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C.Y. Ok et al.
type (intensive chemotherapy versus hypomethylating agents). Approximately 50% of patients with CRIDH+ had MAF below the assay sensitivity of the Sanger sequencing (<10%). This indicates that a NGS-based approach is nec- essary to monitor persistent IDH1/2 mutations. CRIDH+ was associated with an increased risk of relapse (hazard ratio, 3.89; 95% confidence interval: 1.98-7.62; P<0.01) compared to patients with CRIDH-. However, CRIDH+ was not associated with a shorter time to relapse (median 8.1 months versus 6.9 months in patients with CRIDH-; P=0.71). Interestingly, high mutation burden did not correlate with relapse in this study because patients with lower IDH1/2 mutation burden (MAF <10%) relapsed with a similar fre- quency as patients with a higher mutation burden (MAF ≥10%) (77% and 86%, respectively, P=0.66). Accordingly, these data suggest that presence of persistent IDH1/2 mutation in remission is per se associated with relapse in AML patients and that mutation burden does not have an additive predictive effect.
Focusing on a single event (IDH1/2 mutation) as a pre- dictive marker of relapse in AML is potentially problemat- ic because of frequent co-mutations in other genes includ- ing FLT3, NPM1 and DNMT3A. Indeed, co-mutations in other genes were detected in the majority of patients (89%) in this study cohort. However, persistent mutation in other genes in remission was rare, except for DNMT3A. By univariate analysis, CRFLT3+ also showed an increased risk of relapse. This result might not be reliable because only a few patients (n=3) had persistent FLT3 mutation in remission.
We noticed that a few AML patients acquired novel mutations at relapse, but at a relatively low burden (MAF range: 1.5% – 12.2%). These mutations occurred in genes in the activated signaling (FLT3 or KRAS) and tumor sup- pressor (TP53 and WT1) classes, apparently providing either proliferative or survival signals to the IDH-mutated clone.
FC is a powerful tool for detecting residual leukemic cells and can be used to predict relapse in patients with AML. The concordance rate for detecting MRD between FC and molecular methods was 82%, similar to earlier studies.38,39 Positivity for MRD determined by FC was also
associated with an increased risk of relapse in this cohort. Interestingly, patients with positive results according to both methods (CRIDH+/FC+) had a significantly higher risk of relapse compared to those with discordant results (CRIDH+/FC– or CRIDH-/FC+) or negative results by both methods (CRIDH-/FC–). These findings suggest that muta- tional analysis and FC are complementary methods useful for predicting relapse in AML patients in CR or CRi.
The data we present are in accordance with those of a recent study by Jongen-Lavrencic et al., who investigated 430 patients with AML or refractory anemia with excess blasts treated according to the clinical protocol of either the HOVON or SAKK with achievement of either CR or CRi after two cycles of induction chemotherapy.39 Mutational screening was performed at the time of diag- nosis and at CR/CRi using a targeted, 54-gene NGS panel (limit of detection: ≤1% of mutant allele). Their study showed that persistent mutation in genes other than DNMT3A, TET2 and ASXL1 in CR/CRi was an independ- ent risk factor for relapse. IDH1 and IDH2 mutations were included in their study and showed a similar frequency of persistent mutation in CR/CRi (28%). However, the authors did not focus on particular genes with respect to the increased risk of relapse.
To the best of our knowledge, our study is the largest cohort (n=80) investigating the impact of persistent IDH1/2 mutations in CR/CRi in AML patients. However, our study does have some limitations: (i) the time point of IDH1/2 analysis in remission was not uniform, and (ii) our cohort was not sufficiently large to reliably investigate the effect of co-mutations in remission. Larger-scale studies are necessary to reproduce the results of our study.
In summary, approximately 40% of AML patients with an IDH1/2 mutation at initial diagnosis will have persist- ent mutations after therapy in remission bone marrow samples. A persistent IDH1/2 mutation is associated with an increased risk of relapse. Monitoring IDH1/2 mutations in AML patients during remission using a highly sensitive NGS-based assay may provide useful information to guide early interventions with the aim of achieving longer remissions and better outcomes.
References
1. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.
2. Chou WC, Hou HA, Chen CY, et al. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isoci- trate dehydrogenase 1 mutation. Blood. 2010;115(14):2749-2754.
3. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058-1066.
5. Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malig- nancies: associations with prognosis and potential treatment strategies. Leukemia.2014;28(9):1774-1783.
6. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636-3643.
7. Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011;135(1):35- 45.
8. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malig- nancies. Leukemia. 2017;31(2):272-281. Rakheja D, Konoplev S, Medeiros LJ, Chen
W. IDH mutations in acute myeloid leukemia. Hum Pathol. 2012;43(10):1541- 1551.
10. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
11. DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prog- nostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732-736.
12. Sasaki M, Knobbe CB, Munger JC, et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epige- netics. Nature. 2012;488(7413):656-659.
13. Jaiswal S, Fontanillas P, Flannick J, et al. Age- related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371 (26):2488-2498.
14. Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell. 2010;17(3):215-216.
15. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms,
4. Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T. IDH1 mutations are detected in 6.6% of 1414
AML patients and are associated with inter- mediate risk karyotype and unfavorable prognosis in adults younger than 60 years
and unmutated NPM1 status. Blood. 2010;116(25):5486-5496. 9.
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