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

Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany

Gerhard Rogler, Julia Brenmoehl

Department of Internal Medicine I, University of Regensburg, Regensburg, Germany

Hildegard Greinix

Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

Anne Marie Dickinson

School of Laboratory and Clinical Sciences, University of Newcastle on Tyne, Newcastle on Tyne, United Kingdom

Gerard Socie

Hematopoietic Stem-Cell Transplantation unit, Hospital St Louis, Paris, France

Daniel Wolff

Department of Hematology and Oncology, University of Rostock, Rostock, Germany

Juergen Finke

Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany

To the Editor:

In a recent issue of the Journal of Clinical Oncology, Mayor and colleagues reported a retrospective analysis of the prognostic significance of single nucleotide polymorphisms (SNPs) within the pathogen receptor nucleotide-binding oligomerization domain 2 (NOD2)/caspase activating recruitment domain 15 (CARD15) on outcome of allogeneic stem-cell transplantation from unrelated donors (UD). They found a highly significant association of presence of recipient NOD2/CARD15 SNPs with decreased leukemia free survival, as patients with NOD2/CARD15 SNPs had a higher incidence of relapse but no increase in treatment-related mortality (TRM). Their findings are in strong contrast to our previous observations in HLA-identical sibling transplantations where NOD2/CARD15 SNPs were associated with more severe graft-versus-host disease (GVHD), increased TRM, and lower overall survival, but failed to show any impact on relapse rate.^1,2

More recently, we analyzed the prognostic significance of NOD2/CARD15 SNPs in a further cohort of 342 patients receiving UD transplantations. However, in this cohort of patients with a variety of underlying hematologic diseases, we were unable to detect significant effects on both TRM and overall survival, except for a small subgroup of patients receiving transplantations from donors with SNP13 variants, which almost doubled TRM. These data indicated that NOD2/CARD15 polymorphisms might have different effects in genotypically and phenotypically HLA-matched cohorts.

To address the specific impact of NOD2/CARD15 on antileukemic effects as suggested by the findings of Mayor et al, we now reanalyzed the data from 175 patients with acute leukemia receiving a transplantation from an HLA-identical sibling and the 189 patients with acute leukemia receiving UD transplantations in relation to the presence or absence of NOD2/CARD15 SNPs. Whereas the subgroup analysis in siblings again confirmed the strong impact on TRM (increase from 23% in wild-type groups v 53% in the presence of variants), we were unable to detect any effects in UD for all major parameters (TRM, overall survival, and disease-free survival; Fig 1), which is in strong contrast to the report of Mayor et al. In addition, relapse incidence was neither different in HLA-identical sibling transplantations nor in UD transplantations: 31% relapse rate occurred in both, NOD2/CARD15 wild type and variants in HLA-identical sibling stem-cell transplantation, and in 28% in NOD2/CARD15 wild type and 31% in NOD2/CARD15 variants in UD transplantations.

To explain these diverging results we checked for possible differences between the two analyzed cohorts. Our UD cohort was older (median age, 34 years; range, 16 to 62 years), had a higher proportion of early-stage patients, and a higher proportion of AML versus ALL patients (76% v 24%), but a similar extent of HLA-matched transplantations and patients receiving conventional conditioning. The most striking difference, however, was the proportion of patients receiving T-cell depletion, as 49% of transplantations in the wild-type group and 62% of transplantations in the group with NOD2/CARD15 variants were performed without any T-cell depletion. In addition, fewer then 5% of those receiving T-cell depleted grafts in our groups received depletion with Campath, and in line with this, the incidence of grade 2 to 4 GVHD was 48% and of severe grade 3 to 4 GVHD was 22% in our cohort as compared with the low incidences reported in their patients.

In our view, this difference in application of T-cell depletion is most likely to explain the divergent prognostic role of NOD2/CARD15 SNPs. This is in line with observation of the Granell et al,³ as discussed by the authors as an explanation for the absence of association between NOD2/CARD15 SNPs and GVHD. In our view, an alternative hypothesis may be added—up to now it is unclear to what extent T cells contribute to graft-versus-leukemia effects in acute leukemia. It might well turn out that NOD2/CARD15 signaling is also involved in activation of natural-killer cells which are thought to be major players in immunological control of acute leukemias. Finally, the diverging results point to an extremely important additional aspect. By describing clear differences in T-cell depleted versus nondepleted patients, we might be able to adapt our prophylactic strategies based on the genetic repertoire of our patients. Thus, SNP analysis should be continued and included in prospective testing different strategies of immunosuppressive prophylaxis and will hopefully pave the way to individualized strategies in the future.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

ACKNOWLEDGMENTS

Supported by Grants no. QLRT-2000-00010 (Eurobank), QLRT-CT-2001-01936 (TransEurope), and MRTN-CT-2004-512253 (Trans-Net) from the European Commission.

REFERENCES

1. 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]

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. 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]

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