Graft-Versus-Host Disease

Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation

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Abstract

Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.

Introduction

Acute GvHD (aGvHD) is a frequent and sometimes unpredictably severe inflammatory complication occurring after allogeneic hematopoietic cell transplantation (HCT).1 To improve HCT prognosis, various strategies are considered for patients with previously identified aGvHD risk factors, such as patient age and sex, underlying disease, unrelated donors, mismatch in HLA and ABO blood type, stem cell sources or dosage, conditioning regimens and GvHD prophylaxis.2, 3, 4, 5, 6, 7, 8

Although aGvHD is a systemic inflammatory condition, its presentation differs greatly according to the organ involved. In hepatic aGvHD, pathogenetic mechanisms other than those involving the skin or the gut are suspected,9 suggesting the existence of organ-specific risk factors (especially related to pre-transplant liver conditions) in addition to common risk factors mentioned previously. The incidence of hepatic aGvHD is far lower than that of skin or gut aGvHD, and risk factors for hepatic aGvHD may have been overlooked in previous analyses of aGvHD as a whole; therefore, analyses focused on hepatic aGvHD are necessary. If specific risk factors for hepatic aGvHD are confirmed, a new strategy—including modified donor selection and/or GvHD prophylaxis—may reduce hepatic aGvHD incidence and improve prognosis. Hepatic aGvHD often results in HCT-related mortality because of poor response to conventional treatment.10, 11

Previous studies have shown that certain pre-transplant liver conditions are related to higher risk of overall transplant-related mortality (TRM) after HCT; these conditions include chronic hepatitis B or C virus (HBV or HCV) infection,12, 13 pre-transplant liver dysfunction after previous therapies14 or severe iron overload from multiple transfusions.15 However, it has not yet been determined whether these conditions are related to hepatic aGvHD. Therefore, we conducted a cohort study to identify the specific risk factors for hepatic aGvHD focusing on pre-transplant liver conditions, and to determine its cumulative incidence and effects on prognosis after HCT by using the Japanese transplant registry database.

Patients and methods

Inclusion and exclusion criteria

Data for 8443 adult patients (age16 years) with hematological malignancies who underwent a first allogeneic HCT without T-cell depletion using bone marrow from related or unrelated donors, peripheral blood from relatives or a single cord blood unit between 1 January 2008 and 31 December 2012, were obtained from the Transplant Registry Unified Management Program in Japan.16 Patients who underwent HCT using peripheral blood from unrelated donors or a double cord blood unit were excluded because of their small number in our cohort. Patients for whom data for the hematopoietic cell transplant co-morbidity index (including pre-transplant liver dysfunction)17 was not available were also excluded (N=65), and thereby 8378 patients were included in this study. Our protocol complied with the Declaration of Helsinki, and was approved by the Transplant Registry Unified Management Program Data Management Committee and the Ethics Committee of Kyoto University, where this study was performed. Written informed consent to be included in any future retrospective database study was obtained from each patient at each institution.

Data collection and definition of each covariate

From the registry database, we extracted data on pre-transplant liver conditions, such as hepatitis viral infection (surface Ags for HBV (HBsAg) and antibodies for HCV (HCV-Ab)), previous history of multiple erythrocyte transfusions (20 packs) and hematopoietic cell transplant co-morbidity index scores (that included information on pre-transplant hepatic function), in addition to basic characteristics about HCT.

Pre-transplant liver dysfunction was defined as an elevation of transaminase and/or bilirubin levels above the upper normal limit. Extreme elevation of transaminase (>2.5 × upper normal limit) or bilirubin levels (>1.5 × upper normal limit), or the presence of cirrhosis were regarded as severe liver dysfunction, according to the criteria for hematopoietic cell transplant co-morbidity index.17 Patients were divided into standard- and advanced-risk groups according to the previous criteria of disease risk.18 HCT risk was determined as high if hematopoietic cell transplant co-morbidity index total points were three or higher.17 HLA disparity in HLA-A, B and DR Ags was determined at serologic (in bone marrow from related, peripheral blood from relatives and cord blood unit) or genomic levels (in unrelated bone marrow). Definitions of myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) were consistent with those established in the RIC regimen workshop.19 The diagnosis and classification of aGvHD were carried out by attending physicians at each center based on traditional criteria;20, 21 the GvHD guidelines published by the Japan Society for Hematopoietic Cell Transplantation22 recommend that hepatic aGvHD should be diagnosed after excluding such differential diagnoses as viral infection, veno-occlusive disease, drug-induced liver injury and thrombotic microangiopathy by using any available modalities including peripheral blood testing, ultrasonography, computed tomography scan or biopsy.

Statistical analyses

The probability of developing aGvHD was estimated on the basis of cumulative incidence curves, considering early death and relapse as competing risks23 (that is, any aGvHD diagnosed after relapse was not included) in accordance with the statistical guidelines from the European Group for Blood and Marrow Transplantation.24 Univariate analyses of the cumulative incidence of hepatic aGvHD (stage 1) were performed using Gray’s method.25 Factors with significance or borderline significance (P<0.1) in the univariate analyses and those related to pre-transplant liver conditions (HBsAg, HCV-Ab, liver dysfunction and multiple erythrocyte transfusions) were subjected to a multivariate analysis using Fine-Gray proportional hazards models.26 Overall survival (OS) was calculated with the Kaplan–Meier method after the landmark of 60 days from HCT and compared by using log-rank tests; this landmark was set at the time-point when >80% of all aGvHD episodes had been observed. OS was also analyzed with regard to hepatic aGvHD complication as a time-dependent covariate. TRM was analyzed after the same landmark, considering relapse as a competing risk. It should be noted that TRM in our study may not include regimen-related mortality, which usually occurs immediately after HCT. The Cox proportional hazards model was used to evaluate the effect of hepatic aGvHD and other confounding variables on OS; the Fine-Gray proportional hazards model was used for TRM. Statistical analyses were performed using Stata (version 13.1, Stata Corp LP, College Station, TX, USA). The alpha level of all tests or the P-value was set at 0.05.

Results

Patient characteristics

We evaluated 8378 patients aged 16–80 years (median, 49 years) (Table 1). HBsAg and HCV-Ab were positive in 3.5% and 1.5% of patients, respectively. About a quarter of the patients (26.9%) had undergone multiple erythrocyte transfusions (20 packs or more) before HCT. Pre-transplant liver dysfunction was observed in 9.4% of patients; severe cases comprised 1.5% of the cohort. The median follow-up period for survivors was 760 days (range, 31–2075 days) after HCT.

Table 1 Patients characteristics

Cumulative incidence of hepatic aGvHD

The cumulative incidence of hepatic aGvHD in all stages was 6.7% (95% confidence interval (CI), 6.1–7.3%; Figure 1a), and the median time of occurrence was 34 days after HCT. More than 80% of hepatic aGvHD episodes (83.2%) occurred within 60 days after HCT. Among all hepatic aGvHD patients, 33.9% were stage 1, 23.1% were stage 2, 22.2% were stage 3 and 20.8% were stage 4.

Figure 1
figure1

Cumulative incidence and distribution of hepatic aGvHD. (a) Cumulative incidence of hepatic aGvHD. The probability of developing aGvHD was estimated on the basis of cumulative incidence curves, considering early death and relapse as competing risks. The cumulative incidence of hepatic aGvHD in all stages was 6.7% (95% CI, 6.1–7.3%), and the median day of occurrence was 34 days after HCT. More than 80% of hepatic aGvHD episodes (83.2%) occurred within 60 days after HCT. (b) Distribution of aGvHD lesions to each organ among those with grade II–IV aGvHD. Grade II–IV aGvHD was observed in 3356 patients (cumulative incidence, 40.5%; 95% CI, 39.4–41.6%). Among them, skin lesions (stage 1 or higher) was observed in 83.0%, gut (stage 1 or higher) in 56.7%, and liver (stage 1 or higher) in 16.1%. Only 1.6% of grade II–IV aGvHD was composed of a liver lesion alone. (c) Proportion of hepatic aGvHD and its stage according to each grade of aGvHD. Higher stages of hepatic aGvHD were observed in proportion to the higher grades of aGvHD. (d) Difference in cumulative incidence of hepatic aGvHD according to risk factors. The cumulative incidence curves (unadjusted with other confounders) were compared according to pre-transplant HCV-Ab positivity and pre-transplant liver function. Cumulative incidence of hepatic aGvHD was 11.9% in patients with HCV-Ab (in comparison with 6.7% in those without HCV-Ab) and 11.6% in patients with liver dysfunction (in comparison with 6.2% in those with normal liver function). Unadjusted HR was 1.86 and 1.92, and adjusted HR was 1.93 and 1.85, respectively (shown in Table 2).

On the other hand, skin (stage 3–4) and gut (stage 1 or higher) aGvHD were observed more frequently (cumulative incidence, 23.3%; 95% CI, 22.4–24.2%; and 22.9%; 95% CI, 22.0–23.8%, respectively), and were more common targets (skin, 83.0%; gut, 56.7%) of grade II–IV aGvHD (cumulative incidence, 40.5%; 95% CI, 39.4–41.6%) (Figure 1b). Hepatic aGvHD was observed in 16.1% of those with grade II–IV aGvHD: 5.0% with grade II, 30.8% with grade III and 56.3% with grade IV (Figure 1c).

Risk factors for hepatic aGvHD

The univariate analyses showed that HCV-Ab positivity, pre-transplant liver dysfunction, patient sex (male), underlying disease (non-Hodgkin lymphoma), advanced disease risk, donor sources (peripheral blood from relatives), ABO major mismatch, HLA mismatch and GvHD prophylaxis with cyclosporine were risk factors of significance (P<0.05) or borderline significance (P<0.1) (Table 2).

Table 2 Risk factors for hepatic aGvHD

The multivariate analyses showed that HCV-Ab positivity (hazard ratio (HR), 1.93; 95% CI, 1.10–3.38; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; 95% CI, 1.45–2.36; P<0.01) were significant risk factors for hepatic aGvHD along with advanced disease risk, peripheral blood from relatives or unrelated bone marrow, HLA mismatch and use of cyclosporine (Table 2 and Figure 1d). Severity of pre-transplant liver dysfunction was not related to the risk of hepatic aGvHD (data not shown), partially because of the small number of patients with severe liver dysfunction before HCT. HBsAg and multiple erythrocyte transfusions were NS risk factors.

The interaction between HCV-Ab positivity and pre-transplant liver dysfunction on the incidence of hepatic aGvHD reached borderline significance (P=0.06). Therefore, we established a new categorical variable indicating the presence or absence of HCV-Ab with or without liver dysfunction and carried out multivariate analyses with this new variable and other variables listed previously (Supplementary Table 1). As a result, compared with the reference group (normal liver function without HCV-Ab), pre-transplant liver dysfunction was a significant risk factor for development of hepatic aGvHD in HCV-Ab negative patients (HR, 1.73; 95% CI, 1.34–2.24; P<0.01) as well as HCV-Ab positive patients (HR, 6.87; 95% CI, 3.23–14.6; P<0.01). However, HCV-Ab positivity with normal liver function was not a significant risk factor (HR, 1.08; 95% CI, 0.44–2.65; P=0.87).

These two risk factors (HCV-Ab and liver dysfunction) were NS for stage 3–4 skin or gut aGvHD in multivariate analyses, whereas other factors such as disease risk, HCT type, HLA mismatch and GvHD prophylaxis were common risk factors for skin and/or gut aGvHD (Supplementary Table 2). These data indicated that HCV-Ab positivity and liver dysfunction are specific risk factors for hepatic aGvHD.

The relationship of conditioning regimens and incidence of hepatic aGvHD was analyzed. HCV-Ab positivity was a significant risk factor both in MAC and in RIC. Pre-transplant liver dysfunction was also a significant risk factor in MAC (HR, 2.12; 95% CI, 1.59–2.82; P<0.05), although NS in RIC (HR, 1.27; 95% CI, 0.78–2.06; P=0.34) partially because of the relatively small number of patients. Furthermore, we focused on TBI and fludarabine, because previous studies showed that TBI increased overall aGvHD8 and that fludarabine can be a risk factor for post-transplant liver injury in RIC.27 TBI was used in 63.5% of patients receiving MAC and 63.0% of those receiving RIC regimen. As a result, no significant differences were observed between the regimens with and without TBI (HR, 1.12; 95% CI, 0.89–1.43; P=0.32 in MAC; HR, 0.93; 95% CI, 0.67–1.31; P=0.69 in RIC) or fludarabine (HR, 1.17; 95% CI, 0.97–1.48; P=0.16 in MAC; HR, 0.76; 95% CI, 0.40–1.44; P=0.40 in RIC) regarding the incidence of hepatic aGvHD. Any other chemotherapeutic drugs were not significantly related to the incidence of hepatic aGvHD.

Impacts of hepatic aGvHD on OS and TRM

OS was shown to be poorer in patients with hepatic aGvHD complications by using landmark analysis (unadjusted HR, 2.62; P<0.01) in comparison with that in patients without hepatic aGvHD. More than 10% (N=69) of all the patients with hepatic aGvHD (N=554) died before Day 60 (the landmark), so we confirmed the impact of hepatic aGvHD on OS in the analysis regarding hepatic aGvHD as a time-dependent covariate, and obtained almost the same result (HR, 2.98; P<0.01). Moreover, hepatic aGvHD complication was the independent factor that worsened OS at each aGvHD grade (Figure 2 and Table 3); OS at 3 years was lower in patients with grade II aGvHD with hepatic lesions than in those without hepatic lesions (44.1% vs 60.3%). Prognosis of grade III aGvHD without hepatic aGvHD was much better than with hepatic aGvHD (42.5% vs 29.3%). Complication with grade IV aGvHD including hepatic lesions showed by far the worst survival (3-year OS, 5.9%; 95% CI, 2.5–11.5%).

Figure 2
figure2

OS according to each grade of aGvHD with or without hepatic aGvHD. OS was calculated with the Kaplan–Meier method after the landmark of 60 days from HCT according to the grade of aGvHD and the existence of hepatic aGvHD. The complication of hepatic aGvHD was the independent factor worsening OS at each grade of aGvHD. OS at 3 years was lower in patients with grade II aGvHD with hepatic lesions (44.1%; 95% CI, 32.4–52.3%) than those with grade II aGvHD without hepatic lesions (60.3%; 95% CI, 57.8–62.8%). Prognosis of grade III aGvHD without hepatic aGvHD (3-year OS, 45.2%; 95% CI, 39.7–50.6%) was much better than that of grade III aGvHD with hepatic aGvHD (3-year OS, 29.3%; 95% CI, 22.5–36.3%). Complication with grade IV aGvHD including hepatic lesions showed by far the worst survival (3-year OS, 5.9%; 95 % CI, 2.5–11.5%). Existence of hepatic aGvHD can be a strong prognostic factor in each grade of aGvHD (grade II–IV).

Table 3 Impacts of hepatic aGvHD on OS and TRM

Lower OS (or higher overall mortality) in those with hepatic aGvHD was mainly from higher TRM. Complications of hepatic aGvHD increased the HR of TRM by about 1.8–3.9 times in each severity grade of aGvHD from II to IV (Table 3). The most common cause of transplantation-related death in patients with hepatic aGvHD was deterioration of aGvHD (30.3%), followed by bacterial infection (16.9%), hemorrhage (7.9%) and thrombotic microangiopathy (4.5%), whereas infection was the most common cause of TRM (15.3%) in patients without hepatic aGvHD.

Discussion

The present cohort study using a large-scale national registry database in Japan revealed three major findings: (1) the cumulative incidence of total hepatic aGvHD was 6.7%, (2) HCV-Ab positivity and liver dysfunction before HCT were specific significant risk factors for hepatic aGvHD and (3) the complication of hepatic aGvHD had a significant negative impact on OS, mainly because of higher TRM.

Our study succeeded in identifying, for the first time, two specific risk factors for hepatic aGvHD; pre-transplant HCV-Ab positivity and liver dysfunction. These data are valuable from the viewpoint of particular features of hepatic aGvHD. It has been previously shown that local pathogenetic mechanisms underlying liver aGvHD differ from those of the skin and gut, judging from the different composition of infiltrating leukocytes and adhesion molecule expression in the liver.9 Therefore, identifying specific risk factors for hepatic aGvHD is as important as modifying aGvHD treatments to reduce the high incidence of TRM, mainly from aGvHD deterioration and severe infection. Other studies have demonstrated some risk factors for total post-transplant liver dysfunction (comprised of aGvHD, veno-occlusive disease and fulminant liver failure); these risk factors include pre-transplant HCV infection with liver dysfunction,12 HBV infection28 and inclusion of fludarabine in RIC regimens.27 However, these studies could not confirm a significant relationship with each factor and hepatic aGvHD itself, probably because of limited sample sizes (cohort <400 patients).

In addition to determining risk factors for hepatic aGvHD, we have also shown that existence of hepatic aGvHD can be a strong prognostic factor in each grade of aGvHD (grade II–IV). A retrospective cohort study (N=257)29 supports our findings and shows that hepatic aGvHD increased TRM 2.45 times (95% CI, 1.46–4.12) after patients with all grades of aGvHD were analyzed. Hepatic aGvHD remains an independent risk factor for prognosis 40 years after the initial establishment of the aGvHD grading system by Glucksberg et al.20 These data indicate that to reduce TRM related to hepatic aGvHD, new prophylactic strategies for specific liver conditions should be suggested; for example, monitoring of HCV-RNA can be useful in patients with HCV-Ab because it is a sensitive technique to quantify the systemic viral load,30 which is closely related to liver injury.31 HCV viral load may possibly be an important biomarker to evaluate the risk of hepatic aGvHD; this relationship should be analyzed in the future study.

Our study reveals critical aspects of hepatic aGvHD using a large nationwide database in Japan; however, there are some limitations regarding pre-transplant liver dysfunction and the diagnosis of hepatic aGvHD. First, regarding pre-transplant liver dysfunction, our database includes information on HBV or HCV infections and multiple erythrocyte transfusions, whereas the existence of other causes such as liver abscess, suspected drugs and steatohepatitis are unknown. These causes may be common in terms of chronic liver injury or inflammation; however, they should be analyzed separately as candidates for hepatic aGvHD risk factors, not treated as a whole. Moreover, we have data only on HBsAg, not on HBsAb, HBV core Ab or viral load; this may have prevented the detection of the relationship between HBV infection and hepatic aGvHD in this study. In HCV-Ab-positive patients, our database lacks information on HCV-RNA titer, which is necessary for the determination of HCV-related hepatitis.30 Second, data on diagnostic procedures were not available for some patients (30.5%), and it was assumed that hepatic aGvHD diagnoses were made in some of these patients (the number is unknown) without a pathological examination. As previously stated, the guidelines in Japan recommend the use of various diagnostic tools before confirming hepatic aGvHD, especially when pathological examinations are not possible;22 another recommendation recently published by the liver pathology group of the German-Austrian-Swiss working group on GvHD was that hepatic GvHD diagnosis can be made without a liver biopsy if clinical symptoms of hepatic GvHD are present (especially if other organ manifestations are apparent) and the patient responds to GvHD therapy.32 In our cohort, >90% of all hepatic aGvHD cases were accompanied by apparent skin and/or gut aGvHD lesions (Figure 1b). In the sensitivity analyses in which hepatic aGvHD cases diagnosed without biopsies were excluded or treated as cases without hepatic aGvHD, these two liver-specific factors (HCV-Ab and pre-transplant liver dysfunction) were recognized as risk factors for hepatic aGvHD. Moreover, analyses including only severe (stage 2–4, or stage 3–4) hepatic aGvHD proposed the same risk factors. We also confirmed that the occurrence of hepatic aGvHD can be a significant risk factor for the subsequent emergence of chronic GvHD in the liver (P<0.01). These sensitivity and subgroup analyses support the reliability of our main results, including the accuracy of the diagnosis of hepatic aGvHD; however the possibility that post-transplant deterioration of preexisting liver damage was misdiagnosed as hepatic aGvHD cannot completely be excluded especially when skin and/or gut aGvHD were complicated. A prospective study including detailed information on pre-transplant liver function, hepatitis viral status, post-transplant hepatic function and procedures in hepatic aGvHD diagnosis is necessary to overcome these limitations. Data on pathologically-confirmed hepatic aGvHD will be valuable in the validation for our retrospective study.

In summary, we analyzed the incidence of hepatic aGvHD, identified specific risk factors (pre-transplant HCV-Ab positivity and liver dysfunction) and determined the effects on patient prognosis after HCT using a national database. A large-scale prospective study is awaited to decide whether the modification of GvHD prophylaxis, donor selection, conditioning and early intervention may improve the prognosis of patients with high-risk factors, such as those indicated in this study.

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Acknowledgements

We would like to thank all the physicians and data managers at the centers who contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation (JSHCT), the Japan Marrow Donor Program (JMDP), the Japan Cord Blood Bank Network (JCBBN) and Transplant Registry Unified Management Program. We also thank the members of the Data Management Committees of JSHCT, JMDP, JCBBN and Transplant Registry Unified Management Program for their assistance. We also thank Dr Fumiaki Nakamura in the University of Tokyo for his critical advice for statistical analyses. This study was supported by research funding from the Ministry of Education, Science, Sports and Culture in Japan to TK.

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Correspondence to T Kondo.

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Arai, Y., Kanda, J., Nakasone, H. et al. Risk factors and prognosis of hepatic acute GvHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 51, 96–102 (2016) doi:10.1038/bmt.2015.205

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