Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell Transplantation: A Little Methotrexate Goes a Long Way
Authors: Jayesh Mehta, Seema Singhal, Corey Cutler, Joseph H. Antin
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.2.603 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11786594 Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell Transplantation: A Little Methotrexate Goes a Long Way Jayesh MehtaxJayesh MehtaSearch for articles by this author , Seema SinghalxSeema SinghalSearch for articles by this author Corey CutlerxCorey CutlerSearch for articles by this author , Joseph H. AntinxJoseph H. AntinSearch for articles by this author Show More Northwestern University Medical School, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, ILDana-Farber Cancer Institute, Boston, MA https://doi.org/10.1200/JCO.2002.20.2.603 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15012002In Reply:Drs. Mehta and Singhal are correct in pointing out that several important contributing factors influence the development of graft-versus-host-disease (GVHD) after either peripheral-blood stem-cell transplantation (PBSCT) or bone marrow transplantation (BMT). One of the best characterized risk factors for the development of GVHD is the omission of an effective GVHD prophylaxis regimen that includes methotrexate.1 Despite the lack of uniformity in methotrexate regimens in our analysis, we believe the results to be valid for several reasons.Methotrexate can be given according to several different regimens. However, the schedule of 15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6, and +11 remains the standard after allogeneic transplantation. It is to be noted that this regimen was adopted by the transplant community without the benefit of a randomized trial examining the optimal duration or timing of therapy.In our original report,2 six trials utilized the standard dose schedule.3-9 Mehta and Singhal summarize the methotrexate regimens used in some of the trials in their table. However, they misrepresent the trial reported by Bacigalupo et al,10 in which methotrexate was used according to a nonstandard regimen (15 mg/m2 on day +1 and 8 mg/m2 on days +3 and +6), and the trial reported by Vigorito et al,9 in which methotrexate was used according to the standard dose schedule (C. de Souza, personal communication, 2001). Two of the trials that used the standard dose schedule demonstrated a significant increase in the risk of chronic GVHD (relative risk [RR], 1.76 and 95% confidence interval [CI], 1.26 to 2.466,7; RR, 3.65 and 95% CI, 1.75 to 7.588), while the four other studies all demonstrated trends favoring a higher incidence of chronic GVHD after PBSCT (RR range, 1.19 to 1.52, P = not significant).3-5,9 Of the five prospective randomized trials included in our original analysis, three utilized standard-dose methotrexate as GVHD prophylaxis3,5,9 while the two other trials used abbreviated courses.11-13 One of the trials using abbreviated methotrexate independently demonstrated a statistically significant increase in chronic GVHD (RR, 1.82 and 95% CI, 1.10 to 3.00),11 while all four others demonstrated a trend toward increased chronic GVHD after PBSCT (RR range, 1.19 to 1.52, P = not significant).3,5,9,12,13 Of note, a more recently published randomized trial demonstrated a significantly increased rate of chronic GVHD despite full-dose methotrexate,14 while a trend toward increased chronic GVHD was demonstrated in another trial published in abstract format that also used standard-dose methotrexate.15Kumar et al16 have demonstrated that omission of the day +11 dose of methotrexate after allogeneic BMT did not increase the rate of chronic GVHD in a retrospective study of 123 patients (39% v 37%, P = .87).16 In order to determine whether the RR increase in chronic GVHD was due to differences in methotrexate delivery as part of GVHD prophylaxis regimens, we compared RR results from separate meta-analyses stratified by methotrexate regimen. In the trials that used standard-dose methotrexate,3-9 the RR of chronic GVHD after PBSCT when compared with BMT was 1.60 (95% CI, 1.19 to 2.13, P = .002). In trials in which the day +11 methotrexate was omitted in some17 or all of the patients11-13 or in which alternate dosing schedules of methotrexate were used,10,18 the RR of chronic GVHD after PBSCT compared with BMT was 1.49 (95% CI, 1.03 to 2.17, P = .036). These results are not statistically different (P = .76). The trials in which multiple GVHD prophylaxis regimens were used were omitted for this analysis.19-22In the retrospective analysis recently published by Przepiorka et al,1 methotrexate-containing regimens were associated with a lower incidence of chronic GVHD. However, the delivered doses of methotrexate were not determined retrospectively. Furthermore, methotrexate was used in combination with tacrolimus rather than cyclosporine, and this newer combination may be more effective for prevention of GVHD in both the related and unrelated setting.23,24 Within the individual trials we examined, PBSCT and BMT groups received similar GVHD prophylaxis regimens composed of cyclosporine and methotrexate. Because differential or incremental benefits of increased doses of methotrexate have not been demonstrated to exist between peripheral-blood stem-cell or bone marrow grafts despite increased CD3+ and CD34+ cell counts with peripheral-blood stem cells, we felt it was appropriate to pool the relative risks from the individual trials in the meta-analysis.Individual trials are often underpowered to detect small changes in GVHD outcome. Thirteen of the 14 trials we examined showed evidence of increased chronic GVHD after PBSCT when compared with BMT. However, only a few were able to independently demonstrate this statistically. The findings from our meta-analysis support the notion that the incidence of chronic GVHD is greater after PBSCT when compared with BMT.1. Przepiorka D, Anderlini P, Saliba R, et al: Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98:: 1695,2001–1700, Crossref, Medline, Google Scholar2. Cutler C, Giri S, Jeyapalan S, et al: Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: A meta-analysis. J Clin Oncol 19:: 3685,2001–3691, Link, Google Scholar3. Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:: 175,2001–181, Crossref, Medline, Google Scholar4. Lemoli RM, Bandini G, Leopardi G, et al: Allogeneic peripheral blood stem cell transplantation in patients with early-phase hematologic malignancy: A retrospective comparison of short-term outcome with bone marrow transplantation. Haematologica 83:: 48,1998–55, Medline, Google Scholar5. Powles R, Mehta J, Kulkarni S, et al: Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: A randomised trial. Lancet 335:: 1231,2000–1237, Google Scholar6. Russell JA, Brown C, Bowen T, et al: Allogeneic blood cell transplants for haematological malignancy: Preliminary comparison of outcomes with bone marrow transplantation. Bone Marrow Transplant 17:: 703,1996–708, Medline, Google Scholar7. Russell JA, Larratt L, Brown C, et al: Allogeneic blood stem cells and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: Influence of stem cell source on outcome. Bone Marrow Transplant 24:: 1177,1999–1183, Crossref, Medline, Google Scholar8. Üstün C, Arslan Ö, Beksaç M, et al: A retrospective comparison of allogeneic peripheral blood stem cell and bone marrow transplantation results from a single center: A focus on the incidence of graft-vs.-host disease and relapse. Biol Blood Marrow Transplant 5:: 28,1999–35, Crossref, Medline, Google Scholar9. Vigorito AC, Azevedo WM, Marques JFC, et al: A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 22:: 1145,1998–1151, Crossref, Medline, Google Scholar10. Bacigalupo A, Zikos P, Van Lint MT, et al: Allogeneic bone marrow or peripheral blood cell transplants in adults with hematologic malignancies: A single-center experience. Exp Hematol 26:: 409,1998–414, Medline, Google Scholar11. Blaise D, Kuentz M, Fortanier C, et al: Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: A report from the Société Française de Greffe de Moelle. J Clin Oncol 18:: 537,2000–546, Link, Google Scholar12. Schmitz N, Bacigalupo A, Hasenclever D, et al: Allogeneic bone marrow transplantation vs. filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: First results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21:: 995,1998–1003, Crossref, Medline, Google Scholar13. Schmitz N, Beksaç M, Hasenclever D, et al: A randomised study from the European Group for Blood and Marrow Transplantation comparing allogeneic transplantation of filgrastim-mobilised peripheral blood progenitor cells with bone marrow transplantation in 350 patients (pts) with leukemia. Blood 96:: 481a,,2000 (abstr) Google Scholar14. Heldal D, Tjonnfjord G, Brinch L, et al: A randomised study of allogeneic transplantation with stem cells from blood or bone marrow. Bone Marrow Transplant 25:: 1129,2000–1136, Crossref, Medline, Google Scholar15. Simpson DR, Couban S, Bredeson C, et al: A Canadian randomized study comparing peripheral blood (PB) and bone marrow (BM) in patients undergoing matched sibling transplants for myeloid malignancies. Blood 96:: 481a,,2000 (abstr) Google Scholar16. Kumar S, Chen MG, Gastineau DA, et al: Omission of day +11 methotrexate for graft-versus-host disease prophylaxis after allogeneic BMT increases the risk of severe acute graft-versus-host disease. Blood 96:: 398a,,2000 (abstr) Crossref, Medline, Google Scholar17. Solano C, Martinez C, Brunet S, et al: Chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation from matched related donors: A case-control study. Bone Marrow Transplant 22:: 1129,1998–1135, Crossref, Medline, Google Scholar18. Scott MA, Gandhi MK, Jestice HK, et al: A trend towards an increased incidence of chronic graft-versus-host disease following allogeneic peripheral blood progenitor cell transplantation: A case controlled study. Bone Marrow Transplant 22:: 273,1998–276, Crossref, Medline, Google Scholar19. Bensinger WI, Clift R, Martin P, et al: Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: A retrospective comparison with marrow transplantation. Blood 88:: 2794,1996–2800, Crossref, Medline, Google Scholar20. Champlin RE, Schmitz N, Horowitz MM, et al: Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. Blood 95:: 3702,2000–3709, Medline, Google Scholar21. Przepiorka D, Anderlini P, Ippoliti C, et al: Allogeneic blood stem cell transplantation in advanced hematologic cancers. Bone Marrow Transplant 19:: 455,1997–460, Crossref, Medline, Google Scholar22. Storek J, Gooley T, Siadak M, et al: Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood 90:: 4705,1997–4709, Crossref, Medline, Google Scholar23. Nash RA, Antin JH, Karanes C, et al: Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 96:: 2062,2000–2068, Medline, Google Scholar24. Ratanatharathorn V, Nash RA, Przepiorka D, et al: Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 92:: 2303,1998–2314, Medline, Google Scholar