Background
Acute myeloid leukaemia (AML) is a malignant and heterogeneous [
1] haematopoietic disease [
2] characterized by an abnormal growth of proliferative, clonal and highly differentiated white blood cells [
3,
4]. These cells infiltrate the bone marrow and stimulate the production of progenitor or abnormal white cells, preventing the system from maturing its cells to perform adequate defence functions in the organism [
5], and infiltrate other tissues, which can lead to relapse and an increased risk of death [
6].
AML is the most common type of acute leukaemia in the world [
7], with an estimated worldwide prevalence of 160 cases and an incidence of 103 new cases per 100,000 inhabitants in 2016 [
8]. In addition, the number of deaths worldwide in 2012 due to leukaemia was 265,471 [
9]. In the USA, the estimated 5-year survival rate is 26.9% [
10]. Thus, the study of genetic alterations related to the appearance of AML, such as somatic mutations and single-nucleotide polymorphisms (SNPs), has contributed to a better understanding of the mechanisms underlying leukaemogenesis, to improve prognosis [
3,
11‐
13] and to increase the survival of these patients [
2,
5].
AML is treated by a combination of cytarabine with an anthracycline (daunorubicin or idarubicin) [
14], resulting in a remission rate of approximately 80% [
7,
15]. Cytarabine (Ara-C) is an analogue of deoxycytidine [
16], which blocks the synthesis of DNA [
11,
15,
17]. Cytarabine metabolism starts in the cell membrane. This is because the SLCO1B1 and SLC29A1 genes encode membrane transporters that transport Ara-C to the intracellular space [
15,
18,
19]. Subsequently, the DCK gene [
20] encodes the enzyme that catalyzes the rate-limiting first phosphorylation step in the activation of cytarabine to cytarabine monophosphate (Ara-CMP). The NT5C3A gene acts opposite to the DCK gene by reactivating cytarabine [
21]. The gene CDA [
22,
23] is the main gene that promotes the inhibition of the drug through the production of an enzyme that causes irreversible deamination (Ara-U) [
15]. The genes RRM1, RRM2 and RRM2B are responsible for producing enzymes that transform cytidine triphosphate (CTP) to deoxycytidine diphosphate (dCDP) [
24], which is transformed to deoxycytidine triphosphate, which enters the cell nucleus to block DNA synthesis [
15,
25,
26].
Anthracyclines are metabolized in various tissues. Metabolism also begins in the cellular membrane, for example, by the gene SLC22A12 [
27]. Cation-anion transport generates the influx of the drug into cells. Another transporter involved is ABCB1, which belongs to the ABC family and is associated with cellular efflux [
15]. The transformation of the drug to semiquinone is performed by several oxidoreductases, including NOS3, which is a nitric oxide synthase, and is related to the decrease in enzymatic activity [
15,
27].
Genes related to the metabolism of gold standard drugs have SNPs, which are related to the outcomes related to the treatment of AML [
15,
26]. For example, some SNPs (e.g. rs2306744, rs80143932, rs1561876, rs2898950, rs3750117, rs1265138, rs1045642, rs2032582, rs1128503) have been associated with better or worse response to treatment, depending on the genotypes present. On the other hand, other SNPs (e.g. rs4149056, rs532545, rs2072671, rs11231825) have been related to higher or lower toxicity or to overall and/or disease-free survival (e.g. rs2291075, rs1042919, rs1130609, rs5030743, rs2032582, rs1799983) [
15].
Studies on the influence of SNPs on the outcomes of AML have focused on aspects such as survival (SLD and SG) [
28,
29], treatment response [
30] and toxicity [
11,
15,
27,
31]. There is a database registered under HHS and financially supported by NIH/NIGMS. This database collects, curates and disseminates data on the impact of genetic variations in humans on drug responses. This registry was made by annotating genetic variants and gene-drug-disease relationships via literature review and summarizing important pharmacogenomic data and associations between genetic variants and drugs, and drug pathways, among others [
26].
However, the findings in the literature are still insufficient regarding the evaluation of the level of evidence and the risk of bias in studies that address this issue. In addition, there is no other similar review under development registered at PROSPERO [
32]. Therefore, a study that fills these gaps will be important to translate the results into recommendations for clinical practice based on reliable evidence [
15,
26].
Therefore, this study aims to evaluate the impact of SNPs on treatment response, survival and toxicity with cytarabine and anthracyclines in AML patients. Consequently, the study outlines a systematic review protocol that seeks to address this research question. Thus, recommendations and guidelines for interventions in AML patients are expected to rely more on evidence-based practices to contribute to better patient management. In this way, we will know how to improve the survival and quality of life in these patients.
Discussion
AML is the most common type of leukaemia in the world [
7]; hence, many studies have attempted to evaluate better forms of AML treatment. However, to the best of our knowledge, no systematic review has attempted to synthesize the level and quality of evidence on how genetic modifications impact survival, treatment response and toxicity in AML [
12,
13,
15,
29]. In particular, it is necessary to synthesize evidence from the literature about the impact of SNPs on the evaluated outcomes and to consider aspects of the methodological quality of and the level of evidence in the studies. This is necessary for establishing recommendations and guidelines for effectively and safely using these interventions in clinical practice, considering the different effects expected from their use in patients with AML [
15,
26].
Thus, this protocol will provide robust evidence for searches and future studies on the effect SNPs on treatment in patients with AML, thereby presenting and categorizing the existing evidence according to different expected outcomes (e.g. creating a profile that represents greater toxicity or better response), according to the methodological quality, generalization capacity and risk of bias of studies. Moreover, unlike the protocols proposed thus far, the objective of this protocol is to expand the reach of literature search, using databases, clinical trial repositories, and contact with authors, to identify studies evaluating a range of SNPs and not just the influence of a single SNP on a single prognostic endpoint. Thus, we will be able to evaluate the real influence of SNPs, both individually and combined, on the metabolism of chemotherapy drugs used in the standard treatment of AML and on several prognostic outcomes.
Among the limitations of the study will be the large number of SNPs that can be present (apart from those already evaluated) and the great variety of the types and methodologies of studies carried out. However, categorization of the types of studies, SNPs, drugs used and outcomes may help in the search and evaluation of the subgroups generated. Therefore, we can define the subgroups to use in classifying the available evidence (to apply in clinical practice) and the subgroups that will need more studies to define the real clinical effect.
With the results of this systematic review, clinical decisions for AML patients may be expected to rely on evidence-based practices, thus contributing to better patient management. In this way, it will be possible to evaluate where we should invest in larger studies to better define patient profiles that may, for example, respond better or require a lower dose because of higher toxicity. Thus, we will be able to better define how to treat patients with AML to improve their survival and quality of life.