MTHFR polymorphisms’ influence on outcome and toxicity in acute lymphoblastic leukemia patients

Chiusolo, Patrizia; Reddiconto, Giovanni; Farina, G.; Mannocci, Alice; Fiorini, Alessia; Palladino, Mariangela; Torre, Giuseppe La; Fianchi, Luana; Sorà, Federica; Laurenti, Luca; Leone, Giuseppe; Sica, Simona

doi:10.1016/j.leukres.2007.03.028

Cited by 54 publications

(30 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In line with our findings, decreased hematologic toxicity associated with the 1298 AC/CC genotypes was previously described in children with ALL treated with high-dose methotrexate; nevertheless these studies did not find greater toxicity associated with the 677T allele. 12,27 In contrast to what has been observed in childhood ALL, in adult ALL patients treated with methotrexate previous studies have shown a correlation between the MTHFR 677C>T and increases of mucositis and, hepatic and hematologic toxicity, 18,19 in line with our results. It should be noted that the doses of methotrexate administered to our patients during ALL maintenance therapy were lower than the doses used in childhood ALL.…”

Section: Discussionsupporting

confidence: 89%

“…Our results are in line with those previously reported by Chiusolo et al, showing an association between the 677TT variant and a reduced survival among adult ALL patients treated with methotrexate-based maintenance therapy. 19 Similarly, the 677T variant was found to be associated with lower disease-free survival or relapse-free survival in two childhood ALL studies. 26,38 Our result could be partly explained by the fact that 677TT patients conserve more 5,10-methylene-tethahydrofolate in their cells than do carriers of the other genotypes.…”

Section: Discussionmentioning

confidence: 94%

“…16,17 In particular, in adult ALL only MTHFR polymorphisms have been investigated and associated with increased methotrexaterelated toxicity. 18,19 The aim of our study was to investigate the influence of polymorphisms directly involved in the methotrexate pharmacological pathway in relation to the outcome of adult ALL patients treated with methotrexate maintenance therapy. To this purpose we analyzed the effects of the association of polymorphisms in MTHFR, DHFR, RFC and TS genes on therapy-related toxicity and survival.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Ongaro¹,

Mattei²,

Porta³

et al. 2009

Haematologica

View full text Add to dashboard Cite

BackgroundThe antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates. Design and MethodsThe aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia. ResultsPolymorphisms in the genes encoding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and in dihydrofolate reductase (DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13-21.95 and odds ratio 4.57, 95%confidence interval 1.01-20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38-33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00-36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46-8.45). ConclusionsGenotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival. Haematologica 2009;94:1391-1398. doi:10.3324/haematol.2009 This is an open-access paper.Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Ongaro¹,

Mattei²,

Porta³

et al. 2009

Haematologica

View full text Add to dashboard Cite

show abstract

“…Several studies have indeed described an increased risk of toxicity. 7,8 However, not all studies have been able to link presence of the 677T allele to an increased risk of MTX-induced toxicity. [9][10][11] As data published regarding the role of the MTHFR 677 polymorphism are contradictive, we analyzed the association between the MTHFR 677C4T SNP and hepatotoxicity in a Dutch cohort of cancer patients treated with high-dose MTX.…”

Section: Introductionmentioning

confidence: 99%

The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer

et al. 2013

View full text Add to dashboard Cite

Methotrexate (MTX), one of the important pillars in the treatment of different forms of cancer, is associated with the development of hepatotoxicity. The 677C>T variant (rs1801133) in the methylenetetrahydrofolate reductase (MTHFR) gene might affect the development of hepatotoxicity. Results in literature are, however, contradictive. The aim of this study was to evaluate the role of the MTHFR 677C>T polymorphism in MTX-induced hepatotoxicity by analyzing a Dutch cohort of pediatric patients treated with high doses of MTX and subsequently performing a meta-analysis. Ninety-eight patients receiving 542 courses of high-dose MTX were genotyped for the MTHFR 677C>T variant. Hepatotoxicity was evaluated retrospectively according to common terminology criteria for adverse events-National Cancer Institute criteria. The influence of MTHFR 677C>T on hepatotoxicity was examined using a generalized estimating equation (GEE) analysis. A fixed-effect meta-analysis based on this and previous studies investigating the association between the MTHFR 677C>T polymorphism and uniformly coded hepatotoxicity was performed. The GEE analysis showed an increased risk of developing hepatotoxicity for T versus C allele (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.0-3.2, P=0.04). This finding was not supported by the meta-analysis including seven studies and 1044 patients; the OR for the 677T versus C allele was 1.1 (95% CI 0.84-1.5, P=0.25). Heterogeneity between studies was observed, possibly related to differences in MTX dose and leucovorin rescue. In conclusion, in patients with cancer, the MTHFR 677T allele has only a minor role in the development of MTX-induced hepatotoxicity. Observed heterogeneity between studies warrants further study into (tailored) leucovorin rescue.

show abstract

“…However, several studies have shown that the polymorphism of MTHFR is associated with an increased risk of MTX toxicity in patients with acute leukemia [29,30], ovarian cancer [31], breast cancer [32], or HSCT recipients [33][34][35]. Ulrich et al measured the oral mucositis index score [36] in patients with chronic myelogenous leukemia that received HSCT with MTX for the prophylaxis of GVHD [33].…”

Section: Discussionmentioning

confidence: 99%

Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype

et al. 2008

View full text Add to dashboard Cite

Polymorphism in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, has been shown to affect the sensitivity of patients to folate-based drugs such as methotrexate. In this study, we investigated whether a common single nucleotide polymorphism at position 677 in the donor or recipient's MTHFR gene affects the risk for acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling donors when the recipient receives prophylactic treatment with methotrexate for GVHD. MTHFR genotypes were determined in 159 recipients with a hematological disease and their donors using polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA. The 677TT genotype, which encodes an enzyme with approximately 30% of the activity of the wild-type (677CC), was observed in 13% of patients and in 8% of normal donors. Multivariate analyses demonstrated a significant association between 677TT genotype in patients and a lower incidence of grade I-IV acute GVHD (relative risk, 0.35; 95% confidence interval, 0.13-0.95; P = 0.040). There was no association between the incidence of acute GVHD and the donor MTHFR genotypes. These results suggest that greater immunosuppression by methotrexate due to low MTHFR enzyme activity decreases the risk of acute GVHD in recipients of allogeneic HSCT.

show abstract

MTHFR polymorphisms’ influence on outcome and toxicity in acute lymphoblastic leukemia patients

Cited by 54 publications

References 23 publications

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer

Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype

Contact Info

Product

Resources

About