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. 2022 Apr 17;14(4):878. doi: 10.3390/pharmaceutics14040878

Table 1.

Characteristics of the studies included in the systematic review for influx transporters.

SNP Study n Age (Range) Ethnia
(Country)		 HWE LMA Status (%) Chemotherapy Scheme Clinical Outcomes
SLCO1B1
T521C
rs4149056		 Iacobucci et al., 2012 [5] 94 51
(19–65)		 Caucasian
(Italy)		 Yes De novo (80.9%)
Secondary (19.1%)		 Ara C + IDA + FLUDA + GO
  • -

    CR: no influence

  • -

    Toxicity: CC/CT ↑liver toxicity
Drenberg et al., 2016 [13] 1 164 9.1
(0–21)		 White (70%)
Black (20%)
Others (10%)		 Yes De novo Ara 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] 225 52.5
(16–78)		 Caucasian Yes De novo Ara C + IDA
  • -

    CR: no influence

  • -

    Induction death: TT ↑induction death (p: 0.049)

  • -

    Toxicity: no influence
597C>T
rs2291075		 Drenberg et al., 2016 [13] 1 164 9.1
(0–21)		 White (70%)
Black (20%)
Others (10%)		 Yes De novo Ara 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] 1 164 9.1
(0–21)		 White (70%)
Black (20%)
Others (10%)		 Yes De novo Ara 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] 94 51
(19–65)		 Caucasian
(Italy)		 Yes De 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 225 52.5
(16–78)		 Caucasian
(Spain)		 Yes De novo Ara C + IDA
  • -

    CR and induction death: no influence

  • -

    Toxicity: no influence
rs714368
146A>G		 Megías-Vericat et al., 2021 [14] 225 52.5
(16–78)		 Caucasian
(Spain)		 Yes De novo Ara C + IDA
  • -

    CR and induction death: no influence

  • -

    Toxicity: no influence
SLC25A37
rs7818607
(C>A)		 Yee et al., 2013 [16] 2 154 NR Caucasian (Europe) NR NR Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 139 46.3
(15–86)		 Jews (61.2%)
Arabs (38.8%)		 Yes De novo Ara C + ANT ± FLUDA ± MIT
  • -

    OS (TX censured): no influence
C1561T
rs2242046		 Seeringer et al., 2009 [19] 3 322 <60 Caucasian
(Germany)		 NR NR (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] 206 67.2 (22–98) Asian
(China)		 Yes De novo Ara C + ANT
  • -

    CR: no influence

  • -

    OS: no influence

  • -

    RFS: no influence

  • -

    Toxicity: no influence
SLC28A2
rs10519020
(G>C)		 Drenberg et al., 2016 [13] 1 164 9.1
(0–21)		 White (70%)
Black (20%)
Others (10%)		 Yes De novo Ara 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] 2 154 NR Caucasian (Europe) NR NR Ara 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] 4 97 50 (16–76) Asian
(South Korea)		 Yes De novo Ara 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] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara C + IDA
  • -

    CR: A allele ↑CR (p: 0.008; p Bonferroni:0.04) and haplotype ht3 (p: 0.01)
Cao et al., 2017 [20] 206 67.2 (22–98) Asian
(China)		 Yes De novo Ara 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] 100 43
(17–76)		 Asian
(China)		 Yes De novo Ara 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] 39 54
(23–71)		 Asian
(Japan)		 Yes De novo Ara C + IDA or DAUNO (consolidation: Ara C high doses)
  • -

    OS: no influence.

  • -

    TTR: no influence.

  • -

    Hematologic toxicity: no influence.
Kim et al., 2016 [43] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara 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] 100 43
(17–76)		 Asian
(China)		 Yes De novo Ara 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] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara C + IDA
  • -

    CR: no influence, ↑CR haplotype ht3 (p: 0.01)
A>C
rs693955		 Amaki et al., 2015 [46] 39 54
(23–71)		 Asian
(Japan)		 Yes De novo Ara 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] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara C + IDA
  • -

    CR: no influence, ↑CR haplotype ht3 (p: 0.01)
rs507964
(A>C)		 Kim et al., 2016 [43] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara 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] 103 50.4
(16–76)		 Asian
(South Korea)		 Yes De novo Ara 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.