Transplant Toxicities

Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has curative potential against hematological malignancies. However, there are concerns about the associated risk of non-relapse mortality (NRM). We performed a retrospective single-center study to assess changes in outcomes after allo-HSCT and causes of NRM over three 5-year periods. The rates of 2-year NRM and overall survival (OS) were 16% and 59%, respectively. We found a significant decrease in NRM (P<0.001), with 2-year NRM of 26, 14 and 9%, and a significant increase in OS (P=0.005), with 2-year OS of 52%, 58% and 65%, over the three periods (1998–2002, 2003–2007 and 2008–2012), respectively. Of note, a steady improvement was observed in NRM, period by period, among patients aged 50 years or older, patients who underwent HSCT from an unrelated bone marrow donor and patients who underwent HSCT with a reduced-intensity conditioning regimen. Our data showed that the improved NRM can mainly be attributed to a decreased mortality related to infection after starting systemic steroid as GVHD treatment, and a decreased mortality related to organ failure.

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has curative potential against hematological malignancies, but there have always been concerns about the risk of non-relapse mortality (NRM) associated with infection, GVHD and organ dysfunction. Recently, several studies have shown improvements in outcomes of allo-HSCT over the past few decades,1, 2, 3, 4, 5, 6, 7 explained mainly by the decreased risk of NRM.

A study by Horan et al.1 using the Center for International Blood and Marrow Transplant Research database showed a reduction in NRM in patients with AML in CR who received myeloablative HSCT.1 An analysis from the European Group for Blood and Marrow Transplantation focused on causes of mortality after allo-HSCT from an HLA-identical sibling donor, and showed that death from infections was significantly reduced.4 Kurosawa et al.3, 7 analyzed the Japan transplant outcome registry database, and demonstrated that reductions in the incidences of death due to GVHD, infection and organ failure led to a decrease in NRM after allo-HSCT. It may be more important to distinguish between infection after augmentation of immunosuppressive therapy for GVHD and infection without such intervention to further delineate ways of improving HSCT outcomes. However, analyses using these multicenter registry databases allowed the assessment of only the final causes of death, and the diverse clinical courses that led to these causes were not considered. Therefore, we performed a retrospective, single-center study to assess both changes in outcomes after allo-HSCT and causes of NRM, by comprehensively reviewing each patient’s clinical course.

Patients and methods

Patients

This study was approved by the institutional review board of the National Cancer Center Hospital, Tokyo, Japan. We evaluated data on patients aged 16 years or older who had hematological malignancies and received their first allo-HSCT between 1998 and 2012. Patients who received allo-HSCT from an HLA-haploidentical donor (n=4) or an unrelated peripheral stem cell donor (n=4) were excluded because of the small number of such patients in the timeframe considered in this study. A total of 920 patients was included in the analysis.

Transplantation modalities and definitions

Conditioning regimens were classified as reported previously.8, 9 Myeloablative conditioning regimens included cyclophosphamide (Cy, 60 mg/kg for 2 days) plus either busulfan (Bu, orally 4 mg/kg for 4 days or IV 3.2 mg/kg for 4 days) (Bu/Cy) or TBI (12 Gy) (TBI/Cy). Reduced-intensity conditioning regimens included Bu (orally 4 mg/kg for 2 days or IV 3.2 mg/kg for 2 days) plus either fludarabine (Flu, 30 mg/m2 for 6 days) (Flu/Bu) or cladribine (2-CdA, 0.11 mg/kg for 6 days) (2-CdA/Bu). In a subset of patients who received the reduced-intensity conditioning regimen, low-dose TBI (2 or 4 Gy) and/or low-dose antithymocyte globulin (total dose 5–10 mg/kg Fresenius or 2.5–5 mg/kg thymoglobulin) were added. GVHD prophylaxis included cyclosporine or tacrolimus, alone or along with mycophenolate mofetil or the combination of calcineurin inhibitors and methotrexate. Prophylactic therapies against infection included low-dose acyclovir, an anti-fungal agent (fluconazole), and antibiotics for patients with neutropenia. Valacyclovir or posaconazole were not used as prophylactic therapies.

Neutrophil engraftment date was defined as the first of three consecutive days with an absolute neutrophil count of 0.5 × 109/L or higher. Acute and chronic GVHD were diagnosed and graded according to the criteria described previously.10, 11

Causes of death

Causes of NRM were categorized into four groups: infectious disease after augmentation of immunosuppressive therapy (ID with IST), infectious disease without immunosuppressive intervention (ID without IST), organ failure and GVHD. The definition of the first group, ID with IST, is death caused by infectious disease after the augmentation of systemic immunosuppressive treatment for acute or chronic GVHD. In this analysis, this augmentation was defined as the addition of a systemic steroid. The second group, ID without IST, was defined as death caused by infectious disease without the augmentation of the above-mentioned immunosuppressive treatment. The third group, organ failure, was defined as death due to organ damage that was not directly related to infection or GVHD. The fourth group, GVHD, was defined as death due to the direct effects of acute or chronic GVHD itself, such as intestinal bleeding or bronchiolitis obliterans.

Statistical analysis

Data were retrospectively reviewed and analyzed as of October 2014. We used the χ2 analysis and Fisher’s exact test to compare categorical covariates and the Kruskal–Wallis test to compare continuous covariates. We compared overall survival (OS) and NRM after allo-HSCT in three consecutive 5-year periods (1998–2002, 2003–2007 and 2008–2012). NRM was further compared in the three periods in subgroups according to patient age, donor, conditioning regimen, disease risk,12 disease type and hematopoietic cell transplantation comorbidity index (HCT-CI). The probabilities of OS were estimated using the Kaplan–Meier method, and the log-rank test was used to evaluate the differences between groups. NRM was defined as death without recurrent or progressive disease after allo-HSCT. Probabilities of NRM were estimated with the use of cumulative incidence curves, with relapse viewed as a competing risk. Gray’s method was used to evaluate the differences between groups. In cases of allo-HSCT in non-remission status, the date of relapse was defined as the first date of confirmation of relapse by an imaging test or physical presentation, or the first of three consecutive days with an increase in blasts (>5% in bone marrow or peripheral blood). Graft failures were censored at the date of the second allo-HSCT (if performed). Probabilities of chronic GVHD were estimated using cumulative incidence curves, with relapse and death without GVHD considered as competing risks. The rate of acute GVHD was compared between periods by means of logistic regression. Multivariate analysis was performed using a Cox proportional hazard regression model for OS, and competing risk regression by the method of Fine and Gray for NRM. Variables considered in univariate analyses were the years of transplant (1998–2002, 2003–2007 or 2008–2012), patient age at allo-HSCT (<50, 50 or older), patient gender (male, female), disease type (AML/myelodysplastic syndrome (MDS), ALL, malignant lymphoma/adult T-cell leukemia (ATL), CML/myeloproliferative disease (MPD) or others), disease risk (low, intermediate or high), donor source (related, unrelated bone marrow (UBM) or unrelated cord blood (UCB)), conditioning regimens (myeloablative with TBI, myeloablative without TBI or reduced intensity), GVHD prophylaxis (cyclosporine-based or tacrolimus-based), performance status (0 or 1) and HCT-CI13 (0, 1–2 or 3). In multivariate analyses, we included variables with a P-value <0.1 in univariate analyses. All statistical tests were two-sided, and P-values <0.05 were considered significant. Statistical analyses were performed with EZR version 1.27 (Saitama Medical Center, Jichi Medical University, Omiya, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, version 3.1.1). More precisely, it is a modified version of the R commander (version 2.1-2) designed to add statistical functions frequently used in biostatistics.14

Results

Patient characteristics

The detailed characteristics of the 920 patients, grouped according to transplant period, are shown in Table 1. A total of 240, 326 and 354 allo-HSCT procedures were performed in 1998–2002, 2003–2007 and 2008–2012, respectively. Overall, the median age was 48 years and the median follow-up among surviving patients was 50 months. Over the three periods, there were significant changes in the number and proportion of patients with several background characteristics, especially decreases in the number of patients with CML (1998–2002, n=39, 16%; 2003–2007, n=16, 5%; 2008–2012, n=3, 1%), transplants from related peripheral blood donors (n=143, 59%; n=149, 46%; n=94, 27%) and use of cyclosporine (n=240, 100%; n=216, 66%; n=57, 16%), and increases in the number of patients with ATL (n=7, 3%; n=26, 8%; n=44, 12%), high-risk disease (n=74, 31%; n=138, 42%; n=152, 43%), transplants from UBM donors (n=83, 35%; n=133, 41%; n=235, 66%) and use of non-TBI-based myeloablative conditioning regimens (n=38, 16%; n=74, 23%; n=104, 29%). There was no significant difference in HCT-CI among the three periods.

Table 1 Patient characteristics

Engraftment

A total of 887 patients achieved primary engraftment of neutrophils, with a median time of 15 days (range, 5–45 days). The median time to achieve engraftment of neutrophils was longer in the period of 2008–2012 compared with that in 1998–2002 (17 vs 14 days, P<0.001), which may reflect the increased use of UBM donors in the later periods. Among 33 patients who experienced primary graft failure, seven received a second allo-HSCT at a median time of 37 days (range, 31–52 days) after the first HSCT.

NRM, OS and relapse rates over the three periods

Over the 15 years, the overall NRM was 16%, and OS was 59% at 2 years after allo-HSCT. The rates of NRM significantly decreased over time, with 2-year NRM of 26%, 14% and 9% in 1998–2002, 2003–2007 and 2008–2012, respectively (P<0.001; Figure 1). As for relapse, the mid-period of 2003–2007 had the highest rate (28.1, 38.6 and 33.1% at 2 years). We also found a significant improvement in OS (P=0.005; 52, 58 and 65% at 2 years).

Figure 1
figure1

OS, NRM and relapse rate over the three periods.

Subgroup analyses of NRM according to patient background are shown in Figure 2. We observed a significant reduction in NRM over the three periods, both in patients who were 50 years or older (P<0.001; 35, 18, and 9% at 2 years) and in those who were younger than 50 years (P=0.011; 20, 10 and 10%; Figure 2a). As for donors, a significant reduction in NRM was observed among patients who underwent HSCT from a related donor (P<0.001; 25, 9 and 12%) or a UBM donor (P<0.001; 29, 18 and 8; Figure 2b). In patients receiving HSCT from a UCB donor, we did not find a clear change in NRM, partly because of the small number of such patients in each period. In an analysis based on conditioning regimen, a significant reduction in NRM was observed among patients who underwent HSCT with a myeloablative conditioning regimen containing TBI (P=0.005; 27, 13 and 8%) or with a reduced-intensity conditioning regimen (P<0.001; 27, 16 and 9; Figure 2c). As for disease risk, a significant reduction in NRM was observed among patients with intermediate-risk disease (P<0.001; 24, 12 and 9%) or high-risk disease (P=0.002; 30, 13 and 10%; Figure 2d). We also assessed the change in NRM according to HCT-CI, and found that NRM was significantly reduced in all three HCT-CI score groups (HCT-CI=0, P<0.001, 23, 15 and 7%; HCT-CI=1–2, P=0.049, 21, 7 and 9%; HCT-CI3, P=0.012, 50, 19 and 19%; Figure 2e). Of note, a further reduction of NRM in the latest period of 2008–2012 compared with the mid-period of 2003–2007 was seen among patients aged 50 years or older, those who received HSCT from a UBM donor, those who received a reduced-intensity conditioning regimen and those with an HCT-CI score of 0.

Figure 2
figure2

Changes in NRM over the three periods according to (a) age, (b) donor, (c) conditioning regimen, (d) disease risk and (e) HCT-CI score.

In multivariate analyses, the hazard ratios (HRs) for NRM in 2003–2007 and 2008–2012 compared with that in 1998–2002 were 0.53 (95% confidence interval (CI): 0.38–0.73, P<0.001) and 0.27 (95% CI: 0.18–0.41, P<0.001), respectively (Table 2). The HR for NRM in 2008–2012 was significantly lower compared with that in 2003–2007 (0.52, 95% CI: 0.34–0.79, P=0.002). The HR for overall mortality in 2008–2012 was significantly lower compared with that in 1998–2002 (0.67, 95% CI: 0.51–0.86, P=0.002), and that compared with that in 2003–2007 was 0.79 (95% CI: 0.62–1.00, P=0.05). Multivariate analysis for NRM indicated that younger age, female gender and HCT-CI of 0 or 1–2 compared with 3 were independently associated with a lower risk of NRM. Multivariate analysis for overall mortality indicated that female gender, performance status of 0, lower disease risk and HCT-CI of 0 or 1–2 were independently associated with a lower risk of mortality. The combination of female donor to male patient was found to be independently associated with worse NRM (HR=1.41, 95% CI: 1.03–1.93, P=0.03) when substituted for gender; however, the impact was not statistically significant for survival (HR=1.23, 95% CI: 0.99–1.52, P=0.055). Multivariate analysis showed no reduction in relapse rates over the three periods, and HRs in 2003–2007 and 2008–2012 were higher compared with that in 1998–2002.

Table 2 Multivariate analyses for NRM and overall mortality

GVHD

Compared with that in 1998–2002, there was a lower risk of grade III–IV acute GVHD in 2003–2007 (odds ratio 0.61; 95% CI: 0.39–0.94; P=0.026) and in 2008–2012 (odds ratio 0.41; 95% CI: 0.26–0.65; P<0.001; Table 3). The risks of stage 2–4 and 3–4 liver GVHD and stage 2–4 and 3–4 gut GVHD decreased over the three periods. The risks of stage 2–4 and 3–4 skin GVHD were higher in 2008–2012 compared with that in 1998–2002.

Table 3 Comparison of GVHD in three time periods

The cumulative incidence of chronic GVHD in patients who survived 100 days or more was compared among the three periods. Because of the loss of follow-up, 20 patients were not evaluable for chronic GVHD. There was a trend toward a decrease in the risk of chronic GVHD in recent years (Table 3). When analyzed separately for the grade of chronic GVHD, we found a lower risk of limited chronic GVHD in 2003–2007 (odds ratio 0.40; 95% CI: 0.22–0.72; P=0.002) and in 2008–2012 (odds ratio 0.46; 95% CI: 0.26–0.79; P=0.005) compared with that in 1998–2002.

Cause of NRM

A total of 180 patients died due to causes other than disease progression or recurrence (Supplementary Table 1). In 28 patients, the specific cause of death was not determined from the chart review. Eleven patients died from secondary cancers and 10 from causes not related to HSCT (e.g., accident). The remaining causes of NRM were categorized into four groups as described in the Materials and methods: ID with IST (n=54), ID without IST (n=22), organ failure (n=40) and GVHD (n=15). Patients in these groups demonstrated median OS times, respectively, of 249 days (range, 64–1974), 55 days (8–1009), 91 days (11–1564) and 214 days (50–2025). Ten of 22 patients in ID without IST group died from infectious disease during the neutropenic period before engraftment.

We found a significant reduction in the cumulative incidence of death due to ID with IST (P=0.012; 7.1, 5.1 and 2.8% at 2 years) or to organ failure (P=0.038; 7.6, 3.2 and 2.5%) over the three periods (Figure 3). The proportions of death due to ID without IST and to GVHD decreased; however, the differences were not statistically significant.

Figure 3
figure3

Cumulative incidences of mortality from four different causes: ID with IST, ID without IST, organ failure and GVHD.

Discussion

The rates of NRM and OS after allo-HSCT improved significantly over the three consecutive 5-year periods at our center. These results are compatible with prior reports.1, 2, 3, 4, 5, 6, 7 There were remarkable changes in patient background characteristics over the three periods, such as an increased number of cases of HSCT from a UBM donor, older patients and patients with high-risk disease. Despite the extended application of HSCT to these more vulnerable patients, there was an improvement in outcome after HSCT.

A constant improvement was observed in NRM over the 15 years, in patients aged 50 years or older, those who underwent bone marrow transplantation from an unrelated donor and those who were conditioned with reduced-intensity regimens. Impressively, 2-year NRM among patients aged 50 years or older improved to 9% in 2008–2012 compared with 34% in the earliest period of 1998–2002. Although NRM was significantly reduced in all patient subgroups in later periods as compared with that in 1998–2002, the difference in NRM between the 2003–2007 and 2008–2012 periods was not significant except in the above-mentioned subgroups. One explanation may be that the outcomes of HSCT in patients with relatively lower NRM risk, such as in younger patients or those receiving HSCT from a related donor, already improved to a certain extent in 2003–2007, and further improvements were not achieved in the latest period. Additionally, because related donors or UBM donors were chosen in most HSCT procedures conducted at our center in the overall study period, we did not have sufficient data on the outcomes of HSCT from UCB or haploidentical donors. Although the risk of NRM after HSCT from a UCB donor has been reported to be higher,3 both UCB and haploidentical donors may serve as promising donor sources, especially when a patient without an HLA-matched related donor needs to undergo an urgent HSCT. It is necessary to further evaluate the improvements in outcomes of HSCT from these alternative donors.

We found a significant decrease in mortality related to infection after systemic steroid therapy, which may have contributed to the reduction in NRM. One possible explanation for this change is a decreased incidence of grade III–IV acute GVHD, particularly involving the gut and liver. Advances in HLA typing technology15 and GVHD prophylaxis,16 as well as early detection of and intervention in GVHD,17 may have reduced the incidence of lethal GVHD. A decrease in severe gut GVHD may have resulted in a lower risk of bacterial infection due to bacterial translocation from the intestinal tract.18 Another possible explanation for the reduction in infection-related mortality is the recent progress in the treatment of and prophylaxis against infectious diseases. Administration of systemic steroids as GVHD treatment is a known risk factor for infection.19 As for fungal infection, we found a decrease in the number of deaths regardless of GVHD/immunosuppression background (Supplementary Table 1). More prompt diagnosis with the advent of monitoring technology (e.g., galactomannan enzyme immunoassay20), early computed tomography scan policy for suspected fungal infection, and the use of newer anti-fungal agents such as voriconazole may have had a role in the reduced number of deaths from fungal infections, including invasive aspergillosis.21 We adopted preemptive treatment using ganciclovir or valganciclovir against CMV based on weekly monitoring of C7-HRP (CMVpp65) since 2002.22 As systemic steroid administration causes hyperglycemia, a well-established risk factor for infectious diseases,23 better glucose control after allo-HSCT in recent years might have contributed to the reduced incidence of lethal infections in patients receiving systemic steroid administration for GVHD.24 In addition, use of IV Ig for patients with low IgG value (<500 mg/dL) may have helped decrease the incidence of severe infection.

As for the incidence of chronic GVHD, we found a trend toward a decrease in the risk of chronic GVHD in recent years, and the decrease was specifically significant in limited chronic GVHD. Our finding was inconsistent with the report from the Center for International Blood and Marrow Transplant Research that they observed an increased incidence of cGVHD in more recent years.25 The authors showed the increase in number of the use of PBSC grafts over time (from 17% in the earliest period to 63% in the latest). In addition, they showed in their analysis that the use of PBSC graft was an independent factor associated with higher risk of cGVHD. The use of PBSC in our institution apparently decreased (from 59 to 27%), which could explain this discrepancy.

We also found a significant decrease in mortality related to organ failure, mainly of the liver and lung. Gooley et al.2 reported a similar reduction in the risk of liver, kidney and lung toxicities. Various factors may have contributed to the improvement regarding organ damage. The routine administration of ursodeoxycholic acid may have had a role in reducing hepatic complications.26, 27 Furthermore, the reduction in the risk of severe GVHD may have led to the improved outcomes.

The improved OS rates were derived mainly from decreased NRM rates and not from decreased relapse rates. Further studies of pre- and post-HSCT interventions for reducing relapse rates are warranted. Recently reported interventions include the use of clofarabine in conditioning regimens,28 early intervention for minimal residual disease29, 30 and post-HSCT maintenance therapy with novel, less toxic agents such as hypomethylating agents31 or tyrosine kinase inhibitors.32

Our study has several limitations, and thus the results must be interpreted with caution. These include the retrospective nature of the study and the associated risk of confounding variables. The short follow-up time, especially in the latest period, may have led to the underestimation of late adverse effects such as secondary cancer, late-term infection and chronic GVHD.

In summary, our single-center analysis showed an improvement in NRM and a reduction in the risks of death due to infection and organ failure after allo-HSCT over the past 15 years. The next step is to improve the outcomes of HSCT using newer approaches such as the use of haploidentical donors, which would further extend one of the main benefits of HSCT, namely a reduction in the risk of relapse, to a broader range of patients.

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Acknowledgements

This work was supported by grants from the Japanese Ministry of Health, Labor and Welfare and the National Cancer Research and Development Fund (26-A-26). We thank the medical, nursing, data-processing, laboratory, and clinical staff at the National Cancer Center Hospital, Tokyo, Japan for their important contributions to this study and their dedicated care of the patients.

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Correspondence to S Kurosawa.

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Tanaka, Y., Kurosawa, S., Tajima, K. et al. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 51, 553–559 (2016) doi:10.1038/bmt.2015.330

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