Allografting

Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry

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Abstract

The outcomes for allogeneic hematopoietic cell transplantation (allo-HCT) are heavily influenced by non-relapse mortality (NRM). We retrospectively assessed the changes in the incidence and causes of NRM after allo-HCT over the past 12 years. NRM, relapse rate and OS were analyzed using the Japan transplant outcome database of 6501 adult patients with acute leukemia or myelodysplastic syndrome who received their first allo-HCT in remission from 1997 through 2008. In multivariate analysis in patients aged 16–49 years, the adjusted hazard ratios (HRs) for NRM for 2001–2004 and 2005–2008 were 0.78 (95% confidence interval, 0.65–0.93) and 0.64 (0.54–0.78), respectively, compared with 1997–2000. The HR for overall mortality in 2005–2008 was 0.81 (0.70–0.93) compared with 1997–2000. In patients aged 50–70 years, the HRs for NRM and overall mortality in 2005–2008 were 0.56 (0.46–0.68) and 0.66 (0.47–0.93), respectively, compared with those in 2001–2004. We found that causes of death that contributed to the changes in NRM varied among subgroups. In conclusion, our study indicated that the incidence of NRM after allo-HCT has significantly decreased over the past 12 years, which has led to an improvement of OS, and also showed reductions in NRM in subgroups consisting of older patients and those who received unrelated cord blood transplantation.

Introduction

Allogeneic hematopoietic cell transplantation (allo-HCT) has been recognized as a potent strategy for curing hematological malignancies. However, there have always been concerns about the risk of non-relapse mortality (NRM). As the risk of relapse is known to be significantly reduced after allo-HCT, the outcome of and indications for allo-HCT are heavily influenced by the risk for NRM.

Over the past few decades, many changes have been made to improve the outcome after allo-HCT, including improvements in the conditioning regimen, donor selection, and prophylaxis and treatment for organ complications, GVHD and infectious diseases, which have led to a reduction in NRM.1, 2, 3, 4

Although an improvement in NRM has been reported in relatively younger patients who have received allo-HCT from a BM or peripheral blood (PB) donor, NRM has not been fully examined in other settings, such as in elderly patients, or in cord blood (CB) transplantation.

To evaluate the effects of these advances, we retrospectively assessed the changes in the incidence and causes of NRM over the past 12 years, using a nationwide registry database of more than 6000 patients who received various types of allo-HCT.

Patients and methods

Data source

The clinical data were extracted from a nationwide transplant outcome registry database provided by the Japan Society for Hematopoietic Cell Transplantation (JSHCT), the Japan Marrow Donor Program (JMDP) and the Japan Cord Blood Bank Network (JCBBN). The JSHCT collect clinical data through the Transplant Registry Unified Management Program, as described previously.5 This study was approved by the data management committees of JSHCT, JMDP and JCBBN, and by the Institutional Review Board at the National Cancer Center Hospital.

Patients and definitions

We evaluated the data on patients aged between 16 and 70 years who had AML, acute lymphocytic leukemia (ALL) or myelodysplastic syndrome (MDS), and who received their first allo-HCT between 1997 and 2008. We compared the incidence of NRM after allo-HCT in three consecutive 4-year periods (1997–2000, 2001–2004 and 2005–2008) for younger patients (16–49 years), and in the latter two periods for older patients (50–70 years). NRM was defined as death without recurrent disease after allo-HCT. Analyses were performed for patients with acute leukemia/MDS in remission or low-risk MDS (refractory anemia with or without ringed sideroblast: RA/RARS). Analyses were performed on the basis of patients’ age (16–49 years and 50–70 years) and donor source (HLA-6/6-serum-matched or 1-Ag-mismatched related, unrelated BM and unrelated CB). In the era considered by this study, only BM from unrelated volunteer donors was used in Japan. In 2003, JMDP nationally recommended DNA typing of HLA-A and B, as well as HLA-DRB1. Since 2005, JMDP required all the candidates of unrelated allo-HCT to examine high-resolution typing of HLA-A, B and DRB1, and also recommended high-resolution typing of the C-locus. Conditioning regimens were classified as indicated by Giralt et al.6 The incidences of mortality associated with GVHD, infection and organ failure were analyzed. In patients who had multiple causes among GVHD, infection and organ failure, information regarding the main cause of death was prioritized.

Statistical analysis

Data were retrospectively reviewed and analyzed as of June 2011. Among the three time periods, patient characteristics were compared using the χ2 test. The primary end point of the study was NRM after allo-HCT. Probabilities of NRM and relapse were estimated with the use of cumulative incidence curves, with relapse viewed as a competing risk of NRM, and with NRM viewed as a competing risk of relapse. The Pepe and Mori test was used to evaluate the differences between groups. For the 151 patients (2%) who were known to have relapsed but whose date of relapse was unavailable, mid-point imputation was performed by substituting the midpoint from HCT to date of last contact as the date of relapse. The probability of OS was estimated using the Kaplan-Meier product limit method, and 95% confidence intervals (CIs) were calculated using the Greenwood formula. To compare the OS between groups, the log-rank test was used. Incidences of NRM, relapse and OS were estimated as probabilities at 3 years from allo-HCT. Multivariate analyses for NRM and relapse were performed using competing risk regression by the method of Fine and Gray, and for OS using a Cox proportional hazard regression model. The multivariate analyses were performed separately among patients aged 16–49 years and patients aged 50–70 years, where the year of allo-HCT (1997–2000 vs 2001–2004 or 2005–2008 among younger patients, 2001–2004 vs 2005–2008 among older patients or those who received unrelated CB transplantation (UCBT)), disease type (AML vs ALL or MDS), patient age (16–29 years vs 30–39 or 40–49 among younger patients, 50–59 vs 60–70 among older patients), patient gender (male vs female), donor source (HLA-6/6-Ag-matched sibling vs other family donors, HLA-6/6-Ag-matched unrelated BM, mismatched unrelated BM or unrelated CB) and conditioning regimens (myeloablative vs reduced-intensity) were considered as covariates. Multivariate analyses were also performed separately for those receiving related allo-HCT, where HLA-6/6-Ag-matched sibling vs other family donors were considered as covariates for the donor source, those receiving unrelated BM transplantation (UBMT), where HLA-6/6-Ag-matched unrelated BM vs mismatched BM were considered as covariates, and those who received UCBT, where the covariates above were examined other than the donor source. We considered two-sided P-values of <0.05 to be statistically significant. Statistical analyses were performed with SAS version 9.1.3 (SAS, Cary, NC, USA) and the SPSS software version 11.0.1 (SPSS, Chicago, IL, USA).

Results

Patients

A total of 6501 patients registered from 266 institutions across the country5 were analyzed, with a median age of 40 years and a median follow-up of 39 months. Characteristics of the patients and transplantation procedures according to the time period are shown in Table 1. The overall proportions of AML, ALL and MDS were 53%, 34% and 13%, respectively. A total of 1354, 2292 and 2855 allo-HCTs were performed in 1997–2000, 2001–2004 and 2005–2008, respectively. The number and proportion of patients aged 50–70 years (1997–2000, n=123, 9%; 2001–2004, n=617, 27%; 2005–2008, n=1054, 37%), allo-HCT from an unrelated CB donor (n=14, 1%; n=321, 14%; n=534, 19%), and the use of a reduced-intensity conditioning regimen (n=21, 2%; n=394, 17%; n=689, 24%) increased over the three periods. Most of the myeloablative conditioning regimens (96%) consisted of high-dose CY with TBI or BU. Tacrolimus-based GVHD prophylaxis increased, especially in allo-HCT from an unrelated BM and CB donor (BM: n=218, 37%; n=579, 58%; n=945, 72%; CB: n=3, 21%; n=99, 31%; n=229, 43%).

Table 1 Patients’ characteristics according to the time period of transplant

Outcomes of allo-HCT over the three periods

The incidence of NRM of the entire 6501 patients was 23% at 3 years after allo-HCT (Figure 1a). Overall, 265 patients died of acute or chronic GVHD (median OS: 143 days, range: 18–3360), 497 died of infection (median OS: 116 days, range: 0–3184) and 500 died of organ failure (median OS: 145 days, range: 0–4013).

Figure 1
figure1

NRM over the past 12 years among 6501 patients who received allo-HCT in remission is shown in (a). NRM according to age (b) and donor source (c) are also shown.

Older patients had a significantly higher incidence of NRM than younger patients (31% vs 20%, P<0.001, Figure 1b). The donor source significantly affected the incidence of NRM, and unrelated CB had the highest risk of NRM (related, 17%; unrelated BM, 25%; unrelated CB, 31%, P<0.001, Figure 1c). In a comparison of the outcome after allo-HCT among the three time periods in the overall 6501 patients (Figure 2), there were no linear improvements in NRM and OS over the three periods (NRM: 23%, 25% and 21%; OS: 61%, 57% and 60% at 3 years after allo-HCT). By the multivariate analysis that adjusted for disease type, patient age, patient gender, donor source and conditioning regimens, in younger patients (Table 2), the hazard ratios (HRs) for NRM in 2001–2004 and 2005–2008 compared with 1997–2000 were 0.78 (95% CI 0.65–0.93, P=0.005) and 0.64 (95% CI 0.54–0.78, P<0.001), respectively. The HR for overall mortality in 2005–2008 was significantly lower than that in 1997–2000 (HR 0.81, 95% CI 0.70–0.93, P=0.004). The HRs for relapse did not differ significantly among the periods. In older patients, the HRs for NRM and overall mortality in 2005–2008 compared with 2001–2004 were 0.56 (95% CI 0.46–0.68, P<0.001) and 0.66 (95% CI 0.47–0.93, P=0.017), respectively. However, the HR for relapse in 2005–2008 significantly increased (HR 1.53, 95% CI 1.20–1.97, P=0.001).

Figure 2
figure2

NRM and OS at 4-year periods (1997–2000, solid line; 2001–2004, dotted line; 2005–2008, dashed line) in the overall patients.

Table 2 Multivariate analyses for NRM, relapse and overall mortality after allo-HCT among the three periods

Allo-HCT from an HLA-matched or 1-Ag-mismatched related donor

In younger patients who received allo-HCT from a related donor (Figure 3a), the incidence of NRM remained rather low throughout the 12 years. Although NRM and OS slightly improved in 2005–2008, the differences were not statistically significant.

Figure 3
figure3

(a) NRM and OS at 3 years from HCT among younger patients (16–49 years) who received allo-HCT from a related donor were 15%, 16% and 12% (P=0.127), and 67%, 66% and 68% (P=0.564), respectively in the period of 1997–2000 (n=587, solid line), 2001–2004 (n=620, dotted line) and 2005-2008 (n=639, dashed line). (b) NRM and OS among older patients (50–70 years) who received related donor transplantation were 28% and 17% (P<0.001) and 52% and 57% (P=0.085), respectively in the period of 2001–2004 (n=293, dotted line) and 2005–2008 (n=321, dashed line). (c) NRM and OS among younger patients who received allo-HCT from an unrelated BM donor were 28%, 24% and 22% (P<0.001), and 60%, 60% and 63% (P=0.022), respectively in the period of 1997–2000 (n=560, solid line), 2001–2004 (n=803, dotted line) and 2005-2008 (n=839, dashed line). (d) NRM and OS among older patients who received allo-HCT from an unrelated BM donor were 39% and 27% (P=0.004) and 45% and 54% (P=0.026), respectively in the period of 2001–2004 (n=195, dotted line) and 2005–2008 (n=473, dashed line). (e) Non-relapse mortality and OS among younger patients who received allogeneic hematopoietic cell transplantation from an unrelated cord blood donor were 25% and 25% (P=0.986), and 55% and 65% (P=0.068), respectively in the period 2001–2004 (n=214, dotted line) and 2005–2008 (n=292, dashed line). (f) Non-relapse mortality and OS among older patients who received allogeneic hematopoietic cell transplantation from an unrelated cord blood donor were 51% and 37% (P=0.017), and 29% and 44% (P=0.011), respectively in the period of 2001–2004 (n=107, dotted line) and 2005–2008 (n=242, dashed line).

In older patients who received allo-HCT from a related donor, NRM was significantly reduced in 2005–2008 compared with 2001–2004 (Figure 3b, HR 0.62, 95% CI 0.44–0.88, P=0.007, Table 2). The incidences of death associated with organ failure and GVHD were significantly reduced in 2005–2008 (organ failure, 11 and 6%, P=0.007; GVHD, 6 and 3%, P=0.015, Figure 4a). In contrast, a significant increase in relapse was observed in 2005–2008 compared with 2001–2004 (21 and 36%, P<0.001, data not shown), and the same result was also shown by a multivariate analysis (HR 1.97, 95% CI 1.38–2.81, P<0.001, Table 2). This result remained the same when the analyses were restricted to HCT using reduced-intensity regimens or myeloablative regimens. Consequently, the improvement in OS in 2005–2008 was not statistically significant (Figure 3b and Table 2).

Figure 4
figure4

Change in the causes of NRM among different time periods is shown. Cumulative incidences of death due to GVHD, infection and organ failure are separately presented in each time period. (a) In older patients who received allo-HCT from a related donor, the incidences of death associated with organ failure and GVHD were significantly reduced in 2005–2008 (organ failure, 11 and 6%, P=0.007; GVHD, 6 and 3%, P=0.015). (b) In younger patients who received allo-HCT from an unrelated BM donor, the incidences of death associated with GVHD and organ failure were significantly reduced (GVHD, 7, 4 and 4%, P=0.011; organ failure, 12, 10 and 8%, P=0.002). (c) In older patients who received allo-HCT from an unrelated BM donor, the incidences of death associated with infection and organ failure were reduced in 2005–2008 (infection, 14 and 10%, P=0.054; organ failure, 14 and 8%, P=0.049).

Allo-HCT from an unrelated BM donor

A significant reduction in NRM was seen over the three periods among younger patients who received allo-HCT from an unrelated BM donor (Figure 3c), with the HRs of 0.69 (95% CI 0.55–0.88, P=0.003) and 0.61 (95% CI 0.47–0.78, P<0.001) in 2001–2004 and 2005–2008, respectively (Table 2). The incidences of death associated with GVHD and organ failure were significantly reduced over the three periods (GVHD, 7, 4 and 4%, P=0.011; organ failure, 12, 10 and 8%, P=0.002, Figure 4b). OS significantly improved in 2005–2008 (Figure 3c and Table 2).

In older patients who received allo-HCT from an unrelated BM donor, NRM and OS significantly improved in 2005–2008 compared with 2001–2004 (Figure 3d). The HR for NRM in 2005–2008 was 0.58 (95% CI 0.41–0.82, P=0.002). The incidences of death associated with infection and organ failure were reduced in 2005–2008 (infection, 14 and 10%, P=0.054; organ failure, 14 and 8%, P=0.049, Figure 4c). We found a significant reduction in mortality rates associated with bacterial and fungal infection.

Allo-HCT from an unrelated CB donor

In younger patients who received allo-HCT from an unrelated CB donor, there was no significant difference in the incidence of NRM between the two periods (Figure 3e). In this group, there was a marked reduction in the relapse rate (25 and 18%, P=0.018, data not shown; HR 0.66, 95% CI 0.43–1.00, P=0.049, Table 2). OS was better in 2005–2008; however, the difference was not statistically significant.

Significant improvements in NRM and OS were observed in 2005–2008 among older patients who received UCBT (Figure 3f). The HRs for NRM and overall mortality in 2005–2008 were 0.57 (95% CI 0.40–0.83, P=0.003) and 0.67 (95% CI 0.49–0.91, P=0.010), respectively. Reductions in the incidences of death associated with GVHD and infection seemed to contribute to the improvements in NRM (GVHD, 7 and 3%, P=0.163; infection, 23 and 13%, P=0.136). The mortality rate due to bacterial infection was significantly reduced.

Incidence of and mortality after severe acute GVHD

In subgroups that showed a significant reduction in the incidence of NRM, younger patients who received UBMT, older patients who received related HCT and older patients who received UCBT showed significant reductions in the incidence of GVHD-related mortality. In younger patients who received UBMT, the incidence of severe acute GVHD was significantly reduced over the three periods (16, 15 and 12% at 100 days after allo-HCT, P=0.021). In older patients who received related HCT, the incidence of severe acute GVHD was reduced in 2005–2008 relative to 2001–2004, but this difference was not statistically significant (14 and 10%, P=0.099). In older patients who received UCBT, there was no remarkable reduction in the incidence of severe acute GVHD in the later period (18 and 16%, P=0.542). However, the mortality rate was significantly reduced among older patients who suffered severe acute GVHD after UCBT (92 and 67% at 3 years after allo-HCT, P=0.022).

Discussion

In this study that used a large database of 6501 patients, we found that the incidence of NRM after allo-HCT for adult patients has significantly decreased over the past 12 years, which has led to an improvement of OS. As prior studies have primarily focused on the changes in NRM among younger patients who received allo-HCT with myeloablative conditioning,2, 4 this is the first study to show the changes in NRM in subgroups comprising older patients and UCBT.

We found that demographic, disease and transplantation characteristics have been changing, as previous studies reported.1, 2, 4 The marked increase in the number of older patients, allo-HCT with reduced-intensity conditioning and UCBT might reflect an increase in allo-HCT for ‘more vulnerable’ patients. Gooley et al.1 reported that the hematopoietic cell transplantation-specific comorbidity index (HCT-CI)7 scores were higher in HCT recipients in more recent time periods. Unfortunately, we were not able to evaluate HCT-CI in the current study because of a lack of information.

Among patients who received related HCT, remarkable improvement in NRM was observed in older patients. Another distinguishing finding was an increase in relapse in overall older patients, especially among those who received related HCT in remission. There was no recent shift in the use of allo-HCT in a later remission state, and we obtained a similar result when the analyses were restricted to HCT using reduced-intensity regimens or myeloablative regimens. In addition, the proportional use of anti-thymocyte globulin has remained unchanged over the periods. Less use of PB donors and more aggressive selection of older patients as indicated for allo-HCT may have affected the result. Despite this increase in relapse, older patients who received HCT in remission showed, by multivariate analyses, a significant reduction in mortality with a remarkable reduction in HRs for NRM irrespective of donor sources.

In analyses based on the donor source, UBMT showed remarkable improvements in NRM and OS throughout the age subgroups. Along with high-resolution donor–recipient HLA matching,8, 9 the lesser proportion of donor/patient pairs with allele mismatches may have reduced the incidence of GVHD-related mortality, and contributed to the improvement in outcomes after UBMT.

Among patients who received UCBT, we found a decreased risk of relapse in younger patients with no change in NRM. On the other hand, older patients had a decreased risk of NRM with no change in relapse. These outcomes may be explained by the changes in clinical practice in 2001–2004, ‘learning phase’ of UCBT, and that after 2005, including the indication of UCBT and the prophylaxis and treatment for GVHD/infection.

A recent reduction in the incidence of GVHD-related mortality was observed in younger patients receiving UBMT and older patients receiving related allo-HCT or UCBT. With the changes in prophylaxis and treatment against GVHD including high-resolution donor–recipient HLA matching,8, 9 the incidence of grade 3 to 4 severe acute GVHD has decreased in younger patients receiving UBMT and older patients receiving related HCT, which may have led to the reduction in GVHD-related mortality in these subgroups. Interestingly, in older patients receiving UCBT, there was no reduction in the incidence of severe acute GVHD; however, the mortality rate among those who developed severe acute GVHD was reduced. The prompt initiation of treatment after a more thorough examination to diagnose GVHD,10 supportive care and nutritional management may have improved the prognosis of those who had severe GVHD. Alternatively, the unique HLA epidemiological genetics of Japanese patients may have affected the results.11, 12

A recent reduction in the incidence of infection-related mortality was observed in older patients receiving UBMT or UCBT. New antifungal drugs, including mold-active azoles, micafungin or liposomal amphotericin B, are now more likely to be administered as empiric or preemptive strategies for patients who have a positive galactomannan Ag test or pulmonary nodules.1, 13, 14 As GVHD and infection have been reported to be associated with each other’s development and exacerbation,13, 15, 16, 17, 18 an improved control of severe GVHD may have led to the reduction of the risk of infection-related mortality.13, 14

We included all of the organ toxicities that were documented after allo-HCT as the cause of organ failure-related mortality, including conditioning regimen-related toxicity,19, 20 lung injury15 and late effects on any organs.21 We observed a reduction in the incidence of organ failure-related mortality in older patients receiving related HCT and those who received UBMT. In the future, more detailed analyses are warranted based on each specific organ toxicity.

As this analysis is based on a retrospectively collected multicenter database, our results may be susceptible to the disadvantages of any retrospective study, such as the heterogeneity in the treatment strategies chosen at the discretion of the physicians. Because of the nature of the multicenter registry, detailed data were not available regarding the incidences of infection and specific organ failure, and prophylactic treatment toward infection. Although we acknowledge this limitation, the results obtained from this large database that contains clinical data on over 6000 patients should provide valuable information. In addition, for the first time, we found reductions in NRM in subgroups consisting of older patients and those who received UCBT. We also showed the causes of death that contributed to the reduction of NRM in each donor/age subgroup. By further evaluating the risks of NRM and relapse in each demographic subgroup, we would be able to more clearly define the indications for allo-HCT, and tailor the strategy for individual patients.

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Acknowledgements

This work was supported by grants from the Japanese Ministry of Health, Labour and Welfare, and the National Cancer Research and Development Fund (23-A-28). The results were presented at the 52nd Annual Meeting of the American Society of Hematology in Orlando, FL, USA, 7 December 2010.

Author contributions: SK designed the study, prepared the data file, performed the analysis, interpreted the data and wrote the manuscript; KY contributed to the study design, data file preparation, data analysis and interpretation of the data; TY was primarily responsible for the study design, data analysis and interpretation of the data; YA reviewed and cleaned the data, interpreted the data and helped to write the manuscript; TNI reviewed, cleaned and interpreted the data, HA, ST, KM, ST, TE, HO and MK obtained and interpreted the data; JT, KK, KK, RS, YM and HS reviewed, cleaned and interpreted the data; TF designed the study, interpreted the data and helped to write the manuscript.

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Correspondence to T Fukuda.

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Kurosawa, S., Yakushijin, K., Yamaguchi, T. et al. Changes in incidence and causes of non-relapse mortality after allogeneic hematopoietic cell transplantation in patients with acute leukemia/myelodysplastic syndrome: an analysis of the Japan Transplant Outcome Registry. Bone Marrow Transplant 48, 529–536 (2013) doi:10.1038/bmt.2012.172

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Keywords

  • leukemia
  • allogeneic hematopoietic cell transplantation
  • non-relapse mortality
  • GVHD
  • cord blood transplantation

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