Adverse impact of IDH1 and IDH2 mutations in primary AML: Experience of the Spanish CETLAM group

doi:10.1016/j.leukres.2012.03.019

Leukemia Research

Volume 36, Issue 8, August 2012, Pages 990-997

https://doi.org/10.1016/j.leukres.2012.03.019 Get rights and content

Abstract

The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML.

Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations.

IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations.

IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status.

Introduction

Acute myeloid leukemia (AML) is caused by somatic mutations in genes that control normal cell proliferation and differentiation. Characterization of these genes has allowed a more refined classification of AML, enabling the identification of potential therapeutic targets and the definition of prognostic subgroups [1].

Genetic lesions of isocitrate dehydrogenases 1 (IDH1) and 2 (IDH2) have been identified as early steps in the progression of gliomas to high-grade tumors [2], [3]. Whole DNA genome sequencing has revealed that IDH1 and IDH2 may also be mutated in acute myeloid leukemia (AML) samples [4]. Additional studies in large AML cohorts have confirmed this finding and have demonstrated that these lesions may also be present in myelodysplastic and myeloproliferative disorders. In the AML setting, and in sharp contrast with findings in gliomas, IDH1 and IDH2 mutations are frequently associated with blastic transformation or aggressive forms [5], [6], [7], [8].

Ongoing studies indicate that the mechanisms of leukemogenesis associated with IDH1 and IDH2 mutations involve functional shifts in metabolic pathways with generation of 2-hydroxyglutarate [9], [10], [11], increases in the production of reactive oxygen species (ROS), cooperation with other oncogenes [12] and hypermethylation that disrupts TET2 function [13], [14]. Findings about the possible adverse prognosis of these mutations in normal karyotype AML have aroused great interest because they could provide additional prognostic stratification and guide post-remission treatment.

In this study, the Spanish CETLAM group analyzed the frequency and clinical impact of IDH1, IDH2 and TET2 mutations in a large series of adults with primary AML.

Section snippets

Materials and methods

Patients included were between 17 and 73 years of age. They were all treated according to the CETLAM-03 protocol and had a stored DNA sample for molecular study.

Induction therapy consisted of 1 or 2 courses of idarubicin 12 mg/m² IV days 1,3,5, cytarabine 500 mg/m²/12 h over 2 h IV days 1,3,5,7 and etoposide 100 mg/m² IV on days 1, 2 and 3. This was followed by a consolidation phase with mitoxantrone 12 mg/m² IV from days 4 to 6, and cytarabine 500 mg/m²/12 h IV from days 1 to 6. Patients also received

IDH1 and IDH2 mutations are commonly found in de novo AML

From a cohort of 685 consecutive cases enrolled in the CETLAM protocol between 2004 and 2010, the present series included the 275 AML patients for whom a DNA sample was available. Patients’ characteristics are summarized in Table 1. There were 161 (59%) males and 114 (41%) women. Cytogenetic groups according to the MRC classification were: favorable, 25; intermediate, 179; and adverse, 35. No cytogenetic study was available in 36 patients. A normal karyotype was identified in 120 (43%)

Discussion

In this multicentric study in the Spanish population we found that IDH mutations are common in AML, since they are present in 22.5% of patients with a normal karyotype. Outcome was poor in patients with IDH mutations and normal karyotype and also in those with IDH mutations and the favourable genotype (NPM or CEBPA mutated/FLT3 wt genotype). This is a relevant finding because these patients with the favourable genotype are usually treated less intensively sparing BMT. Significantly, most

Conflict of interest statement

There is no conflict of interest to disclose.

Acknowledgments

This work was supported by the following grants: Fundación Mutua Madrileña to JN 08/FMMA, PI 10/0173 and JS FMMA 2006-168; ISCIII PI052312, PI 080672, RD06/0020/0101 and EC07/90065, 2009-SGR-168 from Plà de Recerca de Catalunya, Marató de TV3 (100830/31/32) and a grant from Fundació Cellex, Spain. We are grateful to the CETLAM participating hospitals.

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Specific point mutations in the IDH1 and 2 genes result in the production of mutant enzymes that convert isocitrate to (R)-2-hydroxyglutarate (R-2HG), an oncometabolite that competitively inhibits α-ketoglutarate dependent processes, including epigenetic regulation. Clinical outcomes for patients with IDH-mutated AML (mIDH AML) have generally been shown to be comparable to those of patients with wildtype-IDH AML (wtIDH).3-12 Accordingly, the presence of an IDH mutation has historically had little impact on clinical decision-making.
Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes.
In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML.
Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15).
Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).
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However, the prognostic impact of R140Q may be dependent on co-occurring mutations. For instance, AML patients harboring the mIDH2 R140Q in conjunction with NMP1 gene mutation in have been identified as having a worse overall survival16. In other words, mIDH2 R140Q also maybe result in a poor prognosis.
Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.
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In patients with isocitrate dehydrogenase (IDH)–mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010–eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.
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Mutations in isocitrate dehydrogenase (IDH)1/2 genes result in nicotinamide adenine dinucleotide phosphate-dependent reduction of α-ketoglutarate and formation of 2-hydroxyglutarate, which blocks normal cellular differentiation and promotes leukemogenesis. Nearly 20% of acute myeloid leukemia (AML) patients carry IDH1/2 mutations. Although multiple investigators have described the prognostic implications of IDH mutations in AML patients receiving chemotherapy, the effect of these mutations on outcomes after allogeneic (allo) hematopoietic cell transplantation (HCT) is unknown.
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Adverse impact of IDH1 and IDH2 mutations in primary AML: Experience of the Spanish CETLAM group

Abstract

Introduction

Section snippets

Materials and methods

IDH1 and IDH2 mutations are commonly found in de novo AML

Discussion

Conflict of interest statement

Acknowledgments

Am J Pathol

Cancer Cell

Am J Pathol

Cancer Cell

J Mol Diagn

Blood

Blood

Blood

Blood

Blood

Blood

Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia

N Engl J Med

An integrated genomic analysis of human glioblastoma multiforme

Science

Recurring mutations found by sequencing an acute myeloid leukemia genome

N Engl J Med

Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms

N Engl J Med

Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q)

Leukemia

IDH2 somatic mutations in chronic myeloid leukemia patients in blast crisis

Leukemia

IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis

Leukemia