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Editorials
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Figure 1. The use of 2nd-generation tyrosine kinase inhibitors (2G-TKI) can overcome the adverse effect of somatic mutation in epigenetic modifier genes in chronic myeloid leukemia (CML) patients. Incidence of achievement of major molecular response (MR3) following imatinib therapy (A) or 2G-TKI (B) according to the presence of somatic mutation in epigenetic modifier gene in newly diagnosed chronic phase CML patients. N: number; HR: hazard ratio; CI: confidence interval.
neoplasms (MPN).6 For example, mutation profiles are used for the initial risk assessment of AML such as inclusion of several high-risk markers such as mutations in TP53, RUNX1, and ASXL1 and high allelic ratio of FLT3-ITD in the revised European LeukemiaNet risk stratification sys- tem.7 The decision for further consolidation therapy between allogeneic HCT versus conventional consolidation therapy can be made based on the ELN risk stratification system.7 In addition, there is growing evidence to suggest that NGS-based measurable residual disease status could predict long-term outcomes in AML patients after induction chemotherapy8 or after allogeneic HCT.9 Accordingly, a next-generation sequencing (NGS)-based genomic test is being incorporated into clinical practice in a diverse subtype of hematologic malignancies. So, what about in CML?
A series of previous studies have reported consistent findings on the genomics in CML;10–13 1) somatic muta- tions, particularly those in epigenetic modification path- way, are recurrently identified in CML patients with a prevalence of approximately 30-40%; 2) increasing fre- quency of the mutation was associated with TKI resist- ance and progression to advanced disease in comparison to optimal response to TKI therapy or chronic phase (CP) disease; 3) somatic mutation in epigenetic modification pathway has adverse prognostic implication. The ASXL1 mutation is most commonly detected mutation in CP- CML patients with a prevalence of 9.7%, while it was detected with a higher frequency of 15.1% in advanced phase CML patients.13 RUNX1 mutations and IKZF1 exon deletions were strongly associated with disease progres- sion, given that it was more frequently detected in advanced phases.13 With respect to adverse prognostic implications of mutation in epigenetic modification path- way, Kim et al. reported that patients carrying gene muta- tion in the epigenetic modification pathway showed infe- rior complete cytogenetic response at 12 months (53% vs.
79%; P=0.02), major molecular response at two years (35% vs. 62%; P=0.04), and MR4.5 at three years (26% vs. 47%; P=0.03).10 Although successful replication to confirm those findings is required with well-curated clin- ical outcome data, and inclusion of larger cohorts, the study of Nteliopoulos et al.14 presented in this issue of the Journal has validated the adverse prognostic impact of somatic mutation in the epigenetic modification pathway in the patients treated with imatinib. What is interesting in this study is that an adverse prognosis from a somatic mutation in the epigenetic modification pathway can be abrogated by the use of 2nd generation TKI, which is very intriguing.
Nteliopoulos et al.14 have profiled genetic variants in epigenetic modifiers, including 71 candidate genes for predicting response to TKI therapy and progression to advanced disease. Out of 124 patients (including 62 patients treated with imatinib and 62 patients with 2nd generation TKI), they reported that 30% of patients carry somatic variants in at least one of ASXL1, IKZF1, DNMT3A, CREBBP, which is consistent with results from the previous studies. Non-responders have higher fre- quencies of somatic variants in those genes as compared to responders. When treatment outcomes were analyzed according to the TKI subtype and the presence of a muta- tion in epigenetic modifier gene, molecular response (MR3) in those with the mutation was significantly infe- rior to those without mutation when treated with ima- tinib (P=0.048) (Figure 1). On the other hand, the similar prognostic effect of a mutation in the epigenetic modi- fiers was not observed in patients treated with 2nd genera- tion TKI (P=0.25) (Figure 1). Not only for MR3, but also analyses on other clinical end points showed that an adverse prognostic effect from mutations in epigenetic modifier genes are significantly reduced by the use of 2nd generation TKI. The next step is validation and confirma-
haematologica | 2019; 104(12)