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ARTICLE
Combination of Low-Dose, Short-Course Mycophenolate Mofetil With Cyclosporine and Methotrexate for Graft-Versus-Host Disease Prophylaxis in Allogeneic Stem Cell Transplant

Objectives: With the standard regimen for graft-versus-host disease prophylaxis in allogeneic stem cell transplant with human leukocyte antigen-matched donor, grade II-IV acute graft-versus-host disease occurs in 30% to 50% of sibling and up to 80% of unrelated recipients. Studies with limited patient numbers have shown efficacy and safety of mycophenolate mofetil for graft-versus-host disease prophylaxis. We investigated the effect of low-dose mycophenolate mofetil added to a standardized prophylaxis regimen for graft-versus-host disease in related human leukocyte antigen-matched allogeneic stem cell transplant.

Materials and Methods: In this prospective randomized clinical trial, we compared cyclosporine and metho­trexate versus the combination of cyclosporine, methotrexate, and mycophenolate mofetil in all patients who underwent human leukocyte antigen-compatible related donor allogeneic stem cell transplant for acute leukemia during 3 years at the Bone Marrow Transplant Unit at Namazi Hospital, Shiraz University of Medical Sciences (Shiraz, Iran).

Results: All 134 patients in both groups underwent successful engraftment. Recovery times for neutrophils and platelets were not significantly different between groups (P < .05). Incidence of acute graft-versus-host disease in the cyclosporine, methotrexate, and mycophenolate mofetil group was less than in the cyclosporine and methotrexate group (21.6% vs 40.9%; P = .041). Incidence of grade II-IV acute graft-versus-host disease in the mycophenolate mofetil group was 15.2% versus the control group at 33% (P = .045).

Conclusions: Our single-center study suggests the combination of mycophenolate mofetil, cyclosporine, and methotrexate is superior to the standard regimen of cyclosporine and methotrexate for graft-versus-host disease prophylaxis after human leukocyte antigen-matched related donor allogeneic stem cell transplant.


Key words : Acute leukemia, Bone marrow transplant, Malignant hematological disorder

Introduction

Allogeneic stem cell transplant (allo-SCT) is widely used as a curative treatment for some malignant and nonmalignant hematological disorders. Clinical graft-versus-host disease (GVHD) is associated with a graft-versus-tumor effect that is important for successful allo-SCT. However, excessive GVHD increased the morbidity and mortality associated with allo-SCT, and this is the major cause of non-relapse mortality. Despite the potential benefit of mild GVHD, it is important to use GVHD prophylaxis to avoid these morbidities and mortalities.

The GVHD prophylaxis regimen has been subjec­ted to important changes to improve the outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT). In the 1970s and early 1980s, methotrexate (MTX) was used for GVHD prophylaxis.1,2 Since 1980, a calcineurin inhibitor, cyclosporin A (CSA), in combination with a short course of MTX has been used, which proved to be better than either MTX or CSA alone for preventing GVHD.1 With this combination for GVHD prophylaxis, grade II-IV acute GVHD occurs in 30% to 50% of sibling recipients and up to 80% of unrelated recipients.3

Mycophenolate mofetil (MMF), an inhibitor of purine nucleotide synthesis, is an immunosup­pressive drug that has an inhibitory effect on the proliferation of T and B lymphocytes. This agent has been successfully applied in the prevention and treatment of graft rejection in solid-organ transplant.

Mycophenolic acid, the active metabolite of MMF, selectively targets activated lymphocytes so it can augment the action of immunosuppressant drugs without adding toxicities.4 Mycophenolate mofetil has a synergistic effect with CSA to enhance engraftment after nonmyeloablative preparatory regimens.

Mycophenolate mofetil has been used successfully in association with CSA, sirolimus, tacrolimus, and other drugs for GVHD prophylaxis. However, experience with the MTX, CSA, and MMF combination regimen is still limited. The European Society for Blood and Marrow Transplantation surveyed its 372 member centers that are presently performing allogeneic transplants with regard to strategies for prevention and treatment of GVHD. This survey was in 2010, and 79 centers from 25 countries participated. The combination of CSA and MMF was used by 11% of the centers. In approximately 30% of the centers, MMF was used for some groups of patients given myeloablative conditioning.5

The optimal combination regimen for MMF, as well as the optimal time course and dose, requires further investigation. Therefore, we decided to study the impact of low-dose MMF added to a standardized prophylaxis regimen for acute GVHD in related HLA-matched allo-SCT.

Materials and Methods

Study setting and study subjects
We conducted this study in the Bone Marrow Transplant Unit at Namazi Hospital, Shiraz University of Medical Sciences; this hospital is the referral center for other southern cities of our country (Iran). All patients who underwent HLA-compatible related donor allo-SCT for acute leukemia during the 3-year study period were enrolled in this study.

All patients received a conditioning regimen of busulfan at 14 to 16 mg/kg orally (1 mg/kg every 6 h for 14-16 doses) or 12.8 mg/kg intravenously (0.8 mg/kg every 6 h for 14-16 doses) and cyclophosphamide at 120 to 160 mg/kg (40 mg/kg per day for 3-4 d).

Donor-recipient matching
Serological typing and molecular typing for class I and II antigens were performed for all recipients and their donors. Donors were matched for HLA types A, B, C, and DR.

Graft-versus-host disease prophylaxis
The patients received GVHD prophylaxis either as the triple combinations of CSA + MMF + MTX or as CSA + MTX, with randomized selection according to a random-number table, generating 2 trial arms with a control-to-case ratio of 2:1. Cyclosporine was started 1 day before the transplant, with an intravenous dose of 3 mg/kg until the patient was able to tolerate oral medication, which was then given orally at 5 mg/kg. Methotrexate, 10 mg/m2 of body surface area, was administered intravenously on posttransplant days 1, 3, 6, and 11; 30 mg folinic acid rescue was given every 6 hours for at least 4 doses and was initiated 24 hours after MTX. Mycophenolate mofetil, 500 mg twice daily, was administered starting on posttransplant day 3 and continued until posttransplant day 100 in our experimental group but not in the control group. All patients were observed for 1 year after discharge from the hospital in our center; they were observed weekly in first 3 months and monthly thereafter. Our follow-up for each patient was at least 100 days for detecting any acute GVHD. The main outcome variable was incidence of acute GVHD. Secondary outcome variables included mean time until neutrophil engraftment, treatment related mortality, and incidence of relapse.

Acute graft-versus-host disease diagnosis and treatment
Diagnosis of acute GVHD was according to clinical findings, and suspicious cases were subjected to histological confirmation (including gastrointestinal mucosal biopsy). Grade I GVHD was managed with observation only, but systemic therapy was considered for grade II and greater GVHD. Acute grade II-IV GVHD was treated primarily with systemic steroids (intravenous methylprednisolone up to 2 mg/kg/d). If glucocorticoid treatment was ineffective, then antithymocyte globulin (ATG) was added for patients with severe symptoms. In the control group, if GVHD was unresponsive to steroids, then MMF was also added.

Supportive care
Similar supportive care regimens were applied to both groups. Amphotericin was administered for fungal prophylaxis from posttransplant day 6 until the day of neutrophil engraftment; then fluconazole was substituted until posttransplant day 75 and thereafter for the duration of steroid treatment. Patients received posaconazole or voriconazole as fungal prophylaxis if there was a previous history of fungal infection. Acyclovir was used to treat herpes simplex virus and varicella zoster virus until im­munosuppressive drugs were initiated. Combination trimethoprim-sulfamethoxazole was started from posttransplant day 35 for Pneumocystis jirovecii pneumonia prophylaxis.

Patients were screened for cytomegalovirus reactivation weekly by polymerase chain reaction from the day of stem cell infusion until immuno­suppressive drugs were discontinued. Patients with a positive polymerase chain reaction test received intravenous ganciclovir (5 mg/kg twice daily for 3 wk, then 5 mg/kg/d thereafter) until the result of polymerase chain reaction beğcame negative. Antibacterial prophylaxis by ciprofloxacin (500 mg twice daily) was started when absolute neutrophil count measured < 500/μL, and ciprofloxacin treatment continued until engraftment.

Statistical analyses
We performed data analyses with the Statistical Package for the Social Sciences (SPSS, version 17; IBM, Chicago, IL, USA). We compared quantitative and qualitative variables between the 2 groups by using the t test and chi-square test, respectively. In the subgroups of patients, we used the Mann-Whitney test for comparison of quantitative variables and the Fisher exact test for qualitative variables. P < .05 was considered statistically significant.

Results

In our study, for GVHD prophylaxis, 88 patients received MTX and CSA (control arm) and 46 patients received MMF, MTX, and CSA (MMF arm). Patient demographics are shown Table 1.

All patients in both groups received the same conditioning regimen (busulfan, 14-16 mg/kg; cyclophosphamide, 120-160 mg/kg). The median follow-up of patients in the MMF arm was 20 months, and in the control arm it was 23 months. All patients in both groups developed mucositis for which narcotics were administered for control of pain. The mean time until neutrophil engraftment was 12.7 days in the MMF arm and 12.5 days in the control arm, with no statistically significant difference.

The cumulative incidence of transplant-related mortality at 1 year was 7 deaths (15.2%) in the MMF group (5 patients with severe acute GVHD, 1 with veno-occlusive disease, and 1 with infection) and 11 deaths (12.5%) in the control group (10 patients with severe acute GVHD and 1 with infection), but the difference was not statistically significant.

The incidence of acute GVHD was 40.9% in the control group and 21.7% in the MMF group (P = .041) (Table 2). Grade II-IV GVHD was 15.2% in the MMF arm and 33% in the control arm, with a statistically significant difference (P = .045).

Discussion

Graft-versus-host disease is a potential life-threatening complication in allo-HSCT. The combination of CSA and MTX has been used as the standard GVHD prophylactic regimen for more than 20 years.6 Nevertheless, severe GVHD is still one of the main causes of morbidity and mortality after allo-HSCT.

Some reports have shown efficacy of MMF, either alone or in combination with other agents, to prevent GVHD and to treat acute and chronic GVHD.7-9 Therefore, we designed this study to evaluate the effect of MMF when added to the standard GVHD prophylaxis regimen, ie, the combination of CSA and MTX.

The groups in our study were each given a different regimen for GVHD prophylaxis: one group received MMF, CSA, and MTX, and the other group received CSA and MTX. Neither group had graft failures. The time period for recovery of neutrophils was not significantly different between the 2 groups. The incidence of acute GVHD was lower in the MMF group (21.7%) than in the control group (40.9%), and this difference was statistically significant.

Most studies typically use a combination of CSA and MTX for GVHD prophylaxis in related matched allo-SCT. In those historic studies, the cumulative incidence of grade II-IV acute GVHD ranged between 37.4% and 65%. In a study from China (within the Chinese population), Lai and colleagues reported that the incidence of grade II-IV acute GVHD in comparable settings ranged between 21.6% and 40%.10 In our study, the cumulative incidence of grade II-IV acute GVHD in control and MMF arms was 33% and 15.2%, respectively. The incidence was 26.8% in total, which is comparable with the report from Lai and colleagues.10

Studies on the use of MMF as part of the GVHD prophylaxis regimen have been limited in size and mostly inconclusive, and most of those studies revealed a more favorable toxicity profile for the combination of MMF with a calcineurin inhibitor compared with regimens incorporating MTX. The rates of GVHD were different between the studies. Some studies revealed a higher rate of acute GVHD in patients who received MMF compared with those who received MTX, but other studies showed a lower GVHD rate in those who received MMF.11-13 There are few studies that compare the triple drug combination for GVHD prophylaxis versus the double drug combination.

Ziakas and colleagues performed a meta-analysis of randomized trials to compare the efficacy of different GVHD prophylaxis regimens. They found noninferiority of MMF-based regimens. However, they noted an undefined effectiveness because of the few randomized studies of this regimen in myeloablative allo-SCT.14

Ram and colleagues performed a systematic review and meta-analysis of all trials that compared MMF versus MTX as a GVHD prophylaxis.15 Their search yielded 11 studies, and 3 were randomized-control trials. In their review, the incidence of grade III-IV acute GVHD was higher in patients given MMF (relative risk, 1.61; 95% confidence interval, 1.18-2.3). In patients treated with MMF, the incidence of mucositis was lower, and time to engraftment was shorter. All other analyzed transplant outcomes were comparable. Ram and colleagues concluded that MMF, compared with MTX, is associated with increased severity of acute GVHD.15 In our study, we found that addition of MMF to the GVHD prophylaxis (MTX and CSA) regimen was not associated with greater toxicity, such as mucositis. We also found a lower rate of grade II-IV acute GVHD when MMF was added to the GVHD prophylaxis regimen. However, the MMF and control groups in our study had similar time to engraftment (12.7 vs 12.5 days, respectively).

Iida and colleagues16 evaluated the safety and efficacy of MMF in unrelated donor HSCT. The incidences of grade II-IV and grade III-IV acute GVHD were reported as 38.3% and 14.5%, respectively. Their conclusions were the same as those of Ram and colleagues, ie, MMF is safe and effective for the prevention of acute GVHD in unrelated donor HSCT.16 In our study, we also demonstrated the safety of MMF.

Lai and colleagues studied a prophylactic regimen that combined CSA and MTX with a short 30-day course of low-dose MMF (500 mg/day).10 That study included 100 patients who were undergoing peripheral blood allo-SCT from full-match related donors or 1 antigen-mismatched related donors. The cumulative incidence of acute GVHD was 16% (grade II-IV, 9.5%; grade III-IV, 1%). The cumulative incidence of transplant-related mortality at 100 days and 3 years was 6% and 13%, respectively. Lai and colleagues concluded that there was a dramatic decrease in the risk of severe acute GVHD without an increase in relapse or any adverse event by adding MMF to standard GVHD prophylaxis.10 Incidence of acute GVHD in their study was much less than in our study and most other studies. Lai and colleagues did not have a control group, and theirs was a prospective study; in contrast, our study compared the MMF-containing regimen with the standard regimen (CSA and MTX).

In a small study with 30 patients with advanced hematological malignancies who received unrelated donor grafts, MMF was added on posttransplant day 10 in combination with CSA for reduced conditioning regimens or in combination with CSA and MTX for myeloablative treatment.17 Acute GVHD ≥ grade II was observed in 19 patients (63%). Two patients (6.6%) had grade III GVHD, and 3 patients (10%) had grade IV GVHD. Kasper and colleagues concluded that the MMF schedule appeared to be safe and feasible for prophylaxis of severe acute GVHD for high-risk patients.17 Their study was on patients with unrelated donor grafts who are at higher risk for GVHD; however, all patients in our study underwent transplant from related HLA-matched donors.

Another study18 reported the results of HLA-matched unrelated donor allo-SCT with a combination of MMF, MTX, and CSA for GVHD prophylaxis in 139 patients with hematological malignancies. In that study, the incidence of grade II-IV acute GVHD was 43%, and grade III-IV acute GVHD was 17.3%. The cumulative incidence of transplant-related mortality was 7.9% at 100 days and 29.7% at 3 years. Three-year overall survival rate was 58.7%, disease-free survival rate was 5.3%, and relapse incidence was 19.6%. Their study suggested that the combination of MMF with CSA and MTX may be effective for the prophylaxis of acute and chronic GVHD in unrelated donor transplant.18 Their study did not have a control group, and it was performed on unrelated donor transplants.

The incidence of transplant-related mortality at 1 year in our study was 15.2% and 12.5% for the MMF and control arms, respectively, which is comparable with other studies.10,18

In 2002, Wang and colleagues19 compared standard GVHD prophylaxis regimen (CSA and MTX) with a regimen containing MMF (MMF, CSA, and MTX) in HLA-matched related donor and unrelated donor allo-SCT. Twenty-six patients were in the CSA and MTX group, and 13 patients were in the triple combination MMF, CSA, and MTX group. In the triple combination group, MMF at 2 g/day was added orally from posttransplant day 1 to day 28. For every patients in both groups, engraftment was successful. The incidence of acute GVHD in the MMF group (7.6%) was significantly less than in the control group (46.2%). The incidence of grade I-II acute GVHD in the MMF group was 0, whereas the incidence in the control group was 23%. Therefore, Wang and colleagues concluded that the regimen of MMF, CSA, and MTX for prevention of acute GVHD in peripheral blood allo-SCT is more efficient than the regimen of CSA and MTX, without adversely affecting the engraftment and relapse rates.19

As mentioned above, few studies have evaluated the efficacy of adding MMF to a standard regimen (CSA and MTX) for the prevention of acute GVHD following allo-SCT.

There are recommendations on the use of polyclonal ATG or anti-T lymphocyte globulin (ATLG) for the prevention of GVHD after allo-HSCT. Clinical trials have documented the efficacy of ATG/ATLG to prevent acute and chronic GVHD after allo-HSCT for malignant and nonmalignant diseases. Results of these studies showed ATG/ATLG effectively prevents GVHD, particularly chronic GVHD.20-22 In unrelated donor SCT, ATG has become a major player, as 2 randomized trials showed a positive effect mainly in chronic GVHD.23,24

Recently, in a comprehensive review of articles released up to October 2018 from Bonifazi and colleagues,25 ATG/ATLG was strongly recommended as part of a preoperative myeloablative conditioning regimen to prevent severe acute and chronic GVHD in patients undergoing matched or mismatched unre­lated donor bone marrow or peripheral blood allo-HSCT in malignant diseases. It was also recommended preoperatively for HLA-identical sibling peripheral HSCT. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG treatment may be appropriate to reduce the incidence of acute and chronic GVHD, but a higher risk of relapse must be considered.25

A number of practical issues regarding the use of ATG/ATLG are not clear; the interplay of a large number of factors affecting outcomes after HSCT make it difficult to interpret the data on the efficacy of ATG/ATLG for GVHD prophylaxis. Therefore, additional large prospective investigations and clinical trials are needed to compare the effects of ATG versus MMF for prophylaxis of acute GVHD in matched sibling donors and unrelated donors.

The primary limitation of our study is the small sample size, and these results need to be verified in larger prospective multicenter randomized trials. Additionally, the follow-up is short and does not adequately address potential differences in chronic GVHD. Finally, our study only included HLA-matched related donor transplant recipients, so we need to evaluate this regimen in the context of higher risk allo-SCT scenarios, such as unrelated donor or mismatched donor transplants.

Conclusions

Our single-center prospective study results suggest that the combination of MMF, CSA, and MTX may be superior to the standard regimen of CSA and MTX for GVHD prophylaxis after HLA-matched related donor allo-SCT. However, multicenter studies on larger populations are needed to evaluate the true effects of adding MMF to the standard GVHD prophylaxis regimen. Also, it is reasonable to evaluate this triple regimen in higher risk transplant scenarios, such as mismatched and haploidentical allo-SCT.


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DOI : 10.6002/ect.2020.0004


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From the 1Hematology Research Center and Bone Marrow Transplantation Center, Shiraz University of Medical Sciences, Shiraz, Iran; and the 2Family Medicine Department and Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Acknowledgements: The authors thank the Vice Chancellor for Research of Shiraz University of Medical Sciences for supporting this research. This article is partly based on a thesis performed by Shirin Haghighat with grant number 91-6308.
Corresponding author: Mani Ramzi, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Phone: +98 71 36474301
E-mail: ramzim@sums.ac.ir