The use of reduced intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) can result in a significant decrease in early procedure-related toxicity in patients not eligible for standard myeloablative regimens. However, acute graft-versus-host disease (aGVHD) remains a matter of concern after RIC allo-SCT, and its incidence might be expected to be higher in elderly and high-risk patients. This report investigated mycophenolate mofetil (MMF) and cyclosporin A (CsA) combination (n=14) in comparison to CsA alone (n=20) for GVHD prophylaxis in cancer patients aged over 50 years (27 haematological malignancies and seven solid tumours) receiving an HLA-identical sibling antithymocyte-globulin (ATG)-based RIC allo-SCT. Baseline demographic characteristics and risk factors for aGVHD were comparable between both groups. Although MMF administration was not associated with any significant toxicity, the cumulative incidence of any form of GVHD was comparable between both groups (cumulative incidence of grade II–IV aGVHD, 50% (95% CI, 28–72%) for CsA alone, as compared to 64% (95% CI, 39–89%) to CsA and MMF, P=NS), suggesting that adjunction of MMF to CsA is feasible, but does not translate towards a significant reduction of aGVHD, at least in the context ATG-based RIC allo-SCT.
The use of reduced intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) resulted in a significant decrease in early procedure-related toxicity in patients not eligible for standard myeloablative regimens.1, 2, 3, 4, 5 Several groups have shown that administration of highly immunosuppressive drugs including fludarabine, antithymocyte globulin (ATG), or low-dose total body irradiation can result in durable donor cell engraftment. However, although graft-versus-host disease (GVHD) is usually associated with a powerful graft-versus-tumour effect (GVT) effect protecting patients against relapse,6 acute GVHD (aGVHD) remains a matter of concern after RIC allo-SCT,6, 7 and its incidence might be expected to be higher in elderly patients.8, 9 Nonetheless, RIC allo-SCT represents a promising strategy for elderly or heavily pretreated cancer patients.10, 11 Thus, novel approaches for GVHD prophylaxis are needed in the RIC transplant setting in order to further decrease procedure-related toxicities, especially GVHD. In this regard, the use of mycophenolate mofetil (MMF) for prophylaxis of aGVHD is rapidly increasing.12, 13, 14, 15, 16, 17, 18 This report investigated the use of MMF/cyclosporin A (CsA) combination for GVHD prophylaxis in patients aged over 50 years receiving an HLA-identical sibling RIC allo-SCT.
Patients and methods
In all, 34 consecutive patients treated with RIC allo-SCT were included in this analysis. This was a retrospective analysis of two groups of patients having the same demographic and transplant procedure characteristics (except for GVHD prophylaxis, Table 1 and see below) and treated within the same period in a single institution (Institut Paoli-Calmettes, Marseille). The eligibility criteria for RIC allo-SCT were detailed elsewhere.6, 19 Written informed consent was obtained from each patient and donor. The study was performed according to institutional guidelines. All donors were HLA-A-, HLA-B-, and HLA-DR-identical siblings. This series did not include patients with one antigen-mismatched transplants. All patients received the preparative regimen as inpatients in private rooms, and remained hospitalised until haematopoietic and clinical recovery. The preparative regimen was adapted from Slavin et al,1 with fludarabine 30 mg/m2 for 6 or 5 consecutive days, oral busulphan 8 mg/kg total dose and a single ATG (thymoglobulin; Genzyme-SangStat, Lyon, France) dose of 2.5 mg/kg. Supportive care and anti-microbial prophylaxis were reported previously.19 The first patients from this series (n=20; group I) received CsA alone for GVHD prophylaxis. The next patients (n=14; group II) received CsA and MMF. CsA was administered at a dose of 3 mg/kg/day by continuous intravenous infusion starting from day −2, and changed to twice daily oral dosing as soon as tolerated. CsA doses were adjusted to achieve blood levels between 150 and 250 ng/ml and to prevent renal dysfunction. MMF was given at a fixed oral dose of 500 mg × 4/day starting from day +2 after allo-SCT. No treatment adjustment was performed for MMF. Per protocol, MMF was tapered over 4 weeks starting from day 60 and CsA from day 90 if no GVHD appeared. Of note, during the whole study period supportive care was comparable between patients from groups I and II. Of note, CMV infection management was similar between both groups. All blood products were filtered but not CMV screened. In the first 100 days post allo-SCT, patients were assessed at least once per week for CMV infection by antigenaemia assay (CINAkit, Argene Biosoft, France; in a positive specimen, results were reported as number of antigen positive cells). A patient was considered positive when having at least two infected cells out of 2 × 105 leucocytes, in order to initiate pre-emptive ganciclovir therapy. All patients with a positive CMV antigenaemia received pre-emptive ganciclovir therapy (5 mg/kg intravenously twice daily) for 14 days. Patients did not receive systematic maintenance therapy after pre-emptive therapy or routine prophylactic intravenous immunoglobulins.
All patients received peripheral blood stem cells mobilised with G-CSF from an HLA-identical sibling donor. aGVHD and chronic GVHD (cGVHD) were evaluated according to the standard criteria as detailed elsewhere.20 All data were computed using SEM software (SILEX, Mirefleurs, France). Detailed statistical methods were described elsewhere.6, 20 The probability of developing aGVHD was depicted by calculating the cumulative incidence. The probability of overall survival (OS) was estimated using the Kaplan–Meier product-limit estimates.
Patients included in this analysis were aged over 50 years (median, 56; range, 50–63 years). The first 20 patients received CsA alone for GVHD prophylaxis (group I). However, in an attempt to decrease the incidence of aGVHD in this category of elderly and high-risk patients, we performed a pilot study to assess the benefit of MMF use in addition to CsA for GVHD prophylaxis. Thus, the following 14 patients received MMF in addition to CsA as indicated in patients and methods (group II). Baseline demographic characteristics and analysis of risk factors for aGVHD were comparable between both groups (Table 1). No major toxicities were associated with the administration of MMF, and the rate of CMV reactivation was comparable between the two groups (group I, 25%; group II, 29%; P=NS) in the first 3 months after allo-SCT. The cumulative incidence of grade I–IV aGVHD at day 100 was 70% (95% CI, 50–90%) in patients receiving CsA alone as compared to 64% (95% CI, 39–89%) in those receiving the CsA and MMF combination (P=NS). The cumulative incidences of grade II–IV and grade III–IV aGVHD were 50% (95% CI, 28–72%) and 30% (95% CI, 10–50%), respectively, in group I as compared to 64% (95% CI, 39–89%) and 36% (95% CI, 11–61%) in group II (P=NS; Figure 1a). The median time to onset of aGVHD was comparable between both groups (median, 30 vs 34 days, P=NS). In patients evaluable for cGVHD, the incidence of cGVHD (limited and extensive forms) was also comparable between groups I and II (88 vs 83%, P=NS).
After a median follow-up of 467 (range, 54–1081) days for surviving patients, the 1-year OS was comparable between groups I and II (Figure 1b). Overall, four deaths were attributed to disease progression. Three patients died of aGVHD, while four patients died from cGVHD, and one patient dying from infection, with no significant difference between both groups.
This pilot study suggests that adjunction of MMF to CsA is feasible, but apparently not associated with a significant reduction of aGVHD rate following ATG-based RIC allo-SCT for elderly patients. Previous reports in the standard myeloablative setting suggested that MMF might be a safe option for GVHD prophylaxis and treatment.14, 21 Moreover, the MMF and CsA combination was able to sustain stable mixed chimeras with an acceptable rate of aGVHD after low-dose total-body-irradiation-based RIC allo-SCT.2 It is possible that CsA and the inclusion of a potent T-cell depleting agent such as ATG in our RIC regimen might have been sufficient for GVHD prophylaxis, precluding precise estimation of the putative benefit of MMF that selectively targets activated lymphocytes.22 In this regard, it has also been shown that the inclusion of other potent T-cell depleting agents such as CAMPATH could abrogate the risk of severe aGVHD in high-risk patients.23 Nevertheless, such regimen was associated with a poor immune recovery profile and a high risk of severe and fatal infections.24 However, one must acknowledge that inclusion of a T-cell depleting agent in the RIC regimen does not completely explain the little benefit observed with the CsA and MMF combination. This is illustrated by the short time observed before the onset of aGVHD in both groups. Owing to the decreased bioavailability of MMF, it is also possible that the absence of dose adjustment of MMF blood levels might have contributed to a decreased efficacy.21
From a statistical point of view, our analysis included a relatively small number of patients. Only a fully powered and randomised study would allow drawing definitive conclusions with regard to the benefit of the CsA/MMF combination. Results from this small study might pave the way for such randomised large-scale study. Nevertheless, it is worthwhile noting that studies showing benefit with MMF prophylaxis also combined other immunosuppressive agents in addition to CsA.14, 25 Although we have currently suspended the use of the CsA/MMF combination in this group of high-risk elderly patients, we cannot definitely exclude that the combination of other immunosuppressive agents with MMF, such as short-course methotrexate in addition to CsA, might contribute to a better GVHD prophylaxis. Strategies aiming to improve GVHD prophylaxis after RIC allo-SCT must also take into account the kinetic of full donor chimerism establishment (especially lymphoid cells). In our previous studies, we could show that the fludarabine–busulphan–ATG RIC regimen is usually associated with rapid conversion to full donor chimerism early after transplantation.26 This is in sharp contrast with the Seattle RIC regimen including fludarabine and low-dose total body irradiation that is truly nonmyeloablative.2
The rapidly increasing use in elderly and high-risk patients and evolving nature of RIC allo-SCT emphasise the need for renewed clinical research of GVHD prophylaxis that may have a significant impact on the probability of a favourable outcome.
Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.
Niederwieser D, Maris M, Shizuru JA et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620–1629.
McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.
Martino R, Caballero MD, Canals C et al. Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study. Br J Haematol 2001; 115: 653–659.
Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531–4536.
Mohty 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.
Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.
Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older. Blood 1986; 67: 770–776.
Ringden O, Horowitz MM, Gale RP et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA 1993; 270: 57–60.
Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.
Blaise D, Bay JO, Faucher C et al. Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood 2004; 103: 435–441.
Basara N, Blau WI, Romer E et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD in bone marrow transplant patients. Bone Marrow Transplant 1998; 22: 61–65.
Basara N, Blau IW, Willenbacher W et al. New strategies in the treatment of graft-versus-host disease. Bone Marrow Transplant 2000; 25 (Suppl. 2): S12–S15.
Basara N, Blau WI, Kiehl MG et al. Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone marrow transplant patients. Clin Transplant 2000; 14: 121–126.
Basara N, Fauser AA . Safety profile of mycophenolate mofetil. Bone Marrow Transplant 2000; 26: 1362–1363.
Basara N, Gunzelmann S, Willenbacher W et al. New immunosuppressants in BMT/GVHD. Transplant Proc 2001; 33: 2220–2222.
Basara N, Kiehl MG, Blau W et al. Mycophenolate mofetil in the treatment of acute and chronic GVHD in hematopoietic stem cell transplant patients: four years of experience. Transplant Proc 2001; 33: 2121–2123.
Baudard M, Vincent A, Moreau P et al. Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients. Bone Marrow Transplant 2002; 30: 287–295.
Mohty M, Jacot W, Faucher C et al. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen. Leukemia 2003; 17: 2168–2177.
Mohty M, Kuentz M, Michallet M et al. Chronic graft versus host disease after allogeneic blood stem cell transplantation: long term results of a randomized study. Blood 2002; 100: 3128–3134.
Bornhauser M, Schuler U, Porksen G et al. Mycophenolate mofetil and cyclosporine as graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Transplantation 1999; 67: 499–504.
Vogelsang GB, Arai S . Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplant 2001; 27: 1255–1262.
Kottaridis PD, Milligan DW, Chopra R et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000; 96: 2419–2425.
Perez-Simon JA, Kottaridis PD, Martino R et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002; 100: 3121–3127.
Kiehl MG, Schafer-Eckart K, Kroger M et al. Mycophenolate mofetil for the prophylaxis of acute graft-versus-host disease in stem cell transplant recipients. Transplant Proc 2002; 34: 2922–2924.
Faucher C, Mohty M, Vey N et al. Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen. Exp Hematol 2003; 31: 873–880.
We thank the nursing staff for providing excellent care for our patients. We thank D Maraninchi (Institut Paoli-Calmettes) for helpful discussions. We also thank the following physicians at the Institut Paoli-Calmettes for their important study contributions and dedicated patient care: T Aurran, AC Braud, R Bouabdallah, C Chabannon, A Charbonnier, RT Costello, A Goncalves, V Ivanov, P Ladaique, JM Schiano de Collela, and F Viret.
About this article
Cite this article
Mohty, M., de Lavallade, H., Faucher, C. et al. Mycophenolate mofetil and cyclosporine for graft-versus-host disease prophylaxis following reduced intensity conditioning allogeneic stem cell transplantation. Bone Marrow Transplant 34, 527–530 (2004). https://doi.org/10.1038/sj.bmt.1704640
- mycophenolate mofetil
- reduced intensity conditioning
- allogeneic stem cell transplantation
Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT
Bone Marrow Transplantation (2020)
Mycophenolate mofetil administered every 8 hours in combination with tacrolimus is efficacious in the prophylaxis of acute graft versus host disease in childhood, adolescent, and young adult allogeneic stem cell transplantation recipients
Pediatric Blood & Cancer (2018)
Pharmacokinetics of intravenous mycophenolate mofetil in allogeneic hematopoietic stem cell-transplanted Japanese patients
Cancer Chemotherapy and Pharmacology (2018)
Current Opinion in Ophthalmology (2017)
Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution
Bone Marrow Transplantation (2016)