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mutation that persisted at high levels in hematologic remission, consistent with the presence of this mutation in pre-leukemic hematopoietic stem cells. Unlike AML blasts, these hematopoietic stem cells survive chemother- apy and persist in remission bone marrow, providing a potential reservoir for leukemic progression.30 In our study, 5/7 (71%) patients with persistent clonal hematopoiesis with IDH1/2 mutations relapsed or progressed toward myelodysplastic syndrome, suggesting that these patients may be at high risk of hematologic evolution and should probably be monitored more closely. Klco et al. showed that initiating mutations, such as DNMT3A, TET2, and IDH1/2 mutations, are less likely to be cleared after chemotherapy than cooperating mutations,31 in accor- dance with our own and previous data.25,32 Furthermore, the prognostic value of persisting somatic mutations in complete remission appears to vary depending on the gene involved. Recent studies suggested that the presence of persistent mutations in DNMT3A, TET2 or ASXL1 lacks prognostic impact in terms of AML relapse or survival,33,34 in contrast with what we observed for IDH1/2 mutations.
Patients with IDH1/2 mutations are candidates for tar- geted therapies. Small-molecule inhibitors of mutant IDH1 such as ivosidenib or IDH2 such as the recently approved enasidenib are currently under clinical investigation and, when used as single agents, have shown promising results in patients with AML or myelodysplastic syndrome as a first-line treatment or in relapsed or refractory diseases.9 These molecules have been shown to induce differentia- tion of primary leukemic cells in vitro35,36 and in vivo37 to pro- mote clinical responses. Future studies should determine whether patients with high levels of IDH1/2-VAF after induction therapy could benefit from a consolidation or maintenance therapy including IDH1/2 inhibitors. Ultimately, one could imagine that the use of these small
molecules might also be considered in patients with per- sistence of clonal hematopoiesis with IDH1/2 mutations, although clearance of the clone carrying the drug targets seems to occur only in a small subset of treated patients, even with the most potent inhibitors.38 Additionally, pre- clinical and clinical data indicate that IDH1/2 mutations may identify patients likely to respond to pharmacological BCL-2 inhibition.39,40 The use of IDH1/2-VAF monitoring in patients treated with an IDH1/2 or BCL-2 inhibitor, such as venetoclax, could therefore contribute to the evaluation of treatment efficacy.
In conclusion, our study is the first to show that IDH1/2 mutant allele fraction in complete remission after induc- tion therapy significantly correlates with disease-free sur- vival, independently of pretreatment prognostic factors. However, this difference did not translate into distinct overall survival rates in our cohort. Our data provide evi- dence that IDH1/2 mutant allele fraction has the potential to become a useful tool for the management of AML patients as a biomarker of treatment response, in addition to being a molecular predictor of response to targeted ther- apies. Further studies based on larger cohorts of patients are required to confirm and extend our findings, and to address the question of whether the residual level of IDH1/2 mutation may help to refine the assignment into distinct risk groups and guide the decision of whether to perform allogeneic stem cell transplantation or give target- ed therapies.
Acknowledgments
This work was supported by the Association Laurette Fugain, the Ligue Contre le Cancer (North Center), the SIRIC ONCOLille, the North-West Canceropole (GIRCI AAP-AE 2015_53), and the Institut National du Cancer - Direction Generale de l’Offre de Soin (INCA-DGOS_9967).
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