To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II–IV and III–IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.
Umbilical cord blood transplantation (UCBT) has been established as an alternative donor source for hematopoietic stem cell transplantation.1, 2, 3, 4, 5, 6 Since a new combination for a reduced intensity conditioning (RIC) regimen and UCBT was introduced, transplant outcomes with RIC-UCBT have improved in recent years, and RIC-UCBT has been recognized as a reasonable alternative donor source to unrelated bone marrow (BM).7, 8 As a part of conditioning and GvHD prophylaxis, anti-thymocyte globulin (ATG) has been used in Europe and US; however, the use of ATG in UCBT is reportedly associated with detrimental immunological recovery and worse survival outcomes.9, 10, 11, 12, 13, 14 Since the incidence of severe acute GvHD after UCBT is similar to that of matched unrelated donor transplantation,15, 16, 17 the choice of GvHD prophylaxis is important for optimal transplant outcomes. In the historical data on RIC-UCBT, a high incidence of pre-engraftment immunological reactions and subsequent GvHD was observed with single-agent GvHD prophylaxis using only a calcineurin inhibitor (CNI).18, 19 The combination of methotrexate (MTX) or mycophenolate mofetil (MMF) with CNI has since been attempted. Comparative studies on CNI alone and CNI plus MTX or MMF demonstrated that both combinations of prophylaxis resulted in significant improvements in survival after UCBT.20, 21 The standard GvHD prophylaxis in UCBT is a combination of CNI and MTX or MMF in Japan.22, 23 However, a detailed comparison has not yet been conducted between MTX and MMF in RIC-UCBT; therefore, we performed the present study in order to compare the CNI plus MTX regimen with the CNI plus MMF regimen.
Patients and methods
Data collection and source
All the transplantation data for the present study were obtained from the Transplant Registry Unified Management Program database.24, 25, 26 Inclusion criteria for the present study were as follows: (1) patients aged 16 years or older with AML or ALL, (2) first allogeneic transplant between 2000 and 2012, (3) RIC regimen, (4) UCB as the donor source and (5) the 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 the following: (1) double-unit UCBT, (2) in vivo T-cell depletion with ATG and (3) the data missing regarding the survival status or the date of last contact. Conditioning intensities were classified as reported previously.27 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.
CB selection strategy
A common UCB unit selection strategy is to choose a UCB unit with total nucleated cell count >2.0 × 107/kg recipient weight within a 2-loci mismatch among HLA-A, -B and -DR loci at the Ag level. Among them, the UCB unit with the higher CD34+ cell dose is typically selected.28
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 established criteria.29, 30 Relapse was defined as the recurrence of the underlying hematological disease. Non-relapse mortality (NRM) was defined as death during continuous remission. relapse-free survival (RFS) was defined as survival in a state of continuous remission.
All categorical variables such as patients, diseases and transplantation characteristics were compared using χ2 statistics, and all quantitative variables such as ages, weights and cell doses were compared using Mann–Whitney U test. The probabilities of OS and RFS were calculated using the Kaplan–Meier survival estimate.31 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.32 Relapse was the competing risk for NRM, while that for relapse was NRM. Death without an event was the competing risk for hematopoietic recovery and acute and chronic GvHD. In the analysis of OS, death from any cause was considered an event. In the analysis of RFS, 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 RFS and OS.33 Competing risk regression models using Fine-Gray method were applied for NRM, relapse, and acute and chronic GvHD.34 By utilizing risk factors, a final multivariate regression model was constructed to assess differences in the GvHD prophylaxis methods at each endpoint. 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 (MTX-containing vs MMF-containing), was considered in all steps of model construction. Other variables tested were patient age (continuous variable), patient sex (male vs female), donor sex (male vs female), the use of TBI (TBI-regimen vs non-TBI regimen), conditioning regimen (Flu+Bu±regimen vs Flu+CY±regimen vs Flu + Mel±regimen vs others), HLA disparity in -A/B/DR loci (HLA serological mismatch equal to or more than 2 Ag vs less than 2 Ag), disease status at transplantation (standard-risk vs high-risk), and transplant period (before 2009 vs 2010–2012). The standard-risk for AML was defined as first and second CR, with all others being considered high-risk. The standard-risk for ALL included CR1 alone, with CR2, further CR and non-remission being defined as high-risk. Differences were considered significant when P<0.05. All statistical analyses were performed with Stata software version 12 (College Station, TX, USA) and EZR statistical software (Saitama Medical Center, Jichi Medical University, Saitama, Japan).35
Patient and UCB graft characteristics
A total of 748 patients were included after the application of inclusion and exclusion criteria (Table 1). The median patient age was 60 years (range, 17–82 years); patient age was significantly older in the MMF+ group (median age: MTX+ group, 59; MMF+ group, 61; P<0.001, Mann–Whitney U test). The median patient weight was 55 kg (range, 34–88 kg). Transplantation year was not significantly different between the MTX+ group and the MMF+ group (P=0.71). Conditioning regimens mostly consisted of fludarabine and another cytotoxic agent with low-dose TBI. The median TBI dose was 2–4 Gy in each group. Approximately 60% of UCBT were 2 out of 6 Ag mismatches among HLA-A/B/DR Ag. The median follow-up period for surviving patients was 26.1 months (range, 2.7–143.8 months).
Neutrophil recovery was significantly better in the MMF+ group (median days for recovery (cumulative incidence): MTX+ group, 25 days (66.8%; 95%CI, 62.3–71.0); MMF+ group, 21.5 days (81.7%; 95%CI, 76.8–85.6); P<0.0001, Fine-Gray) (Figure 1a). In a multivariate competing risk regression analysis, the likelihood of recovery was significantly greater in the MMF+ group than in the MTX+ group (Table 2). Furthermore, platelet recovery of greater than 50 000/μL was significantly better in the MMF+ groups (median days for recovery [cumulative incidence]: MTX+ group, 45.5 days (51.4%; 95%CI, 46.7–56.0); MMF+ group, 45.5 days (60.3%; 95%CI, 54.4–65.6)) (Figure 1b; P=0.025, Fine-Gray). The likelihood of recovery was significantly greater in the MMF+ group than in the MTX+ group (Table 2). Conditioning regimen was not a significant factor in the final model of multivariate competing risk regression analysis.
Acute and chronic GvHD
In multivariate analyses, the risk of grade II–IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (Table 2). The cumulative incidence curve of grade II–IV acute GvHD was depicted for a dichotomous comparison between the MTX+ and MMF+ groups (Figure 2a).
In multivariate analyses, the risk of grade III–IV acute GvHD was higher in the MMF+ group than in the MTX+ group (Table 2). The cumulative incidence curve of grade III–IV acute GvHD was depicted for a dichotomous comparison between the MTX+ and MMF+ groups (Figure 2b).
The risk of developing extensive chronic GvHD was not significantly affected by the GvHD prophylaxis method in multivariate analyses using the competing risk regression model (Table 2). A similar RR was observed for the MTX+ and MMF+ groups (RR, 1.21; 95% CI (0.70–2.08); P=0.50, the MTX+ group as a reference).
In multivariate analyses using the competing risk regression model, the risk of NRM in the MMF+ group was slightly higher compared with the MTX+ group in AML (RR; MMF+ group; 1.33, 95% CI (1.00–1.78), P=0.054; MTX+ group as a reference), whereas there was no significant difference between the MTX+ group and MMF+ group in ALL (RR; MMF+ group; 0.82, 95% CI (0.41–1.64), P=0.57; MTX+ group as a reference) (Supplementary Table S1).
In terms of relapse and survival, AML and ALL were analyzed separately in the multivariate competing risk regression model because the disease was significant factor in the multivariate analyses when the disease factor (AML vs ALL) was involved as a covariate. Disease status at transplantation (standard-risk vs high-risk) had a significant impact as a primarily important factor for the risk of relapse (RR, 4.04, 95% CI (3.04–5.38), P<0.0001 for the MTX+ vs MMF+ comparison). Therefore, we adopted risk-stratified analyses for the relapse and survival of AML and ALL (Table 3 and Supplementary Table S2). In standard-risk AML, no significant differences were observed in the MTX+ vs MMF+ comparison (Table 3). In high-risk AML, the risk of relapse was significantly lower in the MMF+ group than in the MTX+ group (Table 3). The cumulative incidence curve of relapse was shown for each GvHD prophylaxis group for standard-risk disease (MTX+, 19.0% (95% CI, 13.5-25.3%); MMF+, 18.3% (95% CI, 11.2–26.8%); P=0.65, Fine-Gray) (Figure 3a) and high-risk disease (MTX+, 56.8% (95% CI, 49.7–63.3%); MMF+, 44.9% (95% CI, 36.9–52.5%); P=0.013, Fine-Gray) (Figure 3b).
In multivariate analyses of ALL, no significant differences were observed in the risk of relapse among each categorized group or in the MTX+ vs MMF+ group comparison (Supplementary Table S2).
CNS complications and causes of death
In our previous study on GvHD prophylaxis in myeloablative UCBT, we observed a significant difference in the incidence of central nervous system (CNS) complications between GvHD prophylaxes, which was significantly higher after Tac plus MMF prophylaxis. In the present study, the incidences of CNS complications after RIC-UCBT were 31 out of 446 (7.0%) for the MTX group, 27 out of 302 (8.9%) for the MMF group (χ2 test, P=0.32). No significant differences were noted in the incidence of CNS complications between the MTX+ and MMF+ groups. Although details on CNS complications were not obtained due to the lack of data, most CNS complications would consist of HHV6 encephalitis syndrome, which reportedly associated with the incidence of acute GvHD.36 Relapse was the leading cause of death after UCBT in the MTX and MMF groups, whereas no rejection/graft failure was observed in the MMF group (Table 4).
In multivariate analyses using Cox’s proportional hazard model, RFS was similar in the MTX+ vs MMF+ group comparison for standard-risk disease (Table 3). In the high-risk disease, the risk of RFS was slightly lower in the MMF+ group than in the MTX+ group (Table 3). RFS was depicted by Kaplan–Meier estimates for standard-risk and high-risk disease. There was no significant difference between MTX+ and MMF+ group in standard-risk disease, whereas there was a tendency for superior RFS in the MMF+ group in the high-risk disease (Figures 3c and d).
In multivariate analyses, OS was similar in the MTX+ vs MMF+ group comparison for standard-risk and high-risk disease (Table 3). OS was depicted by Kaplan–Meier estimates for standard-risk and high-risk disease; however, there was no significant difference between MTX+ and MMF+ group (Supplementary Figure S1).
In multivariate analyses of ALL, no significant difference was observed in the risk of RFS in the MTX+ vs MMF+ group comparison for standard-risk disease (Supplementary Table S2). Regarding high-risk disease, the MMF+ group was associated with a marginally lower risk of RFS than the MTX+ group (RR, 0.51; 95% CI (0.26–1.01); P=0.053) (Supplementary Table S2).
In multivariate analyses, OS was similar in the MTX+ vs MMF+ group comparison for standard-risk disease (Supplementary Table S2). In high-risk disease, the MMF+ group was associated with a significantly lower risk of OS (RR, 0.50; 95% CI (0.25–0.99); P=0.048) (Supplementary Table S2).
In the present study, we investigated better GvHD prophylaxis methods after adult single-unit RIC-UCBT. As we already demonstrated in a previous study on myeloablative UCBT, CNI plus MTX prophylaxis showed a significantly lower incidence of severe GvHD.37 However, in terms of relapse, CNI plus MMF prophylaxis was better, particularly for high-risk AML.37 In contrast to the previous findings, the engraftment of neutrophils and platelets was significantly better in the MMF+ group than in the MTX+ group in the present study. Although MMF+ group was associated with the significantly lower relapse of high-risk disease, we did not observe significant differences for RFS and OS. We speculate that the reason for this was that the potential benefit of lower relapse may have been cancelled out by the marginally higher risk of NRM.
The cumulative incidence of neutrophil and platelet engraftment was significantly higher in the MMF+ group than in the MTX+ group. In a previous study on myeloablative UCBT, we did not observe significant differences in the cumulative incidence of engraftment between the MTX+ and MMF+ groups.37 The reason why we observed this dissociation between myeloablative UCBT and RIC-UCBT may be as follows. Recipient lymphocytes are supposed to be more profoundly depleted by myeloablative conditioning than by the RIC setting, and recipient lymphocytes may survive RIC. These recipient lymphocytes may then initiate immunological rejection or inhibit engraftment, and potentially increase the incidence of graft failure.38 Given the effects of MTX against proliferating lymphocytes, MTX+ prophylaxis may excessively suppress donor-derived lymphocytes, which are expected to facilitate engraftment.39, 40, 41 The effects of facilitating cells may be important in the RIC setting because the depletion of host-derived lymphocytes in the RIC setting may be incomplete and, thus, immunological competition between host- and donor-derived cells may also occur more frequently. On the other hand, MMF is given continuously, preventing proliferation by inhibiting enzymes utilized by proliferating T- and B-lymphocytes.42 Therefore, MMF does not kill facilitating cells and it merely prevents proliferation. These differences in the mode of action may translate into the outcomes observed in the present study. Also the canine experiments of Seattle group demonstrated a similar observation, which was that the 2 Gy TBI conditioning led to sustained engraftment only together with MMF but not with MTX due to an increased rejection after MTX.43 Therefore, preventing the activation and proliferation of donor-derived immune cells without killing lymphocytes may be a future direction for GvHD prophylaxis, in which successful engraftment is assured and severe GvHD is simultaneously controlled.44
The use of MMF correlated with a higher incidence of grade II–IV and III–IV acute GvHD. Nevertheless, the increase observed in the incidence of severe GvHD did not dramatically enhance NRM or lead to inferior survival. A recent study reported that the incidence of grade I–II acute GvHD was associated not only with a low risk of relapse, but also with a low risk of NRM, and provides a survival benefit in UCBT.45 Although we observed a possible association between an increase in the incidence of severe GvHD and reductions in relapse after the use of MMF in high-risk AML recipient, we only noted a marginal increase in NRM in AML. These results indicate that severe GvHD after UCBT may be more manageable than that after other stem cell sources.46, 47
In terms of RFS and OS, we did not observe significant differences between the MTX+ group and MMF+ group in a multivariate analysis on AML patients. Nevertheless, in the risk-stratified analysis, the MTX+ and MMF+ groups demonstrated similar risks for survival in standard-risk disease, whereas the MMF+ group had a slightly lower risk of RFS in high-risk disease. In a previous study on myeloablative UCBT, we found a similar pattern of outcomes for OS; however, the MTX+ group was associated with a significantly lower incidence of CNS complications than the MMF+ group in despite the similar survival outcome between the MTX+ group and the MMF+ group. Thus, we concluded that MTX is preferable for standard-risk disease, whereas MMF is better for high-risk disease in myeloablative UCBT.37 Herein, we did not observe a clear difference in the incidence of CNS complications between the MTX+ and MMF+ groups in the current study. Since we demonstrated superior engraftment and similar survival in the MMF+ group, we concluded that MMF+ prophylaxis might be preferable, particularly for high-risk disease, in RIC-UCBT. Several dosing protocols have been described for short-term MTX, and the total dose of MTX markedly varies among different dose schedules. Therefore, careful comparisons of MTX+ prophylaxis groups including doses and schedules are needed in order to draw any solid conclusions. We are currently planning another study to investigate the possible effects of the doses of MTX and MMF for GvHD prophylaxis after UCBT.
There were some limitations to the present study. Since this is a retrospective study, the results obtained must be carefully interpreted. We observed significant differences in the patient age and conditioning regimen between the MTX+ and MMF+ groups. Although we conducted multivariate analyses to consider background differences, we still have to be aware of unrecognized bias because of the retrospective nature of this study. Furthermore, there were several missing data points due to the lack of data.
In summary, our results suggest that MMF+ prophylaxis may be preferable for single-unit RIC-UCBT because engraftment was significantly better after MMF+ prophylaxis. On the other hand, due to the increase in the incidence of severe GvHD in the MMF+ prophylaxis, the use of MTX might be occasionally suitable choice for standard-risk disease.
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We thank all the physicians and data managers at the institutes that contributed the valuable data on transplantation to the JSHCT and all the members of the data management committees of the JSHCT. This study was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI 15K09497 to ST) from the Japan Society for the Promotion of Science (JSPS).
ST designed the research, analyzed the data, and wrote the manuscript. YKu, SY, AW, JK, YI and TY analyzed the data and helped write the manuscript. SMiz, NU, YKo, NA, HO, HK, YN, SMiy, MO, and IA collected the patient data. TF, TI and YA supervised the data management. MM and TT designed and supervised the research. All authors reviewed and approved the final version of the manuscript.
The authors declare no conflict of interest.
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Terakura, S., Kuwatsuka, Y., Yamasaki, S. et al. GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transplant 52, 1261–1267 (2017) doi:10.1038/bmt.2017.116
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