Graft-Versus-Host Disease

Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil

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Abstract

In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II–IV and III–IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.

Introduction

Umbilical cord blood transplantation (UCBT) is increasingly being utilized as an alternative donor source for adult hematological diseases,1, 2, 3, 4, 5 and UCB has been recognized as an established alternative donor source comparable to unrelated bone marrow (BM)/PBSC.6, 7, 8 The incidence of severe acute GvHD after UCBT is similar to that of matched unrelated donor transplantation.9, 10, 11 Thus, the choice of GvHD prophylaxis is important for improving transplant outcomes. Anti-thymocyte globulin (ATG) was initially used in Europe and the US; however, its role in UCBT is still under debate.12, 13, 14 Recent publications showed that ATG can cause delayed immune reconstitution and subsequently reduce survival after UCBT.15, 16 In Japan, standard GvHD prophylaxis in UCBT has involved a combination of calcineurin inhibitor (CNI) and methotrexate (MTX) or mycophenolate mofetil (MMF).17, 18 Thus we determined to investigate better GvHD prophylaxis after UCBT without ATG.

A previous study demonstrated that two-drug combination prophylaxis was better than single-agent prophylaxis in terms of survival after UCBT.19 Furthermore, comparative studies on a CNI alone with CNI plus MTX or MMF showed that addition of both agents to CNI resulted in significant improvements in survival after UCBT.20, 21 Several prospective studies and meta-analyses have shown that MMF is a reasonable substitute for MTX that achieves similar outcomes with potential reductions in toxicity after sibling or unrelated BMT/PBSCT.22, 23, 24, 25, 26 However, MTX and MMF in UCBT have not yet been compared in detail. Therefore, to investigate the better combination of CNI and either MTX or MMF, we conducted the present study to compare CNI plus MTX and CNI plus MMF regimens.

Subjects and methods

Data collection and sources

The Transplant Registry Unified Management Program (TRUMP) is a unified database of four registries in Japan, including The Japan Marrow Donor Program, The Japan Cord Blood Bank Network, The Japanese Society of Pediatric Hematology/Oncology and The Japan Society for Hematopoietic Cell Transplantation, and was developed by the Japanese Society of Hematopoietic Cell Transplantation (JSHCT).27, 28, 29 All transplantation data in the present study were obtained from the TRUMP database.

Patients

Inclusion criteria for the present study were as follows: (1) patients 16 years of age or older with ALL or AML, (2) first allogeneic transplant performed between 2000 and 2012, (3) a myeloablative conditioning regimen, (4) UCB as the donor source and (5) data for GvHD prophylaxis were available and GvHD prophylaxis consisted of CNI (tacrolimus (Tac) or cyclosporine A (CyA)) with either MTX or MMF. Exclusion criteria were patients with (1) double-unit UCBT, (2) in vivo T-cell depletion with ATG or (3) data missing regarding the survival status or date of last contact. Conditioning intensities were classified as reported previously.30 Since the CyA plus MMF combination was only administered to 17 patients, these patients were excluded from the present study. The retrospective study protocol was approved by the Institutional Review Board of Nagoya University Graduate School of Medicine, and written informed consent was obtained from each patient in accordance with the Declaration of Helsinki.

Definitions

Neutrophil recovery was defined as an absolute neutrophil count of at least 500/μL for three consecutive time points. Platelet recovery was defined as a count of 50 000/μL without transfusion support. The diagnosis and clinical grading of acute and chronic GvHD were performed according to the established criteria.31, 32 Relapse was defined as recurrence of the underlying hematological disease. Non-relapse mortality (NRM) was defined as death during continuous remission. Leukemia-free survival (LFS) was defined as survival in a state of continuous remission.

Statistical analysis

All categorical variables such as patient, disease and transplantation characteristics were compared using χ2 statistics, and all quantitative variables such as age, weight and cell dose were compared using the Kruskal–Wallis test. The probabilities of overall survival (OS) and LFS were calculated using the Kaplan–Meier survival estimate.33 The probabilities of neutrophil and platelet recovery, acute and chronic GvHD, NRM and relapse were calculated using the cumulative incidence estimate to consider competing risks.34 In NRM, relapse was the competing risk, whereas that for relapse was NRM. In hematopoietic recovery and acute and chronic GvHD, death without the event was the competing risk. In the analysis of OS, death from any cause was considered an event. In the analysis of LFS, relapse or death from any cause was considered an event. The log-rank test was used for group comparisons.

Cox’s proportional hazards univariate and multivariate regression models were applied to identify significant risk factors for LFS and OS.35 Competing risk regression models were applied for NRM, relapse and acute and chronic GvHD. By utilizing these risk factors, a final multivariate regression model was constructed to assess differences in GvHD prophylaxis methods at each end point. Multivariate models were built using a backward stepwise selection method with a threshold P-value <0.1. Results are expressed as relative risk (RR) with the 95% confidence interval (95% CI). The proportional hazards assumption was tested for all variables considered in the multivariate analysis, and no violations occurred. Regardless of the level of significance, the main variable of interest, GvHD prophylaxis (each CNI and MTX/MMF combination method or MTX-containing vs MMF-containing prophylaxis), was considered in all steps of model construction. In AML, standard risk was defined as first and second complete remission (CR), and all others were considered an advanced risk. In ALL, standard risk included CR1 alone; and CR2, further CR, and non-remission were defined as advanced risk. Differences were considered significant when P<0.05. All statistical analyses were performed with Stata software version 12 (StataCorp LP, College Station, TX, USA).

Results

Patient characteristics

Patient and transplant characteristics are summarized in Table 1. A total of 1516 patients were included. Median patient weight was 55 kg. The average weights of male and female patients were 61 and 49 kg, respectively. More than two thirds of UCBT (74.4%) were performed after 2006. All transplants with Tac plus MMF were performed after 2006. Patients with AML were more likely to have advanced risk disease at the time of transplantation than those with ALL (P<0.0001). Conditioning regimens mostly consisted of TBI-containing regimens. GvHD prophylaxis with CyA plus MTX and Tac plus MTX accounted for most transplants, whereas the Tac plus MMF combination was used for 138 transplants. In terms of conditioning, the Tac plus MMF group included significantly more non-TBI regimens than the other groups (P<0.0001, χ2-test). The Tac plus MMF group included more fludarabine-containing conditioning regimes, but these were considered to be myeloablative conditioning regimens.30, 36 Patient age was significantly older in the Tac plus MMF group (median age: CyA plus MTX; 38, Tac plus MTX; 39, Tac plus MMF; 51, P<0.0001, Kruskal–Wallis test). Approximately 70% of UCBT were 2/6 antigen-mismatches among HLA-A/B/DR antigens. The median follow-up period for surviving patients was 40.4 months (range, 2.0–141.0 months). Higher patient age is usually translated into lower survival, and non-TBI regimen was reportedly associated with improved survival.37, 38

Table 1 Patient and transplant characteristics

Hematopoietic recovery

Neutrophil recovery was not significantly different among any of the GvHD prophylaxis groups (CyA plus MTX, median, 22 days (cumulative incidence, 79.5%); Tac plus MTX, 22 days (82.1%); Tac plus MMF, 20 days (83.3%)). Furthermore, platelet recovery of more than 50 000/μL showed no significant difference among any of the GvHD prophylaxis groups (CyA plus MTX, median, 47 days (cumulative incidence, 65.1%); Tac plus MTX, 49 days (67.3%); Tac plus MMF, 54 days (61.7%)).

Acute and chronic GvHD

The incidence of grade II–IV acute GvHD was lower after Tac-based prophylaxis (CyA-based, 38.1% (95% CI, 34.8–41.4); Tac-based, 33.6% (95% CI, 30.1–37.1)) (RR, 0.77, 95% CI (0.64–0.92), P=0.003, CyA-based prophylaxis as a reference). Among each GvHD prophylaxis group, the incidence of grade II–IV acute GvHD was significantly higher in the Tac plus MMF group than in the CyA plus MTX group, but was significantly lower in the Tac plus MTX group (Table 2). A comparison with the MTX-containing group revealed that the MMF-containing group had a significantly higher RR of grade II–IV acute GvHD (Table 2). The cumulative incidence curve of grade II–IV acute GvHD was depicted for each GvHD prophylaxis group (Figure 1a).

Table 2 Adjusted comparison of various transplant outcomes
Figure 1
figure1

Cumulative incidence of severe acute GvHD in each GvHD prophylaxis group. Cumulative incidence curves of severe acute GvHD are shown for each GvHD prophylaxis group. (a) Grade II–IV acute GvHD and (b) grade III–IV acute GvHD. The cumulative incidences of acute GvHD at day 100 for the CyA plus MTX group, Tac plus MTX group and Tac plus MMF group were 38.1, 28.3 and 54.9%, respectively, in (a); 8.9, 5.8 and 16.1%, respectively, in (b).

The incidence of grade III–IV acute GvHD was similar between CyA-based and Tac-based prophylaxis (CyA-based, 8.9% (95% CI, 7.1–11.0); Tac-based, 7.8% (95% CI, 6.0–11.0) (RR, 0.88, 95% CI (0.62–1.26), P=0.49, CyA-based prophylaxis as a reference). However, Tac plus MTX was associated with a significantly lower risk of grade III–IV acute GvHD, whereas Tac plus MMF was associated with a significantly higher risk than that of CyA plus MTX (Table 2). A comparison with the MTX-containing group showed that the RR of grade III–IV acute GvHD was significantly higher in the MMF-containing group (Table 2). The cumulative incidence curve of grade III–IV acute GvHD was depicted for each GvHD prophylaxis group (Figure 1b).

To investigate the possible difference of organ involvement of GvHD, maximum GvHD stage in each organ according to MTX-containing vs MMF-containing prophylaxis is shown (Table 3). In comparison with a previous report containing mostly BMT and PBSCT, the incidence of skin GvHD was lower after UCBT. However, the incidence of gut and liver GvHD was similar.39 Comparing MTX-containing group with MMF-containing group, the incidence of gut GvHD was significantly higher in MMF-containing group (P<0.0001, χ2 test).

Table 3 Organ involvement of acute GvHD according to GvHD prophylaxis

In multivariate analyses using the competing risk regression model, the incidence of extensive chronic GvHD was significantly lower with Tac-based prophylaxis than with CyA-based prophylaxis (RR, 0.70, 95% CI (0.51–0.95), P=0.022). Among each GvHD prophylaxis group, the RR was significantly lower in the Tac plus MTX group than in the CyA plus MTX group (RR, 0.70, 95% CI (0.51–0.98), P=0.035), whereas it was similar in the Tac plus MMF group and CyA plus MTX group. The RR was similar in the MTX-containing vs MMF-containing groups (RR, 0.77, 95% CI (0.43–1.38), P=0.38, MTX-containing group as a reference).

NRM

In multivariate analyses using the competing risk regression model to compare each categorized GvHD prophylaxis group or MTX-containing vs MMF-containing method, no significant difference was observed in the risk of NRM (Table 2).

Relapse

Relapse risk was not primarily influenced by the GvHD prophylaxis method. Disease status at transplantation (standard risk vs advanced risk) was a primary factor for RR for relapse risk (3.93 for the CyA-based vs Tac-based comparison; 4.03 for each categorized group comparison; 4.03 for the MTX-containing vs MMF-containing group comparison). Although each GvHD prophylaxis group had similar RR, only the Tac plus MMF group had a significantly lower RR than the CyA plus MTX group (Table 2). The cumulative incidence curve of relapse was shown for each GvHD prophylaxis group in standard risk disease (Figure 2a) and advanced risk disease (Figure 2b). Although we observed a similar risk of relapse in standard risk disease, a significant difference was observed between the CyA or Tac plus MTX group and Tac plus MMF group in advanced risk disease (Figures 2a and b).

Figure 2
figure2

Cumulative incidence of relapse in each GvHD prophylaxis group. Cumulative incidence curves of relapse are shown for each GvHD prophylaxis group. (a) Standard risk disease and (b) advanced risk disease. The 2-year cumulative incidences of relapse for the CyA plus MTX group, Tac plus MTX group and Tac plus MMF group were 14.5, 17.1 and 12.7%, respectively, in (a); 47.1, 49.4 and 33.4%, respectively, in (b).

CNS complications and causes of death

The incidences of central nervous system (CNS) complications except CNS relapse were 26 out of 824 (3.2%) for the CyA plus MTX group, 21 out of 554 (3.8%) for the Tac plus MTX group and 14 out of 138 (10.1%) for the Tac plus MMF group (P=0.0001). Details of CNS complications were unknown due to the lack of data. The leading cause of death after UCBT was infection in the Tac plus MMF group and relapse in the CyA or Tac plus MTX group (Table 4).

Table 4 Cause of death according to GvHD prophylaxis

LFS

In multivariate analyses using Cox’s proportional hazard model, there was no significant difference between the CyA plus MTX group and Tac plus MMF group, whereas the Tac plus MTX group showed a similar RR to that of the CyA plus MTX group (Table 2). In addition, there was no significant difference between the MTX-containing group and MMF-containing group (Table 2).

OS

In multivariate analyses for OS, CyA-based prophylaxis demonstrated a similar risk for mortality to Tac-based prophylaxis (data not shown). A significant difference was observed in OS between the MTX-containing group and MMF-containing group (Table 2). The Tac plus MMF group had a significantly lower RR of overall mortality than the CyA plus MTX group, whereas the Tac plus MTX group had a similar RR to the CyA plus MTX group (Table 2). In order to further assess potential differences in the risk of overall mortality among GvHD prophylaxis groups, we performed subgroup analyses with multivariate analyses. In the standard risk group, there was no significant difference in the RR of overall mortality between the CyA/Tac plus MTX and Tac plus MMF groups (RR, 1.31, 95% CI, 0.77–2.23, P=0.32, CyA/Tac plus MTX group as a reference, adjusted with non-TBI regimen). In the advanced risk group, the Tac plus MMF group had a significantly lower RR of overall mortality than the CyA/Tac plus MTX group (RR, 0.68, 95% CI, 0.49–0.95, P=0.024, CyA/Tac plus MTX group as a reference, adjusted with patient age). No significant interaction for overall mortality was observed between disease status (standard risk vs advanced risk) and GvHD prophylaxis (MTX vs MMF) (P-value for the interaction variable=0.19). In order to show differences among each GvHD prophylaxis group, Kaplan–Meier curves for each disease risk group were shown (Figures 3a and b), although there was no significant difference.

Figure 3
figure3

Probabilities of OS by GvHD prophylaxis. Kaplan–Meier curves are shown for each GvHD prophylaxis group. (a) Standard risk disease and (b) advanced risk disease. The 4-year probabilities of OS for the CyA plus MTX group, Tac plus MTX group and Tac plus MMF group were 61.3, 65.6 and 56.3%, respectively, in (a); 30.9, 28.4 and 34.9%, respectively, in (b).

Discussion

In the present study, we investigated transplant outcomes after adult single-unit UCBT in order to identify better GvHD prophylaxis methods without the use of ATG. No significant difference was observed between CyA-based and Tac-based prophylaxis for any transplant outcome. In each categorized-group comparison, the Tac plus MMF group had a significantly higher risk of grade II–IV and grade III–IV acute GvHD than the CyA plus MTX group. Furthermore, in the MTX-containing vs MMF-containing group comparison, the MMF-containing group had a significantly higher risk of both grade II–IV and grade III–IV GvHD. However, the increment in severe GvHD did not lead to a subsequent increase in NRM or worse OS in UCBT. Since the organ involvement of GvHD was more severe in the gut after MMF-containing prophylaxis, we reasoned that the dissociation between an increase in GvHD and constant NRM was mainly because of better response to steroid therapy, which is consistent with the findings of the Minnesota group and ours.40, 41

The median days until engraftment was 2 days earlier in the MMF-containing group than in the MTX-containing group. This result was consistent with previous findings for BMT/PBSCT, in which the median days until engraftment was 4 days earlier in the MMF-containing group.22, 23, 24, 25, 26 Based on the cytotoxic effects of MTX and smaller nucleated cell number transplanted in UCBT, an even larger difference may be expected in the median days until engraftment between BMT/PBSCT and UCBT. However, we only observed a small difference, which may have been due to the different graft compositions between BMT/PBSCT and UCBT such as stem cell, T cells and other accessory cells.42, 43

In terms of OS, we observed a significant difference between the MTX-containing group and MMF-containing group in the multivariate analysis on all patients. Additionally, in a subgroup analysis, the MTX-containing and MMF-containing groups had similar risks of overall mortality in standard risk disease, whereas the MMF-containing group had a significantly lower risk of overall mortality in advanced risk disease. The reason why we observed such clinical differences between MTX and MMF might be due to the difference of mode of action. MMF is a potent immunosuppressant that stops T- and B-cell proliferation, but not kill the lymphocyte. However, MTX is a folic acid analog that is used as chemotherapeutic agent against various types of cancers. We also found that the MTX-containing method was associated with a significantly lower incidence of CNS complications than the MMF-containing group. In previous studies, the incidence of CNS complications, including HHV-6 encephalitis, was ~10% among UCBT recipients and ~1% among BMT/PBSCT recipients.44, 45 In the present analysis, the incidence of CNS complications was significantly lower after CyA/Tac plus MTX than after Tac plus MMF. In several retrospective studies, the development of GvHD and engraftment syndrome represented significant risk factors for HHV-6 encephalitis. Taken together, the use of MTX may contribute to reducing the incidence of severe acute GvHD and subsequent CNS complications. Therefore, our results support the use of MTX with CNI for standard risk disease and the use of MMF with Tac for advanced risk disease.

There are several limitations to the present study. Since this was a retrospective study, the results need to be interpreted with caution. We observed significant differences in the conditioning regimens and patient age between the MTX-containing and MMF-containing groups. Although we conducted multivariate analyses to consider these significant factors, we still have to factor in unrecognized bias due to the retrospective nature of this study. Furthermore, dose data for MTX and MMF were not available because this was a registry data analysis. We know of several dosing protocols for short-term MTX, such as 5–5–5, 10–7–7 and 15–10–10 mg/m2 on days 1, 3 and 6, respectively, or others. If we compare the total dose of MTX in the above three regimens, there is an ~2.3-fold difference between the highest and lowest dose. Therefore, differences in transplant outcomes are expected. The most frequently adopted dose for MMF varied between 1000 and 2000 mg/day, as reported in previous studies.20, 46 However, intensified MMF dosing and higher trough levels were positively associated with a reduced incidence of severe GvHD after UCBT.47, 48 Therefore, it is important to compare MTX and MMF including doses and schedules. We are now planning another study to investigate the effects of MTX and MMF doses for GvHD prophylaxis after UCBT.

Our results suggest that MTX-containing prophylaxis is preferable for standard risk disease, whereas the Tac plus MMF combination is preferable for advanced risk disease after UCBT. In order to establish the preferential doses of MTX and MMF, we are planning to conduct a study, including additional data collection. Once we establish the recommended doses for MTX and MMF, a prospective study is warranted in order to identify the optimal GvHD prophylaxis method for UCBT.

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Acknowledgements

We thank all the physicians and data managers at the institutes who contributed valuable data on transplantation to JSHCT and all members of the data management committees of JSHCT.

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Correspondence to S Terakura.

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The authors declare no conflict of interest.

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Terakura, S., Wake, A., Inamoto, Y. et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant 52, 423–430 (2017) doi:10.1038/bmt.2016.255

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