MATERIALS ANS METHODS

Search strategy and selection of studies

In accordance with the PRISMA guidelines, two independent reviewers (JMV and PM) conducted this systematic review.6 The following databases were searched without restrictions: Pubmed, EMBASE, the Cochrane Central Register, the ProQuest Medical Library, the EBSCOhost Online Research Databases, the Web of Science, and the Database of Abstracts of Reviews of Effects (DARE). In addition, the reference lists of important studies and reviews were hand-searched. Available abstracts and oral communications from conferences of the American Society of Hematology, the American Society of Clinical Oncology, and the European Hematology Association were also reviewed. Reference lists of relevant reviews and studies were searched manually. The last literature search was on November 12, 2018.

Similar keywords were used in different databases: “isocitrate dehydrogenase inhibitor 1” or “inhibitor of mutant isocitrate dehydrogenase 1” or “IDH1 mutated” and “acute myeloid leukemia” [Mesh] and relapse or refractory or resistance or recurrence or recrudescence or “salvage therapy” or “salvage treatment”.

The study selection was conducted by both authors independently. In cases of disagreement, a third reviewer (EB) adjudicated. Inclusion criteria were studies using IDH1mut inhibitors in IDH1mut adult AML patients, especially in the subset of R/R AML, studies evaluating effectiveness and/or safety of IDH1mut inhibitors in IDH1mut R/R AML, with at least CR rate or overall survival (OS), studies analyzing combinations of IDH1mut inhibitors with other agents in R/R AML, and studies analyzing untargeted therapies that might be employed in the treatment of IDH1mut R/R AML.

Our systematic search obtained 59 citations from databases and journals, and 19 records were identified through other sources (Figure 1). Of the 78 citations selected for full reading, 46 fulfilled the inclusion criteria and 22 were included. Agreement on study selection among the reviewers was excellent (kappa =0.97).

Data extraction

From the selected studies, we extracted data on study design, chemotherapy scheme, AML status, median age, CR, OS, and safety data. Different CR rates were reported in the included studies, including CR with incomplete blood count recovery (CRi), CR without platelet recovery (CRp), and CR with partial hematological recovery (CRh). Median CR duration (mCRD) is reported when data were available.

DIAGNOSIS AND EPIDEMIOLOGY OF IDH1mut AML

IDH1 mutation

The IDH1 enzyme is encoded by the IDH1 gene on chromosome 2q33.3 and localized in the cytoplasm and peroxisomes.3,7,8 The IDH1 gene normally encodes NADPH-dependent enzyme that catalyze the conversion of isocitrate to αKG. IDH1mut reduces αKG to the oncometabolite D2HG, causing its accumulation.3,9,10 Biochemical studies have shown that D2HG production can potentially affect epigenetic regulation and cell differentiation through inhibition of both histone and DNA demethylation.11

In AML, the most frequently detected IDH1mut is located in the Arg132 residue (R132), modifying the substrate-binding arginine of the enzyme catalytic domain for R132H, R132C, R132G, R132L, or R132S residues. The results of R132 IDH1mut are hypermethylation of DNA and histones and a block in differentiation that implies the presence of leukemogenic myeloid progenitor cells.7 Despite these effects, IDHmut enzymes alone do not cause leukemic transformation in mice. Several studies have demonstrated that IDH mutations tend to occur in combination with other mutations, suggesting cooperation to drive leukemogenesis in human AMLs.12 Mutations in IDH1 and IDH2 are thought to be mutually exclusive, although occasionally in rare AML, patients have concurrent mutations in both IDH1 and IDH2.8,13

IDH1 epidemiology

Several studies have demonstrated that IDH1mut and IDH2mut are associated with older age and confer an adverse prognosis, especially IDH1mut in AML with a cytogenetically normal karyotype (CN-AML).8,14 Other covariants are associated with IDH1mut, including intermediate-risk cytogenetics, a higher platelet count, increased bone marrow–blast percentage at diagnosis, FLT3-ITD and NPM1mutations,3,8,14,15 and rarely related to therapy-related AML, TET2, and WT1 mutations.3,16,17

IDH1 comutations

A meta-analysis performed by Patel et al found that NPM1 is the most frequent concurrent mutation (87/144; 60.4%), followed by FLT3-ITD (37/146; 25.3%) and CEBPA (14/155; 9.0%).18 In several studies, it has been shown that a heterogeneous pattern of certain gene mutations is associated with different prognostics. In CN-AML, a favorable genotype is defined by the association of NPM1 or CEBPA mutation without either FLT3-ITD nor IDH1 mutations.16 Furthermore, IDH1 mutations confer adverse prognoses in CN-AML with NPM1 mutation without FLT3-ITD.8,14,19

IDH1mut diagnosis

IDHmut testing is essential in the clinical setting to identify AML patients who may benefit from targeted IDH treatments. Several methods are used to test IDH mutations from patients with hematologic malignancies, including Sanger sequencing, PCR-based methods, and next-generation sequencing (NGS).3,20–25 Sanger sequencing has been the classical way to detect IDHmut. However, this procedure is low sensitive and produces slow turnaround, and thus might be less suitable as a molecular diagnostic tool.

PCR-based methods are rapid and not expensive methods to detect known mutations. Because IDH1mut are recurrently located at codon 132 in exon 4 of the IDH1 gene, several PCR-based methods have been developed to detect them.3,20,21 Recently, new digital PCR technology (BEAMing) enabled IDH1mut detection up to 5 different mutations (R132S, R132G, R132C, R132H, and R132L) from a single sample with higher sensitivity than NGS (lower limit of detection 0.02–0.04%).24 NGS is used as a substitute for PCR and Sanger sequencing in many academic medical centers, and gene panels are used for diagnostic and prognostic purposes. It allows quantification of variant allele frequency (VAF) and the detection of co-occurring mutations.25 Serial monitoring by NGS has been employed in clinical trials to detect minimal residual disease (MRD) after therapy with IDHmut inhibitors.26

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