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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2283-2283
CORRESPONDENCE
To the editor:
Attribution of posttransplantation toxicity to methotrexate
regarding genotype of methylenetetrahydrofolate reductase gene
(MTHFR) polymorphism needs further clarification
Ulrich et al recently reported the association between a
polymorphism of folate-metabolizing enzyme, methylenetetrahydrofolate reductase gene (MTHFR), 677C>T and risk of
posttransplantation complications.1 The authors showed the
significantly reduced oral mucositis index scores,2 and
not significant but delayed hematologic recovery among patients with
the TT genotype, compared with those with the CC genotype. They
hypothesized that a modification of toxicity by MTHFR
genotype was due to methotrexate (MTX) use for posttransplantation
prophylaxis for graft-versus-host disease (GVHD) because MTX is the
antifolate drug whose common toxicity includes oral mucositis and
hematologic complications.3 Previously, a similar finding
that the grade 4 neutropenia (NCI-CTC criteria) following MTX including
adjuvant-combined chemotherapy for breast cancer is more frequently
observed among TT genotype was reported by Toffoli et al.4
Although we basically agree with the concept that genetic variation of
MTHFR may predispose certain kinds of clinical/preclinical
status as we have already reported,5 we are hesitant to
view MTX as a modifier of the causal association between the
genotype and toxicity. In general, oral mucositis may occur in the conditioning regimens
applied in their study even if they do not include MTX. As Ulrich et al
mentioned, the most important point is the imbalances in folate pools
in those with the TT genotype, which results in the decreased
availability of folate for recovery by DNA synthesis. This
means the MTHFR genotype represents a lesser
ability to recover from the chemotherapy, not only by means of
MTX. Their study did not examine the difference in toxicity for
patients treated with MTX compared with those treated without MTX. In
addition, no information on other important factors regarding oral
mucositis, such as the pretransplantation condition of the oral cavity
or HLA-matching status, was provided in this study. Because oral
mucositis has been recognized as one of the prognostic factors for
hematopoietic cell transplantation,6 a study exploring the
predisposing factors would be important for clinical situations. We
believe that these factors should be taken into account before drawing
final conclusions and starting a dose-adjustment study of MTX for GVHD prophylaxis.
Keitaro Matsuo, Ritsuro Suzuki, Yasuo Morishima, and Nobuyuki Hamajima
Correspondence: Keitaro Matsuo, Aichi Cancer Center Research
Institute, Division of Epidemiology and Prevention, 1-1 Kanokoden
Chikusa-ku Nagoya 464-8681, Japan;
e-mail:kmatsuo{at}aichigw.aichi-cc.pref.aichi.jp
References
1.
Ulrich CM, Yasui Y, Storb R, et al.
Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.
Blood.
2001;98:231-234[Abstract/Free Full Text].
2.
Schubert MM, Williams BE, Lloid ME, Donaldson G, Chapko MK.
Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation.
Cancer.
1992;69:2469-2477[CrossRef][Medline]
[Order article via Infotrieve].
3.
Cehu E, Allegra C.
Antifolates. In:
Chabner B,Longo D, eds.
Cancer Chemotherapy and Biotherapy. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1996:109-148.
4.
Toffoli G, Vernosi A, Boiocchi M, Crivellari D.
MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF).
Ann Oncol.
2000;11:373-374[Free Full Text].
5.
Matsuo K, Suzuki R, Hamajima N, et al.
Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma.
Blood.
2001;97:3205-3209[Abstract/Free Full Text].
6.
Sonis ST, Oster G, Fuchs H, et al.
Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantaion.
J Clin Oncol.
2001;19:2201-2205[Abstract/Free Full Text].
Response:
MTHFR polymorphism, DNA repair capacity, and methotrexate
toxicity
Matsuo et al raise the question of whether the MTHFR
677C>T polymorphism may affect oral mucositis in
marrow-transplantation patients, independent of treatment with the
antifolate drug methotrexate (MTX). The mechanism we proposed for
explaining our findings1 involves (a) decreased provision
of folate for nucleotide synthesis among patients with lower MTHFR
activity (TT genotype), (b) a decreased ability for DNA repair, and
therefore (c) greater damage and delayed healing of the oral mucosa
among these patients. Naturally, one can expect similar effects in any
situation involving the need for DNA repair. As we discussed, the
conditioning regimens used in marrow-transplantation patients
(cyclophosphamide / total body irradiation [Cy/TBI] or
busulfan/cyclophosphamide [Bu/Cy]) by themselves induce oral mucositis. But while the conditioning regimens result in oral mucositis, MTX has
"additive" effects: when administered after transplantation for
acute graft-versus-host disease (GVHD) prophylaxis, it can substantially increase the level of mucosal damage and delay healing. We have shown that, among marrow-transplant patients with Cy/TBI or
Bu/Cy conditioning, MTX administration results in 45% of
patients experiencing severe oral mucositis, compared with 8% of
patients without MTX.2 Others have reported similar
results.3 Thus a substantial amount of oral mucositis in the transplantation
setting can be attributed to MTX administration, and an effect of the
MTHFR polymorphism can be more easily observed in this
situation of extreme folate depletion. One may expect a close link
between a polymorphism affecting the balance of folate metabolites and
the effect of an antifolate drug. Our group,4 as well as others,5,6 has shown
that the risk of colorectal neoplasia associated with the MTHFR
polymorphism varies by folate status, with an increased risk
observed only among individuals with low folate intake or biomarkers
indicating low folate status. Our findings on MTX toxicity, which
induces a folate-depleted state, are consistent with this model of
gene-nutrient interaction. Matsuo et al were further concerned that information on the
pretransplantation condition of the oral cavity or HLA-matching status
was not considered. HLA-matching status was in our population equivalent to the type of conditioning regimen and was adjusted for in
the statistical analyses. Oral mucositis scores before transplantation
were extremely low (usually 0-1) and did not affect our results.
Nevertheless, we agree with Matsuo et al that our findings need to be
replicated in other populations, and the occurrence of GVHD needs to be
evaluated before dose adjustment of MTX should be considered.
Cornelia M. Ulrich, Rainer Storb, Mark M. Schubert, and John D. Potter
Correspondence: Cornelia M. Ulrich, Fred Hutchinson Cancer
Research Center, Cancer Prevention Research Program, 1100 Fairview Ave
N, MP-900, Seattle, WA 98105-1024; e-mail: nulrich{at}fhcrc.org
References
1.
Ulrich CYM, Yasui Y, Storb R, et al.
Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.
Blood.
2001;98:231-234.
2.
Storb R, Deeg HJ, Whitehead J, et al.
Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia.
N Engl J Med.
1986;314:729-735[Abstract].
3.
Dahllof G, Heimdahl A, Modeer T, Twetman S, Bolme P, Ringden O.
Oral mucous membrane lesions in children treated with bone marrow transplantation.
Scand J Dent Res.
1989;97:268-277[Medline]
[Order article via Infotrieve].
4.
Ulrich CM, Kampman E, Bigler J, et al.
Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?
Cancer Epidemiol Biomark Prev.
1999;8:659-668[Abstract/Free Full Text].
5.
Ma J, Stampfer MJ, Giovannucci E, et al.
Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.
Cancer Res.
1997;57:1098-1102[Abstract/Free Full Text].
6.
Chen J, Giovannucci E, Kelsey K, et al.
A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer.
Cancer Res.
1996;56:4862-4864[Abstract/Free Full Text].
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