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ACAs characterised for blast phase-CML after TKI therapy


Leukemia 2016; Advance online publication

: Researchers have characterised the pattern of additional chromosomal aberrations (ACAs) in patients with chronic myeloid leukaemia in the blast phase (BP–CML) who have received tyrosine kinase inhibitor (TKI) therapy.

Contrary to earlier studies of patients in the acute and chronic phases, the impact of ACAs on prognosis did not differ between those with traditional major-route ACAs and minor-route ACAs, defined widely as alterations making up at least 10% and less than 10% of ACAs in affected patients, respectively.

The pattern of ACAs was also different from that detected in BP–CML patients in the era before TKI therapy, observe Shimin Hu, from The University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

“Undoubtedly, TKI treatment is involved in inducing the changes”, they write, noting that three-quarters of the BP–CML patients with a 3q26.2 rearrangement also had ABL1 kinase domain mutations, which is significantly higher than average for BP–CML patients.

“We propose that TKI resistance has an important role in the changing landscape of ACAs in BP”, the authors say.

The study determined ACA status in 354 patients with BP–CML, 21 of whom were in BP at diagnosis and treated with TKIs, while the remainder who were diagnosed during accelerated or chronic phase disease were given TKI therapy before blastic transformation.

As published in Leukemia, 76.3% of study participants had ACAs, with 25.2% having a single aberration and 74.8% complex ACAs, defined as the presence of at least two aberrations.

ACAs were significantly more common in the 240 patients with myeloid BP than in the 106 patients with a lymphoid immunophenotype, at 79.6% versus 69.8%.

Twenty-nine different ACAs occurred at a frequency of 2.0% or more, most commonly the major-route changes of chromosome 8 trisomy (28.1%), an additional Philadelphia chromosome (26.3%), 3q26.2 rearrangement (15.2%), loss of chromosome 7 (13.3%) and isochromosome 17q (10.7%).

And analysis showed that while most of the common ACAs tended to come with other alterations, 39% of patients with a 3q26.2 rearrangement had no additional aberrations.

Lineage also affected distribution of common ACAs. Trisomies of chromosomes 8 and 19, 3q26.2 rearrangement and isochromosome 17q were significantly more common in patients with myeloid versus lymphoid immunophenotype, with no cases of 3q26.2 rearrangement in the lymphoid patients, whereas loss of chromosome 7 was more common in lymphoid than myeloid patients.

Among the 270 patients with ACAs, survival was comparable between the 125 patients with traditional major-route ACAs and the 145 patients with minor-route ACAs, regardless of whether the ACAs were single or complex.

Similarly, survival was comparable between the 176 patients with the ACAs affecting over 10% of the BP patients and those with less common ACAs, regardless of ACA complexity, although patients with these frequent ACAs had a longer time between initial CML diagnosis and BP diagnosis and were more likely to have complex ACAs than those with less common alterations.  

There was also no difference between patients with the frequent and less frequent ACAs specific to the BP group when they were stratified by myeloid and lymphoid immunophenotypes.

The researchers note that while 3q26.2 rearrangement was “very rare” before the use of TKIs, it occurred in 15.2% of patients in the current study, 72.7% of whom also had ABL1 mutations. This was significantly higher than the 49.2% carriage of ABL1 mutations for the 177 patients without the rearrangement or the 46.6% of 133 patients with other ACAs.

Finally, the team used Pearson correlation analysis to determine linkage between seven different common ACAs in the BP group, finding that the presence of 3q26.2 rearrangement, loss of chromosome 7 and isochromosome 17q tended to occur independently of each other and other ACAs. By contrast, there is often overlap of trisomy of chromosomes 8, 19, 21 or the emergence of an additional Philadelphia chromosome, the authors report.

“Although the type of ACAs conferred no prognostic value in BP, the linkage relationship between common ACAs in BP revealed by Pearson correlation analysis may help extrapolate their roles in blastic transformation”, Hu et al conclude.

By Lynda Williams, Senior medwireNews Reporter

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