clonal aberrations was 7.5 months (range 3-15 months). This corresponds to the literature, reporting median intervals from 5 to 24 months.…”

“…Trisomy 8 and monosomy 7 were found as the most frequent abnormalities. 1,7 Reciprocal translocations were described in Philadelphia independent clonal evolution in the literature. 1,4,8 Reciprocal translocations involving 8q have not been reported so far in Philadelphia independent clonal evolution.…”

“…This corresponds to the literature, reporting median intervals from 5 to 24 months. 1,7,8 From diagnosis of CML to the first occurrence of the Ph independent clonal changes, the median Interval from diagnosis of CML to the first occurrence of the Ph independent clonal changes.…”