Chromosome 3q26.2 rearrangements linked to poor CML prognosis

By Lynda Williams, Senior medwireNews Reporter

Rearrangements of chromosome 3q26.2 have a significant negative impact on patients with chronic myeloid leukaemia, suggests research published in Blood.

Patients with such abnormalities had shorter overall survival than patients affected by other chromosomal abnormalities and were less likely to respond to tyrosine kinase inhibitor (TKI) therapy.

This poor prognosis may be related to overexpression of the EVI1 oncogene associated with the chromosome rearrangement, leading to BCR–ABL1 independent signalling, explain Shimin Hu, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

They recommend that “[i]ntensive therapy, stem cell transplantation or investigational therapy targeted to EVI1 should be considered” for patients with 3q26.2 abnormalities whose disease is not controlled by TKIs.

Overall, 5.8% of 2013 CML patients in the study carried abnormalities in chromosome 3, with chromosomal 3q26.2 rearrangements making up 50% of cases. Rearrangements not involving the 3q26.2 locus were detected in 32% of patients and a gain or loss of part or all of the chromosome was seen in 18%.

The researchers found that 3q26.2 rearrangements emerged during all stages of CML, with 33% occurring during chronic phase, 17% in acute phase and 50% in blast phase, but patients whose rearrangement occurred during the chronic or acute phase had a high rate of transformation to the blast phase.

TKI therapy was given to 82% of patients with chromosome 3 abnormalities with variable response, the researchers observe.

Just three (6%) of the 47 patients with 3q26.2 rearrangements achieved a complete cytogenetic response (CCyR); this was transient in two cases and relapse occurred after 12 months in the third patient. Two (4%) of these patients achieved a major molecular response (MMR), while two further patients who did not achieve a CCyR to TKIs achieved remission following allogeneic stem cell transplantation.

By contrast, patients with other chromosome 3 abnormalities had a significantly higher response to TKI therapy, with 42% achieving a CCyR and 29% MMR.

Overall survival was significantly shorter in patients with 3q26.2 rearrangements than those with different chromosome 3 rearrangements, although patients with deletion or addition of chromosome 3 had comparable survival to those with 3q26.2 changes.

Multivariate analysis also determined that overall survival was significantly poorer in 23 patients with only 3q26.2 rearrangements than in 248 patients whose chromosomal aberrations did not affect chromosome 3, including those who had trisomy 8.

But the 35 patients who had 3q26.2 rearrangements and additional chromosomal aberrations did not have poorer survival than the 23 patients who had only 3q26.2 changes, indicating that the poor prognosis is “not dependent on other concurrent chromosomal abnormalities”.

By contrast, patients with chromosomal aberrations not affecting chromosome 3 had a poorer survival if they had multiple aberrations rather than just one abnormality.

Finally, patients with abnormalities of chromosome 3 other than 3q26.2 rearrangement had poorer survival than those whose aberrations affected different chromosomes.

“The mechanisms that mediate the poorer survival in these patients remain unknown and likely vary from case to case as the chromosomal changes in these two groups are very heterogeneous”, the researchers comment.

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