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IDH2 mutations in acute myeloid leukemia

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Pages 1733-1741 | Received 06 Apr 2023, Accepted 07 Jul 2023, Published online: 18 Jul 2023

References

  • Babakhanlou R, Ravandi-Kashani F. SOHO state of the art updates and next questions - The role of maintenance therapy in acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2023;23(1):1–7. doi:10.1016/j.clml.2022.11.003
  • Montalban-Bravo G, DiNardo C. The role of IDH mutations in acute myeloid leukemia. Future Oncol. 2018;14(10):979–993. doi:10.2217/fon-2017-0523
  • Pollyea DA, Kohrt HE, Medeiros BC. Acute myeloid leukaemia in the elderly: a review. Br J Haematol. 2011;152(5):524–542. doi:10.1111/j.1365-2141.2010.08470.x
  • Nassereddine S, Lap CJ, Haroun F, et al. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann Hematol. 2017;96(12):1983–1991. doi:10.1007/s00277-017-3161-0
  • Knick Ragon B, DiNardo C. Targeting IDH1 and IDH2 mutations in acute myeloid leukemia. Curr Hematol Malig Rep. 2017;12(6):537–546. doi:10.1007/s11899-017-0418-6
  • Dang L, Yen K, Attar EC. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann Oncol. 2016;27(4):599–608. doi:10.1093/annonc/mdw013
  • McMurry H, Fletcher L, Traer E. IDH inhibitors in AML – promise and pitfalls. Curr Hematol Malig Rep. 2021;16(2):207–217. doi:10.1007/s11899-021-00619-3
  • Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932–941. doi:10.1093/jnci/djq187
  • Fujii T, Khawaja MR, DiNardo CD, et al. Targeting isocitrate dehydrogenase (IDH) in cancer. Discovery Medicine. 2016;21(117):373–380.
  • Cerchione C, Romano A, Daver N, et al. IDH1/IDH2 inhibition in acute myeloid leukemia. Front Oncol. 2021;11:639387. doi:10.3389/fonc.2021.639387
  • Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2010;28(14):2348–2355. doi:10.1200/JCO.2009.27.3730
  • 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. doi:10.1200/JCO.2010.28.3762
  • Caramazza D, Lasho TL, Finke CM, et al. IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia. Leukemia. 2010;24(12):2120–2122. doi:10.1038/leu.2010.213
  • Pardanani A, Patnaik MM, Lasho TL, et al. Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del (5q). Leukemia. 2010;24(7):1370–1372. doi:10.1038/leu.2010.98
  • Stein E. IDH2 inhibition in AML: finally progress? Best Pract Res Clin Haematol. 2015;28(2–3):112–115. doi:10.1016/j.beha.2015.10.016
  • DiNardo CD, Propert KJ, Loren AW, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121(24):4917–4924. doi:10.1182/blood-2013-03-493197
  • Janin M, Mylonas E, Saada V, et al. Serum 2-hydroxyglutarate production in IDH1 and IDH2- mutated de novo acute myeloid leukemia: a study by the acute leukemia french association group. J Clin Oncol. 2014;32(4):297–305. doi:10.1200/JCO.2013.50.2047
  • Figueroa ME, Wahab OA, Lu C, et al. Leukemia IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–567. doi:10.1016/j.ccr.2010.11.015
  • Ye D, Guan KL, Xiong Y. Metabolism, activity and targeting of D- and L-2- Hydroxyglutarates. Trends Cancer. 2018;4(2):151–165. doi:10.1016/j.trecan.2017.12.005
  • 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. doi:10.1056/NEJMoa1516192
  • Kernytsky A, Wang F, Hansen E, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015;125(2):296–303. doi:10.1182/blood-2013-10-533604
  • Guo JU, Su Y, Zhong C, et al. Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA methylation and beyond. Cell Cycle. 2011;10(16):2662–2668. doi:10.4161/cc.10.16.17093
  • 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. doi:10.1056/NEJMoa0903840
  • Kosmider O, Gelsi-Boyer V, Slama L, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia. 2010;24(5):1094–1096. doi:10.1038/leu.2010.52
  • Heiblig M, Hachem-Khalife S, Willekens C, et al. Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation. Expert Rev Precis Med Drug Dev. 2020;5(6):421–428. doi:10.1080/23808993.2020.1831909
  • Patnaik MM, Hanson CA, Hodnefield JM, et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo clinic study of 277 patients. Leukemia. 2012;26(1):101–105. doi:10.1038/leu.2011.298
  • Lasho TL, Jimma T, Finke CM, et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood. 2012;120(20):4168–4171. doi:10.1182/blood-2012-05-429696
  • 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. doi:10.1056/NEJMoa1408617
  • Zink F, Stacey SN, Norddahl GL, et al. Clonal hematopoiesis, with and without candidate driver mutations, is commonly in the elderly. Blood. 2017;130(6):742–752. doi:10.1182/blood-2017-02-769869
  • Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264–278. doi:10.1016/j.cell.2012.06.023
  • Molenaar RJ, Thota S, Nagata Y, et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia. 2015;29(11):2134–2142. doi:10.1038/leu.2015.91
  • Chou WC, Peng KY, Lei WC, et al. Persistence of mutant isocitrate dehydrogenase in patients with acute myeloid leukemia in remission. Leukemia. 2012;26(3):527–529. doi:10.1038/leu.2011.215
  • Debarri H, Lebon D, Roumier C, et al. IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the acute leukemia french association. Oncotarget. 2015;6(39):42345–42353. doi:10.18632/oncotarget.5645
  • Malcovati L, Galli A, Travaglino E, et al. Clinical significance of somatic mutations in unexplained blood cytopenia. Blood. 2017;129(25):3371–3378. doi:10.1182/blood-2017-01-763425
  • Patel KP, Ravandi F, Ma D, et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Leuk Lymphoma. 2023;135(1):1–11. doi:10.1309/AJCPD7NR2RMNQDVF
  • DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;30(4):980–984. doi:10.1038/leu.2015.211
  • DiNardo CD, Ravandi F, Agresta S et al.: Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol, 2015; 90(8): 732–736 doi:10.1002/ajh.24072
  • Boddu P, Takahashi K, Pemmaraju N, et al. Influence of IDH on FLT3-ITD status in newly diagnosed AML. Leukemia. 2017;31(11):2526–2529. doi:10.1038/leu.2017.244
  • Brunner AM, Neuberg DS, Wander SA, et al. Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia. Cancer. 2019;125(4):541–549. doi:10.1002/cncr.31729
  • Babakhanlou R, Ravandi-Kashani F. Non-intensive acute myeloid leukemia therapies for older patients. Expert Rev Hematol. 2023;16(3):171–180. doi:10.1080/17474086.2023.2184342
  • Xu Q, Li Y, Lv N, et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis. Clin Cancer Res. 2017;23(15):4511–4522. doi:10.1158/1078-0432.CCR-16-2628
  • Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–1089. doi:10.1056/NEJMoa1112304
  • Ravandi F, Patel K, Luthra R, et al. Prognostic significance of alterations in IDHEnzyme isoforms in patients with AMLTreated with High-Dose cytarabine andIdarubicin. Cancer. 2012;118(10):2665–2673. doi:10.1002/cncr.26580
  • Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am J Hematol. 2015;90(5):e77–e79. doi:10.1002/ajh.23965
  • Jin J, Hu C, Yu M, et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLOS One. 2014;9(6):e100206. doi:10.1371/journal.pone.0100206
  • DiNardo CD, Patel KP, Garcia-Manero G, et al. Lack of association of IDH1, IDH2 and DNMT3A mutations with outcome in older patients with acute myeloid leukemia treated with hypomethylating agents. Leuk Lymphoma. 2014;55(8):1925–1929. doi:10.3109/10428194.2013.855309
  • Mehta SV, Shukla SN, Vora HH. Overexpression of BCL-2 protein predicts chemoresistance in acute myeloid leukemia. Its correlation with FLT3. Neoplasma. 2013;60(6):666–675. doi:10.4149/neo_2013_085
  • Chan SM, Thomas D, Corces-Zimmerman MR, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21(2):178–184. doi:10.1038/nm.3788
  • Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieved antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–208. doi:10.1038/nm.3048
  • Jilg S, Reidel V, Müller-Thomas C, et al. Blockage of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia. 2016;30(1):112–123. doi:10.1038/leu.2015.179
  • Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase 2 study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–1117. doi:10.1158/2159-8290.CD-16-0313
  • Cathelin S, Sharon D, Subedi A, et al. Combination of enasidenib and venetoclax shows superior anti-leukemic activity against IDH2 mutated AML in patient-derived xenograft models. Blood. 2018;132(Supplement 1):562–562. doi:10.1182/blood-2018-99-119688
  • DiNArdo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629. doi:10.1056/NEJMoa2012971
  • Pollyea DA, DiNardo CD, Arellano ML, et al. Results of venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with acute myeloid leukemia with IDH 1/2 mutations. Blood. 2020;136(Supplement 1):5–7. doi:10.1182/blood-2020-134736
  • Lachowiez CA, Reville PK, Kantarjian H, et al. Contemporary outcomes in IDH-mutated acute myeloid leukemia: the impact of co-occurring NPM1 mutations and venetoclax-based treatment. Am J Hematol. 2022;97(11):1443–1452. doi:10.1002/ajh.26694
  • Pollyea DA, DiNardo CD, Arellano ML, et al. Impact of venetoclax and azacitidine in treatment-naïve patients with acute myeloid leukemia and IDH1/2 mutations. Clin Cancer Res. 2022;28(13):2753–2761. doi:10.1158/1078-0432.CCR-21-3467
  • Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2021;137(13):1792–1803. doi:10.1182/blood-2017-04-779405
  • Montesinos P, Sanz MA. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature. Mediterr J Hematol Infect Dis. 2011;3(1):e2011059. doi:10.4084/MJHID.2011.059
  • Fathi AT, DiNardo CD, Kline I, et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase ½ study. JAMA Oncol. 2018;4(8):1106–1110. doi:10.1001/jamaoncol.2017.4695
  • De Botton S, Montesinos P, Schuh AC, et al. Enasidenib vs. conventional care in older patients with late-stage mutant IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;141(2):156–167. doi:10.1182/blood.2021014901
  • Pollyea DA, Tallman MS, de Botton S, et al. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019;33(11):2575–2584. doi:10.1038/s41375-019-0472-2
  • DiNardo C, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia (AG221-AML-005): a single-arm, phase 1b and randomized, phase 2 trial. Lancet Oncol. 2021;22(11):1597–1608. doi:10.1016/S1470-2045(21)00494-0
  • Venugopal S, Takahashi K, Daver N, et al. Efficacy and safety of enasidenib and azacytidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy. Blood Cancer J. 2022;12(1):10. doi:10.1038/s41408-021-00604-2
  • Atluri H, Maiti A, Sasaki K, et al. Phase Ib/2 study of oral decitabine/cedazuridine (ASTX727) and venetoclax in combination with the targeted mutant IDH1 inhibitor ivosidenib or the targeted mutant IDH2 inhibitor enasidenib in IDH mutated acute myeloid leukemia. Blood. 2022;140(Supplement 1):6170–6172. doi:10.1182/blood-2022-164986
  • Quek L, David MD, Kennedy A, et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med. 2018;24(8):1167–1177. doi:10.1038/s41591-018-0115-6
  • Stein EM, DiNardo CD, Fathi AT, et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.  Blood. 2021;137(13):1792–1803. doi:10.1182/blood.2020007233
  • Bullinger L. IDH2 inhibition: another piece to the puzzle. Blood. 2019;133(7):625–626. doi:10.1182/blood-2018-12-891481
  • Chen EC, Li S, Eisfeld AK, et al. Outcomes for patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Transplant Cell Ther. 2021;27(6):479.e1 – 479–e7. doi:10.1016/j.jtct.2021.02.028
  • Kunadt D, Stasik S, Metzeler KH, et al. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation. J Hematol Oncol. 2022;15(1):126. doi:10.1186/s13045-022-01339-8
  • Fathi AT, Kim HT, Soiffer RJ, et al. Enasidenib as maintenance following allogeneic hematopoietic cell transplantation for IDH2-mutated myeloid malignancies. Blood Adv. 2022;6(22):5857–5865. doi:10.1182/bloodadvances.2022008632
  • Zhuang X, Pei HZ, Li T, et al. The molecular mechanisms of resistance to IDH inhibitors in acute myeloid leukemia. Front Oncol. 2022;12:931462. doi:10.3389/fonc.2022.931462
  • Wang F, Morita K, DiNardo CD, et al. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nat Commun. 2021;12(1):2607. doi:10.1038/s41467-021-22874-x
  • Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732–741. doi:10.1182/blood-2017-04-779447
  • Abelson S, Collord G, Ng SWK, et al. Prediction of acute myeloid leukemia risk in healthy individuals. Nature. 2018;559(7714):400–404. doi:10.1038/s41586-018-0317-6

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