|Year : 2023 | Volume
| Issue : 2 | Page : 87-94
Molecular alterations in IDH 1/2 genes among Iraqi adult acute myeloid leukemia patients: Their response to treatment
Haider Hasan Jaleel Al-Shammari1, Haithem Ahmed Al-Rubaie1, Ihsan Mardan Al-Badran2
1 Department of Pathology and Forensic Medicine, College of Medicine, University of Baghdad, Baghdad, Iraq
2 Department of Pathology and Forensic Medicine, Al-Zahraa College of Medicine, University of Basrah, Basrah, Iraq
|Date of Submission||28-Aug-2022|
|Date of Decision||19-Oct-2022|
|Date of Acceptance||02-Jan-2023|
|Date of Web Publication||27-Jul-2023|
Prof. Haithem Ahmed Al-Rubaie
College of Medicine, University of Baghdad, Baghdad
Source of Support: None, Conflict of Interest: None
BACKGROUND: The recurrent somatic variations in IDH1/2 genes in AML play imperative roles in epigenetic dysregulation and the pathogenesis of AML, which could be useful prognostic markers for risk stratification.
AIM: The aim of the study was to detect the frequency of R132 mutations in the IDH1 gene and R140Q mutation in the IDH2 gene with their treatment outcomes.
PATIENTS, MATERIALS AND METHODS: IDH molecular alterations were detected by high-resolution-melting (HRM)-based real-time PCR assay in 56 newly diagnosed AML patients.
RESULTS: IDH molecular alterations were identified in 39.3% of AML patients; IDH1 R132 and IDH2 R140Q mutations were present in 32.1% and 12.5% of patients, respectively. The mean age of patients with mutant IDH (52±14.87 years) is higher than in wild type (41.68±20.4 years), P = 0.041. Females were seen in 53% of mutant IDH patients while in the wild-type 73.3% were males (P = 0.038). There were significantly lower mean levels of hemoglobin, absolute neutrophil count, and platelet count in mutant IDH than in wild-type (P = 0.015, 0,.03 and 0.01, respectively). After induction remission therapy, 68.2% of mutated IDH and 64.7% of unmutated IDH patients didn't achieve complete remission (P > 0.05). After 6 months; 59.1% of mutated IDH and 64.7% of unmutated IDH had unfavorable outcomes (P > 0.05).
CONCLUSIONS: IDH mutations are common in Iraqi adult AML patients and present in older age and females predominance with lower Hb level, WBC count, absolute neutrophil count, platelet count, and less extramedullary involvement. There is an insignificant association with treatment outcomes.
Keywords: Acute myeloid leukemia, high-resolution-melting-polymerase chain reaction, IDH1/2
|How to cite this article:|
Jaleel Al-Shammari HH, Al-Rubaie HA, Al-Badran IM. Molecular alterations in IDH 1/2 genes among Iraqi adult acute myeloid leukemia patients: Their response to treatment. J Appl Hematol 2023;14:87-94
|How to cite this URL:|
Jaleel Al-Shammari HH, Al-Rubaie HA, Al-Badran IM. Molecular alterations in IDH 1/2 genes among Iraqi adult acute myeloid leukemia patients: Their response to treatment. J Appl Hematol [serial online] 2023 [cited 2023 Oct 4];14:87-94. Available from: https://www.jahjournal.org/text.asp?2023/14/2/87/382417
| Introduction|| |
Point mutations in exon 4 of IDH1 gene occur consistently at an arginine residue in codon 132 (IDHR132) in the frequency of 2%–14% of acute myeloid leukemia (AML) patients. The point mutations of exon 4 in IDH2 have been reported in 1%–19% of AML cases, predominantly IDH2R140 rather than IDH2R172 alterations in the prevalence of 80% and 20% of IDH2 mutations, respectively.,, IDH genetic alterations could be present in secondary AML from myeloproliferative neoplasms or myelodysplastic syndrome with frequency about 9%.
The data about the prognostic impact of IDH1/2 mutations in AML have been conflicting. Different studies have shown that IDH1/2 mutations are associated with a worse prognosis, a better prognosis, or have no association at all. It appears likely that the impact of IDH1/2 mutations on clinical outcomes may depend on the specific patient population.,
| Patients and Methods|| |
Fifty-six newly diagnosed adult AML patients were included in this cross-sectional study. There were 49 de novo AML patients and 7 AML cases secondary to chronic myeloid leukemia or myelodysplastic syndrome. Patients with AML-M3 were excluded. Informed consents had been obtained from all of participants. This study was approved by the Research Ethics Committee, College of Medicine and in accordance to the Declaration of Helsinki. The diagnosis of AML was based on the cytomorphological features, French − American − British (FAB) criteria, and immunophenotyping.
Standard induction chemotherapy (7 + 3 regimen); daunorubicin IV infusion in a dose of 60–90 mg/m2 on days 1–3, and Cytarabine continuous IV infusion of 100–200 mg/m2 per a day on days 1–7. Consolidation therapy (high-dose cytarabine [HiDAC] or IDAC consolidation courses) 4 weeks apart had been given for included patients. Seventeen patients were older than 60 years or with comorbidity; 10 patients had received low dose cytarabine 20 mg/m2/12 h for 10 days every month; and seven patients received azacitidine 75 mg/m2, SC, day 1–7.
Patients were followedup after induction therapy by examining complete blood picture, blood film, and bone marrow [BM] to assess response status as complete remission (CR): Absolute neutrophil count (ANC) >1.0 × 109/L, platelet count >100 × 109/L, and no blast cells in blood film and blast cells <5% of nucleated cells in BM with no extra medullary involvement or not in CR (NR) or induction death. Patients were further followed-up for 6 months, but unfortunately, data about some patients were lost.
DNA was extracted from whole peripheral blood (PB) by using WizPrep™ gDNA Mini Kit, Korea; the DNA was examined for the goodness and quantity by Quantus Fluorometer (Promega, USA).
Molecular alterations in IDH1/2 genes were analyzed by high-resolution-melting (HRM) real-time polymerase chain reaction (PCR) assay, two primers (F and R) were used for each gene (IDH1 and IDH2) provided by (Macrogene company, Korea), the sequences of the primers and the reaction conditions adopted from the study of Berenstein et al. 2014. The mixture of the reaction per run for the detection of either IDH1 R132 or IDH2 R140Q mutations was carried out on (Mic quantitative PCR [qPCR] Cycler Bio Molecular System, Australia) and composed of; 5 μL of GoTag qPCR Master Mix (Promega, USA), 0.5 μL of each primer; sequences of primers were: IDH1-hrmF 5'-GTCAAATGTGCCACTATCACTC-3', IDH1-hrmR 5'-GCCAACATGACTTACTTGATCC-3' both with 219 bp length and IDH2-hrmF 5'-GCTTGGGGTTCAAATTCTGG-3', IDH2-hrmR 5'-CTCTCCACCCTGGCCTAC-3' with product length 248 bp and all with annealing temperature (60°C), 1 μL of DNA template completed with 3 μL nuclease free water to final volume of 10 μL for aliquot per a single run. The conditions of cycling were initial denaturation in 95°C hold for 5 min for one cycle followed by 40 cycles of denaturation at 95°C for 30 s, annealing at 60°C for 30 s, and extension at 72°C for 30 s. Melting on green by holding at 95°C for 15 s then hold at 45°C for 60 s and lastly melt from 50°C to 95°C at 0.3°C/s. Positive control and negative nontemplate controls were included in each run. The interpretation of results was carried out on software of Mic qPCR Cycler Bio Molecular System, Australia and was based on the graphs of fluorescence against temperature, normalized fluorescence to normal, shifted melting temperature curves. Fifteen samples (9 for IDH1 and 6 for IDH2) were verified for the presence or absence of mutations through sequencing technique performed in Macrogene company, Korea. Patient samples showing IDH mutations by Sanger sequencing were used as positive controls in PCR run.
Description of numerical values expressed as mean ± standard deviation (SD), median, ranges, and qualitative data was expressed as frequency and percentages. The association between categorical data was done by using Person Chi-square or Fisher exact test and the statistical difference between two independent means of quantitative data was examined by Student's t-test. P ≤ 0.05 considered statistically significant.
| Results|| |
The mean (±SD) age of AML patients was 45.73 ± 18.9 years, and a median of 46 years, with a range of 15–85 years. There were 30 (53.6%) males and 26 (46.4%) females.
The mean of PB blast percentage was 59.5 ± 29.2% and for BM blast percentage was 68.1 ± 21.2%. The range of the blast percentage in PB was (5%–99%) and for BM blast was (26%–95%), the median of PB blast was 64% and for BM blast was 75%.
The frequency of combined IDH1/2 mutations was 39.3% (22/56). The clinical and hematological parameters at the diagnosis of AML patients in mutant- and wild-type IDH are shown in [Table 1]. The mean age of mutant IDH patients is significantly higher than patients with normal IDH (P = 0,041). IDH mutation in males is less frequent than that in females (P = 0.038). The ANC, hemoglobin level, and platelet count are lower in patients with IDH mutation than those with wild-type IDH (P = 0.03, 0.015, and 0.01, respectively). Furthermore, extramedullary involvement, namely lymphadenopathy, splenomegaly, and hepatomegaly is less frequently encountered in patients with mutated IDH (P = 0.018). There were no significant differences in the outcomes between mutated and unmutated IDH patients whether after induction remission therapy or after follow-up for 6 months (P > 0.05).
|Table 1: Clinical and laboratory characteristics of acute myeloid leukemia patients at diagnosis and comparison between patients with and without various IDH1/2 mutations|
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IDH1 R132 mutations were detected in 32.1% of patients (18/56) showing two types of missense mutations; 7 with IDH1 R132G mutation and 11 with IDH1 R132C mutation, IDH1 R132H mutation was not detected. The mean age of patients positive for IDH1 mutations was significantly higher than that of patients negative for the mutations (P = 0.02) and there was female predominance in patients having IDH1 mutations (P = 0.037). Platelet count was significantly lower in patients with IDH1 mutations (P = 0.042). There were insignificant associations between mutated forms and those negative for this mutation with outcomes after induction chemotherapy or after 6 months of follow-up. Ten out of 18 patients with IDH1 R132 mutations deceased so they had unfavorable outcomes.
IDH2 R140Q mutation was determined in 7 of 56 patients (12.5%). Only hemoglobin level was significantly lower in IDH R140Q-mutated patients than those negative for the mutation (P = 0.002), the other clinical and laboratory characteristics and outcomes to treatment showed insignificant associations (P > 0.05).
Three patients harbored both mutations IDH1 R132G and IDH2 R140Q, but there was no significant association between IDH1 and IDH2 mutations (P > 0.05).
| Discussion|| |
The frequency and the effect of IDH1/2 molecular alterations on response to the treatment and disease outcomes in AML varied in different studies. Sample size, environmental effects on specific population, selection of patients according to the AML subtypes, the presence of cytogenetic abnormalities, and the methods used for detection of the molecular abnormalities of IDH1/2 genes, all of these factors may contribute to these variations.
The incidence of combined IDH1/2 mutations (39.3%) was lower than that reported in a French study, 64.6% reported by Janin et al. 2014 and higher than 19% of Chotirat et al. in 2012, 18.2% of Chou et al. in 2011, 16% of Paschka et al. in 2010, and 14.3% in an Egyptian study reported by ElNahass et al. in 2020.
The frequency of IDH1 R132 mutations (32.1%) is higher than that reported by Janin et al. 2014 (24.3%), Salem et al. 2017 (18%), Paschka et al. 2010 (7.6%), Chou et al. 2011 (6.1%), Patel et al. 2011 (6%), ElNahass et al. 2020 (2.9%), and Elsayed et al. 2014 (IDH1 R132C mutation was not detected).
The frequency of IDH2 R140Q mutation (12.5%) is close to 11.4% of ElNahass et al. and 10.2% in an Iranian study of Saadi et al., but it is higher than other studies; Paschka et al. 2010, a Sweden study of Willander et al. 2014, and Olarte et al. 2019, (8.7%, 7.9%, and 5.9%, respectively).
In contrasts to our results where mutations in IDH1 gene is higher than IDH2 gene, Chou et al. 2011 reported a higher incidence of IDH2 R140Q mutation (9.2%) than IDH1 (6.1%) and Paschka et al. 2010 IDH1 (7.6%), and IDH2 (8.7%). However, Berenstein et al. 2014 reported comparable results: IDH1 R132 mutations 15.3% more frequent than IDH2 R140Q mutation (6.7%); these findings might be related to differences in population characteristics, sample size, and different methods used for the detection of IDH molecular alterations. The comparison of the frequencies of IDH1/2 mutations in various studies is shown in [Table 2].
|Table 2: Comparative demonstration of the frequency of IDH1/2 mutations in various studies|
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The absence of significant association between IDH1 and IDH2 mutations suggests that these molecular alterations are mutually exclusive.,
IDH1 R132 or IDH2 R140Q mutations had a tendency to increase with patient's age that was consistent with Willander et al. 2014 and Paschka et al. 2010. Female predominance in the studied Iraqi AML patients with IDH mutations is also noticed in Chotirat et al. 2012 and Willander et al. 2014 studies.
In relation to hematological parameters, the association of IDH2 R140Q mutation and IDH1 R132 mutations with decreased white blood count (WBC) count and ANC was comparable to other studies. In this study, platelet count was significantly lower in patients having IDH mutations than in patients without these mutations which was in accordance with Saadi et al. in 2018 and Salem et al. in 2017 but in contrast to Chou et al. in 2011 study.
Most of patients with IDH1/2 mutations categorized in (M0, M1, and M2) FAB subtypes and these finding consistent with many previous studies Janin et al. in 2014 and Salem et al. in 2017.
Prognosis of Iraqi AML patients with IDH mutations was one of the important goals of the current study as there were no available Iraqi studies about the effect of positivity of IDH1 R132 and IDH2 R140Q mutations on induction therapy and 6 months' follow-up outcomes, 11/18 patients with IDH1 R132 mutations and 6/7 of patients with IDH2 R140Q mutation were insignificantly observed to have poor outcomes on induction therapy, while 6/18 and 1/6 patients positive for IDH1 R132 and IDH2 R140Q mutations, respectively, did not achieve CR with unfavorable outcomes after 6 months of patients monitoring, these observations were comparable to previous studies who showed bad effect of IDH1/2 mutations on disease outcomes as in Salem et al. in 2017, Abd El Maksoud et al. in 2019, and Wagner et al. in 2010.
However, the data about the prognostic impact of IDH1/2 mutations in AML have been conflicting. Different studies have shown that IDH1/2 mutations are associated with a worse prognosis, a better prognosis, or have no association at all. It appears likely that the impact of IDH1/2 mutations on clinical outcomes may depend on the specific patient population.,
HRM analysis is the best screening method to determine the heterogeneity of IDH1 mutations. Furthermore, for the identification of mutations in IDH2 hM analysis showed approximately 98% concordance with Sanger sequencing. Another study compared HRM to Sanger sequencing on 146 AML BM samples for validation and showed near-perfect concordance for all positive and negative results for IDH1 (98%) and IDH2 (94%).
IDH1 and IDH2 R140 are usually found in combination with NPM1 mutations, while IDH2 R172 is mutually exclusive with NPM1 mutations. In addition, IDH1 and IDH2 mutations co-occur with FLT3-ITD in 15%–27% and 8%–30% of AML patients, respectively. The prognostic genetic risk stratification in AML includes a long list of abnormalities but the associations between the abnormalities as for FLT3-ITD with NPM1 should be studied which may locate the patient in low-, intermediate-, or high-risk category.
Various subtypes of IDH mutations might contribute to different prognosis and be allowed to stratify intermediate-risk AML further.
Increasing evidence of clinical role of DNMT3A and IDH1/2 mutations highlights the need for a robust and inexpensive test to identify these mutations in routine diagnostic workup. Herein, we compared routinely used direct sequencing method with HRM assay for screening DNMT3A and IDH1/2 mutations in patients with AML. Very high concordance between HRM and Sanger sequencing was shown.
Unfortunately, at the time of the study, only some patients had done genetic studies for FLT3-ITD, NPM1, t (8;21), inv16, t (16;16), and t (15;17). All our patients had DNMT3A R882H mutation tested by HRM-PCR and only five patients were positive.
There is no current evidence that DNMT3A and IDH1/IDH2 mutations warrant their assignment to a distinct ELN prognostic group. The presence of DNMT3A, IDH1, or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents.
| Conclusion|| |
In conclusion, IDH1/2 molecular alterations observed as common finding in Iraqi adult newly diagnosed AML patients and were higher than many other populations. IDH alterations are associated with older age, female predominance, lower WBC count, ANC, hemoglobin level, and platelet count, and less extramedullary involvement at the time of diagnosis. There is no association between IDH1 R132 mutations and IDH2 R140Q mutation and there is insignificant association with treatment outcome. Assessment of IDH1/2 mutations in cytogenetically normal AML is recommended. Association of NPM1 and FLT3 should be excluded to unravel clearly the prognostic significance of these alterations.
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Conflicts of interest
There are no conflicts of interest.
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