Graft Versus Host Disease

Mycophenolate mofetil and cyclosporine for graft-versus-host disease prophylaxis following reduced intensity conditioning allogeneic stem cell transplantation

Summary:

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.

Main

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.

Table 1 Patients and donors characteristics and analysis of risk factors for acute GVHD according to GVHD prophylaxis regimen

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.

Results

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).

Figure 1
figure1

(a) Cumulative incidence of grade II–IV aGVHD and (b) OS according to GVHD prophylaxis regimen.

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.

Discussion

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.

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Acknowledgements

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.

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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

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Keywords

  • mycophenolate mofetil
  • GVHD
  • reduced intensity conditioning
  • allogeneic stem cell transplantation

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