scholarly journals Isocitrate dehydrogenase inhibitors in acute myeloid leukemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiaoyan Liu ◽  
Yuping Gong
Keyword(s):  
Acute Myeloid Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Acquired Resistance ◽  
Tca Cycle ◽  
Idh Mutation ◽  
Hematopoietic Stem ◽  
Idh Mutations ◽  
Key Enzyme ◽  
Acute Myeloid

Abstract Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH mutation produces a neomorphic enzyme, which can lead to the abnormal accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20% of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140, and IDH2 R172. Different mutant isoforms have different prognostic values. In recent years, IDH inhibitors have shown good clinical response in AML patients. Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by Agios Pharmaceuticals, have been approved by the Food and Drug Administration on 1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory (R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy for R/R AML is efficacious and safe; however, there are problems, such as primary or acquired resistance. Clinical trials of IDH inhibitors combined with hypomethylating agents or standard chemotherapy for the treatment of R/R AML or newly diagnosed AML, as well as in post hematopoietic stem cell transplantation as maintenance therapy, are ongoing. This article summarizes the use of IDH inhibitors in AML with IDH mutations.

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

2010 ◽  
Vol 28 (22) ◽  
pp. 3636-3643 ◽  
Author(s):  
Peter Paschka ◽  
Richard F. Schlenk ◽  
Verena I. Gaidzik ◽  
Marianne Habdank ◽  
Jan Krönke ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Idh Mutation ◽  
Internal Tandem Duplication ◽  
Idh Mutations ◽  
Idh1 And Idh2 Mutations ◽  
Flt3 Internal Tandem Duplication ◽  
Acute Myeloid

Purpose To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML). Patients and Methods We studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years. Results IDH mutations were found in 129 patients (16.0%) —IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P < .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P < .001); cytogenetically normal (CN) –AML (P< .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P < .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [RFS]; P = .046 was restricted to this patient subset). Conclusion IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.

scholarly journals Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition

Haematologica ◽  
2020 ◽  
Author(s):  
Bing Z. Carter ◽  
Po Yee Mak ◽  
Wenjing Tao ◽  
Marc Warmoes ◽  
Philip L. Lorenzi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Metabolism ◽  
Acquired Resistance ◽  
Leukemia Cell ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.

scholarly journals Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 121 (24) ◽  
pp. 4917-4924 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Kathleen J. Propert ◽  
Alison W. Loren ◽  
Elisabeth Paietta ◽  
Zhuoxin Sun ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Therapeutic Monitoring ◽  
Monitoring Tool ◽  
Key Points ◽  
Idh Mutations ◽  
Acute Myeloid

Key Points Serum 2HG analysis by LC-MS can accurately identify patients with AML with and without IDH mutations. Oncometabolite testing of serum 2HG is indicated as a diagnostic, prognostic, and therapeutic monitoring tool in AML.

scholarly journals Relapse of Acute Myeloid Leukemia after Allogeneic Stem Cell Transplantation: Prevention, Detection, and Treatment

2019 ◽  
Vol 20 (1) ◽  
pp. 228 ◽  
Author(s):  
Christina Rautenberg ◽  
Ulrich Germing ◽  
Rainer Haas ◽  
Guido Kobbe ◽  
Thomas Schroeder
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
B Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Idh Mutations ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT.

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