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In Reply

Anthony Nolan Research Institute, Royal Free Hospital; Department Haematology, Royal Free and UCL School of Medicine, London, United Kingdom

Bronwen E. Shaw

Anthony Nolan Research Institute, Royal Free Hospital; Department Haemato-Oncology, Royal Marsden Hospital, Surrey, United Kingdom

Derralynn A. Hughes, Hazael Maldonado-Torres, J. Alejandro Madrigal

Anthony Nolan Research Institute, Royal Free Hospital; Department Haematology, Royal Free and UCL School of Medicine, London, United Kingdom

Satish Keshav

Department of Gastroenterology, John Radcliffe Hospital, Oxford, United Kingdom

Steven G.E. Marsh

Anthony Nolan Research Institute, Royal Free Hospital; Department Haematology, Royal Free and UCL School of Medicine, London, United Kingdom

The impact of single nucleotide polymorphisms (SNPs) of the nucleotide-binding oligomerization domain containing 2 (NOD2)/caspase recruitment domain family, member 15 (CARD15) gene on the outcome of hematopoietic stem-cell transplantation (HSCT) is increasingly emerging.¹-⁵ As pointed out by Holler et al, we have shown a highly significant effect of NOD2/CARD15 gene SNPs on the outcome of unrelated donor (UD) HSCT for acute leukemia.¹ The correspondence from Holler and colleagues describes the results of a study on a similar cohort of previously genotyped HSCT pairs. In contrast to what we described, Holler et al found no impact of NOD2/CARD15 SNPs on any transplantation outcome variable in an UD-HSCT setting for acute leukemia. However, there was a significant effect on overall survival in related donor (RD) HSCT pairs. We welcome this data as it reinforces our belief that there is an important role for NOD2 in the field of transplantation, particularly in acute leukemia, and that each patient needs to be considered individually. It also confirms the need for genotyping both donors and recipients before transplantation.

The authors have attributed the differences seen to the near universal use of T-cell depletion and the high use of Campath (Schering Health Care Ltd, West Sussex, United Kingdom) in our cohort. We agree that the use of Campath in T-cell depletion is more prevalent in our cohort which in turn has almost certainly affected the incidence of acute graft-versus-host disease seen. The recipients included in this study are from a total of 25 different allogeneic SCT centers and are thus representative of a large proportion of the transplantation community in the United Kingdom.

One of the factors that may have contributed to the lack of significance of NOD2/CARD15 SNPs on UD-HSCT outcome in the study by Holler et al compared with our original study is the higher incidence of recipients with acute myeloid leukemia (AML; 74% v 50%, respectively).¹ We showed in our study that the effect of NOD2/CARD15 SNPs was significant in the acute lymphoblastic leukemia subgroup but not significant in AML. Thus, any affect of SNPs on transplantation outcome may have been masked by the cohort being predominantly made up of AML recipients. It would be interesting to discover whether the results were replicated in a solely acute lymphoblastic leukemia cohort.

Despite the differences in the cohorts, these two studies highlight a significant role of NOD2/CARD15 SNPs in acute leukemia irrespective of donor source. Holler et al have added fuel to our argument that prospectively knowing donor and recipient NOD2/CARD15 genotype will improve the outcome of HSCT. It is important therefore, that further studies are carried out on more transplantation pairs in order to establish the mechanism by which NOD2 acts and what effect, if any, is seen with other disease groups.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Mayor NP, Shaw BE, Hughes DA, et al: 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. J Clin Oncol 25:4262-4269, 2007[Abstract/Free Full Text]

2. Holler E, Rogler G, Brenmoehl J, et al: Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: Effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 107:4189-4193, 2006[Abstract/Free Full Text]

3. Holler E, Rogler G, Herfarth H, et al: Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 104:889-894, 2004[Abstract/Free Full Text]

4. Granell M, Urbano-Ispizua A, Arostegui JI, et al: Effect of NOD2/CARD15 variants in T-cell depleted allogeneic stem cell transplantation. Haematologica 91:1372-1376, 2006[Abstract/Free Full Text]

5. Elmaagacli AH, Koldehoff M, Hindahl H, et al: Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation 81:247-254, 2006[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mayor, N. P. Articles by Marsh, S. G.E. Search for Related Content PubMed Articles by Mayor, N. P. Articles by Marsh, S. G.E. Social Bookmarking                            What's this?