Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor
Shaimaa Elmahdi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHideki Muramatsu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAtsushi Narita
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYuka Torii
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorOlfat Ismael
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorNozomu Kawashima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYusuke Okuno
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYuko Sekiya
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYinyan Xu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorXinan Wang
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAsahito Hama
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYoshinori Ito
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYoshiyuki Takahashi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Seiji Kojima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Seiji Kojima, MD, PhD, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Tel.: +81 52 744 2294
Fax: +81 52 744 2974
E-mail: [email protected]
Search for more papers by this authorShaimaa Elmahdi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorHideki Muramatsu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAtsushi Narita
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYuka Torii
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorOlfat Ismael
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorNozomu Kawashima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYusuke Okuno
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYuko Sekiya
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYinyan Xu
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorXinan Wang
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorAsahito Hama
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYoshinori Ito
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorYoshiyuki Takahashi
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Search for more papers by this authorCorresponding Author
Seiji Kojima
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Seiji Kojima, MD, PhD, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Tel.: +81 52 744 2294
Fax: +81 52 744 2974
E-mail: [email protected]
Search for more papers by this authorAbstract
We analyzed the correlation between rabbit ATG (rATG) serum levels and clinical outcomes in 37 children who received rATG at a total dose of 10 or 15 mg/kg during HSCT conditioning from an alternative donor. Fourteen patients had advanced malignant diseases, 13 had severe AA, and 10 had inherited disorders. Complete engraftment was achieved in all patients, and no rejection occurred. The cumulative incidence of grades II–IV acute GVHD and extensive chronic GVHD was 27% (95% CI, 12.5–39.6%) and 8.1% (95% CI, 0–23.1%), respectively. Multivariate analysis identified lower rATG levels at week 4 as an independent risk factor in the development of grades II–IV acute GVHD (p = 0.037). Serious infections were not observed in any patient following HSCT. No correlation was found between EBV reactivation and rATG levels at week 2 and week 4 after HSCT. Furthermore, no correlation was found between relapse and rATG levels two and four wk post-transplantation. The probability of five-yr OS among patients was 70.3% (95% CI, 59.8–79.2%). Our results suggest that targeted rATG administration may protect patients from severe acute GVHD without increasing the risk of EBV reactivation or relapse.
Supporting Information
| Filename | Description |
|---|---|
| petr12620-sup-0001-FigS1-S3.pptxapplication/mspowerpoint, 110.3 KB | Figure S1 Rabbit ATG levels two and four wk post-HSCT vs. (a) patients body weight (kg), (b) lymphocyte count pretreatment (/μL) and (c) nucleated cell dose (×108/kg). Figure S2 Receiver-operator characteristic (ROC) curve, constructed using the rabbit IgG level with a maximum sum of sensitivity and specificity for detecting the cut-off level of ATG for acute GVHD grades II–IV at week 4 post-HSCT. Figure S3 EBV reactivation and EBV copy/mL in HSCT patients and EBV-LPD patients. |
| petr12620-sup-0002-TableS1.xlsxMS Excel, 36.8 KB | Table S1 Characteristics of EBV-LPD cases. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Handgretinger R, Klingebiel T, Lang P, et al. Megadose transplantation of purified peripheral blood CD34(+) progenitor cells from HLA-mismatched parental donors in children. Bone Marrow Transplant 2001: 27: 777–783.
- 2Klingebiel T, Lang P, Schumm M, et al. Experiences with haploidentical stem cell transplantation in children with acute lymphoblastic leukemia. Pathol Biol 2005: 53: 159–161.
- 3Kojima S, Matsuyama T, Kato S, et al. Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: The Japan Marrow Donor Program. Blood 2002: 100: 799–803.
- 4Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012: 120: 1185–1196.
- 5Bacigalupo A, Hows J, Gordon-Smith EC, et al. Bone marrow transplantation for severe aplastic anemia from donors other than HLA identical siblings: A report of the BMT Working Party. Bone Marrow Transplant 1988: 3: 531–535.
- 6Handgretinger R, Klingebiel T, Lang P, Gordon P, Niethammer D. Megadose transplantation of highly purified haploidentical stem cells: Current results and future prospects. Pediatr Transplant 2003: 7(Suppl 3): 51–55.
- 7Keever CA, Small TN, Flomenberg N, et al. Immune reconstitution following bone marrow transplantation: Comparison of recipients of T-cell depleted marrow with recipients of conventional marrow grafts. Blood 1989: 73: 1340–1350.
- 8Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993: 328: 593–602.
- 9Margolis DA, Casper JT. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol 2000: 37: 43–55.
- 10Klingebiel T, Cornish J, Labopin M, et al. Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: Impact of center size: An analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood 2010: 115: 3437–3446.
- 11Lang P, Greil J, Bader P, et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis 2004: 33: 281–287.
- 12Bourdage JS, Hamlin DM. Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation 1995: 59: 1194–1200.
- 13Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Investig 2004: 114: 1209–1217.
- 14Rebellato LM, Gross U, Verbanac KM, Thomas JM. A comprehensive definition of the major antibody specificities in polyclonal rabbit antithymocyte globulin. Transplantation 1994: 57: 685–694.
- 15Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: Long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 2006: 12: 560–565.
- 16Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood 2001: 98: 2942–2947.
- 17Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: A randomised, open-label, multicentre phase 3 trial. Lancet Oncol 2009: 10: 855–864.
- 18Mohty M, Bay JO, Faucher C, et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003: 102: 470–476.
- 19Remberger M, Svahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem-cell transplantation. Transplantation 2004: 78: 122–127.
- 20Deeg HJ, Storer BE, Boeckh M, et al. Reduced incidence of acute and chronic graft-versus-host disease with the addition of thymoglobulin to a targeted busulfan/cyclophosphamide regimen. Biol Blood Marrow Transplant 2006: 12: 573–584.
- 21Remberger M, Persson M, Mattsson J, Gustafsson B, Uhlin M. Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation. Transpl Immunol 2012: 27: 59–62.
- 22Remberger M, Sundberg B. Rabbit-immunoglobulin G levels in patients receiving thymoglobulin as part of conditioning before unrelated donor stem cell transplantation. Haematologica 2005: 90: 931–938.
- 23Remberger M, Sundberg B. Low serum levels of total rabbit-IgG is associated with acute graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation: Results from a prospective study. Biol Blood Marrow Transplant 2009: 15: 996–999.
- 24Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med 2005: 56: 29–44.
- 25Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 2013: 48: 452–458.
- 26Hoshino Y, Kimura H, Tanaka N, et al. Prospective monitoring of the Epstein-Barr virus DNA by a real-time quantitative polymerase chain reaction after allogenic stem cell transplantation. Br J Haematol 2001: 115: 105–111.
- 27Kojima S, Horibe K, Inaba J, et al. Long-term outcome of acquired aplastic anaemia in children: Comparison between immunosuppressive therapy and bone marrow transplantation. Br J Haematol 2000: 111: 321–328.
- 28Kobayashi S, Ito M, Sano H, et al. T-cell-replete haploidentical stem cell transplantation is highly efficacious for relapsed and refractory childhood acute leukaemia. Transfus Med 2014: 24: 305–310.
- 29Liu D, Huang X, Liu K, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children. Biol Blood Marrow Transplant 2008: 14: 469–477.
- 30Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood 1999: 94: 2208–2216.
- 31Zutter MM, Martin PJ, Sale GE, et al. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood 1988: 72: 520–529.
- 32Gerritsen EJ, Stam ED, Hermans J, et al. Risk factors for developing EBV-related B cell lymphoproliferative disorders (BLPD) after non-HLA-identical BMT in children. Bone Marrow Transplant 1996: 18: 377–382.
- 33Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: Current status and future perspectives. Blood 2011: 118: 6006–6017.
- 34D'Aveni M, Aissi-Rothe L, Venard V, et al. The clinical value of concomitant Epstein Barr virus (EBV)-DNA load and specific immune reconstitution monitoring after allogeneic hematopoietic stem cell transplantation. Transpl Immunol 2011: 24: 224–232.
- 35Hoegh-Petersen M, Goodyear D, Geddes MN, et al. High incidence of post transplant lymphoproliferative disorder after antithymocyte globulin-based conditioning and ineffective prediction by day 28 EBV-specific T lymphocyte counts. Bone Marrow Transplant 2011: 46: 1104–1112.
- 36Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood 2009: 113: 4992–5001.
- 37Storek J, Mohty M, Boelens JJ. Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015: 21: 959–970.
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