Next Article in Journal
Transdermal Delivery of Metformin Using Dissolving Microneedles and Iontophoresis Patches for Browning Subcutaneous Adipose Tissue
Next Article in Special Issue
DNA Copy Number Aberrations and Expression of ABC Transporter Genes in Breast Tumour: Correlation with the Effect of Neoadjuvant Chemotherapy and Prognosis of the Disease
Previous Article in Journal
Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2
Previous Article in Special Issue
Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia

1
Servicio de Farmacia, Área del Medicamento, Hospital Universitario y Politécnico La Fe, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain
2
Servicio de Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain
3
Instituto de Investigación Sanitaria La Fe, Avda. Fernando Abril Martorell 106, 46026 Valencia, Spain
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(4), 878; https://doi.org/10.3390/pharmaceutics14040878
Submission received: 25 February 2022 / Revised: 11 April 2022 / Accepted: 14 April 2022 / Published: 17 April 2022
(This article belongs to the Special Issue The Role of SLC and ABC Transporters in Anti-cancer Drug Delivery)

Abstract

:
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes.

1. Introduction

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous hematologic malignant disease characterized by an excess of blast cells in bone marrow and blood. Approximately 60–80% of young AML patients achieve complete remission (CR) using conventional 3 + 7 schedules of anthracyclines and cytarabine, which might be followed by an allogeneic hematopoietic stem cell transplant (allo-HSCT) to prevent relapse [1,2]. Unfortunately, half of these patients finally relapsed or died from different causes, including: low efficacy eliminating the minimal residual disease, severe toxicity of chemotherapy, refractory disease. This interindividual variability of outcomes between AML patients could be related to their genetic variability [3,4].
Drug uptake by blast cells can be affected by different transporters, including influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps, respectively [3,4]. Previous pharmacogenetic studies have suggested that single nucleotide polymorphisms (SNPs) of SLC and ABC transporters may play a promising role in drug exposure and have been associated with clinical response and toxicity [3,4,5,6,7]. However, the findings and the interpretation of these individual studies appear contradictory and inconclusive. Furthermore, for new targeted therapies, potential drug–drug interactions with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic anion transporting polypeptides (OATP) were tested in preclinical studies, but the influence of SNPs in these transporters is unknown in these new therapies. We performed a systematic review of all the studies that have analyzed polymorphisms of membrane transporters in AML patients.

2. Materials and Methods

Search Strategy and Selection of Studies

A systematic search was performed following the PRISMA guidelines by two independent reviewers (JEMV and ASA) [8]. Pubmed, EMBASE, the Cochrane Central Register, the Web of Science and the Database of Abstracts of Reviews of Effects (DARE) databases were searched without restrictions. In addition, the reference lists of important studies and reviews were hand searched. The reference lists of relevant reviews and studies were manually searched. The last literature search was conducted on 26 January 2022. This systematic review was included in the PROSPERO registry (ID 314292).
Similar keywords were used in different databases: (“ATP-binding cassette transporters” [MeSH Terms] or “organic anion transporters” [MeSH] or “organic cation transport proteins” [MeSH]) and “acute myeloid leukemia” [MeSH].
Studies that fulfilled the following criteria were included: (1) studies based on clinical data in AML patients (excluding preclinical and in vitro studies); (2) AML studies analyzing the associations between ABC and/or SLC polymorphisms and clinical response to chemotherapy; and (3) AML studies analyzing the impact on safety of ABC and/or SLC polymorphisms.

3. Results

Our systematic search obtained 569 citations from databases and journals and 21 records were identified through other sources (Figure 1). Of the 44 citations selected for full reading, 37 fulfilled the inclusion criteria and were included. The agreement in the study selection between the reviewers was excellent (kappa = 0.97).

3.1. Influx Transporters: SLC Family

The intake by blast cells and other tissues of the antineoplastics employed in AML therapy and other xenobiotics is mediated by SLC transporters, a family that includes more than 400 transporters. Different SLC transporters have been related to anthracycline uptake, especially the organic anion transporter polypeptide-1B1 (OATP1B1, encoded by SLCO1B1) and the organic cation transporter SLC22A16 (Figure 2). However, cytarabine is mainly transported by human equilibrative nucleoside transporter (hENT1 and hENT2, encoded by the SLC29A1 and SCL29A2 genes; Figure 2), and in lower proportions by the human concentrative nucleoside transporters (hCNT3 encoded by the SLC28A3 gene).
The OATP1B1 (SLCO1B1) is predominantly expressed in the liver and is involved in the hepatic uptake and plasma clearance of several organic anionic compounds, including anthracyclines and other drugs such as statins [9,10,11,12]. The most relevant SLCO1B1 polymorphisms are 521T>C (rs4149056), 388A>G (rs2306283) and 597C>T (rs2291075), which are partially in linkage disequilibrium. The minor allele of rs4149056 has been consistently associated with a lower hepatic uptake and higher drug circulating concentrations, increasing the plasma levels and the risk of toxicity in tissues [10,11]. In AML studies (Table 1), the variant allele of SLCO1B1 rs4149056 was associated with a higher liver toxicity in adult patients [5] and higher overall survival (OS) in AML children [13]. In a recent study, the wild-type TT genotype of this SNP was related to a higher induction death, probably associated with a higher idarubicin uptake in tissues and therefore a higher potential toxicity [14]. The previous study in AML pediatric patients also obtained a higher OS and event-free survival (EFS) in carriers of the variant allele of the SLCO1B1 polymorphism (rs2291075), as well as those of the SLCO1B1 haplotype *1A/*1A,*1B/*1B (rs2291075, rs4149056 and rs2306283) [13].
SLC22A12 encodes a solute carrier that is mainly expressed in kidney and other tissues and is involved in urate–anion exchange [15]. Moreover, it is associated with the transport of different drugs, especially uricosurics (allopurinol and oxypurinol). The wild-type homozygote of SLC22A12 rs11231825 showed a higher infusion-related reactions after gemtuzumab ozogamicin administration (Table 1) [5]. An association between the wild-type genotypes of different SLC22A12, SLC25A37 and SLC28A3 polymorphisms showed a lower disease-free survival (DFS), although these associations were lost after the correction for multiple testing (Table 1) [16].
SLC22A16 encodes an organic cation transporter of L-carnitine, a metabolism cofactor related to different disease states. This carrier also imports several drugs, including anthracyclines. This transporter is constitutively expressed in the brain and kidney. SLC22A16 is over-expressed in AML and is related to the growth and viability of the blast cells, providing a potential target for future AML therapies [17]. In breast cancer cohorts, variant alleles of SLC22A16 (rs714368) were found to be related to higher exposure levels of doxorubicin and doxorubicinol [6] and dose delays by anthracycline toxicities (lower with rs714368, rs6907567, rs723685 and higher with rs12210538) [7]. In a recent AML study, associations were not observed between SLC22A16 rs12210538 and rs714368 and response or safety outcomes (Table 1) [14].
The concentrative nucleoside transporter hCNT1 encoded by the SLC28A1 gene has a substrate specificity for physiological pyrimidine nucleosides. Besides this function, hCNT1 has been implicated in tumor suppression. Various SLC28A1 SNPs were analyzed in several AML studies [18,19,20] (Table 1). Carriers of the SLC28A1 rs2242046 polymorphism showed a higher neutropenia [19], whereas studies with SLC28A1 rs2290272 [18] and SLC28A1 rs8025045 [20] did not find any clinical association. SLC28A2 encodes a sodium-dependent selective transporter of purines expressed in the kidney and other tissues. Only a pediatric AML study found a lower OS and EFS with the wild-type genotype of SLC28A2 rs10519020 [13].
hCNT3 (SLC28A3 gene) is a sodium-dependent pyrimidine and purine nucleoside carrier expressed in the pancreas, trachea, bone marrow and mammary glands. hCNT3 is a minor cytarabine transporter compared to hENT1, and this carrier has been associated with the uptake of different anthracyclines [21]. In four pediatric cancer cohorts, the variant alleles of SLC28A3 rs7853758 and rs885004 were correlated with cardiotoxicity associated with anthracyclines (doxorubicin and daunorubicin) [22,23,24,25], whereas this finding with SLC28A3 rs7853758 was not reproduced in cohorts of breast cancer [26,27] or B-cell lymphoma [28]. SLC28A3 rs7853758 and rs885004 SNPs are in high linkage disequilibrium and have been related to lower expression in different cell lines [29,30]. Only one study in AML patients has reported an association of SLC28A3 rs11140500 with a lower DFS, but the significance disappeared after Bonferroni correction (Table 1) [16].
hENT1 (encoded by the SLC29A1 gene) is responsible for up to 80% of cytarabine influx in blast cells. Schemes with high doses of cytarabine (2–3 g/m2 daily), used in consolidation or intensification therapy, can saturate the pump-mediated transport of hENT1 with concentrations >10 µmol/L and produce free diffusion into the cell [31,32]. Nevertheless, intracellular cytarabine concentrations obtained with induction therapy (200 mg/m2) are mediated by hENT1 [33]. Moreover, the intracellular influx is strongly correlated with the abundance of hENT1 in cell surface [34], so the bioavailability and clinical response depend on hENT1 expression [35]. In addition, SLC29A1 expression can be affected by hypoxia inducible factor 1 (Hif-1) at the promoter or by the transcription factor peroxisome proliferator activated receptorα (PPARα) [36,37]. In AML, patients with a low SLC29A1 mRNA expression had a significantly shorter DFS and OS in an adult cohort [38], but this had no influence in a pediatric AML cohort [39].
Two nonsynonymous and four synonymous polymorphisms were identified in a functional study of SLC29A1, but no influence in cytarabine uptake was measured [40]. In contrast, the haplotype of three SLC29A1 polymorphisms (−1345C>G, −1050G>A and 706G>C) was correlated with higher mRNA expression [41]. Another study showed only a modest elevation in hENT1 gene expression with the variant −706G>C, but no influence on cytarabine toxicity in normal blood cells [42]. The minor alleles of SLC29A1 polymorphisms only reach relevant frequencies in Asian populations, as is reflected in AML studies (Table 1). The variant A allele SLC29A1 rs3734703 was associated with a lower OS and RFS alone [43] or combined with TYMS rs2612100 [44], but a higher CR was related to the A allele [20] and CC + AA genotypes [43]. The SLC29A1 rs9394992 polymorphism was related to a lower CR [43], OS, DFS and mRNA expression, and a higher relapse rate (RR) [45], but no influence was found in another cohort [46]. Similarly, the variant allele of SLC29A1 rs324148 (alone or in combination rs9394992) was associated with a lower OS, DFS and mRNA expression, and a higher RR [45], as well as a higher CR haplotype ht3 with rs3734703, rs9394992, rs693955, rs507964 and rs747199 but had no effect alone [43]. On the other hand, the SLC29A1 rs693955 polymorphism was correlated to a lower time to relapse and neutropenia recovery [4].

3.2. Efflux Transporters: ABC Family

The ABC family of transporters includes several efflux pumps involved in the active efflux of drugs and xenobiotics from inside the cells with a potential increase in drug resistance [47]. The effect of these pumps is well-known in anthracycline disposition in blast cells and tissues, highlighting ABCB1, ABCC1, ABCC3 and ABCG2 (Figure 2) [47,48]. In addition, cytarabine uptake is influenced by two members of the “multidrug resistance-associated protein” (MRP) family, MRP7 and MRP8 (encoded by ABCC10 and ABCC11 genes), which have been related to deoxynucleotide efflux (Figure 2) [49,50].
The P-glycoprotein (P-gp), encoded by the ABCB1 gene, is the most studied efflux pump of the ABC family. The pharmacogenetics of ABCB1 have been widely analyzed in AML patients (Table 2), especially ABCB1 3435C>T (rs1045642), 2677G>A/T (rs2032582) and 1236C>T (rs1128503) polymorphisms [13,16,19,20,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69]. An in vitro study associated the P-gp expression with a lower intracellular daunorubicin accumulation [70]. The pharmacokinetics of daunorubicin and its metabolite daunorubicinol were not affected by ABCB1 polymorphisms, nor was mRNA expression in an Indian AML cohort [69]. However, previous studies in breast cancer have shown a higher doxorubicin clearance and lower peak levels of doxorubicinol with the wild-type haplotype of ABCB1 [47].
Lower pump function was related to the variant alleles of ABCB1, favoring anthracycline intracellular accumulation with a higher potential efficacy and toxicity [61,71,72], but some studies did not reproduce this effect [51,54,58]. Following this hypothesis, better responses (higher CR and survival rates) has been reported in AML cohorts with different ABCB1 polymorphisms [51,57,59,61,63,65,66,67,68], whereas in other studies, these SNPs showed no influence or a worse response [20,53,54,55,56,58,62,64] (Table 2). This finding of a higher CR and OS with variant alleles of ABCB1 3435C>T, 2677G>A/T and 1236C>T was reproduced in two meta-analyses [73,74]. The study of Rafiee et al. showed an association between these 3 ABCB1 SNPs and a higher EFS and DFS and a lower relapse rate on gemtuzumab ozogamicin, highlighting the role of P-gp in calicheamicin efflux [64].
The toxicity of anthracyclines has only been evaluated in four AML studies, showing no associations in two studies [54,56] and relevant anthracycline related-toxicities in two studies [60,62]. He et al. found higher nausea and vomiting grades (3/4) with wild-type genotypes of ABCB1 3435C>T and 2677G>A/T (alone and in haplotype) in an Asian cohort [60]. On the other hand, in a Caucasian cohort, the variant alleles of ABCB1 3435C>T, 2677G>A/T and 1236C>T and their haplotypes were associated with higher organ toxicities (renal, hepatic and neutropenia), as well as with higher induction death [62]. In other malignancies, ABCB1 SNPs were correlated with higher cardiotoxicity [22,23,75,76], but this was not reproduced in these AML studies [54,56,60,62], nor in a large study analyzing the potential correlation between ABCB1 polymorphisms and the left ventricular ejection fraction (LVEF) [77].
ABCB11 encodes a canalicular transporter of bile salts also called the “bile salt export pump” (BSEP) which has been associated with the efflux of some anticancer drugs in liver cells. The ABCB11 rs4668115 and ABCB4 rs2302387 polymorphisms reduced transporter expression and were found to be related to ≥grade 3 transaminitis after anthracycline infusion (mithramycin) in patients with refractory thoracic malignancies [78]. The wild-type genotype of ABCB11 rs4668115 was correlated with a lower OS and EFS in AML patients (Table 2) [13].
ABCC1 encodes the MRP1 pump, which mediates the export of organic anions and drugs from the cytoplasm, including methotrexate, antivirals and anthracyclines. The function of this pump confers resistance to anticancer drugs by decreasing their accumulation in cells and by mediating ATP- and GSH-dependent drug export [79]. Pharmacokinetic in vitro studies have shown decreased transport and higher maximum velocity (Vmax) of doxorubicin disposition with ABCC1 (rs60782127) [80], whereas MRP expression reduced the intracellular daunorubicin accumulation [70]. Previous studies in other cancers have associated ABCC1 (rs3743527, rs246221, rs4148350) with higher cardiotoxicity [22,23,27,81]. A small cohort performed in an Arab population correlated the expression of 4 ABCC1 SNPs with a lower CR, drug sensitivity and relapsed/refractory disease in acute leukemia (Table 2) [82]. Subsequently, several AML studies analyzed the role of different ABCC1 genotypes in clinical outcomes and safety (Table 2) [20,56,62,83]. Despite the fact that the association between cardiotoxicity and ABCC1 polymorphisms was not reproduced in AML [20,56,62,83], ABCC1 rs4148350 was related to hepatotoxicity [62], ABCC1 rs212090 with gastrointestinal toxicity and rs212091 and rs3743527 with myelosuppression [20]. In addition, the ABCC1 rs212090 and rs3743527 variant alleles showed lower survival rates, whereas ABCC1 rs129081 increased OS and DFS [83].
ABCC2 expresses MPR2, an export pump localized to the apical membrane of polarized cells, especially those hepatocytes with functions in biliary transport. This protein appears to contribute to the drug resistance of different anticancer drugs including anthracyclines [84]. Polymorphisms of ABCC2 have been correlated with anthracycline toxicities in other malignancies: cardiotoxicity in non-Hodgkin lymphoma (rs45511401) [26], in survivors of HSCT (rs8187710) [85] and in pediatric cancer (rs4148350) [22], febrile neutropenia in breast cancer (rs4148350) [27] and leucopenia in osteosarcoma (17222723) [86]. In AML patients, only one cohort has analyzed ABCC2 rs8187710, without any significant influence in response or toxicity [62].
ABCC3 encodes a protein that may play a role in biliary transport and the intestinal excretion of organic anions, which is also related to drug efflux. The expression of ABCC3 was found to be significantly higher in AML patients resistant to daunorubicin [87]. Clinical studies in AML cohorts corroborated this finding with ABCC3 polymorphisms (Table 2) [16,18,88]. A lower DFS was reported with variant alleles of ABCC3 polymorphisms (rs4148405, rs1989983, rs2301835, rs8079740), whereas other ABCC3 (rs2277624, rs757420) SNPs showed a higher DFS [16]. A similarly higher OS was observed with the variant allele of ABCC3, rs4793665 [18]. A recent cohort reproduced the previous findings of lower OS rates with the minor allele of ABCC3, rs4148405 [88].
The ABCC10 and ABCC11 genes encode the MRP7 and MRP8 pumps which can efflux cytarabine in blast cells [49,50]. Unfortunately, we have not found any studies regarding the genetic variability of ABCC10 and ABCC11 in AML populations. Sorafenib, an FLT3 inhibitor employed in AML, produces the inhibition of ABC pumps, avoiding the efflux of cytarabine by MRP7 and MRP8 pumps and thereby increasing the cytarabine-sensitivity of blast cells [89,90].
The ABCG2 gene expresses the “breast cancer resistant protein” (BCRP), a well-known ABC pump responsible for anthracycline efflux [91]. BCRP is localized in the cell membranes of epithelial cells of the small intestine, liver, kidney, brain and placenta [92]. In AML, an overexpression of ABCG2 was observed in 33% of blast cells and this BCRP expression correlated with a worse prognosis and lower OS [93,94,95,96]. The two most common ABCG2 SNPs are rs2231137 and rs2231142, and the minor alleles of these SNPs are related to a reduced level of BCRP expression [92]. No influence in anthracycline pharmacokinetics was reported with ABCG2 in an AML cohort with daunorubicin (rs2231137, rs2231142, rs769188) [69] or a breast cancer cohort with doxorubicin (rs2231142) [47]. Several studies have described the impact of ABCG2 genotypes in AML (Table 2) [18,56,62,97,98]. Contradictory results were observed with ABCG2 rs2231137, showing a lower OS and lower risk of toxicities ≥ grade three with the GG wild-type genotype in a Caucasian cohort [56], but a higher OS and DFS in a mixed AML/ALL Asian cohort [97] and no influence in a Caucasian cohort [62]. On the other hand, three different cohorts reproduced an increase in OS in wild-type ABCG2 rs2231142 carriers [56,97,98] and cardiac and lung toxicities were associated with the variant allele in another study [62]. Similar OS and DFS increases were obtained with the wild-type genotype of ABCG2 rs2231149, as well as with its haplotype with the ABCG2 rs2231137 and rs2231142 polymorphisms [97]. No effect in LVEF was observed with 16 different ABCG2 polymorphisms in a large study [77].

3.3. SNP-SNP Combinations of Transporters

Most of the included pharmacogenetic studies employed the candidate genes approach based on the pharmacologic pathway of the drugs. The drug intake depends on the combination of input and output transporters, but only a few studies analyzed the genetic variability of both types of carriers together. A recent study explored the combination of SLC wild-type genotypes (functional SLCO1B1 and/or SLC22A16), ensuring the anthracycline uptake in cells, with the variant genotypes of ABC pumps (defective expression of ABCB1, ABCC1, ABCC2 or ABCG2), avoiding anthracycline expulsion [14]. Several novel findings were reported with the combinations of ABCB1 and SLC polymorphisms, including higher hepatic and renal toxicities, mucositis and neutropenia, as well as a higher incidence of induction death (Table 3). All of these are probably associated with a higher intracellular idarubicin accumulation and have been previously reported with ABCB1 SNPs [62]. In addition, the combination of the SLC22A16 rs714368 wild-type genotype with the variant allele of ABCG2 rs2231142 was related to a higher cardiac toxicity (Table 3), reproducing the previous association [62]. On the other hand, no associations were found with ABCC1 rs4148350 and ABCC2 rs8187710 SNPs combined with SLCO1B1/SLC22A16 wild-type genotypes. Combinations of SLCO1B1 and ABC polymorphisms were also described with irinotecan [99,100] and statins [101,102]. Regarding cytarabine intake, two different studies analyzed the combined influence of SNPs in SLC29A1 with genes of the main enzymes of the cytarabine pathway (DCK, CDA, etc.) [43,44], but the combination with ABC pumps was not explored.

4. Conclusions

Transporters of the SLC and ABC families play crucial roles in the absorption, disposition and elimination of antineoplastic drugs. In AML, the expression of these transporters has been proposed as one of the main drug resistance mechanisms and has been widely studied for standard chemotherapy 3 + 7 schedules based on anthracyclines and cytarabine. However, the impact of genetic variability in the SLC and ABC genes remains controversial. This review aims is to demonstrate that polymorphisms in transporter genes may have a potential impact on the clinical outcomes of AML therapy.
Despite this, only a few studies have analyzed the role of SLC carriers in AML therapy; promising findings were obtained with polymorphisms in the SLCO1B1 and SLC29A1 genes. Variant alleles of SLCO1B1 were correlated with a lower function, decreasing anthracycline hepatic uptake and metabolism [10,11] and showed higher survival rates and toxicity in AML studies [5,13,14]. Polymorphisms of SLC29A1, responsible for cytarabine uptake, showed a relevant impact on CR and survival rates, especially in Asian populations [20,42,43,44,45].
Meanwhile, the variant alleles of ABCB1 have been widely studied in AML, demonstrating a clear association with lower pump function, as well as higher CR and survival rates in meta-analyses [73,74]. The influence of ABCB1 polymorphisms in anthracycline-related toxicities remains more controversial in AML, with scarce relevant findings [60,62] and without evidence of higher cardiotoxicity unlike studies in other malignancies [22,23,75,76]. Encouraging relationships were discovered in AML studies with ABCC1 [20,62,82,83] and ABCG2 polymorphisms [56,62,97,98].
SNP–SNP combinations of transporters could play a crucial role in characterizing the anthracycline pathway, which involves complex pharmacokinetic and pharmacodynamic mechanisms, although this was only evaluated in a Caucasian AML cohort [14]. In addition, it has been hypothesized that SNP–SNP combinations could increase the power of detection of significant associations where individual SNPs of SLC or ABC genes only demonstrate a minor effect that could be affected by their combination [103]. Combinations of transporters with other relevant SNPs such as enzymes have been explored in previous studies in AML with cytarabine [43,44].
The influence of ABC pumps in anthracycline pharmacokinetics has been suggested in vitro [70,80] and studies in other cancers [47], but a population pharmacokinetic study performed in AML failed to reproduce these findings with ABCB1 and ABCG2 polymorphisms [68]. Furthermore, the AML studies included did not analyze the influence of transporter SNPs together in drug pharmacokinetic levels and clinical response. In this line, a study in AML demonstrated a correlation between cytarabine plasma level and CDA genotype, the main enzyme responsible for liver metabolism of cytarabine [104]. In chronic myeloid leukemia, a relevant decrease in imatinib clearance was associated with variant alleles of ABCB1 and SLCO1B3 [105]. Similarly, in acute lymphoblastic leukemia, the SLCO1B1 521T>C SNP reduced methotrexate clearance [106]. Previous reviews focused on the impact of ABC and SLC SNPs in drug bioavailability have found the same limited evidence of PK studies in the AML context [47,107,108].
The influence of genetic variability in AML therapy has been previously analyzed by other authors, especially focused of the main SNPs of the cytarabine and anthracycline metabolic pathways [3,4,109,110] or only in SNPs of transporter genes [47,107,108,111]. Pinto et al. [112] recently performed a systematic review of the general state of pharmacogenetics in AML including, as a novelty, polymorphisms with a potential impact in new targeted therapies (e.g., FLT3 inhibitors, GO, hypomethylating agents and IDH inhibitors). On the other hand, our review centers on evaluating the influence of polymorphisms in transporter genes (SLC and ABC and their combinations) in AML studies, which was briefly explained in this recent review [112].
Most of the reported pharmacogenetic studies were performed in patients treated with a standard 3 + 7 scheme with a candidate genes approach. The importance of pharmacogenetics for the multiple new drugs recently approved for AML treatment remains unknown. Although these therapies are more tolerable than classical antineoplastics, potential drug–drug interactions involving P-gp, BCRP and OATP transporters have been described [113]. The genetic variability of SLC and ABC genes should be analyzed in further studies involving these novel therapies. In this line, a higher response to gemtuzumab ozogamicin was reported with the variant alleles of ABCB1 in a pediatric cohort [63], but no influence was observed in adult AML patients treated with gemtuzumab ozogamicin and decitabine [64].
In conclusion, pharmacogenetic studies based on candidate genes have reported relevant associations between SNPs in transporters (SLC and ABC) with AML outcomes and safety profiles. Unfortunately, most of these studies were observational and involved retrospective cohorts, and only anecdotally were these transporter genes analyzed together with metabolic enzymes, molecular targets and DNA repair genes. In the future, randomized clinical trials on larger populations including those of different age, ethnic and therapy groups should be developed in order to validate the clinical benefit of pharmacogenetics in AML patients.

Author Contributions

J.E.M.-V. and P.M. participated in discussions and development of the manuscript, A.S.-A., D.M.-C. and J.L.P. contributed to correcting the draft manuscript, provided additional recommendations and have read and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by grants from the “Instituto Carlos III” (PIE13/00046) and the “Instituto Investigación Sanitaria La Fe” 2013/0331 and 2019-052-1 assigned to the Pharmacy and Hematology Departments. In addition, this work was partially supported by the Cooperative Research Thematic Network (RTICC), grant RD12/0036/014 (ISCIII & ERDF).

Conflicts of Interest

P.M. reports these potential conflicts of interest, AbbVie: advisory board, speakers bureau, research support; Astellas: research support, consultant, speakers bureau, advisory board; Agios: consultant; Tolero Pharmaceutical: consultant; Glycomimetics: consultant; Forma Therapeutics: consultant; Celgene: research support, consultant, speakers bureau, advisory board; Daiichi Sankyo: research support, consultant, speakers bureau, advisory board; Incyte: speakers bureau, advisory board; Janssen: research support, speakers bureau, advisory board; Karyopharm: research support, advisory board; Novartis: research support, speakers bureau, advisory board; Pfizer: research support, speakers bureau, advisory board; Teva: research support, speakers bureau, advisory board. D.M.-C. reports these potential conflicts of interest, Astellas: speakers bureau, advisory board; Daiichi Sankyo: advisory board; Jazz Pharmaceuticals: advisory board, speakers bureau; Novartis: advisory board; Teva: speakers bureau, advisory board. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

References

  1. Tallman, M.S.; Wang, E.S.; Altman, J.K.; Appelbaum, F.R.; Bhatt, V.R.; Bixby, D.; Coutre, S.E.; De Lima, M.; Fathi, A.T.; Fiorella, M.; et al. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2019, 17, 721–749. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Medeiros, B.C.; Chan, S.M.; Daver, N.G.; Jonas, B.A.; Pollyea, D.A. Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. Am. J. Hematol. 2019, 94, 803–811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Megías-Vericat, J.E.; Montesinos, P.; Herrero, M.J.; Bosó, V.; Martínez-Cuadrón, D.; Poveda, J.L.; Sanz, M.Á.; Aliño, S.F. Pharmacogenomics and the treatment of acute myeloid leukemia. Pharmacogenomics 2016, 17, 1245–1272. [Google Scholar] [CrossRef] [PubMed]
  4. Megias-Vericat, J.E.; Martinez-Cuadron, D.; Herrero, M.J.; Alino, S.F.; Poveda, J.L.; Sanz, M.A.; Montesinos, P. Pharmaco-genetics of metabolic genes of anthracyclines in acute myeloid leukemia. Curr. Drug Metab. 2018, 19, 55–74. [Google Scholar] [CrossRef]
  5. Iacobucci, I.; Lonetti, A.; Candoni, A.; Sazzini, M.; Papayannidis, C.; Formica, S.; Ottaviani, E.; Ferrari, A.; Michelutti, A.; Simeone, E.; et al. Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin. Pharm. J. 2012, 13, 335–341. [Google Scholar] [CrossRef]
  6. Lal, S.; Wong, Z.W.; Jada, S.R.; Xiang, X.; Chen Shu, X.; Ang, P.C.; Figg, W.D.; Lee, E.J.; Chowbay, B. Novel SLC22A16 polymorphisms and influence on doxorubicin pharmacokinetics in Asian breast cancer patients. Pharmacogenomics 2007, 8, 567–575. [Google Scholar] [CrossRef]
  7. Bray, J.; Sludden, J.; Griffin, M.J.; Cole, M.; Verrill, M.; Jamieson, D.; Boddy, A.V. Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br. J. Cancer 2010, 102, 1003–1009. [Google Scholar] [CrossRef] [Green Version]
  8. Liberati, A.; Altman, D.G.; Tetzlaff, J.; Mulrow, C.; Gøtzsche, P.C.; Ioannidis, J.P.; Clarke, M.; Devereaux, P.J.; Kleijnen, J.; Moher, D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: Explanation and elaboration. BMJ 2009, 339, b2700. [Google Scholar] [CrossRef] [Green Version]
  9. Lee, H.H.; Leake, B.F.; Kim, R.B.; Ho, R.H. Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance. Mol. Pharmacol. 2017, 91, 14–24. [Google Scholar] [CrossRef] [Green Version]
  10. Niemi, M.; Pasanen, M.K.; Neuvonen, P.J. Organic Anion Transporting Polypeptide 1B1: A Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake. Pharmacol. Rev. 2011, 63, 157–181. [Google Scholar] [CrossRef]
  11. Oshiro, C.; Mangravite, L.; Klein, T.; Altman, R. PharmGKB very important pharmacogene: SLCO1B1. Pharm. Genom. 2010, 20, 211–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Durmus, S.; Naik, J.; Buil, L.; Wagenaar, E.; van Tellingen, O.; Schinkel, A.H. In vivo disposition of doxorubicin is affected by mouse Oatp1a/1b and human OATP1A/1B transporters. Int. J. Cancer. 2014, 135, 1700–1710. [Google Scholar] [CrossRef] [PubMed]
  13. Drenberg, C.D.; Paugh, S.W.; Pounds, S.B.; Shi, L.; Orwick, S.J.; Li, L.; Hu, S.; Gibson, A.A.; Ribeiro, R.C.; Rubnitz, J.; et al. Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia. Clin. Pharmacol. Ther. 2016, 99, 651–660. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Megías-Vericat, J.E.; Martínez-Cuadrón, D.; Herrero, M.J.; Rodríguez-Veiga, R.; Solana-Altabella, A.; Boluda, B.; Balles-taLópez, O.; Cano, I.; Acuña-Cruz, E.; Cervera, J.; et al. Impact of combinations of single-nucleotide polymorphisms of anthracycline transporter genes upon the efficacy and toxicity of induction chemo-therapy in acute myeloid leukemia. Leuk. Lymphoma. 2021, 62, 659–668. [Google Scholar] [CrossRef] [PubMed]
  15. Yee, S.W.; Giacomini, K.M. Emerging Roles of the Human Solute Carrier 22 Family. Drug metabolism and disposition: The biological fate of chemicals. Drug Metab. Dispos. 2021, 50. [Google Scholar] [CrossRef]
  16. Yee, S.W.; Mefford, J.A.; Singh, N.; Percival, M.M.; Stecula, A.; Yang, K.; Witte, J.S.; Takahashi, A.; Kubo, M.; Matsuda, K.; et al. Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. J. Hum. Genet. 2013, 58, 353–361. [Google Scholar] [CrossRef] [PubMed]
  17. Wu, Y.; Hurren, R.; MacLean, N.; Gronda, M.; Jitkova, Y.; Sukhai, M.A.; Minden, M.D.; Schimmer, A.D. Carnitine transporter CT2 (SLC22A16) is over-expressed in acute myeloid leukemia (AML) and target knockdown reduces growth and viability of AML cells. Apoptosis 2015, 20, 1099–1108. [Google Scholar] [CrossRef]
  18. Müller, P.; Asher, N.; Heled, M.; Cohen, S.B.; Risch, A.; Rund, D. Polymorphisms in transporter and phase II metabolism genes as potential modifiers of the predisposition to and treatment outcome of de novo acute myeloid leukemia in Israeli ethnic groups. Leuk. Res. 2008, 32, 919–929. [Google Scholar] [CrossRef]
  19. Seeringer, A.; Yi-Jing, H.; Schlenk, R.; Doehner, K.; Kirchheiner, J.; Doehner, H. 9242 Pharmacogenetic factors in metabolism, transport and toxicity of cytarabine treatment in patients with AML. Eur. J. Cancer Suppl. 2009, 7, 572–573. [Google Scholar] [CrossRef]
  20. Cao, H.X.; Miao, C.F.; Yan, L.; Tang, P.; Zhang, L.R.; Sun, L. Polymorphisms at microRNA binding sites of Ara-C and an-thracyclines-metabolic pathway genes are associated with outcome of acute myeloid leukemia patients. J. Transl. Med. 2017, 15, 235. [Google Scholar] [CrossRef] [Green Version]
  21. Gray, J.H.; Owen, R.P.; Giacomini, K.M. The concentrative nucleoside transporter family, SLC28. Pflügers Archiv. 2004, 447, 728–734. [Google Scholar] [CrossRef] [PubMed]
  22. Visscher, H.; Ross, C.J.; Rassekh, S.R.; Barhdadi, A.; Dubé, M.P.; Al-Saloos, H.; Sandor, G.S.; Caron, H.N.; van Dalen, E.C.; Kremer, L.C.; et al. Canadian Pharmacogenomics Network for Drug Safety Consortium. Pharmacogenomic prediction of anthracycline-induced cardio-toxicity in children. J. Clin. Oncol. 2012, 30, 1422–1428. [Google Scholar] [CrossRef] [PubMed]
  23. Visscher, H.; Ross, C.J.; Rassekh, S.R.; Sandor, G.S.; Caron, H.N.; Van Dalen, E.C.; Kremer, L.C.; Van Der Pal, H.J.; Rogers, P.C.; Rieder, M.J.; et al. Validation of variants inSLC28A3andUGT1A6as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr. Blood Cancer 2013, 60, 1375–1381. [Google Scholar] [CrossRef] [PubMed]
  24. Aminkeng, F.; Bhavsar, A.P.; Visscher, H.; Rassekh, S.R.; Li, Y.; Lee, J.W.; Brunham, L.R.; Caron, H.N.; van Dalen, E.C.; Kremer, L.C.; et al. Canadian Phar-macogenomics Network for Drug Safety Consortium. A coding variant in RARG confers susceptibility to anthracy-cline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015, 47, 1079–1084. [Google Scholar] [CrossRef] [PubMed]
  25. Sági, J.C.; Egyed, B.; Kelemen, A.; Kutszegi, N.; Hegyi, M.; Gézsi, A.; Herlitschke, M.A.; Rzepiel, A.; Fodor, L.E.; Ottóffy, G.; et al. Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. BMC Cancer 2018, 18, 704. [Google Scholar] [CrossRef]
  26. Wojnowski, L.; Kulle, B.; Schirmer, M.; Schlüter, G.; Schmidt, A.; Rosenberger, A.; Vonhof, S.; Bickeböller, H.; Toliat, M.R.; Suk, E.-K.; et al. NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity. Circulation 2005, 112, 3754–3762. [Google Scholar] [CrossRef] [Green Version]
  27. Vulsteke, C.; Pfeil, A.M.; Maggen, C.; Schwenkglenks, M.; Pettengell, R.; Szucs, T.D.; Lambrechts, D.; Dieudonné, A.-S.; Hatse, S.; Neven, P.; et al. Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Breast Cancer Res. Treat. 2015, 152, 67–76. [Google Scholar] [CrossRef]
  28. Reichwagen, A.; Ziepert, M.; Kreuz, M.; Gödtel-Armbrust, U.; Rixecker, T.; Poeschel, V.; Reza Toliat, M.; Nürnberg, P.; Tzvetkov, M.; Deng, S.; et al. Association of NADPH oxidase poly-morphisms with anthracycline-induced cardiotoxicity in the RICOVER60 trial of patients with aggressive CD20(+) B-cell lymphoma. Pharmacogenomics 2015, 16, 361–372. [Google Scholar] [CrossRef]
  29. Zeller, T.; Wild, P.; Szymczak, S.; Rotival, M.; Schillert, A.; Castagne, R.; Maouche, S.; Germain, M.; Lackner, K.; Rossmann, H.; et al. Genetics and beyond--the tran-scriptome of human monocytes and disease susceptibility. PLoS ONE 2010, 5, e10693. [Google Scholar] [CrossRef] [Green Version]
  30. Dimas, A.S.; Deutsch, S.; Stranger, B.E.; Montgomery, S.B.; Borel, C.; Attar-Cohen, H.; Ingle, C.; Beazley, C.; Arcelus, M.G.; Sekowska, M.; et al. Common Regulatory Variation Impacts Gene Expression in a Cell Type–Dependent Manner. Science 2009, 325, 1246–1250. [Google Scholar] [CrossRef] [Green Version]
  31. White, J.C.; Rathmell, J.P.; Capizzi, R.L. Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J. Clin. Investig. 1987, 79, 380–387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Kessel, D.; Hall, T.C.; Rosenthal, D. Uptake and phosphorylation of cytosine arabinoside by normal and leukemic human blood cells in vitro. Cancer Res. 1969, 29, 459–463. [Google Scholar] [PubMed]
  33. Sundaram, M.; Yao, S.Y.; Ingram, J.C.; Berry, Z.A.; Abidi, F.; Cass, C.E.; Baldwin, S.A.; Young, J.D. Topology of a Human Equilibrative, Nitrobenzylthioinosine (NBMPR)-sensitive Nucleoside Transporter (hENT1) Implicated in the Cellular Uptake of Adenosine and Anti-cancer Drugs. J. Biol. Chem. 2001, 276, 45270–45275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Gati, W.P.; Paterson, A.R.; Larratt, L.M.; Turner, A.R.; Belch, A.R. Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular es nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein. Blood 1997, 90, 346–353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Zhang, J.; Visser, F.; King, K.M.; Baldwin, S.A.; Young, J.D.; Cass, C.E. The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer Metastasis Rev. 2007, 26, 85–110. [Google Scholar] [CrossRef]
  36. Eltzschig, H.K.; Abdulla, P.; Hoffman, E.; Hamilton, K.E.; Daniels, D.; Schonfeld, C.; Loffler, M.; Reyes, G.; Duszenko, M.; Karhausen, J.; et al. HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J. Exp. Med. 2005, 202, 1493–1505. [Google Scholar] [CrossRef]
  37. Montero, T.D.; Racordon, D.; Bravo, L.; Owen, G.I.; Bronfman, M.L.; Leisewitz, A.V. PPARalpha and PPARgamma regulate the nucleoside transporter hENT1. Biochem. Biophys. Res. Commun. 2012, 419, 405–411. [Google Scholar] [CrossRef]
  38. Galmarini, C.M.; Thomas, X.; Calvo, F.; Rousselot, P.; Rabilloud, M.; El Jaffari, A.; Cros, E.; Dumontet, C. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br. J. Haematol. 2002, 117, 860–868. [Google Scholar] [CrossRef]
  39. Jaramillo, A.C.; Hubeek, I.; Broekhuizen, R.; Pastor-Anglada, M.; Kaspers, G.J.L.; Jansen, G.; Cloos, J.; Peters, G.J. Expression of the nucleoside transporters hENT1 (SLC29) and hCNT1 (SLC28) in pediatric acute myeloid leukemia. Nucleosides Nucleotides Nucleic Acids 2020, 39, 1379–1388. [Google Scholar] [CrossRef]
  40. Osato, D.H.; Huang, C.C.; Kawamoto, M.; Johns, S.J.; Stryke, D.; Wang, J.; Ferrin, T.E.; Herskowitz, I.; Giacomini, K.M. Functional characterization in yeast of genetic variants in the human equilibrative nucleoside transporter, ENT1. Pharmacogenetics 2003, 13, 297–301. [Google Scholar] [CrossRef]
  41. Myers, S.N.; Goyal, R.K.; Roy, J.D.; Fairfull, L.D.; Wilson, J.W.; Ferrell, R.E. Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1. Pharm. Genom. 2006, 16, 315–320. [Google Scholar] [CrossRef] [PubMed]
  42. Parmar, S.; Seeringer, A.; Denich, D.; Gärtner, F.; Pitterle, K.; Syrovets, T.; Ohmle, B.; Stingl, J.C. Variability in transport and biotransformation of cytarabine is associated with its toxicity in peripheral blood mononuclear cells. Pharmacogenomics 2011, 12, 503–514. [Google Scholar] [CrossRef] [PubMed]
  43. Kim, J.-H.; Lee, C.; Cheong, H.S.; Koh, Y.; Ahn, K.-S.; Kim, H.-L.; Shin, H.D.; Yoon, S.-S. SLC29A1 (ENT1) polymorphisms and outcome of complete remission in acute myeloid leukemia. Cancer Chemother. Pharmacol. 2016, 78, 533–540. [Google Scholar] [CrossRef] [PubMed]
  44. Kim, K.I.; Huh, I.-S.; Kim, I.-W.; Park, T.; Ahn, K.-S.; Yoon, S.-S.; Yoon, J.-H.; Oh, J.M. Combined interaction of multi-locus genetic polymorphisms in cytarabine arabinoside metabolic pathway on clinical outcomes in adult acute myeloid leukaemia (AML) patients. Eur. J. Cancer 2012, 49, 403–410. [Google Scholar] [CrossRef] [PubMed]
  45. Wan, H.; Zhu, J.; Chen, F.; Xiao, F.; Huang, H.; Han, X.; Zhong, L.; Zhong, H.; Xu, L.; Ni, B.; et al. SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: An in vitro study. J. Exp. Clin. Cancer Res. 2014, 33, 90. [Google Scholar] [CrossRef] [PubMed]
  46. Amaki, J.; Onizuka, M.; Ohmachi, K.; Aoyama, Y.; Hara, R.; Ichiki, A.; Kawai, H.; Sato, A.; Miyamoto, M.; Toyosaki, M.; et al. Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy. Int. J. Hematol. 2015, 101, 543–553. [Google Scholar] [CrossRef] [PubMed]
  47. International Transporter Consortium; Giacomini, K.M.; Huang, S.M.; Tweedie, D.J.; Benet, L.Z.; Brouwer, K.L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; et al. Membrane transporters in drug development. Nat. Rev. Drug Discov. 2010, 9, 215–236. [Google Scholar]
  48. Lal, S.; Wong, Z.W.; Sandanaraj, E.; Xiang, X.; Ang, P.C.S.; Lee, E.J.D.; Chowbay, B. Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. 2008, 99, 816–823. [Google Scholar] [CrossRef]
  49. Guo, Y.; Köck, K.; Ritter, C.A.; Chen, Z.-S.; Grube, M.; Jedlitschky, G.; Illmer, T.; Ayres, M.; Beck, J.F.; Siegmund, W.; et al. Expression of ABCC-Type Nucleotide Exporters in Blasts of Adult Acute Myeloid Leukemia: Relation to Long-term Survival. Clin. Cancer Res. 2009, 15, 1762–1769. [Google Scholar] [CrossRef] [Green Version]
  50. Hopper-Borge, E.; Xu, X.; Shen, T.; Shi, Z.; Chen, Z.-S.; Kruh, G.D. Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B. Cancer Res. 2009, 69, 178–184. [Google Scholar] [CrossRef] [Green Version]
  51. Illmer, T.; Schuler, U.S.; Thiede, C.; I Schwarz, U.; Kim, R.B.; Gotthard, S.; Freund, D.; Schäkel, U.; Ehninger, G.; Schaich, M. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002, 62, 4955–4962. [Google Scholar] [PubMed]
  52. Kaya, P.; Gündüz, U.; Arpaci, F.; Ural, A.U.; Guran, S. Identification of polymorphisms on theMDR1 gene among Turkish population and their effects on multidrug resistance in acute leukemia patients. Am. J. Hematol. 2005, 80, 26–34. [Google Scholar] [CrossRef] [PubMed]
  53. Kim, D.H.; Park, J.Y.; Sohn, S.K.; Lee, N.Y.; Baek, J.H.; Jeon, S.B.; Kim, J.G.; Suh, J.S.; Do, Y.R. Multidrug resistance-1 gene polymorphism associated with the treatment outcomes in de novo acute myeloid leukemia. J. Clin. Oncol. 2005, 23, 6550. [Google Scholar] [CrossRef]
  54. Van Der Holt, B.; Vandenheuveleibrink, M.; Van Schaik, R.H.N.; Van Der Heiden, I.P.; Wiemer, E.A.C.; Vossebeld, P.J.M.; Löwenberg, B.; Sonneveld, P. ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients. Clin. Pharmacol. Ther. 2006, 80, 427–439. [Google Scholar] [CrossRef]
  55. Hur, E.-H.; Lee, J.-H.; Lee, M.J.; Choi, S.-J.; Lee, J.-H.; Kang, M.J.; Seol, M.; Jang, Y.E.; Lee, H.-J.; Kang, I.-S.; et al. C3435T polymorphism of the MDR1 gene is not associated with P-glycoprotein function of leukemic blasts and clinical outcome in patients with acute myeloid leukemia. Leuk. Res. 2008, 32, 1601–1604. [Google Scholar] [CrossRef]
  56. Hampras, S.S.; Sucheston, L.; Weiss, J.; Baer, M.R.; Zirpoli, G.; Singh, P.K.; Wetzler, M.; Chennamaneni, R.; Blanco, J.G.; Ford, L.; et al. Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia. Int. J. Mol. Epidemiol. Genet. 2010, 1, 201–207. [Google Scholar]
  57. Gréen, H.; Falk, I.J.; Lotfi, K.; Paul, E.; Hermansson, M.; Rosenquist, R.; Paul, C.; Nahi, H. Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype. Pharm. J. 2010, 12, 111–118. [Google Scholar] [CrossRef]
  58. Scheiner, M.A.M.; Vasconcelos, F.d.C.; Matta, R.R.d.; Figueira, R.D.B., Jr.; Maia, R.C. ABCB1 genetic variation and P-glycoprotein expression/activity in a cohort of Brazilian acute myeloid leukemia patients. J. Cancer Res. Clin. Oncol. 2012, 138, 959–969. [Google Scholar] [CrossRef]
  59. Jakobsen Falk, I.; Fyrberg, A.; Paul, E.; Nahi, H.; Hermanson, M.; Rosenquist, R.; Höglund, M.; Palmqvist, L.; Stockelberg, D.; Wei, Y.; et al. Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype. Br. J. Haematol. 2014, 167, 671–680. [Google Scholar] [CrossRef] [Green Version]
  60. He, H.; Yin, J.-Y.; Xu, Y.-J.; Li, X.; Zhang, Y.; Liu, Z.-G.; Zhou, F.; Zhai, M.; Li, Y.; Li, X.-P.; et al. Association of ABCB1 Polymorphisms with the Efficacy of Ondansetron in Chemotherapy-induced Nausea and Vomiting. Clin. Ther. 2014, 36, 1242–1252.e2. [Google Scholar] [CrossRef]
  61. He, H.; Yin, J.; Li, X.; Zhang, Y.; Xu, X.; Zhai, M.; Chen, J.; Qian, C.; Zhou, H.; Liu, Z. Association of ABCB1 polymorphisms with prognostic outcomes of anthracycline and cytarabine in Chinese patients with acute myeloid leukemia. Eur. J. Clin. Pharmacol. 2015, 71, 293–302. [Google Scholar] [CrossRef] [PubMed]
  62. Megías-Vericat, J.E.; Montesinos, P.; Herrero, M.J.; Moscardó, F.; Bosó, V.; Rojas, L.; Martínez-Cuadrón, D.; Hervás, D.; Boluda, B.; García-Robles, A.; et al. Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia. Leuk. Lymphoma. 2017, 58, 1197–1206. [Google Scholar] [CrossRef] [PubMed]
  63. Rafiee, R.; Chauhan, L.; Alonzo, T.A.; Wang, Y.-C.; Elmasry, A.; Loken, M.R.; Pollard, J.; Aplenc, R.; Raimondi, S.; Hirsch, B.A.; et al. ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: A report from Children’s Oncology Group AAML0531 Trial. Blood Cancer J. 2019, 9, 51. [Google Scholar] [CrossRef] [PubMed]
  64. Short, N.J.; Richard-Carpentier, G.; Kanagal-Shamanna, R.; Patel, K.P.; Konopleva, M.; Papageorgiou, I.; Pemmaraju, N.; Borthakur, G.; Ravandi, F.; DiNardo, C.D.; et al. Impact of CD33 and ABCB1 single nucleotide polymorphisms in patients with acute myeloid leukemia and advanced myeloid malignancies treated with de-citabine plus gemtuzumab ozogamicin. Am. J Hematol. 2020, 95, E225–E228. [Google Scholar] [CrossRef]
  65. van den Heuvel-Eibrink, M.M.V.D.; Wiemer, E.A.C.; de Boevere, M.J.; van der Holt, B.; Vossebeld, P.J.M.; Pieters, R.; Sonneveld, P. MDR1 gene–related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood 2001, 97, 3605–3611. [Google Scholar] [CrossRef] [Green Version]
  66. Kim, Y.-K.; Bae, S.-Y.; Kim, H.N.; Kim, N.Y.; Kim, H.J.; Bang, S.-M.; Jo, D.-Y.; Won, J.-H.; Lee, N.-R.; Kwak, J.-Y.; et al. Prognostic Impact of DNA Repair and MDR-1 Gene Polymorphisms In De Novo Acute Myeloid Leukemia with t(8;21) or Inv(16). Blood 2010, 116, 1714. [Google Scholar] [CrossRef]
  67. Kim, Y.-K.; Kim, H.-N.; Lee, I.-K.; Bang, S.-M.; Jo, D.-Y.; Won, J.-H.; Kwak, J.-Y.; Yim, C.-Y.; Yang, D.-H.; Lee, J.-J.; et al. Prognostic Significance of ABCB1 (MDR1) Gene Polymorphisms in De Novo Acute Myeloid Leukemia with t(8;21) or inv(16). Blood 2007, 110, 4271. [Google Scholar] [CrossRef]
  68. Monzo, M.; Brunet, S.; Urbano-Ispizua, A.; Navarro, A.; Perea, G.; Esteve, J.; Artells, R.; Granell, M.; Berlanga, J.; Ribera, J.M.; et al. Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. Blood 2006, 107, 4871–4879. [Google Scholar] [CrossRef] [Green Version]
  69. Varatharajan, S.; Panetta, J.; Abraham, A.; Karathedath, S.; Mohanan, E.; Lakshmi, K.M.; Arthur, N.; Srivastava, V.M.; Nemani, S.; George, B.; et al. Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia. Cancer Chemother. Pharmacol. 2016, 78, 1051–1058. [Google Scholar] [CrossRef]
  70. Borg, A.G.; Burgess, R.; Green, L.M.; Scheper, R.J.; Yin, J.A.L. P-glycoprotein and multidrug resistance-associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells. Br. J. Haematol. 2000, 108, 48–54. [Google Scholar] [CrossRef]
  71. Seedhouse, C.H.; Grundy, M.; White, P.; Li, Y.; Fisher, J.; Yakunina, D.; Moorman, A.; Hoy, T.; Russell, N.; Burnett, A.; et al. Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials. Clin. Cancer Res. 2007, 13, 7059–7066. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Lamba, J.; Strom, S.; Venkataramanan, R.; Thummel, K.E.; Lin, Y.S.; Liu, W.; Cheng, C.; Lamba, V.; Watkins, P.B.; Schuetz, E. MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype. Clin. Pharmacol. Ther. 2006, 79, 325–338. [Google Scholar] [CrossRef] [PubMed]
  73. Megías-Vericat, J.E.; Rojas, L.; Herrero, M.J.; Bosó, V.; Montesinos, P.; Moscardó, F.; Poveda, J.L.; Sanz, M.Á.; Aliño, S.F. Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: A systematic review and meta-analysis of observational studies. Pharm. J. 2015, 15, 109–118. [Google Scholar] [CrossRef]
  74. Megías-Vericat, J.E.; Rojas, L.; Herrero, M.J.; Bosó, V.; Montesinos, P.; Moscardó, F.; Poveda, J.L.; Sanz, M.Á.; Aliño, S.F. Positive impact of ABCB1 polymorphisms in overall survival and complete remission in acute myeloid leukemia: A systematic review and meta-analysis. Pharm. J. 2016, 16, 1–2. [Google Scholar] [CrossRef] [PubMed]
  75. Hertz, D.L.; Caram, M.V.; Kidwell, K.M.; Thibert, J.N.; Gersch, C.; Seewald, N.J.; Smerage, J.; Rubenfire, M.; Henry, N.L.; Cooney, K.A.; et al. Evidence for association of SNPs in ABCB1 and CBR3 but not RAC2, NCF4 SLC28A3 or TOP2B with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines. Pharmacogenomics 2016, 17, 231–240. [Google Scholar] [CrossRef] [Green Version]
  76. Rossi, D.; Rasi, S.; Franceschetti, S.; Capello, D.; Castelli, A.; De Paoli, L.; Ramponi, A.; Chiappella, A.; Pogliani, E.M.; Vitolo, U.; et al. Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21. Leukemia 2009, 23, 1118–1126. [Google Scholar] [CrossRef] [PubMed]
  77. Lubieniecka, J.M.; Graham, J.; Heffner, D.; Mottus, R.; Reid, R.; Hogge, D.; Grigliatti, T.A.; Riggs, W.K. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase poly-morphisms as a potential risk factor. Front. Genet. 2013, 4, 231. [Google Scholar] [CrossRef] [Green Version]
  78. Sissung, T.M.; Huang, P.A.; Hauke, R.J.; McCrea, E.M.; Peer, C.J.; Barbier, R.H.; Strope, J.D.; Ley, A.M.; Zhang, M.; Hong, J.A.; et al. Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters. Mol. Pharmacol. 2019, 96, 158–167. [Google Scholar] [CrossRef]
  79. Stride, B.D.; Grant, C.E.; Loe, D.W.; Hipfner, D.R.; Cole, S.P.C.; Deeley, R.G. Pharmacological Characterization of the Murine and Human Orthologs of Multidrug-Resistance Protein in Transfected Human Embryonic Kidney Cells. Mol. Pharmacol. 1997, 52, 344–353. [Google Scholar] [CrossRef] [Green Version]
  80. Conrad, S.; Kauffmann, H.-M.; Ito, K.-I.; Leslie, E.; Deeley, R.G.; Schrenk, D.; Cole, S. A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance. Pharmacogenetics 2002, 12, 321–330. [Google Scholar] [CrossRef]
  81. Semsei, A.F.; Erdelyi, D.J.; Ungvari, I.; Csagoly, E.; Hegyi, M.; Kiszel, P.S.; Lautner-Csorba, O.; Szabolcs, J.; Masat, P.; Fekete, G.; et al. ABCC1polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol. Int. 2012, 36, 79–86. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Mahjoubi, F.; Akbari, S.; Montazeri, M.; Moshyri, F. MRP1 polymorphisms (T2684C, C2007T, C2012T, and C2665T) are not associated with multidrug resistance in leukemic patients. Genet. Mol. Res. 2008, 7, 1369–1374. [Google Scholar] [CrossRef] [PubMed]
  83. Kunadt, D.; Dransfeld, C.; Dill, C.; Schmiedgen, M.; Kramer, M.; Altmann, H.; Röllig, C.; Bornhäuser, M.; Mahlknecht, U.; Schaich, M.; et al. Multidrug-related protein 1 (MRP1) polymorphisms rs129081, rs212090, and rs212091 predict survival in normal karyotype acute myeloid leukemia. Ann. Hematol. 2020, 99, 2173–2180. [Google Scholar] [CrossRef] [PubMed]
  84. Cui, Y.; König, J.; Buchholz, J.K.; Spring, H.; Leier, I.; Keppler, D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. 1999, 55, 929–937. [Google Scholar]
  85. Armenian, S.H.; Ding, Y.; Mills, G.; Sun, C.; Venkataraman, K.; Wong, F.L.; Neuhausen, S.L.; Senitzer, D.; Wang, S.; Forman, S.J.; et al. Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Br. J. Haematol. 2013, 163, 205–213. [Google Scholar] [CrossRef] [Green Version]
  86. Windsor, R.E.; Strauss, S.J.; Kallis, C.; Wood, N.E.; Whelan, J.S. Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: A pilot study. Cancer 2012, 118, 1856–1867. [Google Scholar] [CrossRef]
  87. Varatharajan, S.; Abraham, A.; Karathedath, S.; Ganesan, S.; Lakshmi, K.M.; Arthur, N.; Srivastava, V.M.; George, B.; Srivastava, A.; Mathews, V.; et al. ATP-binding casette transporter expression in acute myeloid leukemia: Association with in vitro cytotoxicity and prognostic markers. Pharmacogenomics 2017, 18, 235–244. [Google Scholar] [CrossRef]
  88. Butrym, A.; Łacina, P.; Bogunia-Kubik, K.; Mazur, G. ABCC3 and GSTM5 gene polymorphisms affect overall survival in Polish acute myeloid leukaemia patients. Curr. Probl. Cancer 2021, 45, 100729. [Google Scholar] [CrossRef]
  89. Hu, S.; Chen, Z.; Franke, R.; Orwick, S.; Zhao, M.; Rudek, M.A.; Sparreboom, A.; Baker, S.D. Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters. Clin. Cancer Res. 2009, 15, 6062–6069. [Google Scholar] [CrossRef] [Green Version]
  90. Hu, S.; Niu, H.; Inaba, H.; Orwick, S.; Rose, C.; Panetta, J.; Yang, S.; Pounds, S.; Fan, Y.; Calabrese, C.; et al. Activity of the Multikinase Inhibitor Sorafenib in Combination with Cytarabine in Acute Myeloid Leukemia. JNCI J. Natl. Cancer Inst. 2011, 103, 893–905. [Google Scholar] [CrossRef]
  91. Doyle, L.A.; Yang, W.; Abruzzo, L.V.; Krogmann, T.; Gao, Y.; Rishi, A.K.; Ross, D.D. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA 1998, 95, 15665–15670. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Chen, L.; Manautou, J.E.; Rasmussen, T.P.; Zhong, X.B. Development of precision medicine approaches based on interindividual variability of BCRP/ABCG2. Acta Pharm. Sin. B 2019, 9, 659–674. [Google Scholar] [CrossRef] [PubMed]
  93. Ross, D.D.; Karp, J.E.; Chen, T.T.; Doyle, L.A. Expression of breast cancer resistance protein in blast cells from patients with acute leukemia. Blood 2000, 96, 365–368. [Google Scholar] [CrossRef] [PubMed]
  94. Benderra, Z.; Faussat, A.-M.; Sayada, L.; Perrot, J.-Y.; Chaoui, D.; Marie, J.-P.; Legrand, O. Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias. Clin. Cancer Res. 2004, 10, 7896–7902. [Google Scholar] [CrossRef] [Green Version]
  95. Benderra, Z.; Faussat, A.M.; Sayada, L.; Perrot, J.-Y.; Tang, R.; Chaoui, D.; Morjani, H.; Marzac, C.; Marie, J.-P.; Legrand, O. MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia. Clin. Cancer Res. 2005, 11, 7764–7772. [Google Scholar] [CrossRef] [Green Version]
  96. Tiribelli, M.; Geromin, A.; Michelutti, A.; Cavallin, M.; Pianta, A.; Fabbro, D.; Russo, D.; Damante, G.; Fanin, R.; Damiani, D. Concomitant ABCG2 overexpression and FLT3-ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse. Cancer 2010, 117, 2156–2162. [Google Scholar] [CrossRef]
  97. Wang, F.; Liang, Y.-J.; Wu, X.-P.; Chen, L.-M.; To, K.K.W.; Dai, C.-L.; Yan, Y.-Y.; Wang, Y.-S.; Tong, X.-Z.; Fu, L.-W. Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia. Eur. J. Cancer 2011, 47, 1990–1999. [Google Scholar] [CrossRef]
  98. Tiribelli, M.; Fabbro, D.; Franzoni, A.; Fanin, R.; Damante, G.; Damiani, D. Q141K polymorphism of ABCG2 protein is associated with poor prognosis in adult acute myeloid leukemia treated with idarubicin-based chemotherapy. Haematologica 2013, 98, e28–e29. [Google Scholar] [CrossRef]
  99. Rhodes, K.E.; Zhang, W.; Yang, D.; Press, O.A.; Gordon, M.; Vallböhmer, D.; Schultheis, A.M.; Lurje, G.; Ladner, R.D.; Fazzone, W.; et al. ABCB1, SLCO1B1 and UGT1A1 gene polymorphisms are associated with toxicity in metastatic colorectal cancer patients treated with first-line irinotecan. Drug Metab. Lett. 2007, 1, 23–30. [Google Scholar] [CrossRef]
  100. Sai, K.; Saito, Y.; Maekawa, K.; Kim, S.-R.; Kaniwa, N.; Nishimaki-Mogami, T.; Sawada, J.-I.; Shirao, K.; Hamaguchi, T.; Yamamoto, N.; et al. Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients. Cancer Chemother. Pharmacol. 2010, 66, 95–105. [Google Scholar] [CrossRef]
  101. Peters, B.J.; Rodin, A.S.; Klungel, O.H.; van Duijn, C.M.; Stricker, B.H.C.; Slot, R.V.; de Boer, A.; der Zee, A.-H.M.-V. Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction. Pharmacogenomics 2010, 11, 1065–1076. [Google Scholar] [CrossRef] [PubMed]
  102. Neve, E.P.A.; Artursson, P.; Ingelman-Sundberg, M.; Karlgren, M. An Integrated in Vitro Model for Simultaneous Assessment of Drug Uptake, Metabolism, and Efflux. Mol. Pharm. 2013, 10, 3152–3163. [Google Scholar] [CrossRef] [PubMed]
  103. Lane, H.-Y.; Tsai, G.E.; Lin, E. Assessing Gene-Gene Interactions in Pharmacogenomics. Mol. Diagn. Ther. 2012, 16, 15–27. [Google Scholar] [CrossRef] [PubMed]
  104. Donnette, M.; Solas, C.; Giocanti, M.; Venton, G.; Farnault, L.; Berda-Haddad, Y.; Hau, L.T.T.; Costello, R.; Ouafik, L.; Lacarelle, B.; et al. Simultaneous determination of cytosine arabinoside and its metabolite uracil arabinoside in human plasma by LC-MS/MS: Application to pharmacokinetics-pharmacogenetics pilot study in AML patients. J. Chromatogr. B 2019, 1126–1127, 121770. [Google Scholar] [CrossRef]
  105. Yamakawa, Y.; Hamada, A.; Nakashima, R.; Yuki, M.; Hirayama, C.; Kawaguchi, T.; Saito, H. Association of genetic poly-morphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther. Drug Monit. 2011, 33, 244–250. [Google Scholar] [PubMed]
  106. Zhang, H.; He, X.; Li, J.; Wang, Y.; Wang, C.; Chen, Y.; Niu, C.; Gao, P. SLCO1B1c. 521T>C gene polymorphisms are associated with high-dose methotrexate pharmacokinetics and clinical outcome of pediatric acute lymphoblastic leukemia. Zhonghua Er Ke Za Zhi—Chin. J. Pediatr. 2014, 52, 770–776. [Google Scholar]
  107. Bruhn, O.; Cascorbi, I. Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance. Expert Opin. Drug Metab. Toxicol. 2014, 10, 1337–1354. [Google Scholar] [CrossRef]
  108. Bruckmueller, H.; Cascorbi, I. ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: What is our current understanding? Expert Opin. Drug. Metab. Toxicol. 2021, 17, 369–396. [Google Scholar] [CrossRef]
  109. Roumier, C.; Cheok, M.H. Pharmacogenomics in acute myeloid leukemia. Pharmacogenomics 2009, 10, 1839–1851. [Google Scholar] [CrossRef]
  110. Emadi, A.; E Karp, J. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia. Pharmacogenomics 2012, 13, 1257–1269. [Google Scholar] [CrossRef] [Green Version]
  111. Vasconcelos, F.C.; de Souza, P.S.; Hancio, T.; de Faria, F.C.C.; Maia, R.C. Update on drug transporter proteins in acute myeloid leukemia: Pathological implication and clinical setting. Crit. Rev. Oncol. 2021, 160, 103281. [Google Scholar] [CrossRef] [PubMed]
  112. Pinto-Merino, Á.; Labrador, J.; Zubiaur, P.; Alcaraz, R.; Herrero, M.J.; Montesinos, P.; Abad-Santos, F.; Saiz-Rodríguez, M. Role of Pharmacogenetics in the Treatment of Acute Myeloid Leukemia: Systematic Review and Future Perspectives. Pharmaceutics 2022, 14, 559. [Google Scholar] [CrossRef] [PubMed]
  113. Megías-Vericat, J.E.; Solana-Altabella, A.; Ballesta-López, O.; Martínez-Cuadrón, D.; Montesinos, P. Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. Ann. Hematol. 2020, 99, 1989–2007. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Summary of evidence search and selection.
Figure 1. Summary of evidence search and selection.
Pharmaceutics 14 00878 g001
Figure 2. Key candidate genes involved in drug transport in acute myeloid leukemia.
Figure 2. Key candidate genes involved in drug transport in acute myeloid leukemia.
Pharmaceutics 14 00878 g002
Table 1. Characteristics of the studies included in the systematic review for influx transporters.
Table 1. Characteristics of the studies included in the systematic review for influx transporters.
SNPStudynAge (Range)Ethnia
(Country)
HWELMA Status (%)Chemotherapy SchemeClinical Outcomes
SLCO1B1
T521C
rs4149056
Iacobucci et al., 2012 [5]9451
(19–65)
Caucasian
(Italy)
YesDe novo (80.9%)
Secondary (19.1%)
Ara C + IDA + FLUDA + GO
-
CR: no influence
-
Toxicity: CC/CT ↑liver toxicity
Drenberg et al., 2016 [13] 11649.1
(0–21)
White (70%)
Black (20%)
Others (10%)
YesDe novoAra C + DAUNO + ETOP + MIT
-
OS: TT ↓OS (p: 0.05)
-
EFS: no influence
-
Toxicity: no influence
Haplotype *1A/*1A,*1B/*1B (rs2291075, rs4149056 & rs2306283): ↓OS y ↓EFS
Megías-Vericat et al., 2021 [14]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR: no influence
-
Induction death: TT ↑induction death (p: 0.049)
-
Toxicity: no influence
597C>T
rs2291075
Drenberg et al., 2016 [13] 11649.1
(0–21)
White (70%)
Black (20%)
Others (10%)
YesDe novoAra C + DAUNO + ETOP + MIT
-
OS: CC ↓OS (p: 0.012)
-
EFS: CC ↓EFS (p: 0.006)
-
Toxicity: no influence
Haplotype *1A/*1A,*1B/*1B (rs2291075, rs4149056 & rs2306283): ↓OS y ↓EFS
388A>G
rs2306283
Drenberg et al., 2016 [13] 11649.1
(0–21)
White (70%)
Black (20%)
Others (10%)
YesDe novoAra C + DAUNO + ETOP + MIT
-
OS: no influence
-
EFS: no influence
-
Toxicity: no influence
Haplotype *1A/*1A,*1B/*1B (rs2291075, rs4149056 & rs2306283): ↓OS y ↓EFS
SLC22A12
T1246C
rs11231825
Iacobucci et al., 2012 [5]9451
(19–65)
Caucasian
(Italy)
YesDe novo (80.9%)
Secondary (19.1%)
Ara C + IDA + FLUDA + GO
-
CR: no influence
-
Toxicity: TT/CT ↑fever reaction (associated with GO administration)
rs528211
(G>A)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): GG ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs2360872
(C>T)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): CC ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs505802
(A>G)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): AA ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs524023
(G>A)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): GG ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs9734313
(T>C)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs11231825
(C>T)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): CC ↓DFS (p: 0.0048). No influence in non-Caucasian cohort
rs11606370
(A>C)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): AA ↓DFS (p: 0.005). No influence in non-Caucasian cohort
rs893006
(T>G)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.0055). No influence in non-Caucasian cohort
SLC22A16
rs12210538
1226A>G
Megías-Vericat et al., 2021 [14]22552.5
(16–78)
Caucasian
(Spain)
YesDe novoAra C + IDA
-
CR and induction death: no influence
-
Toxicity: no influence
rs714368
146A>G
Megías-Vericat et al., 2021 [14]22552.5
(16–78)
Caucasian
(Spain)
YesDe novoAra C + IDA
-
CR and induction death: no influence
-
Toxicity: no influence
SLC25A37
rs7818607
(C>A)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): AA ↓DFS (p: 0.0057). No influence in non-Caucasian cohort
rs8534
(C>T)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.0067). No influence in non-Caucasian cohort
CNT1
(SLC28A1)
G565A
rs2290272
Müller et al., 2008 [18]13946.3
(15–86)
Jews (61.2%)
Arabs (38.8%)
YesDe novoAra C + ANT ± FLUDA ± MIT
-
OS (TX censured): no influence
C1561T
rs2242046
Seeringer et al., 2009 [19] 3322<60Caucasian
(Germany)
NRNR (normal cytogenetic status)Ara C + IDA + ETOP
-
Toxicity (hematologic): allele T reduced neutrophils and increased reconstitution time of total white blood cells
rs8025045
(G>T)
Cao et al., 2017 [20]20667.2 (22–98)Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: no influence
SLC28A2
rs10519020
(G>C)
Drenberg et al., 2016 [13] 11649.1
(0–21)
White (70%)
Black (20%)
Others (10%)
YesDe novoAra C + DAUNO + ETOP + MIT
-
OS: GG ↓OS (p: 0.002)
-
EFS: GG ↓EFS (p: 0.001)
SLC28A3
rs11140500
(C>T)
Yee et al., 2013 [16] 2154NRCaucasian (Europe)NRNRAra C + ETOP + BUSUL
(pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.00018). No influence in non-Caucasian cohort
hENT1
(SLC29A1)
C469A
rs3734703
Kim et al., 2013 [44] 49750 (16–76)Asian
(South Korea)
YesDe novoAra C + IDA
-
CR, OS, RFS: no influence individually
-
OS, RFS: AA/AC combined with TYMS AA genotype (rs2612100) ↓OS and RFS (OS loses statistically significant after multivariable analysis)
-
Toxicity (hematologic): no influence
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: A allele ↑CR (p: 0.008; p Bonferroni:0.04) and haplotype ht3 (p: 0.01)
Cao et al., 2017 [20]20667.2 (22–98)Asian
(China)
YesDe novoAra C + ANT
-
CR: CC+AA ↑CR (p: 0.027)
-
OS: AA+CA ↓OS (p: 0.006)
-
RFS: AA+CA ↓RFS (p: 0.003)
-
Toxicity: no influence
C>T
rs9394992
Wan et al., 2014 [45]10043
(17–76)
Asian
(China)
YesDe novoAra C + DAUNO or IDA
-
RR: CC ↓RR (p: 0.0004)
-
OS: CC ↑OS against CT (p: 0.02) and TT (p: 0.005)
-
DFS: CC ↑DFS against CT (p: 0.03) and TT (p: 0.001)
-
mRNA expression: CC ↑expression (p < 0.01)
-
SNP-SNP interaction: CT/TT + CC (rs324148) ↓OS (p < 0.001) and ↓DFS (p: 0.005)
Amaki et al., 2015 [46]3954
(23–71)
Asian
(Japan)
YesDe novoAra C + IDA or DAUNO (consolidation: Ara C high doses)
-
OS: no influence.
-
TTR: no influence.
-
Hematologic toxicity: no influence.
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: T allele ↑CR (p: 0.02; p Bonferroni:NS) and haplotype ht3 (p: 0.01)
T>C
rs324148
Wan et al., 2014 [45]10043
(17–76)
Asian
(China)
YesDe novoAra C + DAUNO or IDA
-
RR: CC ↑RR (p: 0.04)
-
OS: CC ↓OS against CT/TT (p: 0.0001)
-
DFS: CC ↓DFS against CT/TT (p: 0.0001)
-
mRNA expression: TT ↑expression (p < 0.01)
-
SNP-SNP interaction: CC+CT/TT (rs9394992) ↓OS (p < 0.001) and ↓DFS (p: 0.005)
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: no influence, ↑CR haplotype ht3 (p: 0.01)
A>C
rs693955
Amaki et al., 2015 [46]3954
(23–71)
Asian
(Japan)
YesDe novoAra C + IDA or DAUNO (consolidation: Ara C high doses)
-
OS: no influence.
-
TTR: CC ↓TTR (p: 0.00261; 0.0096 in multivariable analysis)
-
Hematologic toxicity: CC ↓neutropenia duration
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: no influence, ↑CR haplotype ht3 (p: 0.01)
rs507964
(A>C)
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: C allele ↑CR (p: 0.03; p Bonferroni:NS) and haplotype ht3 (p: 0.01)
rs747199
(C>G)
Kim et al., 2016 [43]10350.4
(16–76)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: G allele ↑CR (p: 0.02; p Bonferroni:NS) and haplotype ht3 (p: 0.01)
Abbreviations: AMSA: amsacrine; ANT: anthracycline; BUSUL: busulfan; CR: complete remission; DAUNO: daunorubicin; DFS: disease-free survival; EFS: event-free survival; ETOP: etoposide; FLUDA: fludarabine; GO: gemtuzumab–ozogamicin; HWE: Hardy–Weinberg equilibrium; IDA: idarubicin; MIT: mitoxantrone; NR: not reported; OS: overall survival; RFS: relapse-free survival; RR: rate of relapse; TX: hematologic transplant. 1—This study [13] analyzed 1936 SNPs of 225 genes with a multi-SNP-based approach (including ABC and SLC transporters). Only SNPs with significant results were cited. 2—This study [16] analyzed 1659 SNPs of 42 genes with multi-SNP based approach. Only SNPs with significant results were cited. 3—This study [19] included SNPs of genes potentially involved in the response to Ara C (hCNT1, hENT1, hENT2, DCK, CDA), but only specified the SNPs with significant effect. 4—This study [44] included 139 SNPs of 10 genes potentially involved in the response to Ara C, but only specified the SNPs with significant effect.
Table 2. Characteristics of the studies included in the systematic review for polymorphisms of the ABC transporter family.
Table 2. Characteristics of the studies included in the systematic review for polymorphisms of the ABC transporter family.
SNPStudynAge (Range)Ethnia (Country)HWELMA Status (%)Chemotherapy SchemeClinical Outcomes
ABCB1
C3435T
rs1045642
Illmer et al., 2002 [51]40553
(17–78)
Caucasian
(Germany)
YesDe novoAra C+ MIT + ETOP + AMSA
-
CR: no influence.
-
OS and DFS at 4 years (TX censured): CC ↓OS (CC vs. CT p < 0.01, CC vs. CT/TT p: 0.05).
-
Haplotype with G2677T/A and C1236T: wild-type ↓OS and DFS at 4 years.
-
mRNA expression: CC ↓expression (p < 0.05)
Kaya et al., 2005 [52]2836
(20–64)
Arabs
(Turkey)
NRNRAra C + ANT
-
Drug sensitive/resistant: no differences (mixed with ALL cohort)
Kim DH et al., 2006 [53]8139
(15–72)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: CC ↑CR (p: 0.05)
-
OS at 3 years (TX censured): no influence.
-
EFS at 3 years (TX censured): CC ↑EFS (p: 0.01)
-
Haplotype with G2677T/A: wild-type ↑CR and EFS at 3 years.
-
mRNA expression: CC ↓expression (p: 0.03)
Van der Holt et al., 2006 [54] 1150 (130)67
(60–85)
Caucasian
(Netherlands)
NoDe novo: 79Secondary: 21Ara C + DAUNO
-
CR, OS, EFS, DFS at 5 years: no influence.
-
Expression and activity of P-gp: no influence
Hur et al., 2008 [55]20044 (NR)Asian
(South Korea)
YesDe novoAra C + ANT
-
CR, OS, RFS and EFS at 5 years: no influence
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian
(86%) Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
Green et al., 2012 [57]10063
(20–85)
Caucasian
(Europe)
YesDe novo (normal karyotype)Ara C + ANT or MIT +/or Others
-
OS at 4 years (TX censured): no influence
Scheiner et al., 2012 [58] 2109 (44)34
(<1–86)
Others: White (69.7%)
Non-white (30.3%)
NoDe novo: 72.5Secondary: 18.3Ara C + IDA
-
OS at 5 years: no influence.
-
EFS at 5 years: CT ↑EFS (p: 0.001)
-
Expression and activity of P-gp: no influence
Falk et al., 2014 [59] 320159
(18–85)
Caucasian
(Sweden)
YesDe novo (normal karyotype)Ara C + DAUNO or IDA ± ETOP +/or Others
-
CR, OS, EFS: no influence (similar results in FLT3 wild-type subgroup).
He et al., 2014 [60]21543.6
(14–57)
Asian
(China)
YesDe novoAra C (high doses)
-
Toxicity: CC ↑acute nausea and vomiting grades 3/4 (p: 0.035, 0.010). In multivariable CC was a risk factor of vomiting (p: 0.016).
-
Haplotype with ABCB1 G2677T/A (rs2032582) CC/GG ↑acute nausea and vomiting grades ¾ (0.003; 0.026) and multivariable (0.003; 0.039)
He et al., 2015 [61]26345.4
(14–58)
Asian
(China)
YesDe novo (intermediate cytogenetic risk)Ara C + DAUNO ± MIT
-
OS, RFS: TT ↑OS (p: 0.004), ↑RFS (p: 0.019)
-
Haplotype with G2677T/A and C1236T: TTT ↑OS (p < 0.001), ↑RFS (p: 0.005), both maintained in multivariable analysis (p: 0.001 and 0.009).
-
mRNA expression: TTT haplotype ↓mRNA expression than other genotypes (p: 0.004)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT genotype ↑renal toxicity (p: 0.008)
-
Haplotype C3435T, G2677T/A and C1236T: TTT ↑induction death (p: 0.020), ↑renal (p: 0.016) and hepatic (p < 0.001) toxicities.
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: in GO arm CT/TT trend to ↑OS at 5 years (p: 0.068)
-
EFS: in GO arm CT/TT↑EFS at 5 years (p: 0.022)
-
DFS: in GO arm CT/TT↑DFS at 5 years (p: 0.044)
-
RR: in GO arm CT/TT ↓RR at 5 years (p: 0.007)
* These results were observed especially at standard risk group
Short et al., 2020 [64]10468
(24–88)
Caucasian (86%)
Black (13%)
NRAML 82De novo: 43.9Secondary: 56.1GO + DAC
-
CR, ORR, CIR, OS, RFS: no influence
G2677T/A
rs2032582
Van den Heuvel et al., 2001 [65]3034.6
(1–67)
Caucasian
(Netherlands)
NRRelapsed: 100Ara C + ANT + Others
-
OS after relapse at 3 years: GT ↑OS (p: 0.02)
-
RFS after relapse at 3 years: GT ↑RFS (p: 0.002)
Illmer et al., 2002 [51]40553
(17–78)
Caucasian
(Germany)
YesDe novoAra C+ MIT + ETOP + AMSA
-
CR: no influence.
-
OS and DFS at 4 years (TX censured): no influence.
-
Haplotype with C3435T and C1236T: wild-type ↓OS and DFS at 4 years.
-
mRNA expression: GG ↓expression (p: 0.05)
Kaya et al., 2005 [52]2836
(20–64)
Arabs
(Turkey)
NRNRAra C + ANT
-
Drug sensitive/resistant: no differences (mixed with ALL)
Kim DH et al., 2006 [53]8139
(15–72)
Asian
(South Korea)
YesDe novoAra C + IDA
-
CR: GG ↑CR (p: 0.04)
-
OS and EFS at 3 years (TX censured): no influence.
-
Haplotype with C3435T: wild-type ↑CR and EFS at 3 years.
-
mRNA expression: no influence.
Van der Holt et al., 2006 [54] 1150 (142)67
(60–85)
Caucasian
(Netherlands)
YesDe novo: 79Secondary: 21Ara C + DAUNO
-
CR, OS, EFS, DFS at 5 years: no influence.
-
Expression and activity of P-gp: no influence
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
Kim YK et al., 2010 [66]9438
(17–79)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA +BH-AC
-
CR, OS: no influence
-
RR: GG ↑RR (p: 0.031)
-
RFS: GG ↑RFS (p: 0.005)
Green et al., 2012 [57]10063
(20–85)
Caucasian
(Europe)
YesDe novo (normal karyotype)Ara C + ANT or MIT +/or Others
-
OS at 4 years(TX censured): GG ↓OS (p: 0.02)
Falk et al., 2014 [59] 320159
(18–85)
Caucasian
(Sweden)
YesDe novo (normal karyotype)Ara C + DAUNO or IDA ± ETOP +/or Others
-
CR, OS, EFS: no influence
-
FLT3 wild-type subgroup: GG ↑OS (p: 0.039) against GT/TT genotypes.
He et al., 2014 [60]21543.6
(14–57)
Asian
(China)
YesDe novoAra C (high doses)
-
Toxicity: CC ↑acute nausea and vomiting grades 3/4 (p: 0.041, 0.038). Both lost in multivariable analyses.
-
Haplotype with ABCB1 G2677T/A (rs1045642) CC/GG ↑acute nausea and vomiting grades ¾ (0.003; 0.026) and multivariable (0.003; 0.039)
He et al., 2015 [61]26345.4
(14–58)
Asian
(China)
YesDe novo (intermediate cytogenetic risk)Ara C + DAUNO ± MIT
-
OS, RFS: TT ↑OS (p: 0.017), ↑RFS (p: 0.033)
-
Haplotype with C3435T and C1236T: TTT ↑OS (p < 0.001), ↑RFS (p: 0.005), both maintained in multivariable analysis (p: 0.001 and 0.009)
-
mRNA expression: TTT haplotype ↓mRNA expression than other genotypes (p: 0.004)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT genotype ↑renal (p: 0.001), hepatic (p: 0.049) toxicities & ↑time to neutropenia recovery (p: 0.047)
-
Haplotype C3435T, G2677T/A and C1236T: TTT ↑induction death (p: 0.020), ↑renal (p: 0.016) and hepatic (p < 0.001) toxicities.
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: in GO arm GT/TT↑EFS at 5 years (p: 0.016)
-
DFS: in GO arm GT/TT ↑DFS at 5 years (p: 0.048)
-
RR: in GO arm GT/TT ↓RR at 5 years (p: 0.001)
C1236T
rs1128503
Illmer et al., 2002 [51]40553
(17–78)
Caucasian
(Germany)
YesDe novoAra C+ MIT + ETOP + AMSA
-
CR: no influence.
-
OS and DFS at 4 years (TX censured): no influence.
-
Haplotype with C3435T and G2677T/A: wild-type ↓OS and DFS at 4 years.
-
mRNA expression: no influence.
Van der Holt et al., 2006 [54] 1150 (115)67
(60–85)
Caucasian
(Netherlands)
YesDe novo: 79Secondary: 21Ara C + DAUNO
-
CR, OS, EFS, DFS at 5 years: no influence.
-
Expression and activity of P-gp: no influence
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
Kim YK et al., 2010 [66]9438
(17–79)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA +BH-AC
-
CR, RR, OS and RFS: no influence
Green et al., 2012 [57]10063
(20–85)
Caucasian
(Europe)
YesDe novo (normal karyotype)Ara C + ANT or MIT +/or Others
-
OS at 4 years(TX censured): CC ↓OS (p: 0.03)
Scheiner et al., 2012 [58] 2109(44)34
(<1–86)
Others: White (69.7%)
Non-white (30,3%)
YesDe novo: 72.5Secondary: 18.3Ara C + IDA
-
OS at 5 years: CC ↑OS (p: 0.04)
-
EFS at 5 years: CC ↑EFS (p: 0.007)
-
Expression and activity of P-gp: no influence
Falk et al., 2014 [59] 320159
(18–85)
Caucasian
(Sweden)
YesDe novo (normal karyotype)Ara C + DAUNO or IDA ± ETOP +/or Others
-
CR, OS, EFS: no influence
-
FLT3 wild-type subgroup: CC ↑OS (p: 0.017) against CT/TT genotypes.
He et al., 2014 [60]21543.6
(14–57)
Asian
(China)
NoDe novoAra C (high doses)
-
Toxicity: not analyzed (excluded by HWE)
He et al., 2015 [61]26345.4
(14–58)
Asian
(China)
YesDe novo (intermediate cytogenetic risk)Ara C + DAUNO ± MIT
-
OS, RFS: TT ↑OS (p: 0.002), ↑RFS (p: 0.001)
-
Haplotype with C3435T and G2677T/A: TTT ↑OS (p < 0.001), ↑RFS (p: 0.005), both maintained in multivariable analysis (p: 0.001 and 0.009)
-
mRNA expression: TTT haplotype ↓mRNA expression than other genotypes (p: 0.004)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT genotype ↑renal (p: 0.001) and hepatic (p: 0.006) toxicities
-
Haplotype C3435T, G2677T/A and C1236T: TTT ↑induction death (p: 0.020), ↑renal (p: 0.016) and hepatic (p < 0.001) toxicities.
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: in GO arm CT/TT↑EFS at 5 years (p: 0.017)
-
DFS: in GO arm CT/TT trend to ↑DFS at 5 years (p: 0.054)
-
RR: in GO arm CT/TT ↓RR at 5 years (p: 0.003)
Short et al., 2020 [64]10468
(24–88)
Caucasian (86%)
Black (13%)
NRAML 82De novo: 43.9Secondary: 56.1GO + DAC
-
CR, ORR, CIR, OS, RFS: no influence
G1199A
rs2229109
Green et al., 2012 [57]10063
(20–85)
Caucasian
(Europe)
YesDe novo (normal karyotype)Ara C + ANT or MIT +/or Others
-
OS at 4 years(TX censured): GG suggestive ↓OS (p: 0.06)
Falk et al., 2014 [59] 320159
(18–85)
Caucasian
(Sweden)
YesDe novo (normal karyotype)Ara C + DAUNO or IDA ± ETOP +/or Others
-
CR, OS, EFS: no influence (similar results in FLT3 wild-type subgroup).
C174967T
rs6980101
Kim YK et al., 2007 [67]4937
(17–69)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA
-
CR: ↑CT vs. CC (p: 0.03)
-
OS, RFS, RR: no influence
G146792C
rs10256836
Kim YK et al., 2007 [67]4937
(17–69)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA
-
CR: ↑GG vs. GC (p: 0.03)
-
OS, RFS, RR: no influence
T134575A
rs17327442
Kim YK et al., 2007 [67]4937
(17–69)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA
-
CR: ↑TT vs. TA (p: 0.01)
-
OS, RFS, RR: no influence
A113516G
rs4148732
Kim YK et al., 2007 [67]4937
(17–69)
Asian
(South Korea)
NRDe novo (t (8,21) and inv (16))Ara C + IDA
-
CR: ↑AA vs. AG (p: 0.001)
-
OS, RFS, RR: no influence
C193T
rs121918619
Monzo et al., 2006 [67]11044
(16–60)
Caucasian
(Spain)
YesDe novo (intermediate cytogenetic risk)Ara C + IDA + ETOP
-
RR: CC/CT ↑RR (p: 0.02)
-
OS at 2 years: no influence (but affect in multivariable analysis, CC ↑OS)
Illet144MetMonzo et al., 2006 [68]11044
(16–60)
Caucasian
(Spain)
NRDe novo (intermediate cytogenetic risk)Ara C + IDA + ETOP
-
RR, OS: no influence
rs3842
(A>G)
Cao et al., 2017 [20]20667.2
(22–98)
Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: no influence
rs2235015
(G>T)
Rafiee et al., 2019 [63]9429.7 (0–30)Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: in GO arm GG/GT ↓RR at 5 years (p: 0.016)
rs2235033
(T>C)
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: no influence
rs1922242
(A>T)
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: no influence
rs1922240
(T>C)
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: no influence
rs1989830
(C>T)
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: no influence
rs2235040
(G>A)
Rafiee et al., 2019 [63]9429.7
(0–30)
Caucasian (81%)
Black (13%)
Asian (5%)
Others (1%)
YesDe novoAra C + IDA + ETOP ± GO
-
OS: no influence
-
EFS: no influence
-
DFS: no influence
-
RR: no influence
ABCB11
rs4668115
(G>A)
Drenberg et al., 2016 [13] 41649.1
(0–21)
White (70%)
Black (20%)
Others (10%)
YesDe novoAra C + DAUNO + ETOP + MIT
-
OS: GG ↓OS (p: 0.03)
-
EFS: GG ↓EFS (p: 0.05)
ABCC1
T2684CMahjoubi et al., 2008 [82]111NRArabs
(Iran)
NR52 AMLNRNR
-
CR: no influence
-
Expression of ABCC1 related to lower CR, drug sensitive and R/R rate
C2007T
rs2301666
Mahjoubi et al., 2008 [82]111NRArabs
(Iran)
NR52 AMLNRNR
-
CR: no influence
-
Expression of ABCC1 related to lower CR, drug sensitive and R/R rate
G2012T
rs45511401
Mahjoubi et al., 2008 [82]111NRArabs
(Iran)
NR52 AMLNRNR
-
CR: no influence
-
Expression of ABCC1 related to lower CR, drug sensitive and R/R rate
C2665TMahjoubi et al., 2008 [82]111NRArabs
(Iran)
NR52 AMLNRNR
-
CR: no influence
-
Expression of ABCC1 related to lower CR, drug sensitive and R/R rate
T825C
rs246221
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
T1062C
rs35587
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
G4002A
rs2230671
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence
-
Toxicity: no influence
rs4148350
(G>T)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: wild-type GG ↑hepatic severe toxicity grade 3–4 (p: 0.044)
rs129081
(C>G)
Kunadt et al., 2020 [83] 516046
(18–60)
Caucasian
(Germany)
YesNK AMLDe novo: 93.1Secondary: 6.9Ara C + DAUNO
-
CR: no influence
-
OS: GG↑OS at 5 years (p: 0.035)
-
DFS: GG↑DFS at 5 years (p: 0.01)
-
RR: no influence
-
Toxicity: no influence
rs212090
(A>T)
Cao et al., 2017 [20]20667.2
(22–98)
Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: AT ↑gastrointestinal toxicity (p: 0.010)
Kunadt et al., 2020 [83] 516046
(18–60)
Caucasian
(Germany)
YesNK AMLDe novo: 93.1Secondary: 6.9Ara C + DAUNO
-
CR: no influence
-
OS: no influence
-
DFS: TT ↓DFS at 5 years (p: 0.021)
-
RR: no influence
-
Toxicity: no influence
rs212091
(A>G)
Cao et al., 2017 [20]20667.2
(22–98)
Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: GG/AG ↓myelosuppression (p: 0.003)
Kunadt et al., 2020 [83] 516046
(18–60)
Caucasian
(Germany)
YesNK AMLDe novo: 93.1Secondary: 6.9Ara C + DAUNO
-
CR: no influence
-
OS: GG ↓OS at 5 years (p: 0.006)
-
DFS: GG ↓DFS at 5 years (p: 0.018)
-
RR: no influence
-
Toxicity: no influence
rs3743527
(C>T)
Cao et al., 2017 [20]20667.2
(22–98)
Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: TT ↑myelosuppression (p: 0.007)
rs4148380
(G>A)
Cao et al., 2017 [20]20667.2
(22–98)
Asian
(China)
YesDe novoAra C + ANT
-
CR: no influence
-
OS: no influence
-
RFS: no influence
-
Toxicity: no influence
ABCC2
G4544A
rs8187710
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: no influence
ABCC3
45 + 1226 (T>G)
rs4148405
Yee et al., 2013 [16] 6154NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): GG ↓DFS (p: 9.45 × 10−6, remained significant after Bonferroni correction). No influence in non-Caucasian cohort
Butrym et al., 2021 [85]9561
(22–90)
Caucasian
(Poland)
YesDe novoAra C + DAUNO or low dose Ara C or AZA
-
CR: no influence
-
OS: G allele ↓OS (p: 0.017)
rs1989983
(G>A)
Yee et al., 2013 [16] 654NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): AA ↓DFS (p: 0.0017). No influence in non-Caucasian cohort
rs2301835
(C>T)
Yee et al., 2013 [16] 6154NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.0029). No influence in non-Caucasian cohort
rs2277624
(A>G)
Yee et al., 2013 [16] 6154NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): AA ↓DFS (p: 0.004). No influence in non-Caucasian cohort
rs8079740
(A>G)
Yee et al., 2013 [16] 6154NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): GG ↓DFS (p: 0.0078). No influence in non-Caucasian cohort
rs757420
(T>C)
Yee et al., 2013 [16] 6154NRCaucasian
(Europe)
NRNRAra C + ETOP + BUSUL (pre-TX)
-
DFS (preTX): TT ↓DFS (p: 0.0079). No influence in non-Caucasian cohort
C211T
rs4793665
Müller et al., 2008 [18]13946.3
(15–86)
Jews (61.2%)
Arabs (38.8%)
YesDe novoAra C + ANT ± FLUDA ± MIT
-
OS (TX censured): CC ↓OS (p: 0.018)
Butrym et al., 2021 [88]9561
(22–90)
Caucasian
(Poland)
YesDe novoAra C + DAUNO or low dose Ara C or AZA
-
CR: no influence
-
OS: no influence
ABCG2
G34A
rs2231137
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
NRDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): GG ↓OS (p: 0.05)
-
Toxicity: AA/AG ↑ risk of toxicity grade 3 or more
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR: trend to GG ↑CR (p: 0.053). Mixed with ALL patients
-
OS: GG↑OS (p < 0.001). Mixed with ALL patients
-
DFS: GG↑DFS (p < 0.001). Mixed with ALL patients
-
Haplotype GG (rs2231137) with CA (rs2231142) and CT (rs2231149) ↓DFS/OS (p < 0.001)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: no influence
C421A
rs2231142
Müller et al., 2008 [18]13946.3
(15–86)
Jews (61.2%)
Arabs (38.8%)
YesDe novoAra C + ANT ± FLUDA ± MIT
-
OS (TX censured): no influence
Hampras et al., 2010 [56]26161.5
(20–85)
Caucasian (86%)
Others (14%)
(USA)
YesDe novo: 75Secondary: 25Ara C + ANT
-
OS (TX censured): no influence, but unadjusted HR shown AA ↓OS
-
Toxicity: no influence
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR: no influence.
-
OS: CC↑OS (p < 0.05; lost in multivariate analysis). Mixed with ALL patients
-
DFS: no influence. Mixed with ALL patients
-
Haplotype GG (rs2231137) with CA (rs2231142) and CT (rs2231149) ↓DFS/OS (p < 0.001)
Tiribelli et al., 2013 [98]12559.2
(20–84)
Caucasian
(Italy)
YesNRAra C + IDA + FLUDA ± ETOP
-
OS at 3 years: CC and low ABCG2 expression ↑OS (p: 0.02)
-
DFS at 3 years: CC and low ABCG2 expression ↑DFS (p: 0.04)
Megías-Vericat et al., 2017 [62]22552.5
(16–78)
CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: CA genotype ↑cardiac (p: 0.004) and lung (p: 0.038) toxicities
Ile619Ile
(C>T)
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR, OS, DFS: no influence. Mixed with ALL patients
rs2231149
(C>T)
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR: no influence. Mixed with ALL patients
-
OS: CC↑OS (p < 0.01; lost in multivariate analysis). Mixed with ALL patients
-
DFS: CC↑DFS (p < 0.05; lost in multivariate analysis). Mixed with ALL patients
-
Haplotype GG (rs2231137) with CA (rs2231142) and CT (rs2231149) ↓DFS/OS (p < 0.001)
rs2231162
(C>T)
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR, OS, DFS: no influence. Mixed with ALL patients
rs2231164
(C>T)
Wang et al., 2011 [97]14132
(5–70)
Asian
(China)
NRDe novoMixed with ALLAra C + DAUNO/MITO
-
CR, OS, DFS: no influence. Mixed with ALL patients
Abbreviations: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; AMSA: amsacrine; ANT: anthracycline; AZA: azacitidine; BH-AC: N4-behenoyl-1D-arabinofuranosycytosine; BUSUL: busulfan; CIR: cumulative incidence of relapse; CR: complete remission; DAC: decitabine; DAUNO: daunorubicin; DFS: disease-free survival; EFS: event-free survival; ETOP: etoposide; FLUDA: fludarabine; GO: gemtuzumab ozogamicin; HWE: Hardy–Weinberg equilibrium; IDA: idarubicin; MIT: mitoxantrone; NK: normal karyotype; NR: not reported; ORR: overall response rate; OS: overall survival; RFS: relapse-free survival; RR: rate of relapse; R/R: relapse/refractory; TX: hematologic transplant. 1—Allele frequency and treatment outcomes only reported in 115 patients for C1236T, 142 patients for G2677T/A and 130 patients for C3435T. 2—Allele frequency only reported in 103 patients and treatment outcomes only in 44 patients (AML M3 subtype, secondary AML and patients with comorbidities or poor performance status were excluded). 3—A total of 100 patients were previously collected and published in Green et al., 2012 [57]. 4—This study [13] analyzed 1936 SNPs of 225 genes with a multi-SNP-based approach (including ABC and SLC transporters). Only SNPs with significant results were cited. 5—This study [83] included 48 SNPs within 7 genes of 7 ABC transporters (ABCA2, ABCA3, ABCB1, ABCB2, ABCB5, ABCB7 and ABCC1), but only specified the SNPs with significant effect. 6—This study [16] analyzed 1659 SNPs of 42 genes with a multi-SNP-based approach. Only SNPs with significant results were cited.
Table 3. Characteristics of the studies included in the systematic review for SNP–SNP combinations of ABC and SLC transporters.
Table 3. Characteristics of the studies included in the systematic review for SNP–SNP combinations of ABC and SLC transporters.
SNPStudynAge (Range)Ethnia (Country)HWELMA Status (%)Chemotherapy SchemeClinical Outcomes
ABCB1 + SLC
ABCB1 C3435T
rs1045642
SLCO1B1 rs4149056 (T>C)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT + TT genotype ↑hepatic toxicity (p: 0.038)
ABCB1 C3435T
rs1045642
SLC22A16 rs12210538 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT + AA genotype ↑hepatic toxicity (p: 0.019), mucositis (p: 0.004), neutropenia (p: 0.034)
ABCB1 G2677T/A
rs2032582
SLCO1B1 rs4149056 (T>C)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT + TT genotype ↑renal (p: 0.030), hepatic toxicity (p: 0.002)
ABCB1 G2677T/A
rs2032582
SLC22A16 rs12210538 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT + AA genotype ↑hepatic toxicity (p: 0.008)
ABCB1 G2677T/A
rs2032582
SLC22A16rs714368 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT + AA genotype ↑renal (p: 0.026), hepatic toxicity (p: 0.008)
ABCB1 C1236T
rs1128503
SLCO1B1 rs4149056 (T>C)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR: no influence
-
Induction death: TT + TT genotype ↑induction death (p: 0.018)
-
Toxicity: TT + TT genotype ↑renal (p: 0.048), hepatic toxicity (p < 0.001)
ABCB1 haplotype 1
SLCO1B1 rs4149056 (T>C)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR: no influence
-
Induction death: TT/TT/TT + TT genotype ↑induction death (p: 0.009)
-
Toxicity: TT/TT/TT + TT genotype ↑renal (p: 0.017), hepatic toxicity (p < 0.001)
ABCB1 haplotype 1
SLC22A16 rs12210538 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT/TT/TT +AA genotype ↑renal (0.036), hepatic toxicity (p: 0.015)
ABCB1 haplotype 1
SLC22A16 rs714368 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: TT/TT/TT +AA genotype ↑ hepatic toxicity (p: 0.001)
ABCC1 + SLC
ABCC1 rs4148350
SLCO1B1/SLC22A16
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: no influence
ABCC2 + SLC
ABCC2 rs8187710
SLCO1B1/SLC22A16
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: no influence
ABCG2 + SLC
ABCG2
rs2231142 (C>A)
SLC22A16 rs714368 (A>G)
Megías-Vericat et al., 2017 [62]22552.5 (16–78)CaucasianYesDe novoAra C + IDA
-
CR, induction death: no influence
-
Toxicity: AC + AA genotype ↑cardiac toxicity (p: 0.033)
Abbreviations: AML: acute myeloid leukemia; CR: complete remission; HWE: Hardy–Weinberg equilibrium; IDA: idarubicin; NR: not reported; OS: overall survival. 1—The ABCB1 haplotype included the polymorphisms rs1128503, rs1045642 and rs2032582.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Megías-Vericat, J.E.; Martínez-Cuadrón, D.; Solana-Altabella, A.; Poveda, J.L.; Montesinos, P. Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia. Pharmaceutics 2022, 14, 878. https://doi.org/10.3390/pharmaceutics14040878

AMA Style

Megías-Vericat JE, Martínez-Cuadrón D, Solana-Altabella A, Poveda JL, Montesinos P. Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia. Pharmaceutics. 2022; 14(4):878. https://doi.org/10.3390/pharmaceutics14040878

Chicago/Turabian Style

Megías-Vericat, Juan Eduardo, David Martínez-Cuadrón, Antonio Solana-Altabella, José Luis Poveda, and Pau Montesinos. 2022. "Systematic Review of Pharmacogenetics of ABC and SLC Transporter Genes in Acute Myeloid Leukemia" Pharmaceutics 14, no. 4: 878. https://doi.org/10.3390/pharmaceutics14040878

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop