MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

Figures & data

Figure 1 MTX pathway.

Note: MTX and its metabolites are indicated.
Abbreviations: ABCs, ABC family transporters; DHF, dihydrofolate; DHFR, dihydrofolate reductase; MTHFR, methylenetetrahydrofolate reductase; MTX, methotrexate; MTXPG, methotrexate polyglutamated forms; RFC1, reduced folate carrier; SHMT1, serine hydromethyl transferase; SLCs, SLC family transporters; THF, tetrahydrofolate; TS, thymidilate synthase; 5-CH-THF, 5-methyltetrahydrofolate; 5,10-CH2-THF, 5,10-methylenetetrahydrofolate.

Figure 2 Flow diagram of study selection.

Abbreviation: MTX, methotrexate.

Table 1 List of 13 studies that analyzed association between the MTHFR C677T polymorphism and MTX toxicity in pediatric ALL, grouped according to the level of association between the SNP and MTX toxicity

MTHFR C677T
Patient population	MTX dose	Population	Association with toxicity	Reference, year
21 ALL^C	High	Indian	NA	Moulik et al,^Citation31 2016
106 ALL^C	High	Turkish	NA	Yazıcıoğlu et al, ^Citation32 2016
56 ALL or Lymphoma^A	High	Japanese	NA	Tsujimoto et al,^Citation47 2016
53 ALL^A	Low	Japanese	NA	Suzuki et al,^Citation30 2015
91 ALL^C	High	Chinese	NA	Wang et al,^Citation48 2014
499 ALL^A	High	German	NA	Radtke et al,^Citation39 2013
18 ALL^C	High	Brazilian	NA	de Deus et al,^Citation49 2012
100 ALL^A	ND	Korean	NA	Kim et al,^Citation50 2012
109 ALL^C	High	Mexican	−T	Ramírez-Pacheco et al,^Citation24 2016
35 ALL^B	High	Caucasian	−T	Haase et al,^Citation25 2012
161 ALL^C	High	Argentinian	+T	Aráoz et al,^Citation26 2015
127 ALL^C	High	Lebanese	+T	Zgheib et al,^Citation27 2014
103 ALL and NHL^A	High	Japanese	+T	Fukushima et al,^Citation28 2013

Notes: Type of sample: A, normal; B, tumor; C, unknown. High MTX dose =1.5–5 g m⁻²; Low MTX dose =25 mg m^−2.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin Lymphoma; ND, no data; NA, no association between SNP and toxicity; +T, SNP is associated with increased toxicity; −T, SNP is associated with decreased toxicity.

Table 2 Types of toxicities analyzed and the findings in each study of the association between the MTHFR C677T polymorphism and MTX toxicity

MTHFR C677T
Reference, year	MTX kinetics	Hematologic toxicity				Hepatic toxicity	Mucositis	Renal toxicity	Neurotoxicity	Other
		Anemia	Thrombocytopenia	Leukopenia	Neutropenia
Moulik et al,^Citation31 2016	–	NA	NA	–	NA	NA	NA	NA	–	NAa,b
Yazıcıoğlu et al,^Citation32 2016	NAc	NA	NA	NA	NA	NA	NA	NA	NA	–
Tsujimoto et al,^Citation47 2016	–	–	–	–	–	–	–	–	NA	–
Suzuki et al,^Citation30 2015	–	–	–	NA	–	NA	–	–	–	NAb
Wang et al,^Citation48 2014	NAd,e	–	–	–	–	–	–	–	–	–
Radtke et al,^Citation39 2013	NAf,g,h	–	–	–	–	–	NA	–	–	–
de Deus et al,^Citation49 2012	NAc	–	–	–	–	NA	–	NA	–	–
Kim et al,^Citation50 2012	–	–	–	–	–	NA	–	–	–	NA b,i
Ramírez-Pachecoet al,^Citation24 2016	NAc	–	–	NA	–	–	−T	–	–	–
Haase et al,^Citation25 2012	−Tc	−T	–	−T	–	–	–	–	–	−Tj
Aráoz et al,^Citation26 2015	–	NA	NA	+T	+T	NA	NA	–	–	–
Zgheib et al,^Citation27 2014	NAf,g,k	+T	–	–	NA	–	–	–	–	NAb
Fukushima et al,^Citation28 2013	NAc	–	–	–	–	+T	–	–	–	+Tl

Notes: Identifiers:

a febrile neutropenia;

b MTX dose reduction;

c MTX levels;

d dose corrected MTX level;

e percent of MTX >40 mmol/L;

f MTX clearance;

g MTX AUC;

h peak MTX plasma level;

i sepsis;

j rate of cycles with infection;

k time to reach MTX level <0,1 mmol/L;

l MTX administration delay; –, not evaluated.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; NA, no association between SNP and toxicity; +T, SNP is associated with increased toxicity; −T, SNP is associated with decreased toxicity.

Table 3 List of 10 studies that analyzed association between the MTHFR A1298C polymorphism and MTX toxicity in pediatric ALL, grouped according to the level of association between the SNP and MTX toxicity

MTHFR A1298C
Patient population	MTX dose	Population	Association with toxicity	Reference, year
106 ALL^C	High	Turkish	NA	Yazıcıoğlu et al,^Citation32 2016
53 ALL^A	Low	Japanese	NA	Suzuki et al,^Citation30 2015
161 ALL^C	High	Argentinian	NA	Aráoz et al,^Citation26 2015
127 ALL^C	High	Lebanese	NA	Zgheib et al,^Citation27 2014
499 ALL^A	High	German	NA	Radtke et al,^Citation39 2013
18 ALL^C	High	Brazilian	NA	de Deus et al,^Citation49 2012
100 ALL^A	ND	Korean	NA	Kim et al,^Citation50 2012
103 ALL and NHL^A	High	Japanese	−T	Fukushima et al,^Citation28 2013
21 ALL^C	High	Indian	+T	Moulik et al,^Citation31 2016
35 ALL^B	High	Caucasian	+T	Haase et al,^Citation25 2012

Notes: Type of sample: A, normal; B, tumor; C unknown. High MTX dose =1.5–5 g m⁻²; Low MTX dose =25 mg m⁻².

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin Lymphoma; ND, no data; NA, no association between SNP and toxicity; +T, SNP is associated with increased toxicity; −T, SNP is associated with decreased toxicity.

Table 4 Types of toxicities analyzed and the findings in each study of the associations between the MTHFR A1298C polymorphism and MTX toxicity

MTHFR A1298C
Reference, year	MTX kinetics	Hematologic toxicity				Hepatic toxicity	Mucositis	Renal toxicity	Neurotoxicity	Other
		Anemia	Thrombocytopenia	Leukopenia	Neutropenia
Yazıcıoğlu et al,^Citation32 2016	NAa	NA	NA	NA	NA	NA	NA	NA	NA	–
Suzuki et al,^Citation30 2015	–	–	–	NA	–	NA	–	–	–	NAb
Aráozetal,^Citation26 2015	–	NA	NA	NA	NA	NA	NA	–	–	–
Zgheib et al 2014^Citation27	NAc,d,e	NA	–	–	NA	–	–	–	–	NAb
Radtkeetal,^Citation35 2013	NAc,d,f	–	–	–	–	–	NA	–	–	–
de Deus et al,^Citation45 2012	NAa	–	–	–	–	NA	–	NA	–	–
Kim et al,^Citation50 2012	–	–	–	–	–	NA	–	–	–	NAb,g
Fukushima et al,^Citation28 2013	NAa	–	–	–	–	-T	–	–	–	NAh
Mouliketal,^Citation31 2016	–	+T	NA	–	NA	NA	NA	NA	–	NAi,b
Haaseetal,^Citation25 2012	NAa	+T	–	NA	–	–	–	–	–	NAj

Notes: Identifiers:

a MTX levels;

b MTX dose reduction;

c MTX clearance;

d MTX AUC;

e time to reach MTX level <0,1 mmol/L;

f peak MTX plasma level;

g sepsis;

h MTX administration delay;

i febrile neutropenia;

j rate of cycles with infection. –, not evaluated.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; NA, no association between the SNP and toxicity; +T, SNP is associated with increased toxicity; −T, SNP is associated with decreased toxicity.

Table 5 List of 8 studies that analyzed association between the MTHFR C677T polymorphism and outcome

MTHFR C677T
Patient population	MTX dose	Population	Association with outcome	Analyzed event	Reference, year
140 ALL^A	High	Argentinian	NA	EFSa	Leonardi et al,^Citation51 2016
109 ALL^C	High	Mexican	NA	Relapse	Ramírez-Pacheco et al,^Citation24 2016
106 ALL^C	High	Turkish	NA	EFSb	Yazıcıoğlu et al,^Citation32 2016
202 ALL^C	High	Argentinian	NA	EFSc	Aráoz et al,^Citation26 2015
94 ALL^C/141 ALL^C	High	Caucasian/Vietnamese	NA	EFSa	Hoang et al,^Citation52 2015
103 ALL and NHL^A	High	Japanese	NA	EFSb	Fukushima et al,^Citation28 2013
499 ALL^A	High	German	NA	EFS c	Radtke et al,^Citation39 2013
53 ALL^A	Low	Japanese	NA	Relapse	Suzuki et al,^Citation30 2015

Notes: Type of sample: A, normal; C, unknown. High MTX dose =1.5–5 g m⁻²; Low MTX dose =25 mg m⁻². Identifiers:

a event defined as relapse;

b event defined as relapse/death;

c event defined as relapse/death/secondary malignancies.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin Lymphoma; NA, no association between the SNP and outcome; EFS, event free survival.

Table 6 List of 6 studies that analyzed association between the MTHFR A1298C polymorphism and outcome

MTHFR A1298C
Patient population	MTX dose	Population	Association with outcome	Analyzed event	Reference, year
106 ALL^C	High	Turkish	NA	EFSa	Yazıcıoğlu et al,^Citation32 2016
202 ALL^C	High	Argentinian	NA	EFSb	Aráoz et al,^Citation26 2015
94 ALL^C/141 ALL^C	High	Caucasian/Vietnamese	NA	EFSc	Hoang et al,^Citation52 2015
53 ALL^A	Low	Japanese	NA	Relapse	Suzuki et al,^Citation30 2015
499 ALL^A	High	German	−AS	EFSc	Radtke et al,^Citation39 2013
103 ALL and NHL^A	High	Japanese	+AS	EFSb	Fukushima et al,^Citation28 2013

Notes: Type of sample: A, normal; C, unknown. High MTX dose =1.5–5 g m⁻²; Low MTX dose =25 mg m⁻². Identifiers:

a event defined as relapse/death;

b event defined as relapse/death/secondary malignancies;

c event defined as relapse.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; SNP, single-nucleotide polymorphism; MTX, methotrexate; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin Lymphoma; NA, no association between the SNP and outcome; +AS, SNP is associated to increased outcome; −AS, SNP is associated with decreased outcome; EFS, event free survival.

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