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Prognosis of -7/del(7q) in Ph- cells and underlying MDS
in CCA/Ph- CML patients with features of MDS (P=0.006). Mutations were not associated with age and there was no preferentially significant association with -7/del(7q), despite a higher rate of MDS features in this subgroup. As already reported in CML,18–20 ASXL1 is one of the most frequently mutated genes. Although somatic mutation or decreased expression of EZH2 at 7q36.1 plays a role in cancer, the molecular mechanisms responsible for the poor prognosis of chromosome 7 alterations in hematologic diseases remains undefined. In this study, three patients had EZH2 mutations. One of them had -7 CCA/Ph-, thus suggesting a bi-allelic alteration. This patient further progressed to an advanced phase of CML, but the direct role of the EZH2 mutation in this case could not be determined because the frequency of the variant was low (1%) and it was associated with other mutations in ASXL1, CBL, SETBP1 and SRSF2. The two other patients with EZH2 mutations had +8 CCA/Ph-, asso- ciated in one case with an ASLX1 mutation, and neither of them had further disease evolution. It has been described that NGS screening of CML patients in major molecular response revealed a higher rate of other gene mutations in patients with CCA/Ph- than in patients without CCA/Ph-.21 These latter mutational events may therefore be independ- ent, and could result from genetic instability.
In conclusion, in this study we were able to demonstrate the negative prognostic impact of -7/del(7q) CCA/Ph- on the cumulative incidences of MR4.5, event-free survival and
progression-free survival in a cohort of 102 CML patients with CCA/Ph- with a median follow up of more than 6 years. Morphological features of MDS represent a negative prognostic factor for optimal response to treatment, irre- spectively of the type of CCA/Ph-, even though they are more frequent in the -7/del(7q) CCA/Ph- subgroup. NGS screening for MDS/AML mutations failed to clearly explain the underlying high risk of myelodysplastic disease in the -7/del(7q) CCA/Ph- group, but the presence of muta- tions in genes of our MDS/AML panel was statistically associated with morphological features of MDS on bone marrow smears. Further analyses will help to determine whether morphological signs of MDS in the bone marrow and/or MDS mutations at the time of emergence of CCA/Ph- represent a warning signal in these particular CML patients.
Funding
This work was funded with the support of the Fi-LMC group, which received partial contributions from Bristol Myers Squibb, Novartis and Incyte Pharma.
Acknowledgments
The authors would like to thank Laurence Meyer for her mor- phological bone marrow partial review, and Olivier Nibourel, Jean-Michel Cayuela, and Sandrine Hayette for their BCR-ABL1 molecular monitoring data.
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