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© 2002 American Society for Clinical Oncology
Chronic Graft-Versus-Host Disease After Allogeneic Peripheral-Blood Stem-Cell Transplantation: A Little Methotrexate Goes a Long WayNorthwestern University Medical School, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL To the Editor:Cutler et al1 are to be commended for their attempt to answer the question of whether the incidence of chronic graft-versus-host disease (GVHD) is increased with the use of allogeneic peripheral-blood stem-cell transplantation (PBSCT) as an alternative to bone marrow transplantation (BMT) through a meta-analysis. However, we are not certain that their conclusion—that the incidence of chronic GVHD is higher after PBSCT—is entirely accurate. Their analysis did not take into account the one critical factor likely to affect the development of GVHD, the GVHD prophylaxis regimen. We strongly believe that methotrexate not only is a critical component of a standard GVHD prophylaxis regimen (cyclosporine or tacrolimus with methotrexate 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11) but also has to be delivered in a rigorous fashion (all scheduled doses) to be effective.2 The two prospective studies2,3 that did not show a significant increase in chronic GVHD and showed lower relapse and better disease-free survival used the standard methotrexate-containing regimen. All patients in both studies received all the doses of methotrexate. Growth factors were not administererd routinely in either study. Support for our belief that methotrexate is important2 comes from a recent retrospective study showing that methotrexate-containing GVHD prophylaxis was associated with a significantly lower risk of extensive chronic GVHD (risk ratio, 0.35; 95% confidence interval, 0.2 to 0.6; P = .001).4 As described by Przepiorka et al,4 the patients who received tacrolimus-methotrexate GVHD prophylaxis without getting inordinately high doses of CD34+ cells had an actuarial risk of chronic GVHD of 51%, which is comparable to that described by Bensinger et al3 and by us.2 Table 1 shows some of the studies cited by Cutler et al.1 Two8,13 of the four studies that seemed to have used standard methotrexate-containing prophylaxis found an increase in chronic GVHD, whereas two did not.5,7 The two that did show increased chronic GVHD8,13 did not specify whether all four doses of methotrexate were delivered to PBSCT recipients or whether modifications/omissions were made on account of factors such as mucositis. All five studies that used, according to us, suboptimal GVHD prophylaxis6,9-12 or that did not provide details of methotrexate administration14 showed increased chronic GVHD after PBSCT. The European Blood and Marrow Transplant Group study9,10 also used routine granulocyte colony-stimulating factor after transplantation—another potential confounding factor in assessing outcome.
The significantly higher numbers of T cells infused during PBSCT1-15 may mean that alterations in methotrexate dosing and schedules have more profound effects after PBSCT than after BMT. Other than reduced relapse, the higher number of CD34 cells infused (although not excessively so) with PBSCT could translate into decreased treatment-related mortality.15 On the basis of our experience15 and the data from Przepiorka et al showing increased acute16 and chronic4 GVHD with very high CD34+ cell doses, we infuse between 3 and 5 x 106 CD34+ cells/kg recipient body weight. Is there a place for yet another randomized study of BMT and PBSCT? Probably not, not the least because it may be considered unacceptable to perform BMT if PBSCT is possible under optimized clinical conditions. However, it may be worthwhile to study GVHD prophylaxis after PBSCT to see whether the outcome can be improved any further. The comparisons could be standard cyclosporine-methotrexate versus cyclosporine-methotrexate and mycophenolate mofetil or cyclosporine-methotrexate followed by a standard taper (from day 50 to 180) versus an extended taper (eg, from day 100 to 270). REFERENCES
1.
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: 3685–3691, 2001 2. Powles R, Mehta J, Kulkarni S, et al: Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: A randomised trial. Lancet 355: 1231–1237, 2000[CrossRef][Medline]
3.
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: 175–181, 2001
4.
Przepiorka D, Anderlini P, Saliba R, et al: Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98: 1695–1700, 2001 5. 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: 409–414, 1998[Medline]
6.
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: 537–546, 2000
7.
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: 48–55, 1998 8. Russell JA, Larratt L, Brown C, et al: Allogeneic blood stem cell and bone marrow transplantation for acute myelogenous leukemia and myelodysplasia: Influence of stem cell source on outcome. Bone Marrow Transplant 24: 1177–1183, 1999[CrossRef][Medline] 9. 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: 995–1003, 1998[CrossRef][Medline] 10. Schmitz N, Beksac 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 cell cells with bone marrow transplantation in 350 patients (pts) with leukaemia. Blood 96: 481a, 2000 (supply 1) 11. 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: 273–276, 1998[CrossRef][Medline] 12. 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—Spanish Group of Allo-PBT. Bone Marrow Transplant 22: 1129–1135, 1998[CrossRef][Medline] 13. Ustun C, Arslan O, Beksac 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: 28–35, 1999[CrossRef][Medline] 14. Vigorito AC, Azevedo WM, Marques JF, 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: 1145–1151, 1998[CrossRef][Medline] 15. Singhal S, Powles R, Treleaven J, et al: A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings: Should 2 x 106 CD34+ cells/kg be considered the minimum threshold? Bone Marrow Transplant 26: 489–496, 2000[CrossRef][Medline]
16.
Przepiorka D, Smith TL, Folloder J, et al: Risk factors for acute graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 94: 1465–1470, 1999
ResponseDana-Farber Cancer Institute, Boston, MA In 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.15 Kumar 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.19-22 In 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. REFERENCES 1. Przepiorka D, Anderlini P, Saliba R, et al: Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood 98: 1695–1700, 2001 2. 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: 3685–3691, 2001 3. 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: 175–181, 2001 4. 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: 48–55, 1998 5. 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: 1231–1237, 2000 6. 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: 703–708, 1996[Medline] 7. 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: 1177–1183, 1999 8. 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: 28–35, 1999 9. 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: 1145–1151, 1998 10. 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: 409–414, 1998 11. 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: 537–546, 2000 12. 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: 995–1003, 1998 13. 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) 14. 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: 1129–1136, 2000[CrossRef][Medline] 15. 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) 16. 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) 17. 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: 1129–1135, 1998 18. 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: 273–276, 1998
19.
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: 2794–2800, 1996
20.
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: 3702–3709, 2000 21. Przepiorka D, Anderlini P, Ippoliti C, et al: Allogeneic blood stem cell transplantation in advanced hematologic cancers. Bone Marrow Transplant 19: 455–460, 1997[CrossRef][Medline]
22.
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: 4705–4709, 1997
23.
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: 2062–2068, 2000
24.
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: 2303–2314, 1998
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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