Sequential karyotype study on Ph-positive chronic myelocytic leukemia. Significance of additional chromosomal abnormalities during disease evolution

Abstract

Twenty-eight patients with Ph-positive chronic myelocytic leukemia (CML), who all died of the disease, had cytogenetic studies throughout the progression of the disease: at diagnosis, during chronic phase (CP), accelerated phase (AP), and blastic transformation (BT). The aim of this sequential study was to appreciate the frequency and the significance of additional chromosomal abnormalities (ACA) during CML evolution, especially in the CP. In our series ACA were rare (five of 28 patients) and simple (four of five) in CP. They were much more frequent and complex in AP (11 of 16) and in BT (22 of 24) with complex abnormalities (13 of 24). In CP, ACA predictive value for metamorphosis was poor: only three of 13 patients had ACA within 1 year before BT, and only two of 11 within 1 year before AP. ACA were mainly observed during the last period before BT: ten of 17 patients studied within 6 months prior BT had ACA, but by then two of three were in AP. ACA, especially when complex, appear to be a hallmark of CML metamorphosis.

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“…In these cohort cases, the rate of ACA grew gradually from newly diagnosed CP to BC. Although the ACA rate in newly diagnosed CP, CP after therapy, and AP were seldom reported, the rate in BC was only 52.9% in our series, which was lower than 60-80% in previous studies [6,[21][22][23][24][25]. This discrepancy might be attributed to various factors: (1) there were different diagnostic criteria for BC.…”

“…Morphologically and immunophenotypically, myeloid transformation accounts for approximately 70% of CML cases, while lymphoid transformation accounts for 30% [5]. In the course of the disease, additional chromosome abnormalities (ACA) including trisomy 8, duplication of the Ph chromosome, isochromosome 17q [i(17)(q10)], trisomy 19, and trisomy 21 appear gradually [6,7]. Among these ACA, trisomy 8, acquisition of an additional Ph chromosome, and i(17q) have more tendency to myeloid transformation than lymphoid transformation [5,8,9].…”

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“…74,104 Another indicator of progression risk is clonal evolution (ie, the acquisition of ACA in the course of the disease). [105][106][107][108] The relevance of clonal evolution has not changed in the imatinib era. [109][110][111][112] Mutations may be associated with clonal evolution.…”

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“…In 60-80% of the cases, ACA precede or accompany blastic phase [14,15,[23][24][25][26][27][28][29][30][31][32][33], thus there is undoubtedly a strong association between secondary changes and transformation. Furthermore, early studies of splenic CML transformations give rise to strong support for the clinical importance of additional changes, showing that the secondary aberrations appeared in the spleen before bone marrow [34][35][36].…”

“…Third, the number and types of aberrations present during chronic phase and blastic phase may also play a role. Quite often the karyotypic changes observed in the chronic phase are single events, particularly the loss of the Y chromosome, +8, +Ph, and i(17q) [47], while they are multiple and complex in blastic phase [15,31,37,42,46]. The aberrations in i(17q), or other changes that result in loss of 17p seem particularly ominous [15,23,25,37,42.47-49].…”