The association of conditioning regimen with cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation
-
Masoud Mardani
,
Sara Abolghasemi
,
Shiva Shabani
,
Farzaneh Tavakoli
,
Anahita Saeedi
,
Sayeh Parkhideh
,
Abbas Hajifathali
Abstract
Background and Objectives: Infections is yet one of the life-threatening complications of the hematopoietic stem cell transplantation (HSCT). The myeloablative and immunosuppressive conditioning regimens, which are administered before HSCT, dampen the defense capacity of the recipients’ immune systems. In this condition, opportunistic infections, especially viral infections such as cytomegalovirus (CMV) can be reactivated and cause morbidity and mortality in HSCT patients. Here, we aimed to find out any possible relationship between types of conditioning regimen and CMV reactivation in allogeneic HSCT patients.
Materials and Methods: We retrospectively analyzed the data of 145 CMV-seropositive cases out of total 201 allo-HSCT patients, including age, gender, underlying disease, conditioning regimen, prophylaxis regimen and occurrence of acute graft-versus-host disease (aGVHD) to evaluate their roles in CMV reactivation.
Results: Our result showed that conditioning regimen containing Busulfan and Fludarabine (P=0.003) or Cyclophosphamide (P=0.02) significantly decrease the early CMV reactivation. Patients who developed aGVHD (P=0.003) and those who received anti-thymocyte globulin (ATG) as prophylaxis regimen (P=0.002), had 1.84 and 2.63 times higher risks of CMV reactivation, respectively.
Conclusion: Our findings suggest the conditioning regimen, aGVHD and ATG as influencing factors for early CMV reactivation post-HSCT which should be considered in the future studies.
1. Cornelissen JJ, Blaise D. Hematopoietic stem cell transplantation for patients with AML in first complete remission. Blood 2016;127:62-70.
2. Ardakani MT, Mehrpooya M, Mehdizadeh M, Beiraghi N, Hajifathali A, Kazemi MH. Sertraline treatment decreased the serum levels of interleukin-6 and high-sensitivity C-reactive protein in hematopoietic stem cell transplantation patients with depression; a randomized double-blind, placebo-controlled clinical trial. Bone Marrow Transplant 2020;55: 830-832.
3. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA 2006;295:508-518.
4. Bigley A, Baker F, Simpson R. Cytomegalovirus: an unlikely ally in the fight against blood cancers? Clin Exp Immunol 2018; 193:265-274.
5. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010;20:202-213.
6. Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol 2019;29(3):e2034.
7. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26:86-102.
8. Stern L, Withers B, Avdic S, Gottlieb D, Abendroth A, Blyth E, et al. Human cytomegalovirus latency and reactivation in allogeneic hematopoietic stem cell transplant recipients. Front Microbiol 2019;10:1186.
9. Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther 2018;7:1-16.
10. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood 2016;127:2427-2438.
11. Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 2016;3:e119-e127.
12. Takenaka K, Nishida T, Asano-Mori Y, Oshima K, Ohashi K, Mori T, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: the Japan society for hematopoietic cell transplantation transplantation-related complication working group. Biol Blood Marrow Transplant 2015;21:2008-2016.
13. Neumann T, Schneidewind L, Thiele T, Schulze M, Klenner AF, Busemann C, et al. Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation. J Cancer Res Clin Oncol 2016;142:1091-1097.
14. Xuan L, Huang F, Fan Z, Zhou H, Zhang X, Yu G, et al. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol 2012;5:46.
15. Cho S-Y, Lee D-G, Kim H-J. Cytomegalovirus infections after hematopoietic stem cell transplantation: current status and future immunotherapy. Int J Mol Sci 2019;20:2666.
16. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010;23:689-712.
17. Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D, et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol 2013;6:15.
18. Oh SJ, Lee KH, Lee JH, Choi SJ, Kim WK, Lee JS, et al. The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation. J Korean Med Sci 2004;19:172-176.
19. Bartelink I, Van Reij E, Gerhardt C, Van Maarseveen E, De Wildt A, Versluys B, et al. Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Biol Blood Marrow Transplant 2014;20:345-353.
20. Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, DiPersio JF, Uy GL, Westervelt P, et al. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow Transplant 2014;20:46-52.
21. Nakamae H, Kirby KA, Sandmaier BM, Norasetthada L, Maloney DG, Maris MB, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009;15:694-703.
22. Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky performance status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak 2013;13:72.
23. Parkhideh S, Chegeni R, Mehdizadeh M, Roshandel E, Tavakoli F, Hajifathali A. Effects of ABO incompatibility on the outcome of allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci 2019;59:102696.
24. Ghasemi K, Parkhideh S, Kazemi MH, Salimi M, Salari S, Nalini R, et al. The role of serum uric acid in the prediction of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. J Clin Lab Anal 2020;34:e23271.
25. Nagler A, Shimoni A (2019). Conditioning. The EBMT Handbook: Springer, Cham; pp: 99-107.
26. Venton G, Crocchiolo R, Fürst S, Granata A, Oudin C, Faucher C, et al. Risk factors of G anciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients. Clin Microbiol Infect 2014;20:160-166.
27. Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Lawrence SJ, Uy GL, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica 2016;101:e465-e468.
28. Schetelig J, Oswald O, Steuer N, Radonic A, Thulke S, Held T, et al. Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia. Bone Marrow Transplant 2003;32:695-701.
29. Vejražková E, Hubáček P, Plíšková L, Košťál M, Zavřelová A, Štěpánová V, et al. Reduction of Thymoglobuline from 7.5 mg/kg to 6 mg/kg in conditioning regimen extended time to the first cytomegalovirus detection after allogenic haematopoietic stem cell transplantation. Epidemiol Mikrobiol Imunol 2019;68:71-74.
30. Green ML, Leisenring W, Stachel D, Pergam SA, Sandmaier BM, Wald A, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012;18:1687-1699.
31. Martino R, Caballero M, Canals C, San Miguel J, Sierra J, Rovira M, et al. Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2001;28:341-347.
32. Lamba R, Carrum G, Myers G, Bollard C, Krance R, Heslop H, et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant 2005;36:797-802.
33. Matsumura T, Narimatsu H, Kami M, Yuji K, Kusumi E, Hori A, et al. Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients. Biol Blood Marrow Transplant 2007;13:577-583.
34. Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002;99:1978-1985.
35. Pinana J, Martino R, Barba P, Margall N, Roig M, Valcarcel D, et al. Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience. Bone Marrow Transplant 2010;45:534-542.
36. Vaezi M, Kasaeian A, Souri M, Soufiyan F, Boosjin AS, Setarehdan SA, et al. How do donor-recipient CMV serostatus and post-hematopoietic stem cell transplantation CMV reactivation affect outcomes in acute Leukemia patients? Int J Hematol Oncol Stem Cell Res 2017;11:199-208.
37. Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol 2014;5:68.
38. Valadkhani B, Kargar M, Ashouri A, Hadjibabaie M, Gholami K, Ghavamzadeh A. The risk factors for cytomegalovirus reactivation following stem cell transplantation. J Res Pharm Pract 2016;5:63.
39. Resende C, Rezende B, Bernardes P, Teixeira G, Teixeira M, Pinho V, et al. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation. Braz J Med Biol Res 2017; 50(2):e5566.
40. Law AD, Salas MQ, Lam W, Michelis FV, Thyagu S, Lipton JH, et al. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transplant 2018;24:2259-2264.
2. Ardakani MT, Mehrpooya M, Mehdizadeh M, Beiraghi N, Hajifathali A, Kazemi MH. Sertraline treatment decreased the serum levels of interleukin-6 and high-sensitivity C-reactive protein in hematopoietic stem cell transplantation patients with depression; a randomized double-blind, placebo-controlled clinical trial. Bone Marrow Transplant 2020;55: 830-832.
3. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA 2006;295:508-518.
4. Bigley A, Baker F, Simpson R. Cytomegalovirus: an unlikely ally in the fight against blood cancers? Clin Exp Immunol 2018; 193:265-274.
5. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 2010;20:202-213.
6. Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol 2019;29(3):e2034.
7. Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26:86-102.
8. Stern L, Withers B, Avdic S, Gottlieb D, Abendroth A, Blyth E, et al. Human cytomegalovirus latency and reactivation in allogeneic hematopoietic stem cell transplant recipients. Front Microbiol 2019;10:1186.
9. Styczynski J. Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation. Infect Dis Ther 2018;7:1-16.
10. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood 2016;127:2427-2438.
11. Green ML, Leisenring W, Xie H, Mast TC, Cui Y, Sandmaier BM, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 2016;3:e119-e127.
12. Takenaka K, Nishida T, Asano-Mori Y, Oshima K, Ohashi K, Mori T, et al. Cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia who survived to day 100 after transplantation: the Japan society for hematopoietic cell transplantation transplantation-related complication working group. Biol Blood Marrow Transplant 2015;21:2008-2016.
13. Neumann T, Schneidewind L, Thiele T, Schulze M, Klenner AF, Busemann C, et al. Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation. J Cancer Res Clin Oncol 2016;142:1091-1097.
14. Xuan L, Huang F, Fan Z, Zhou H, Zhang X, Yu G, et al. Effects of intensified conditioning on Epstein-Barr virus and cytomegalovirus infections in allogeneic hematopoietic stem cell transplantation for hematological malignancies. J Hematol Oncol 2012;5:46.
15. Cho S-Y, Lee D-G, Kim H-J. Cytomegalovirus infections after hematopoietic stem cell transplantation: current status and future immunotherapy. Int J Mol Sci 2019;20:2666.
16. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010;23:689-712.
17. Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D, et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol 2013;6:15.
18. Oh SJ, Lee KH, Lee JH, Choi SJ, Kim WK, Lee JS, et al. The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation. J Korean Med Sci 2004;19:172-176.
19. Bartelink I, Van Reij E, Gerhardt C, Van Maarseveen E, De Wildt A, Versluys B, et al. Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Biol Blood Marrow Transplant 2014;20:345-353.
20. Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, DiPersio JF, Uy GL, Westervelt P, et al. Protective effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow Transplant 2014;20:46-52.
21. Nakamae H, Kirby KA, Sandmaier BM, Norasetthada L, Maloney DG, Maris MB, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009;15:694-703.
22. Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky performance status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak 2013;13:72.
23. Parkhideh S, Chegeni R, Mehdizadeh M, Roshandel E, Tavakoli F, Hajifathali A. Effects of ABO incompatibility on the outcome of allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci 2019;59:102696.
24. Ghasemi K, Parkhideh S, Kazemi MH, Salimi M, Salari S, Nalini R, et al. The role of serum uric acid in the prediction of graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. J Clin Lab Anal 2020;34:e23271.
25. Nagler A, Shimoni A (2019). Conditioning. The EBMT Handbook: Springer, Cham; pp: 99-107.
26. Venton G, Crocchiolo R, Fürst S, Granata A, Oudin C, Faucher C, et al. Risk factors of G anciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients. Clin Microbiol Infect 2014;20:160-166.
27. Goldsmith SR, Slade M, DiPersio JF, Westervelt P, Lawrence SJ, Uy GL, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica 2016;101:e465-e468.
28. Schetelig J, Oswald O, Steuer N, Radonic A, Thulke S, Held T, et al. Cytomegalovirus infections in allogeneic stem cell recipients after reduced-intensity or myeloablative conditioning assessed by quantitative PCR and pp65-antigenemia. Bone Marrow Transplant 2003;32:695-701.
29. Vejražková E, Hubáček P, Plíšková L, Košťál M, Zavřelová A, Štěpánová V, et al. Reduction of Thymoglobuline from 7.5 mg/kg to 6 mg/kg in conditioning regimen extended time to the first cytomegalovirus detection after allogenic haematopoietic stem cell transplantation. Epidemiol Mikrobiol Imunol 2019;68:71-74.
30. Green ML, Leisenring W, Stachel D, Pergam SA, Sandmaier BM, Wald A, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012;18:1687-1699.
31. Martino R, Caballero M, Canals C, San Miguel J, Sierra J, Rovira M, et al. Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2001;28:341-347.
32. Lamba R, Carrum G, Myers G, Bollard C, Krance R, Heslop H, et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant 2005;36:797-802.
33. Matsumura T, Narimatsu H, Kami M, Yuji K, Kusumi E, Hori A, et al. Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients. Biol Blood Marrow Transplant 2007;13:577-583.
34. Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002;99:1978-1985.
35. Pinana J, Martino R, Barba P, Margall N, Roig M, Valcarcel D, et al. Cytomegalovirus infection and disease after reduced intensity conditioning allogeneic stem cell transplantation: single-centre experience. Bone Marrow Transplant 2010;45:534-542.
36. Vaezi M, Kasaeian A, Souri M, Soufiyan F, Boosjin AS, Setarehdan SA, et al. How do donor-recipient CMV serostatus and post-hematopoietic stem cell transplantation CMV reactivation affect outcomes in acute Leukemia patients? Int J Hematol Oncol Stem Cell Res 2017;11:199-208.
37. Danby R, Rocha V. Improving engraftment and immune reconstitution in umbilical cord blood transplantation. Front Immunol 2014;5:68.
38. Valadkhani B, Kargar M, Ashouri A, Hadjibabaie M, Gholami K, Ghavamzadeh A. The risk factors for cytomegalovirus reactivation following stem cell transplantation. J Res Pharm Pract 2016;5:63.
39. Resende C, Rezende B, Bernardes P, Teixeira G, Teixeira M, Pinho V, et al. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation. Braz J Med Biol Res 2017; 50(2):e5566.
40. Law AD, Salas MQ, Lam W, Michelis FV, Thyagu S, Lipton JH, et al. Reduced-intensity conditioning and dual T lymphocyte suppression with antithymocyte globulin and post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical hematopoietic stem cell transplants for hematological malignancies. Biol Blood Marrow Transplant 2018;24:2259-2264.
| Files | ||
| Issue | Vol 12 No 6 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v12i6.5040 | |
| Keywords | ||
| Cytomegalovirus; Hematopoietic stem cell transplantation; Conditioning regimen | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Mardani M, Abolghasemi S, Shabani S, Tavakoli F, Saeedi A, Parkhideh S, Hajifathali A. The association of conditioning regimen with cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation. Iran J Microbiol. 2020;12(6):636-643.
