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Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation

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Abstract

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5 mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0–41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0–7 (AUC0–7) and 0–32 (AUC0–32) than the grade 0–I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738–1.000). The high C0 (≥ 27.8 µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8 µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

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References

  1. Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, et al. Marrow transplantation from related donors other than HLA-identical siblings. N Engl J Med. 1985;313:765–71.

    Article  CAS  Google Scholar 

  2. Anasetti C, Amos D, Beatty PG, Appelbaum FR, Bensinger W, Buckner CD, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med. 1989;320:197–204.

    Article  CAS  Google Scholar 

  3. Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, Sanders JE, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol. 1990;29:79–91.

    Article  CAS  Google Scholar 

  4. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005;23:3447–54.

    Article  Google Scholar 

  5. O’Donnell PV, Luznik L, Jones RJ, Vogelsang GB, Leffell MS, Phelps M, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8:377–86.

    Article  CAS  Google Scholar 

  6. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Juan W, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.

    Article  CAS  Google Scholar 

  7. Hoegh-Petersen M, Amin MA, Liu Y, Ugarte-Torres A, Williamson TS, Podgorny PJ, et al. Anti-thymocyte globulins capable of binding to T and B cells reduce graft-vs-host disease without increasing relapse. Bone Marrow Transplant. 2013;48:105–14.

    Article  CAS  Google Scholar 

  8. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21:1387–94.

    Article  CAS  Google Scholar 

  9. Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107:3065–73.

    Article  CAS  Google Scholar 

  10. Lee KH, Lee JH, Lee JH, Kim DY, Seol M, Lee YS, et al. Reduced-intensity conditioning therapy with busulfan, fludarabine, and antithymocyte globulin for HLA-haploidentical hematopoietic cell transplantation in acute leukemia and myelodysplastic syndrome. Blood. 2011;118:2609–17.

    Article  CAS  Google Scholar 

  11. Ogawa H, Ikegame K, Yoshihara S, Kawakami M, Fujioka T, Masuda T, et al. Unmanipulated HLA 2–3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006;12:1073–84.

    Article  Google Scholar 

  12. Ogawa H, Ikegame K, Kaida K, Yoshihara S, Fujioka T, Taniguchi Y, et al. Unmanipulated HLA 2–3 antigen-mismatched (haploidentical) bone marrow transplantation using only pharmacological GVHD prophylaxis. Exp Hematol. 2008;36:1–8.

    Article  CAS  Google Scholar 

  13. Tamaki H, Ikegame K, Kawakami M, Fujioka T, Tsuboi A, Oji Y, et al. Successful engraftment of HLA-haploidentical related transplants using nonmyeloablative conditioning with fludarabine, busulfan and anti-T-lymphocyte globulin. Leukemia. 2003;17:2052–4.

    Article  CAS  Google Scholar 

  14. Ikegame K, Yoshida T, Yoshihara S, Daimon T, Shimizu H, Maeda Y, et al. Unmanipulated haploidentical reduced-intensity stem cell transplantation using fludarabine, busulfan, low-dose antithymocyte globulin, and steroids for patients in non-complete remission or at high risk of relapse: a prospective multicenter phase I/II study in Japan. Biol Blood Marrow Transplant. 2015;21:1495–505.

    Article  CAS  Google Scholar 

  15. Remberger 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;15:996–9.

    Article  CAS  Google Scholar 

  16. Chawla S, Dharmani-Khan P, Liu Y, Prokopishyn N, Amlish Munir M, Griffiths C, et al. High serum level of antithymocyte globulin immediately before graft infusion is associated with a low likelihood of chronic, but not acute, graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1156–62.

    Article  CAS  Google Scholar 

  17. Jamani K, Dabas R, Kangarloo SB, Prokopishyn NL, Luider J, Dharmani-Khan P, et al. Rabbit antithymocyte globulin serum levels: factors impacting the levels and clinical outcomes impacted by the levels. Biol Blood Marrow Transplant. 2019;25:639–47.

    Article  CAS  Google Scholar 

  18. Admiraal R, Nierkens S, de Witte MA, Petersen EJ, Fleurke GJ, Verrest L, et al. Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis. Lancet Haematol. 2017;4:e183–91.

    Article  Google Scholar 

  19. Kaida K, Ikegame K, Ikemoto J, Murata R, Irie R, Yoshihara S, et al. Soluble interleukin-2 receptor level on day 7 as a predictor of graft-versus-host disease after HLA-haploidentical stem cell transplantation using reduced-intensity conditioning. Int J Hematol. 2014;99:463–70.

    Article  CAS  Google Scholar 

  20. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1994;1995(15):825–8.

    Google Scholar 

  21. Remberger M, Sundberg B. Rabbit-immunoglobulin G levels in patients receiving thymoglobulin as part of conditioning before unrelated donor stem cell transplantation. Haematologica. 2005;90:931–8.

    CAS  PubMed  Google Scholar 

  22. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  Google Scholar 

  23. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389-401.e1.

    Article  Google Scholar 

  24. Shiratori S, Ohigashi H, Ara T, Yasumoto A, Goto H, Nakagawa M. High lymphocyte counts before antithymocyte globulin administration predict acute graft-versus-host disease. Ann Hematol. 2021;100:1321–8.

    Article  CAS  Google Scholar 

  25. Bouazzaoui A, Spacenko E, Mueller G, Huber E, Schubert T, Holler E, et al. Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs.-host disease of the intestinal tract. Exp Hematol. 2011;39:238-49.e1.

    Article  CAS  Google Scholar 

  26. Kennedy VE, Chen H, Savani BN, Greer J, Kassim AA, Engelhardt BG, et al. Optimizing antithymocyte globulin dosing for unrelated donor allogeneic hematopoietic cell transplantation based on recipient absolute lymphocyte count. Biol Blood Marrow Transplant. 2018;24:150–5.

    Article  CAS  Google Scholar 

  27. Heelan F, Mallick R, Bryant A, Radhwi O, Atkins H, Huebsch L, et al. Does lymphocyte count impact dosing of anti-thymocyte globulin in unrelated donor stem cell transplantation? Biol Blood Marrow Transplant. 2020;26:1298–302.

    Article  CAS  Google Scholar 

  28. Gauntner TD, Brunstein CG, Cao Q, Weisdorf D, Warlick ED, Jurdi NE, et al. Association of CD34 cell dose with 5-year overall survival after peripheral blood allogeneic hematopoietic cell transplantation in adults with hematologic malignancies. Transplant Cell Ther. 2022;28:88–95.

    Article  Google Scholar 

  29. Fujioka T, Tamaki H, Ikegame K, Yoshihara S, Taniguchi K, Kaida K, et al. Frequency of CD4(+)FOXP3(+) regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD. Bone Marrow Transplant. 2013;48:859–64.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the medical, nursing, and laboratory staff of the participating departments for their contributions.

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Authors and Affiliations

  1. Department of Respiratory Medicine and Hematology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Masahiro Teramoto, Hiroya Tamaki, Katsuji Kaida, Keiko Fukunaga, Takayuki Inoue, Kyoko Yoshihara, Satoshi Yoshihara, Kazuhiro Ikegame, Masaya Okada, Yuko Osugi, Hiroyasu Ogawa, Satoshi Higasa & Takashi Kijima

  2. Department of Hematology-Oncology, Chiba Cancer Center, Chiba, Japan

    Satoshi Maruyama

  3. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Azusa Mayumi

  4. Department of Transfusion Medicine and Cell Therapy, Hyogo College of Medicine, Nishinomiya, Japan

    Satoshi Yoshihara

  5. Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe, Japan

    Kunihiko Morita & Kana Matsumoto

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  1. Masahiro Teramoto
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  2. Satoshi Maruyama
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Correspondence to Katsuji Kaida.

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Conflict of interest

SY has received honoraria from Sanofi. MT, SM, HT, KK, AM, KF, TI, KY, KI, MO, YO, HO, SH, KM, KM, and TK declare that they have no conflicts of interest.

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Teramoto, M., Maruyama, S., Tamaki, H. et al. Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation. Int J Hematol 116, 248–257 (2022). https://doi.org/10.1007/s12185-022-03342-8

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