Originally published as JCO Early Release 10.1200/JCO.2007.12.1897 on August 27 2007

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Single Nucleotide Polymorphisms in the NOD2/CARD15 Gene Are Associated With an Increased Risk of Relapse and Death for Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation With Unrelated Donors

Neema P. Mayor, Bronwen E. Shaw, Derralynn A. Hughes, Hazael Maldonado-Torres, J. Alejandro Madrigal, Satish Keshav, Steven G.E. Marsh

From the Anthony Nolan Research Institute, Royal Free Hospital; Department of Haematology, Royal Free and University College London School of Medicine, Royal Free Campus; Royal Marsden Hospital; Department of Medicine, Royal Free and University College London School of Medicine, Royal Free Campus, London, United Kingdom

Address reprint requests to Steven G.E. Marsh, PhD, Anthony Nolan Research Institute, Royal Free Hospital, Pond St, London NW3 2QG, United Kingdom; e-mail: marsh{at}ebi.ac.uk

Purpose Hematopoietic stem cell transplantation (HSCT) is an important option in the management of acute leukemia, but the risk of disease relapse and death remains appreciable. Recent studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15) gene single nucleotide polymorphisms (SNPs), implicated in innate immunity and Crohn's disease, may also affect immune function post-HSCT.

Patients and Methods NOD2/CARD15 genotypes were analyzed in 196 patients diagnosed with acute leukemia and their unrelated donors. The pairs are part of a previously well-characterized cohort with a median follow-up of 2.2 years (range, 0.42 to 6.61 years). T-cell depletion was used in 83% of pairs.

Results NOD2/CARD15 SNPs were associated with a reduction in overall survival (44% v 22%; log-rank P = .0087) due to an increase in disease relapse (32% v 54%; Gray's test P = .001) as compared with wild-type pairs. In multivariate analyses, the two most significant factors impacting outcome were transplantation in relapse and the presence of SNPs. The incidence of acute graft-versus-host disease was low and there was no significant difference due to the presence of SNPs.

Conclusion These data indicate an unrecognized role for the NOD2/CARD15 gene in unrelated donor HSCT for acute leukemia. The increased risk of disease relapse suggests that the wild-type gene product may contribute to a graft-versus-leukemia effect. These data suggest that NOD2/CARD15 genotyping before transplantation may contribute to prognosis and influence clinical management.

published online ahead of print at www.jco.org on August 27, 2007.

Supported by an EU-FP6 project Allostem 503319 and by the Medical Research Council United Kingdom (S.K.).

Presented in part at the Annual Meeting of the American Society of Hematology, December 9-12, 2006; BMT Tandem Meetings, February 8-12, 2007; European Group for Blood and Marrow Transplantation Meeting, March 25-28, 2007; and the European Federation of Immunogenetics, May 5-8, 2007.

S.K. and S.G.E.M. contributed equally to this article.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• NOD2/CARD15 Polymorphisms in Allogeneic Stem-Cell Transplantation From Unrelated Donors: T Depletion Matters
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