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Analysis of BMT CTN-0201 and -0901 samples did not reproduce the reported association between recipient REG3A rs7588571 and chronic GVHD

Bone Marrow Transplantation volume 54, pages 490–493 (2019)Cite this article

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Regenerating islet-derived protein 3 alpha (REG3A) is a C-type lectin constitutively expressed and apically secreted by Paneth cells at high levels, with powerful bactericidal activity against gram-positive bacteria of the gut [1]. By limiting the number of mucosal adherent bacteria, REG3A separates gut microbiota and epithelium, promoting intestinal tolerance to microbial antigens and reducing bacterial translocation [2]. Circulating REG3A has been used as a biomarker of gastrointestinal GVHD, and has been used to predict response to therapy and non-relapse mortality (NRM) [3,4,5]. A recent study reported a novel association between a single-nucleotide polymorphism (SNP rs7588571; minor allele A with frequency 0.49) in the putative promotor region of REG3A and extensive chronic GVHD (ecGVHD) [6]. In that study, performed in 119 evaluable adult Japanese allogeneic HCT recipients, a higher incidence of ecGVHD was observed in patients with the non-GG genotype than in those with the GG genotype (odds ratio in multivariable analysis: 2.6; 95% confidence interval [95% CI]: 1.1–6.0; P = 0.029). No association was found between this SNP and acute GVHD (overall and grade II–IV). All patients received a bone marrow graft from an HLA-matched sibling and GVHD prophylaxis with cyclosporine and methotrexate. The median age was ~37 years and conditioning was myeloablative (MA) in >95% of transplants. Our goal in the present study was to test the reproducibility of the observed association between rs7588571 and ecGVHD using samples from two Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocols 0201 and 0901.

BMT CTN-0201 was a phase 3 randomized multicenter clinical trial (2004–2009, 551 patients) comparing bone marrow (BM) vs. peripheral blood (PB) as graft source in HCT from unrelated donors, and with 2-year overall survival as the primary endpoint [7]. The results demonstrated similar rates of acute GVHD between the groups, but higher rates of cGVHD among recipients of PB grafts (2-year cGVHD: 53% vs. 41% in PB vs. BM groups, respectively). BMT CTN-0901 was a phase 3 randomized multicenter clinical trial (2011–2014, 272 patients, matched sibling or unrelated donors) comparing myeloablative (MA) vs. reduced-intensity (RI) conditioning in patients with acute myeloid leukemia or myelodysplastic syndromes, and with the primary endpoint of 18-month overall survival [8]. The graft source was PB in 92% of patients and BM in 8%. The results demonstrated higher rates of acute and chronic GVHD among MA patients (1.5-year cGVHD: 66% vs. 37% in myeloablative vs. RI, respectively).

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Acknowledgements

Support for the primary clinical trials was provided to the Blood and Marrow Transplant Clinical Trials Network by Grant #U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The Department of Navy, Office of Navy Research, and the National Marrow Donor Program also provided support. Enrollment support was provided by DKMS Germany. Research reported in this publication was also supported by NIH Grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. Any views, opinions, findings, conclusions or recommendations expressed in this material are those of the author(s) and do not reflect the views or the official policy or position of the above-mentioned parties. Armin Rashidi was supported by an American Blood and Marrow Transplantation Young Investigator Award.

Author contribution

AR and RS designed the study. SLY and BT performed the experiments. RS analyzed the data. AR wrote the paper. CA, EKW, BLS, BRB, and DJW critically evaluated the results and enhanced the manuscript.

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  1. These authors contributed equally: Armin Rashidi, Ryan Shanley.

Authors and Affiliations

  1. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA

    Armin Rashidi & Daniel J. Weisdorf

  2. Masonic Cancer Center Biostatistics Core, University of Minnesota, Minneapolis, MN, USA

    Ryan Shanley

  3. Moffitt Cancer Center, Tampa, FL, USA

    Claudio Anasetti

  4. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Edmund K. Waller

  5. Fred Hutchinson Cancer Research Center, University of Washington Medical Center/Seattle Cancer Care Alliance, Seattle, WA, USA

    Bart L. Scott

  6. Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Bruce R. Blazar

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Correspondence to Armin Rashidi.

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Rashidi, A., Shanley, R., Anasetti, C. et al. Analysis of BMT CTN-0201 and -0901 samples did not reproduce the reported association between recipient REG3A rs7588571 and chronic GVHD. Bone Marrow Transplant 54, 490–493 (2019). https://doi.org/10.1038/s41409-018-0331-1

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