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Hepatic sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation in adult patients with idiopathic aplastic anemia
Leukemia Research 37 (2013) 1241–1247
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Hepatic sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation in adult patients with idiopathic aplastic anemia Hawk Kim a,1 , Kyoo-Hyung Lee b,1 , Sang Kyun Sohn c,1 , Chul Won Jung d,1 , Young Don Joo e,1 , Sung Hyun Kim f,1 , Byung Soo Kim g,1 , Jung Hye Choi h,1 , Jae-Yong Kwak i,1 , Min Kyoung Kim j,1 , Sung Hwa Bae k,1 , Ho-Jin Shin l,1 , Jong Ho Won m,1 , Sukjoong Oh n,1 , Won Sik Lee o,1 , Jae-Hoo Park a,1 , Sung-Soo Yoon p,∗,1 a
Divison of Hematology and Hematological Malignancies, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Hemato/Oncology, Kyungpook National University Hospital, Kyungpook National University, Daegu, Republic of Korea d Department of Hemato/Oncology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea e Department of Hemato-Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea f Department of Hemato-Oncology, Dong-A University Medical Center, Dong-A University, Busan, Republic of Korea g Department of Hematology/Oncology, Korea University Hospital Seoul Hospital, Korea University, Seoul, Republic of Korea h Department of Hematology/Oncology, Hanyang University Hospital, Hanyang University, Seoul, Republic of Korea i Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University, Jeonju, Republic of Korea j Department of Hematology/Oncology, Yeungnam University Medical Center, Yeungnam University, Daegu, Republic of Korea k Division of Hematology/Oncology, Daegu Catholic University Hospital, Daegu Catholic University School of Medicine, Daegu, Republic of Korea l Department of Hematology and Oncology, Pusan National University Hospital, Pusan National University, Busan, Republic of Korea m Department of Hematology/Oncology, Soon Chun Hyang University Hospital, Soon Chun Hyang University, Seoul, Republic of Korea n Department of Hematology/Oncology, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea o Department of Hematology/Oncology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea p Department of Internal Medicine, Seoul National University Hospital, Seoul National University, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 8 April 2013 Received in revised form 4 June 2013 Accepted 17 June 2013 Available online 18 July 2013 Keywords: Sinusoidal obstruction syndrome Veno-occlusive disease Aplastic anemia Allogeneic hematopoietic stem cell transplantation
a b s t r a c t We retrospectively investigated the incidence, risk factors, and outcomes of SOS (sinusoidal obstruction syndrome; previously veno-occlusive disease [VOD]) after allogeneic hematopoietic stem cell transplantation (alloHSCT) in aplastic anemia. Two hundred and sixty patients were included in the analysis. SOS developed in 7.3% (n = 19/260) of patients. Classical Cy (200 mg/m2 )-ATG was the most common conditioning regimen (84.2%) in the SOS group. The SOS mortality rate was 4/19 (21.1%). Univariate analyses revealed that Cy 200 mg/m2 conditioning (p = 0.035), classical Cy-ATG conditioning (p = 0.007), and horse ATG conditioning (p < 0.001) were significant risk factors for developing SOS. Multivariate analysis revealed that only horse ATG conditioning was a poor prognostic factor (HR = 3.484; 95% CI 1.226–9.904; p = 0.002). Rabbit ATG (HR 12.719; 95% CI 2.332–69.373; p = 0.003) and weight gain > 10% (HR 35.655; 95% CI 2.208–575.805; p = 0.012) were risk factors in the overall SOS group. Both rabbit ATG conditioning and weight gain of more than 10% were associated with poor overall survival with a median of 1.2 months (5Y survival rate, any risk factor vs. none: 74.6% vs. 0.0%; p < 0.001; Fig. 2) in the SOS group. In conclusion, SOS is a relatively rare (7.3%) but highly fatal (21.1%) acute complication of alloHSCT in AA, and the horse ATG conditioning regimen was a significant risk factor for developing SOS. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction
∗ Corresponding author at: Department of Internal Medicine, Seoul National University Hospital. Seoul National University 101 Daehang-ro, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: +82 2 2072 3079; fax: +82 2 762 9662. E-mail address: [email protected] (S.-S. Yoon). 1 On behalf of The Korean Society of Blood and Marrow Transplantation. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.06.024
Hepatic sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease [VOD]) is a rare complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). The diagnosis of SOS is generally based on clinical features such as hyperbilirubinemia, tender hepatomegaly, and weight gain. In a large study of patients undergoing alloHSCT, the reported incidence
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of SOS was as high as 53% and the case fatality rate was 47% [1–3]. However, the reported incidence and fatality rates of SOS show high variability, ranging from 0% to 70% [4–6]. Recent reports indicate that the incidence and mortality are decreasing. This decline might be caused by the low incidence of SOS among reduced-intensity conditioning and the reduction among those receiving myeloablative alloHSCT from unrelated donors [7,8]. These data not only come from patients with many different diseases, mainly hematologic malignancies, but also from patients with many different conditioning regimens. There have been only a few reports of SOS in AA (aplastic anemia), involving very small numbers of patients. In our previous report of SOS incidence after alloHSCT for AA, 7 of 17 patients who received cyclophosphamide at 200 mg/kg developed SOS (5 mild, 2 moderate) with maximum bilirubin levels of 4.2–21 mg/dL. The maximum weight gain ranged from 3.5 to 29% [9]. Retrospective data obtained after alloHSCT for a few patients with Fanconi anemia or hepatitis-associated AA revealed a similar incidence of veno-occlusive disease (5.9–16.7%) in the cyclophosphamide (Cy)antithymocyte globulin (ATG) arm [10,11]. Many transplantation-related risk factors for SOS have been suggested, such as a high-dose conditioning regimen, busulfan for conditioning, total body irradiation (TBI), graft from unrelated donors or related HLA mismatched transplants, and methotrexate as part of graft versus host disease (GvHD) prophylaxis [1,12–14]. Usually, there is no need for a high-dose or busulfan-containing conditioning regimen for AA patients, which implies that the risk factors for SOS will be different in AA patients. Here we present a retrospective analysis of the incidence, clinical characteristics, and risk factors of SOS after alloHSCT in AA patients. 2. Patients and methods 2.1. Patient eligibility Patients were included if transfusion dependent/severe/very severe acquired aplastic anemia (AA) was diagnosed; if patients were >15 years of age at the time of the alloHSCT treatment; and if patients had undergone alloHSCT from an HLA-matched related donor (MRD) or alternative donor (AD), regardless of immunosuppressive therapy (IST) history. Exclusion criteria were the presence of congenital aplasia, including Fanconi anemia, Diamond–Blackfan syndrome, congenital dyskeratosis, or hypoplastic myelodysplastic syndrome. 2.2. Data collection The original protocol was approved by the Korean Society of Blood and Marrow Transplantation (KSBMT) Clinical Study Committee (approval no. KSBMT07-02) for retrospective comparison between MRD and AD, and by the Cooperative Study Group A for Hematology (C-006A study) phase III prospective trial [15]. These two study populations were combined for this analysis. Data were also collected from patients with pure red cell aplasia and paroxysmal nocturnal hemoglobinuria in the KSBMT07-02 study and from patients with hypoplastic myelodysplastic syndrome in the COSAH (C-006A) study, but such patients were not included in this final analysis. The detailed SOS-related data were collected separately from additional queries for each patient who had developed SOS. 2.3. Evaluation criteria The principal concern of the study was to define the actual incidence of SOS after alloHSCT in adult patients with AA. We also aimed to define which factors influenced the development and final outcome of SOS. SOS was diagnosed using McDonald’s guidelines and modified Seattle criteria [1,4]. At least two of the following three criteria should be present to fit the diagnosis of SOS within 30 days after transplantation: weight gain > 5% from baseline body weight; hepatomegaly with right upper quadrant pain; and hyperbilirubinemia (serum bilirubin > 2 mg/dL). No other explanation for these signs and symptoms were present at the time of diagnosis. The first day on which the clinical criteria were satisfied was defined as day 0 of SOS. Doppler sonogram or other imaging modalities were not required for the diagnosis of SOS in this study. Patients who met the criteria for SOS, but who were not treated and whose illness was self-limiting, were classified as having mild SOS. Those whose SOS resolved but who received treatment, such as diuretics for fluid retention or narcotic analgesics for painful hepatomegaly, were classified as having moderate SOS. Patients who died of SOS or whose SOS had not resolved by 100 days
post-transplant were considered to have severe SOS. All patients who had developed SOS were defined as the SOS group and the others as the no-SOS group. Performance status was graded by ECOG performance scoring. Relapse was defined as the reacquisition of transfusion dependence or fulfillment of severe/very severe criteria after successful engraftment. Other evaluation criteria were the same as in our previous study [15]. 2.4. Statistical analyses All analyses were performed on an intention-to-treat basis. The patients were divided into two groups: a no-SOS group who did not develop hepatic SOS and an SOS group who did develop SOS. The Chi-square test was used to compare categorical variables and Student’s t-test was used to compare continuous variables between any two groups. The start point for the determination of time-dependent parameters was the first day of stem cell infusion. Time to SOS was defined from the first day of stem cell infusion to the day on which SOS was diagnosed. Overall survival was measured from the time of stem cell infusion to the date of death, or the last date on which the patient was known to be alive (this constituted censoring). Survival curves were computed according to the Kaplan–Meier method, and differences in survival were compared by the log-rank test. Death directly due to SOS was defined as an event in SOS-specific survival and SOS-specific mortality. A Cox’s proportional hazard model was used to determine the effects on survival of various prognostic factors, including age, donor/recipient gender matching, number of cells transfused, use of irradiated blood products, time from diagnosis to alloHSCT, stem cell source, dose of irradiation, HLA matching, method of immune suppression used to prevent GvHD, IST history, and type of ATG. All variables were dichotomized and converted into categorical classes. The variables included in the multivariate analysis were the patients’ ages, and all prognostic factors with p-values <0.05 in the univariate analyses. Differences were assessed using a two-sided test at the p = 0.05 level of significance.
3. Results 3.1. Patients Data from 260 adult patients who received alloHSCT for acquired severe aplastic anemia (sAA) between 1985 and 2010 were collected from 15 Korean institutions. The median age was 31.2 (range 14.1–63.6) years; 134 (51.5%) were male; 68.1% of patients had matched-related donors, 82.7% had HLA full-matched donors, and 17.7% had female to male donor–recipient sex-matched donors. Three patients aged less than 15 years (14.1, 14.5, and 14.9 years) were included in the final analysis. The drugs used for the conditioning regimens were cyclophosphamide in 97.7%, ATG in 84.3%, and fludarabine in 33.8%. TBI was incorporated in the conditioning regimen of 9.2% of patients. Table 1 shows the detailed patient characteristics. 3.2. Clinical features of SOS SOS was found in 19/260 (7.3%) of patients. In the SOS group (Table 2), all patients received ATG as the conditioning regimen. Classical Cy (200 mg/kg)-ATG was the most common conditioning regimen (84.2%). The median number of days to SOS was 4 (range, 1–15) days. None of the patients received the TBI conditioning regimen and all of the patients received the Cy conditioning regimen. Sixteen patients (84.2%) received preventive medication for SOS and heparin was the drug used in the majority of them (78.9%). Among the diagnostic criteria for SOS, weight gain was observed in 17 (89.5%), hepatomegaly in 15 (78.9%), and hyperbilirubinemia in 18 (94.7%) patients. The average total bilirubin was 6.65 (range 1.8–26.9) mg/dL. The severity of SOS was mild in 10 (52.6%), moderate in 5 (26.3%), and severe in 4 (21.1%) patients. Treatments for SOS were supportive care (68.4%), ursodeoxycholic acid (15.8%), and corticosteroids (10.5%). Ascites was found in two of the four severe SOS patients. Ultrasound findings in these four severe SOS patients were various: inhomogeneously enhanced liver parenchyma and early opacification of the portal vein in the arterial phase; minimal dilatation of the intrahepatic bile duct; and slightly increased periportal echogenicity. There was no histological confirmation and no autopsies were performed.
H. Kim et al. / Leukemia Research 37 (2013) 1241–1247 Table 1 Patients’ characteristics.
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Table 2 Clinical features of SOS.
Characteristics
No. of patients
%
Characteristics
Gender, male/female Severe/very severe AA Prior IST ATG CsA alloHSCT from MRD HLA full match Viral marker status (donor/recipient) Positive HBs Ag (n = 217/259) Positive anti-HCV Ab (n = 216/203) Positive anti-CMV IgG Ab (n = 170/172) Female to male alloHSCT Year of transplantation 2000 or earlier 2001–2005 2006 or later Compatible ABO typing Conditioning regimen Antithymocyte globulin (ATG) Cy (200 mg/kg)-ATG Fludarabine TBI Cyclophosphamide conditioning 50 mg/kg for 4 days Less than 200 mg/kg GvHD prophylaxis Cyclosporine Methotrexate BM as a stem cell source
134/126 228/15 116 77 80 177 215
51.5/48.5 87.7/5.8 44.6 29.6 30.8 68.1 82.7
7/14 1/8 143/146 46
3.2/5.4 0.5/3.9 84.1/84.9 17.7
50 115 95 125
19.2 44.2 36.5 48.1
219 150 88 24 254 162 98
84.2 57.7 33.8 9.2 97.7 62.3 37.7
246 183 200
94.6 70.4 76.9
Gender, male/female 13/6 Medications history prior to transplantation Vancomycin 6 Acyclovir 17 Conditioning 16 Cy (200 mg/kg)-ATG 19 ATG 16 Prevention of SOS Heparin 15 Prostaglandin E1, glutathione 1 Weight gain 17 15 Tender hepatomegaly 18 Hyperbilirubinemia Year of SOS diagnosis 2000 or earlier 9 5 2001–2005 5 2006 or later Severity 10 Mild 5 Moderate Severe 4 Therapy for SOS 13 Supportive care 3 Ursodeoxycholic acid 2 Corticosteroid Heparin 1 Response to specific SOS therapy Fully recovered 15 Died of SOS 4
Characteristics
Median
Range
Age at alloHSCT, years Months from Dx to alloHSCT Units of PRC transfusion Units of PC transfusion Infused CD34+ cells, ×106 /kg
31.2 6.7 12 86 3.9
14.1–63.6 0–251 0–198 0–1323 0.2–32.1
Abbreviations: AA, aplastic anemia; IST, immune suppression therapy; CsA, cyclosporine A; alloHSCT, allogeneic hematopoietic stem cell transplantation; MRD, HLA-matched related donor; ATG, antithymocyte globulin; TBI, total body irradiation; GvHD, graft versus host disease; BM, bone marrow; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate.
3.3. Frequencies of SOS in each subgroup The frequency of SOS was relatively low in the alloHSCT from matched unrelated donor (MUD) (4.1%) and the fludarabineincorporated conditioning regimen (4.5%) groups, whereas it was relatively high in the HLA mismatch (11.1%) and positive anti-CMV IgG antibody (11.9% in donors and 12.3% in recipients) groups. Notably, there was quite a large difference in SOS frequency between the horse ATG (17.2%) and rabbit ATG (3.4) conditioning regimens (Table 3). There was no SOS after TBI conditioning. There was no significant difference in the frequency of SOS between the Cy-ATG and fludarabine regimens (15/150, 10.0% vs. 4/88, 4.5%; p = 0.134). 3.4. Risk factors predicting the development of SOS The frequency of SOS did not differ significantly in patients older than 31 y (p = 0.565); with months from diagnosis to alloHSCT > 6 months (p = 0.220); prior IST (p = 0.465); prior ATG usage for IST (p = 0.846); matched related donor (p = 0.973); prior transfusion amount (p = 0.773 in PRC and p = 0.641 in PC); HLA mismatch (p = 0.340); female to male donor–recipient matching (p = 1.000); ABO incompatibility (p = 0.680); cyclophosphamide (p = 1.000); ATG conditioning (p = 0.325); fludarabine conditioning (p = 0.221); busulfan conditioning (p = 1.000); TBI conditioning (p = 0.232); cyclosporine prophylaxis for GvHD (p = 0.272); or bone marrow
No. of patients
68.4/31.6 31.6 89.5 84.2 100 84.2 78.9 5.3 89.5 78.9 94.7 47.4 26.3 26.3 52.6 26.3 21.1 68.4 15.8 10.5 5.3 78.9 21.1 Median
Age at transplantation; median, range Months from diagnosis to transplantation Days to SOS Percentage of weight gain Maximal total bilirubin (mg/dL) Maximal direct bilirubin (mg/dL)
%
36.3 3.7 4 10 4.7 2.4
Range 15.6–60.1 0.99–120.1 1–15 10–20 1.8–26.9 0.3–15.6
Abbreviations: Cy, cyclophosphamide; ATG, antithymocyte globulin; SOS, hepatic sinusoidal obstruction syndrome.
as a stem cell source (p = 1.000). However, Cy 200 mg/kg conditioning (p = 0.035) and horse ATG conditioning (p = 0.001) were significant risk factors for the development of SOS in the univariate analyses. Male gender (p = 0.126) and methotrexate for GvHD prophylaxis (p = 0.107) showed marginal significance. Multivariate analysis revealed that only horse ATG conditioning was a poor prognostic factor (HR = 4.360; 95% CI 1.299–14.634; p = 0.017; Table 4). 3.5. Effect of SOS on survival All four cases with severe SOS died. Therefore, the mortality in the SOS group was 4/19 (21.1%). Overall survival was significantly lower than that in the no-SOS group (p = 0.016; Fig. 1A). The probability of mortality due to SOS was not associated with weight gain (p = 1.000), hepatomegaly (p = 0.524), hyperbilirubinemia (p = 1.000), maximal total bilirubin (p = 0.239), or maximal direct bilirubin (p = 0.184). Severity of SOS was highly correlated with overall survival (p = 0.008; Fig. 1B). The 5-year SOS-specific survival rate was 78.0% in the SOS group. 3.6. Risk factors for survival in the SOS group The results of the univariate analyses in Table 5 show that age at alloHSCT > 31 years (p = 0.011), ABO incompatibility (p = 0.047), conditioning rabbit ATG (p = 0.002), no prior use of vancomycin (p = 0.013), and weight gain > 10% (p = 0.036) were significant risk factors for overall survival in the SOS group. Prior PC transfusion > 86 U (p = 0.074) and tender hepatomegaly (p = 0.061) were
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H. Kim et al. / Leukemia Research 37 (2013) 1241–1247
(A)
(B)
1.0
1.0
5 year survival rate: 74.3% vs. 50.7%, p=0.016
Patients without SOS (No SOS group)
0.8
Probability of Overall Survival
0.8
Probability of Overall Survival
5 year survival rate: 70.0% vs. 41.7% vs. 0%, p=0.008
0.6
Patients with SOS (SOS group) 0.4
Mild SOS
0.6
Moderate SOS 0.4
0.2
0.2
Severe SOS
0.0
0.0 0
48
96
144
0
192
24
48
72
96
120
Months after transplantation
Months after tranasplantation
Fig. 1. Overall survival. Overall survival comparing No SOS group and SOS group (A); comparing severity of SOS (B). SOS denotes hepatic sinusoidal obstruction syndrome.
Table 3 Frequencies of sinusoidal obstruction syndrome in each subgroup. Characteristics
No. of patients
Frequency of SOS, n (%)
All patients Gender, male Age > 31 years old Prior IST ATG CsA Donor from MUD HLA mismatch Viral marker status (donor/recipient) Positive HBs antigen Positive anti-HCV antibody Positive anti-CMV IgG antibody Female to male alloHSCT Incompatible ABO matching Conditioning regimen Cyclophosphamide Horse ATG Rabbit ATG Cyclophosphamide-ATG Cyclophosphamide 200 mg/kg Fludarabine TBI GvHD prophylaxis Cyclosporine Methotrexate PB as a stem cell source Units of PRC transfusion > 12 units Units of PC transfusion > 86 units Infused CD34+ cells < 3 × 106 /kg
260 134 134 116 77 80 73 45
19 (7.3) 13 (9.7) 11 (8.2) 10 (8.6) 6 (7.8) 6 (7.5) 3 (4.1) 5 (11.1)
7/14 1/8 143/146 46 125
0 (0)/0 (0) 0 (0)/0 (0) 17 (11.9)/18 (12.3) 3 (6.5) 10 (8.0)
254 72 143 151 160 88 24
19 (7.5) 14 (18.9) 5 (3.4) 16 (10.6) 16 (10.0) 4 (4.5) 0 (0)
246 183 200 170 165 167
17 (6.9) 16 (8.7) 15 (7.5) 13 (7.6) 13 (7.9) 10 (6.0)
Abbreviations: SOS, hepatic sinusoidal obstruction syndrome; IST, immune suppression therapy; CsA, cyclosporine A; MUD, HLA-matched unrelated donor; alloHSCT, allogeneic hematopoietic stem cell transplantation; ATG, antithymocyte globulin; TBI, total body irradiation; GvHD, graft versus host disease; PB, peripheral blood; PRC, packed red cell; PC, platelet concentrate.
poor overall survival with a median of 1.2 months (5YSR, any risk factor vs. none: 74.6% vs. 0.0%; p < 0.001; Fig. 2) in the SOS group. 3.7. Comparison between horse ATG and rabbit ATG Focusing on patients who had SOS, the severity of SOS was mild in 50%, moderate in 35.7%, and severe in 14.3% among patients who had received horse ATG conditioning. However, SOS was mild in 60% and severe in 40% of patients who had received rabbit ATG. When the population was extended to all study patients, 7/72 (9.7%) had mild, 5/72 (6.9%) moderate, and 2/72 (2.8%) severe SOS among patients who had received horse ATG conditioning; 3/143 (2.0%) had mild and 2/143 (1.4%) had moderate SOS among patients who had received rabbit ATG conditioning. SOS-specific mortalities were 2/72 (2.8%) in the horse ATG group and 2/143 (1.4%) in the rabbit ATG group. The SOS-specific mortality rate was higher in the rabbit ATG (n = 2/5, 40%) compared with the horse ATG (n = 2/14, 14.3%) group; however, it was not statistically significant (p = 0.272)
1.0
None of risk factors, Median not reached, 5YSR 74.6% 0.8
Probability of Overall Survival
marginally significant, and these variables were also included in the multivariate analysis. The multivariate analysis showed that only rabbit ATG (HR 12.719; 95% CI 2.332–69.373; p = 0.003) and weight gain > 10% (HR 35.655; 95% CI 2.208–575.805; p = 0.012) were significant risk factors in the SOS group overall. Rabbit ATG conditioning or weight gain of more than 10% were associated with
0.6
p<0.001
0.4
0.2
Presence of any risk factors, Median 1.151 months (95% CI, 0.000-4.902) 0.0 0
24
48 72 Months after transplantation
96
120
Fig. 2. Overall survival according to SOS risk factors. Patients who received rabbit ATG conditioning or weight gain over 10% have significantly poorer survival (median 1.51 months; p < 0.001).
H. Kim et al. / Leukemia Research 37 (2013) 1241–1247
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Table 4 Risk factor analysis on development of sinusoidal obstruction syndrome. Characteristics
Male gender Age at alloHSCT < 31 years old Months from Dx to alloHSCT > 6 Prior IST ATG CsA Prior transfusion PRC < 12 U PC < 86 U alloHSCT from MRD HLA full match Viral marker status (donor/recipient) Positive HBs Ag (n = 217/259) Positive anti-HCV Ab (n = 216/203) Positive anti-CMV IgG Ab (n = 170/172) Female to male alloHSCT Compatible ABO typing Conditioning regimen Cyclophosphamide 200 mg/kg Horse ATG Fludarabine TBI GvHD prophylaxis Cyclosporine Methotrexate BM as a stem cell source Infused CD34+ cells ≥3 × 106 /kg
No. of patients (%)
Univariate
Multivariate
No SOS (n = 241)
SOS (n = 19)
p-Value
HR
121 (50.2) 118 (49.0) 117 (48.5) 106 (44.0) 71 (29.5) 74 (30.7)
13 (68.4) 8 (42.1) 12 (63.2) 10 (52.6) 6 (31.6) 6 (31.6)
0.126 0.565 0.220 0.465 0.846 0.937
1.474 – – – – –
95% CI
84 (34.9) 89 (36.9) 164 (68.0) 201 (83.4)
6 (31.6) 6 (31.6) 13 (68.4) 14 (73.7)
0.773 0.641 0.973 0.340
– – –
– – –
– – –
7 (3.5)/14 (5.8) 1 (0.5)/8 (4.3) 126 (83.4)/128 (83.7) 43 (17.8) 126 (52.3)
0 (0)/0 (0) 0(0)/0 (0) 17 (89.5)/18 (94.7) 3 (15.8) 9 (47.4)
1.000/0.608 1.000/1.000 0.741/0.314 1.000 0.680
– – – – –
– – – – –
– – – – –
144 (59.8) 53 (22.0) 84 (34.9) 24 (10.0)
16 (84.2) 11 (57.9) 4 (21.1) 0 (0)
0.035 0.001 0.221 0.232
2.995 4.360 – –
0.708–12.663 1.299–14.634 – –
0.136 0.017 – –
229 (95.0) 167 (69.3) 185 (76.8) 157 (65.1)
17 (89.5) 16 (84.2) 15 (78.9) 10 (52.6)
0.272 0.107 1.000 0.273
– 1.006 – –
– 0.242–4.191 – –
– 0.993 – –
0.506–4.295 – – – – –
p-Value 0.477 – – – – –
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; alloHSCT, allogeneic hematopoietic stem cell transplantation; Dx, diagnosis; IST, immune suppression therapy; ATG, antithymocyte globulin; CsA, cyclosporine A; PRC, packed red cell; PC, platelet concentrate; MRD, HLA-matched related donor; TBI, total body irradiation; BM, bone marrow.
in the SOS patient population. SOS-specific survival showed the same trend (p = 0.216). 4. Discussion Cyclophosphamide, which is usually incorporated in alloHSCT for AA, is known to be toxic to hepatic sinusoidal endothelial cells and there have been several clinical reports of hepatotoxicity
after cyclophosphamide use. It has been suggested that the high incidence of SOS after alloHSCT in AA might be caused by cyclophosphamide conditioning. Large inter-patient variability was evident after administration of cyclophosphamide at fixed doses, and a correlation was evident between the exposure rate to cyclophosphamide metabolites and the development of SOS [16]. Other studies showed high variability in Cy metabolism exhibiting conditioning-regimen dependent
Table 5 Prognostic factors on survival in patients with SOS. Factor
Female vs. male No prior IST vs. prior IST Age at alloHSCT ≤ 31 years vs. >31 years Time from Dx to alloHSCT ≤ 6 months vs. >6 months Matched related donor vs. others ABO compatible vs. incompatible HLA full match vs. mismatch Others vs. female donor-to-male recipient ECOG performance status at alloHSCT ≤ 1 vs. >1 Prior PRC transfusion ≤ 12 U vs. >12 U Prior PC transfusion ≤ 86 U vs. >86 U Conditioning with vs. without Cy 200 mg/kg Conditioning with horse ATG vs. rabbit ATG BM as a stem cell source vs. Others Infused CD34 infusion ≤ 3 vs. ≤3 (×106 /kg) Prior use of vancomycin vs. not Prior use of acyclovir vs. not Preventive therapy for SOS vs. not Days to SOS ≤ 4 vs. >4 Tender hepatomegaly; No vs. Present Maximal total bilirubin ≤ 5 vs. >5 mg/dL Maximal direct bilirubin ≤ 3 vs. >3 Weight gain ≤ 10 vs. >10%
n
13 vs. 6 9 vs. 10 8 vs. 11 12 vs. 7 13 vs. 6 9 vs. 10 14 vs. 5 16 vs. 3 16 vs. 3 6 vs. 13 6 vs. 13 16 vs. 3 14 vs. 5 15 vs. 4 10 vs. 9 6 vs. 13 17 vs. 2 16 vs. 3 11 vs. 8 4 vs. 15 10 vs. 9 12 vs. 7 18 vs. 1
Univariate analysis
Multivariate analysis
5-Year survival rate (%)
p-Value
HR
59.8 vs. 33.3 61.0 vs. 40.0 87.5 vs. 21.8 65.6 vs. 28.6 50.5 vs. 50.0 77.8 vs. 24.0 46.9 vs. 60.0 50.0 vs. 50.0 53.7 vs. 33.3 62.5 vs. 46.2 83.3 vs. 35.9 60.6 vs. 0.0 69.3 vs. 0.0 59.3 vs. 25.0 58.3 vs. 44.4 100 vs. 28.8 57.0 vs. 0.0 55.0 vs. 33.3 58.9 vs. 37.5 100.0 vs. 37.5 58.3 vs. 40.0 65.6 vs. 19.0 53.5 vs. 0.0
0.163 0.261 0.011 0.191 0.946 0.047 0.565 0.563 0.379 0.492 0.074 0.043 0.002 0.430 0.637 0.013 0.179 0.634 0.112 0.061 0.430 0.062 0.036
– – 1.821 – – 3.032 – – – – 2.810 1.682 12.719 – – >100 – – 2.831 >100 – 2.052 35.655
95% CI – – 0.118–28.017 – – 0.590–15.584 – – – – 0.291–27.089 0.261–10.852 2.332–69.373 – – 0.000–9.16 – – 0.682–11.746 0.000– – 0.482–8.733 2.208–575.805
p-Value – – 0.667 – – 0.184 – – – – 0.372 0.003 – – 0.967 – – 0.152 0.972 – 0.331 0.012
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; IST, immune suppression therapy; alloHSCT, allogeneic hematopoietic stem cell transplantation; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate; Cy, cyclophosphamide; ATG, antithymocyte globulin; BM, bone marrow; SOS, hepatic sinusoidal obstruction syndrome.
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pharmacokinetics/pharmacodynamics, and inter-patient variability in cyclophosphamide metabolites has also been reported in children [17,18]. However, the relationship between cyclophosphamide dose and incidence of SOS is not yet clear, even though personalized Cy dosing has been shown to decrease the maximum value of total serum bilirubin after transplantation and real-time adjustment of Cy dosing was developed as a result [19,20]. In this study, cyclophosphamide was incorporated in the conditioning regimen for almost all of the patients (97.7%) and classical Cy (200 mg/kg)-ATG conditioning was used in 57.7% of patients. Therefore, we were able to analyze the incidence of SOS and the effect of cyclophosphamide conditioning dose on SOS development. The overall incidence of SOS in this study was very low compared with the incidence our previous report, in which all patients received Cy (200 mg/kg)-ATG conditioning (7.3% vs. 41.2%) [9]. This difference might be explained by the fact that almost half of the patients had received cyclophosphamide 200 mg/kg, and the univariate analysis on SOS development seemed to confirm this. However, the multivariate analysis showed that cyclophosphamide 200 mg/kg was not a risk factor for developing SOS (HR = 2.995, 95% CI 0.708–12.663, p = 0.136). Therefore, either cyclophosphamide itself, or a reduced cyclophosphamide dose, cannot clearly explain the reduced rate of SOS in this study. It is possible that there are not only inter-patient but also racial variabilities in Cy metabolism. One report found a relationship between Cy metabolism and liver damage in Asian patients [21]. The study suggested that Cy-induced liver damage was mainly dose-dependent. There is a need for more studies on the dose/toxicity relationship and racial differences in Cy metabolism, including single-nucleotide polymorphisms, in Asian patients. Frequency of SOS was significantly higher in the horse ATG (18.9%) group and lower in the rabbit ATG (3.8%) group in this study. A high incidence and low SOS mortality was found for horse ATG whereas the reverse was found for rabbit ATG. Although horse ATG was a risk factor for developing SOS, rabbit ATG was a risk factor for poor overall survival. This does not mean that SOS after rabbit ATG was more aggressive, despite the low incidence of SOS. Overall, the SOS-specific mortality among all rabbit ATG patients was no higher than that among all horse ATG patients. The SOS-specific mortality and SOS-specific survival rates in the rabbit ATG group, even in those who developed SOS, were no worse than in the horse ATG group. Rather, rabbit ATG seemed to confer some protective effect against SOS. Hence, the incidence of SOS seemed to be lower after rabbit ATG conditioning, although severe cases could not be prevented. Horse ATG has been unavailable in Korea since 2004 and has been replaced by rabbit ATG. This timescale corresponds with the rapid drop in the incidence of SOS in Korea in this study. The different features of the two ATGs could explain these results. An increase in the frequency of regulatory T cells has been observed with rabbit ATG but not with horse ATG, and a marked difference has been shown in the gene-expression profiles of human cells cultured with horse and rabbit ATG [22]. More prolonged lymphopenia follows rabbit ATG administration, and patterns of viral reactivation have been shown to differ between these two ATGs [23]. Horse and rabbit ATGs lead to a similar depletion of CD8+ cytotoxic T cells, but there was a more profound depletion of CD4+ T cells after the use of rabbit ATG [24]. It is not clear whether these different features between the two ATGs could explain the preventive effect of rabbit ATG on SOS development. The patients who developed SOS had poorer survival than those who did not, and the mortality rate in the SOS group was very high under supportive care. In this regard, more effort should be put into prevention and early intervention after selecting high risk SOS. The treatment strategy for SOS is complex because although some patients can recover with supportive care, some patients require specific therapy such as recombinant tissue plasminogen activator or defibrotide to avoid fatality [25,26]. Doppler sonogram or certain
biomarkers can identify early cases, and preventive drugs can be helpful [27–30]. The current definition of severity is based on the final clinical outcome, which does not help to identify candidates for specific therapies. This study revealed that either rabbit ATG or weight gain of more than 10% were risk factors for poor overall survival in the SOS group. Therefore, patients with SOS following rabbit ATG conditioning or weight gain of more than 10% should be considered as candidates for more active therapy in AA. The retrospective data collected in this study have some limitations. First, the diagnosis of SOS was wholly based on the attending physician’s diagnosis according to the clinical criteria, and there was no need for supportive current imaging modalities. Hence, the frequency of SOS could be overestimated because other similar conditions such as hyperacute GVHD or drug-liver injury could not be clearly ruled out. Another problem is the heterogeneity in the use of prophylactic drugs for SOS, although most patients had received heparin for this purpose. In conclusion, SOS is a relatively rare acute complication of alloHSCT in AA (7.3%). Nevertheless, the mortality of SOS is still high (21.1%) under supportive care [30]. The use of a horse ATG conditioning regimen was a significant risk factor for developing SOS, whereas a rabbit ATG conditioning regimen and weight gain >10% were significant risk factors for survival in SOS patients.
Conflict of interest statement All authors have no conflict of interest to declare.
Acknowledgements We thank Mi Young Kim for assisting data collection and management. This work was supported by Priority Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0094050). Contributions: H. K. and S.-S. Y. developed the study concept. H. K., K-H. L., S.-K. S., C.-W. J., Y.-D. J., S.-H. K., B.-S. K., J.-H. C., J.Y. K., M.-S. H., S.-H. B., H.-J. S., J.-H. W., S. O., W.-S. L., J.-H. P., S.-S. Y. performed study. H. K. wrote the manuscript. S.-S. Y. critically reviewed the manuscript.
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Hepatic sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation in adult patients with idiopathic aplastic anemia Hawk Kim a,1 , Kyoo-Hyung Lee b,1 , Sang Kyun Sohn c,1 , Chul Won Jung d,1 , Young Don Joo e,1 , Sung Hyun Kim f,1 , Byung Soo Kim g,1 , Jung Hye Choi h,1 , Jae-Yong Kwak i,1 , Min Kyoung Kim j,1 , Sung Hwa Bae k,1 , Ho-Jin Shin l,1 , Jong Ho Won m,1 , Sukjoong Oh n,1 , Won Sik Lee o,1 , Jae-Hoo Park a,1 , Sung-Soo Yoon p,∗,1 a
Divison of Hematology and Hematological Malignancies, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Hemato/Oncology, Kyungpook National University Hospital, Kyungpook National University, Daegu, Republic of Korea d Department of Hemato/Oncology, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea e Department of Hemato-Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea f Department of Hemato-Oncology, Dong-A University Medical Center, Dong-A University, Busan, Republic of Korea g Department of Hematology/Oncology, Korea University Hospital Seoul Hospital, Korea University, Seoul, Republic of Korea h Department of Hematology/Oncology, Hanyang University Hospital, Hanyang University, Seoul, Republic of Korea i Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University, Jeonju, Republic of Korea j Department of Hematology/Oncology, Yeungnam University Medical Center, Yeungnam University, Daegu, Republic of Korea k Division of Hematology/Oncology, Daegu Catholic University Hospital, Daegu Catholic University School of Medicine, Daegu, Republic of Korea l Department of Hematology and Oncology, Pusan National University Hospital, Pusan National University, Busan, Republic of Korea m Department of Hematology/Oncology, Soon Chun Hyang University Hospital, Soon Chun Hyang University, Seoul, Republic of Korea n Department of Hematology/Oncology, Kangbuk Samsung Hospital, School of Medicine, Sungkyunkwan University, Seoul, Republic of Korea o Department of Hematology/Oncology, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea p Department of Internal Medicine, Seoul National University Hospital, Seoul National University, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 8 April 2013 Received in revised form 4 June 2013 Accepted 17 June 2013 Available online 18 July 2013 Keywords: Sinusoidal obstruction syndrome Veno-occlusive disease Aplastic anemia Allogeneic hematopoietic stem cell transplantation
a b s t r a c t We retrospectively investigated the incidence, risk factors, and outcomes of SOS (sinusoidal obstruction syndrome; previously veno-occlusive disease [VOD]) after allogeneic hematopoietic stem cell transplantation (alloHSCT) in aplastic anemia. Two hundred and sixty patients were included in the analysis. SOS developed in 7.3% (n = 19/260) of patients. Classical Cy (200 mg/m2 )-ATG was the most common conditioning regimen (84.2%) in the SOS group. The SOS mortality rate was 4/19 (21.1%). Univariate analyses revealed that Cy 200 mg/m2 conditioning (p = 0.035), classical Cy-ATG conditioning (p = 0.007), and horse ATG conditioning (p < 0.001) were significant risk factors for developing SOS. Multivariate analysis revealed that only horse ATG conditioning was a poor prognostic factor (HR = 3.484; 95% CI 1.226–9.904; p = 0.002). Rabbit ATG (HR 12.719; 95% CI 2.332–69.373; p = 0.003) and weight gain > 10% (HR 35.655; 95% CI 2.208–575.805; p = 0.012) were risk factors in the overall SOS group. Both rabbit ATG conditioning and weight gain of more than 10% were associated with poor overall survival with a median of 1.2 months (5Y survival rate, any risk factor vs. none: 74.6% vs. 0.0%; p < 0.001; Fig. 2) in the SOS group. In conclusion, SOS is a relatively rare (7.3%) but highly fatal (21.1%) acute complication of alloHSCT in AA, and the horse ATG conditioning regimen was a significant risk factor for developing SOS. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction
∗ Corresponding author at: Department of Internal Medicine, Seoul National University Hospital. Seoul National University 101 Daehang-ro, Jongno-gu, Seoul, 110-744, Republic of Korea. Tel.: +82 2 2072 3079; fax: +82 2 762 9662. E-mail address: [email protected] (S.-S. Yoon). 1 On behalf of The Korean Society of Blood and Marrow Transplantation. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.06.024
Hepatic sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease [VOD]) is a rare complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). The diagnosis of SOS is generally based on clinical features such as hyperbilirubinemia, tender hepatomegaly, and weight gain. In a large study of patients undergoing alloHSCT, the reported incidence
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of SOS was as high as 53% and the case fatality rate was 47% [1–3]. However, the reported incidence and fatality rates of SOS show high variability, ranging from 0% to 70% [4–6]. Recent reports indicate that the incidence and mortality are decreasing. This decline might be caused by the low incidence of SOS among reduced-intensity conditioning and the reduction among those receiving myeloablative alloHSCT from unrelated donors [7,8]. These data not only come from patients with many different diseases, mainly hematologic malignancies, but also from patients with many different conditioning regimens. There have been only a few reports of SOS in AA (aplastic anemia), involving very small numbers of patients. In our previous report of SOS incidence after alloHSCT for AA, 7 of 17 patients who received cyclophosphamide at 200 mg/kg developed SOS (5 mild, 2 moderate) with maximum bilirubin levels of 4.2–21 mg/dL. The maximum weight gain ranged from 3.5 to 29% [9]. Retrospective data obtained after alloHSCT for a few patients with Fanconi anemia or hepatitis-associated AA revealed a similar incidence of veno-occlusive disease (5.9–16.7%) in the cyclophosphamide (Cy)antithymocyte globulin (ATG) arm [10,11]. Many transplantation-related risk factors for SOS have been suggested, such as a high-dose conditioning regimen, busulfan for conditioning, total body irradiation (TBI), graft from unrelated donors or related HLA mismatched transplants, and methotrexate as part of graft versus host disease (GvHD) prophylaxis [1,12–14]. Usually, there is no need for a high-dose or busulfan-containing conditioning regimen for AA patients, which implies that the risk factors for SOS will be different in AA patients. Here we present a retrospective analysis of the incidence, clinical characteristics, and risk factors of SOS after alloHSCT in AA patients. 2. Patients and methods 2.1. Patient eligibility Patients were included if transfusion dependent/severe/very severe acquired aplastic anemia (AA) was diagnosed; if patients were >15 years of age at the time of the alloHSCT treatment; and if patients had undergone alloHSCT from an HLA-matched related donor (MRD) or alternative donor (AD), regardless of immunosuppressive therapy (IST) history. Exclusion criteria were the presence of congenital aplasia, including Fanconi anemia, Diamond–Blackfan syndrome, congenital dyskeratosis, or hypoplastic myelodysplastic syndrome. 2.2. Data collection The original protocol was approved by the Korean Society of Blood and Marrow Transplantation (KSBMT) Clinical Study Committee (approval no. KSBMT07-02) for retrospective comparison between MRD and AD, and by the Cooperative Study Group A for Hematology (C-006A study) phase III prospective trial [15]. These two study populations were combined for this analysis. Data were also collected from patients with pure red cell aplasia and paroxysmal nocturnal hemoglobinuria in the KSBMT07-02 study and from patients with hypoplastic myelodysplastic syndrome in the COSAH (C-006A) study, but such patients were not included in this final analysis. The detailed SOS-related data were collected separately from additional queries for each patient who had developed SOS. 2.3. Evaluation criteria The principal concern of the study was to define the actual incidence of SOS after alloHSCT in adult patients with AA. We also aimed to define which factors influenced the development and final outcome of SOS. SOS was diagnosed using McDonald’s guidelines and modified Seattle criteria [1,4]. At least two of the following three criteria should be present to fit the diagnosis of SOS within 30 days after transplantation: weight gain > 5% from baseline body weight; hepatomegaly with right upper quadrant pain; and hyperbilirubinemia (serum bilirubin > 2 mg/dL). No other explanation for these signs and symptoms were present at the time of diagnosis. The first day on which the clinical criteria were satisfied was defined as day 0 of SOS. Doppler sonogram or other imaging modalities were not required for the diagnosis of SOS in this study. Patients who met the criteria for SOS, but who were not treated and whose illness was self-limiting, were classified as having mild SOS. Those whose SOS resolved but who received treatment, such as diuretics for fluid retention or narcotic analgesics for painful hepatomegaly, were classified as having moderate SOS. Patients who died of SOS or whose SOS had not resolved by 100 days
post-transplant were considered to have severe SOS. All patients who had developed SOS were defined as the SOS group and the others as the no-SOS group. Performance status was graded by ECOG performance scoring. Relapse was defined as the reacquisition of transfusion dependence or fulfillment of severe/very severe criteria after successful engraftment. Other evaluation criteria were the same as in our previous study [15]. 2.4. Statistical analyses All analyses were performed on an intention-to-treat basis. The patients were divided into two groups: a no-SOS group who did not develop hepatic SOS and an SOS group who did develop SOS. The Chi-square test was used to compare categorical variables and Student’s t-test was used to compare continuous variables between any two groups. The start point for the determination of time-dependent parameters was the first day of stem cell infusion. Time to SOS was defined from the first day of stem cell infusion to the day on which SOS was diagnosed. Overall survival was measured from the time of stem cell infusion to the date of death, or the last date on which the patient was known to be alive (this constituted censoring). Survival curves were computed according to the Kaplan–Meier method, and differences in survival were compared by the log-rank test. Death directly due to SOS was defined as an event in SOS-specific survival and SOS-specific mortality. A Cox’s proportional hazard model was used to determine the effects on survival of various prognostic factors, including age, donor/recipient gender matching, number of cells transfused, use of irradiated blood products, time from diagnosis to alloHSCT, stem cell source, dose of irradiation, HLA matching, method of immune suppression used to prevent GvHD, IST history, and type of ATG. All variables were dichotomized and converted into categorical classes. The variables included in the multivariate analysis were the patients’ ages, and all prognostic factors with p-values <0.05 in the univariate analyses. Differences were assessed using a two-sided test at the p = 0.05 level of significance.
3. Results 3.1. Patients Data from 260 adult patients who received alloHSCT for acquired severe aplastic anemia (sAA) between 1985 and 2010 were collected from 15 Korean institutions. The median age was 31.2 (range 14.1–63.6) years; 134 (51.5%) were male; 68.1% of patients had matched-related donors, 82.7% had HLA full-matched donors, and 17.7% had female to male donor–recipient sex-matched donors. Three patients aged less than 15 years (14.1, 14.5, and 14.9 years) were included in the final analysis. The drugs used for the conditioning regimens were cyclophosphamide in 97.7%, ATG in 84.3%, and fludarabine in 33.8%. TBI was incorporated in the conditioning regimen of 9.2% of patients. Table 1 shows the detailed patient characteristics. 3.2. Clinical features of SOS SOS was found in 19/260 (7.3%) of patients. In the SOS group (Table 2), all patients received ATG as the conditioning regimen. Classical Cy (200 mg/kg)-ATG was the most common conditioning regimen (84.2%). The median number of days to SOS was 4 (range, 1–15) days. None of the patients received the TBI conditioning regimen and all of the patients received the Cy conditioning regimen. Sixteen patients (84.2%) received preventive medication for SOS and heparin was the drug used in the majority of them (78.9%). Among the diagnostic criteria for SOS, weight gain was observed in 17 (89.5%), hepatomegaly in 15 (78.9%), and hyperbilirubinemia in 18 (94.7%) patients. The average total bilirubin was 6.65 (range 1.8–26.9) mg/dL. The severity of SOS was mild in 10 (52.6%), moderate in 5 (26.3%), and severe in 4 (21.1%) patients. Treatments for SOS were supportive care (68.4%), ursodeoxycholic acid (15.8%), and corticosteroids (10.5%). Ascites was found in two of the four severe SOS patients. Ultrasound findings in these four severe SOS patients were various: inhomogeneously enhanced liver parenchyma and early opacification of the portal vein in the arterial phase; minimal dilatation of the intrahepatic bile duct; and slightly increased periportal echogenicity. There was no histological confirmation and no autopsies were performed.
H. Kim et al. / Leukemia Research 37 (2013) 1241–1247 Table 1 Patients’ characteristics.
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Table 2 Clinical features of SOS.
Characteristics
No. of patients
%
Characteristics
Gender, male/female Severe/very severe AA Prior IST ATG CsA alloHSCT from MRD HLA full match Viral marker status (donor/recipient) Positive HBs Ag (n = 217/259) Positive anti-HCV Ab (n = 216/203) Positive anti-CMV IgG Ab (n = 170/172) Female to male alloHSCT Year of transplantation 2000 or earlier 2001–2005 2006 or later Compatible ABO typing Conditioning regimen Antithymocyte globulin (ATG) Cy (200 mg/kg)-ATG Fludarabine TBI Cyclophosphamide conditioning 50 mg/kg for 4 days Less than 200 mg/kg GvHD prophylaxis Cyclosporine Methotrexate BM as a stem cell source
134/126 228/15 116 77 80 177 215
51.5/48.5 87.7/5.8 44.6 29.6 30.8 68.1 82.7
7/14 1/8 143/146 46
3.2/5.4 0.5/3.9 84.1/84.9 17.7
50 115 95 125
19.2 44.2 36.5 48.1
219 150 88 24 254 162 98
84.2 57.7 33.8 9.2 97.7 62.3 37.7
246 183 200
94.6 70.4 76.9
Gender, male/female 13/6 Medications history prior to transplantation Vancomycin 6 Acyclovir 17 Conditioning 16 Cy (200 mg/kg)-ATG 19 ATG 16 Prevention of SOS Heparin 15 Prostaglandin E1, glutathione 1 Weight gain 17 15 Tender hepatomegaly 18 Hyperbilirubinemia Year of SOS diagnosis 2000 or earlier 9 5 2001–2005 5 2006 or later Severity 10 Mild 5 Moderate Severe 4 Therapy for SOS 13 Supportive care 3 Ursodeoxycholic acid 2 Corticosteroid Heparin 1 Response to specific SOS therapy Fully recovered 15 Died of SOS 4
Characteristics
Median
Range
Age at alloHSCT, years Months from Dx to alloHSCT Units of PRC transfusion Units of PC transfusion Infused CD34+ cells, ×106 /kg
31.2 6.7 12 86 3.9
14.1–63.6 0–251 0–198 0–1323 0.2–32.1
Abbreviations: AA, aplastic anemia; IST, immune suppression therapy; CsA, cyclosporine A; alloHSCT, allogeneic hematopoietic stem cell transplantation; MRD, HLA-matched related donor; ATG, antithymocyte globulin; TBI, total body irradiation; GvHD, graft versus host disease; BM, bone marrow; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate.
3.3. Frequencies of SOS in each subgroup The frequency of SOS was relatively low in the alloHSCT from matched unrelated donor (MUD) (4.1%) and the fludarabineincorporated conditioning regimen (4.5%) groups, whereas it was relatively high in the HLA mismatch (11.1%) and positive anti-CMV IgG antibody (11.9% in donors and 12.3% in recipients) groups. Notably, there was quite a large difference in SOS frequency between the horse ATG (17.2%) and rabbit ATG (3.4) conditioning regimens (Table 3). There was no SOS after TBI conditioning. There was no significant difference in the frequency of SOS between the Cy-ATG and fludarabine regimens (15/150, 10.0% vs. 4/88, 4.5%; p = 0.134). 3.4. Risk factors predicting the development of SOS The frequency of SOS did not differ significantly in patients older than 31 y (p = 0.565); with months from diagnosis to alloHSCT > 6 months (p = 0.220); prior IST (p = 0.465); prior ATG usage for IST (p = 0.846); matched related donor (p = 0.973); prior transfusion amount (p = 0.773 in PRC and p = 0.641 in PC); HLA mismatch (p = 0.340); female to male donor–recipient matching (p = 1.000); ABO incompatibility (p = 0.680); cyclophosphamide (p = 1.000); ATG conditioning (p = 0.325); fludarabine conditioning (p = 0.221); busulfan conditioning (p = 1.000); TBI conditioning (p = 0.232); cyclosporine prophylaxis for GvHD (p = 0.272); or bone marrow
No. of patients
68.4/31.6 31.6 89.5 84.2 100 84.2 78.9 5.3 89.5 78.9 94.7 47.4 26.3 26.3 52.6 26.3 21.1 68.4 15.8 10.5 5.3 78.9 21.1 Median
Age at transplantation; median, range Months from diagnosis to transplantation Days to SOS Percentage of weight gain Maximal total bilirubin (mg/dL) Maximal direct bilirubin (mg/dL)
%
36.3 3.7 4 10 4.7 2.4
Range 15.6–60.1 0.99–120.1 1–15 10–20 1.8–26.9 0.3–15.6
Abbreviations: Cy, cyclophosphamide; ATG, antithymocyte globulin; SOS, hepatic sinusoidal obstruction syndrome.
as a stem cell source (p = 1.000). However, Cy 200 mg/kg conditioning (p = 0.035) and horse ATG conditioning (p = 0.001) were significant risk factors for the development of SOS in the univariate analyses. Male gender (p = 0.126) and methotrexate for GvHD prophylaxis (p = 0.107) showed marginal significance. Multivariate analysis revealed that only horse ATG conditioning was a poor prognostic factor (HR = 4.360; 95% CI 1.299–14.634; p = 0.017; Table 4). 3.5. Effect of SOS on survival All four cases with severe SOS died. Therefore, the mortality in the SOS group was 4/19 (21.1%). Overall survival was significantly lower than that in the no-SOS group (p = 0.016; Fig. 1A). The probability of mortality due to SOS was not associated with weight gain (p = 1.000), hepatomegaly (p = 0.524), hyperbilirubinemia (p = 1.000), maximal total bilirubin (p = 0.239), or maximal direct bilirubin (p = 0.184). Severity of SOS was highly correlated with overall survival (p = 0.008; Fig. 1B). The 5-year SOS-specific survival rate was 78.0% in the SOS group. 3.6. Risk factors for survival in the SOS group The results of the univariate analyses in Table 5 show that age at alloHSCT > 31 years (p = 0.011), ABO incompatibility (p = 0.047), conditioning rabbit ATG (p = 0.002), no prior use of vancomycin (p = 0.013), and weight gain > 10% (p = 0.036) were significant risk factors for overall survival in the SOS group. Prior PC transfusion > 86 U (p = 0.074) and tender hepatomegaly (p = 0.061) were
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H. Kim et al. / Leukemia Research 37 (2013) 1241–1247
(A)
(B)
1.0
1.0
5 year survival rate: 74.3% vs. 50.7%, p=0.016
Patients without SOS (No SOS group)
0.8
Probability of Overall Survival
0.8
Probability of Overall Survival
5 year survival rate: 70.0% vs. 41.7% vs. 0%, p=0.008
0.6
Patients with SOS (SOS group) 0.4
Mild SOS
0.6
Moderate SOS 0.4
0.2
0.2
Severe SOS
0.0
0.0 0
48
96
144
0
192
24
48
72
96
120
Months after transplantation
Months after tranasplantation
Fig. 1. Overall survival. Overall survival comparing No SOS group and SOS group (A); comparing severity of SOS (B). SOS denotes hepatic sinusoidal obstruction syndrome.
Table 3 Frequencies of sinusoidal obstruction syndrome in each subgroup. Characteristics
No. of patients
Frequency of SOS, n (%)
All patients Gender, male Age > 31 years old Prior IST ATG CsA Donor from MUD HLA mismatch Viral marker status (donor/recipient) Positive HBs antigen Positive anti-HCV antibody Positive anti-CMV IgG antibody Female to male alloHSCT Incompatible ABO matching Conditioning regimen Cyclophosphamide Horse ATG Rabbit ATG Cyclophosphamide-ATG Cyclophosphamide 200 mg/kg Fludarabine TBI GvHD prophylaxis Cyclosporine Methotrexate PB as a stem cell source Units of PRC transfusion > 12 units Units of PC transfusion > 86 units Infused CD34+ cells < 3 × 106 /kg
260 134 134 116 77 80 73 45
19 (7.3) 13 (9.7) 11 (8.2) 10 (8.6) 6 (7.8) 6 (7.5) 3 (4.1) 5 (11.1)
7/14 1/8 143/146 46 125
0 (0)/0 (0) 0 (0)/0 (0) 17 (11.9)/18 (12.3) 3 (6.5) 10 (8.0)
254 72 143 151 160 88 24
19 (7.5) 14 (18.9) 5 (3.4) 16 (10.6) 16 (10.0) 4 (4.5) 0 (0)
246 183 200 170 165 167
17 (6.9) 16 (8.7) 15 (7.5) 13 (7.6) 13 (7.9) 10 (6.0)
Abbreviations: SOS, hepatic sinusoidal obstruction syndrome; IST, immune suppression therapy; CsA, cyclosporine A; MUD, HLA-matched unrelated donor; alloHSCT, allogeneic hematopoietic stem cell transplantation; ATG, antithymocyte globulin; TBI, total body irradiation; GvHD, graft versus host disease; PB, peripheral blood; PRC, packed red cell; PC, platelet concentrate.
poor overall survival with a median of 1.2 months (5YSR, any risk factor vs. none: 74.6% vs. 0.0%; p < 0.001; Fig. 2) in the SOS group. 3.7. Comparison between horse ATG and rabbit ATG Focusing on patients who had SOS, the severity of SOS was mild in 50%, moderate in 35.7%, and severe in 14.3% among patients who had received horse ATG conditioning. However, SOS was mild in 60% and severe in 40% of patients who had received rabbit ATG. When the population was extended to all study patients, 7/72 (9.7%) had mild, 5/72 (6.9%) moderate, and 2/72 (2.8%) severe SOS among patients who had received horse ATG conditioning; 3/143 (2.0%) had mild and 2/143 (1.4%) had moderate SOS among patients who had received rabbit ATG conditioning. SOS-specific mortalities were 2/72 (2.8%) in the horse ATG group and 2/143 (1.4%) in the rabbit ATG group. The SOS-specific mortality rate was higher in the rabbit ATG (n = 2/5, 40%) compared with the horse ATG (n = 2/14, 14.3%) group; however, it was not statistically significant (p = 0.272)
1.0
None of risk factors, Median not reached, 5YSR 74.6% 0.8
Probability of Overall Survival
marginally significant, and these variables were also included in the multivariate analysis. The multivariate analysis showed that only rabbit ATG (HR 12.719; 95% CI 2.332–69.373; p = 0.003) and weight gain > 10% (HR 35.655; 95% CI 2.208–575.805; p = 0.012) were significant risk factors in the SOS group overall. Rabbit ATG conditioning or weight gain of more than 10% were associated with
0.6
p<0.001
0.4
0.2
Presence of any risk factors, Median 1.151 months (95% CI, 0.000-4.902) 0.0 0
24
48 72 Months after transplantation
96
120
Fig. 2. Overall survival according to SOS risk factors. Patients who received rabbit ATG conditioning or weight gain over 10% have significantly poorer survival (median 1.51 months; p < 0.001).
H. Kim et al. / Leukemia Research 37 (2013) 1241–1247
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Table 4 Risk factor analysis on development of sinusoidal obstruction syndrome. Characteristics
Male gender Age at alloHSCT < 31 years old Months from Dx to alloHSCT > 6 Prior IST ATG CsA Prior transfusion PRC < 12 U PC < 86 U alloHSCT from MRD HLA full match Viral marker status (donor/recipient) Positive HBs Ag (n = 217/259) Positive anti-HCV Ab (n = 216/203) Positive anti-CMV IgG Ab (n = 170/172) Female to male alloHSCT Compatible ABO typing Conditioning regimen Cyclophosphamide 200 mg/kg Horse ATG Fludarabine TBI GvHD prophylaxis Cyclosporine Methotrexate BM as a stem cell source Infused CD34+ cells ≥3 × 106 /kg
No. of patients (%)
Univariate
Multivariate
No SOS (n = 241)
SOS (n = 19)
p-Value
HR
121 (50.2) 118 (49.0) 117 (48.5) 106 (44.0) 71 (29.5) 74 (30.7)
13 (68.4) 8 (42.1) 12 (63.2) 10 (52.6) 6 (31.6) 6 (31.6)
0.126 0.565 0.220 0.465 0.846 0.937
1.474 – – – – –
95% CI
84 (34.9) 89 (36.9) 164 (68.0) 201 (83.4)
6 (31.6) 6 (31.6) 13 (68.4) 14 (73.7)
0.773 0.641 0.973 0.340
– – –
– – –
– – –
7 (3.5)/14 (5.8) 1 (0.5)/8 (4.3) 126 (83.4)/128 (83.7) 43 (17.8) 126 (52.3)
0 (0)/0 (0) 0(0)/0 (0) 17 (89.5)/18 (94.7) 3 (15.8) 9 (47.4)
1.000/0.608 1.000/1.000 0.741/0.314 1.000 0.680
– – – – –
– – – – –
– – – – –
144 (59.8) 53 (22.0) 84 (34.9) 24 (10.0)
16 (84.2) 11 (57.9) 4 (21.1) 0 (0)
0.035 0.001 0.221 0.232
2.995 4.360 – –
0.708–12.663 1.299–14.634 – –
0.136 0.017 – –
229 (95.0) 167 (69.3) 185 (76.8) 157 (65.1)
17 (89.5) 16 (84.2) 15 (78.9) 10 (52.6)
0.272 0.107 1.000 0.273
– 1.006 – –
– 0.242–4.191 – –
– 0.993 – –
0.506–4.295 – – – – –
p-Value 0.477 – – – – –
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; alloHSCT, allogeneic hematopoietic stem cell transplantation; Dx, diagnosis; IST, immune suppression therapy; ATG, antithymocyte globulin; CsA, cyclosporine A; PRC, packed red cell; PC, platelet concentrate; MRD, HLA-matched related donor; TBI, total body irradiation; BM, bone marrow.
in the SOS patient population. SOS-specific survival showed the same trend (p = 0.216). 4. Discussion Cyclophosphamide, which is usually incorporated in alloHSCT for AA, is known to be toxic to hepatic sinusoidal endothelial cells and there have been several clinical reports of hepatotoxicity
after cyclophosphamide use. It has been suggested that the high incidence of SOS after alloHSCT in AA might be caused by cyclophosphamide conditioning. Large inter-patient variability was evident after administration of cyclophosphamide at fixed doses, and a correlation was evident between the exposure rate to cyclophosphamide metabolites and the development of SOS [16]. Other studies showed high variability in Cy metabolism exhibiting conditioning-regimen dependent
Table 5 Prognostic factors on survival in patients with SOS. Factor
Female vs. male No prior IST vs. prior IST Age at alloHSCT ≤ 31 years vs. >31 years Time from Dx to alloHSCT ≤ 6 months vs. >6 months Matched related donor vs. others ABO compatible vs. incompatible HLA full match vs. mismatch Others vs. female donor-to-male recipient ECOG performance status at alloHSCT ≤ 1 vs. >1 Prior PRC transfusion ≤ 12 U vs. >12 U Prior PC transfusion ≤ 86 U vs. >86 U Conditioning with vs. without Cy 200 mg/kg Conditioning with horse ATG vs. rabbit ATG BM as a stem cell source vs. Others Infused CD34 infusion ≤ 3 vs. ≤3 (×106 /kg) Prior use of vancomycin vs. not Prior use of acyclovir vs. not Preventive therapy for SOS vs. not Days to SOS ≤ 4 vs. >4 Tender hepatomegaly; No vs. Present Maximal total bilirubin ≤ 5 vs. >5 mg/dL Maximal direct bilirubin ≤ 3 vs. >3 Weight gain ≤ 10 vs. >10%
n
13 vs. 6 9 vs. 10 8 vs. 11 12 vs. 7 13 vs. 6 9 vs. 10 14 vs. 5 16 vs. 3 16 vs. 3 6 vs. 13 6 vs. 13 16 vs. 3 14 vs. 5 15 vs. 4 10 vs. 9 6 vs. 13 17 vs. 2 16 vs. 3 11 vs. 8 4 vs. 15 10 vs. 9 12 vs. 7 18 vs. 1
Univariate analysis
Multivariate analysis
5-Year survival rate (%)
p-Value
HR
59.8 vs. 33.3 61.0 vs. 40.0 87.5 vs. 21.8 65.6 vs. 28.6 50.5 vs. 50.0 77.8 vs. 24.0 46.9 vs. 60.0 50.0 vs. 50.0 53.7 vs. 33.3 62.5 vs. 46.2 83.3 vs. 35.9 60.6 vs. 0.0 69.3 vs. 0.0 59.3 vs. 25.0 58.3 vs. 44.4 100 vs. 28.8 57.0 vs. 0.0 55.0 vs. 33.3 58.9 vs. 37.5 100.0 vs. 37.5 58.3 vs. 40.0 65.6 vs. 19.0 53.5 vs. 0.0
0.163 0.261 0.011 0.191 0.946 0.047 0.565 0.563 0.379 0.492 0.074 0.043 0.002 0.430 0.637 0.013 0.179 0.634 0.112 0.061 0.430 0.062 0.036
– – 1.821 – – 3.032 – – – – 2.810 1.682 12.719 – – >100 – – 2.831 >100 – 2.052 35.655
95% CI – – 0.118–28.017 – – 0.590–15.584 – – – – 0.291–27.089 0.261–10.852 2.332–69.373 – – 0.000–9.16 – – 0.682–11.746 0.000– – 0.482–8.733 2.208–575.805
p-Value – – 0.667 – – 0.184 – – – – 0.372 0.003 – – 0.967 – – 0.152 0.972 – 0.331 0.012
Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval; IST, immune suppression therapy; alloHSCT, allogeneic hematopoietic stem cell transplantation; Dx, diagnosis; PRC, packed red cell; PC, platelet concentrate; Cy, cyclophosphamide; ATG, antithymocyte globulin; BM, bone marrow; SOS, hepatic sinusoidal obstruction syndrome.
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pharmacokinetics/pharmacodynamics, and inter-patient variability in cyclophosphamide metabolites has also been reported in children [17,18]. However, the relationship between cyclophosphamide dose and incidence of SOS is not yet clear, even though personalized Cy dosing has been shown to decrease the maximum value of total serum bilirubin after transplantation and real-time adjustment of Cy dosing was developed as a result [19,20]. In this study, cyclophosphamide was incorporated in the conditioning regimen for almost all of the patients (97.7%) and classical Cy (200 mg/kg)-ATG conditioning was used in 57.7% of patients. Therefore, we were able to analyze the incidence of SOS and the effect of cyclophosphamide conditioning dose on SOS development. The overall incidence of SOS in this study was very low compared with the incidence our previous report, in which all patients received Cy (200 mg/kg)-ATG conditioning (7.3% vs. 41.2%) [9]. This difference might be explained by the fact that almost half of the patients had received cyclophosphamide 200 mg/kg, and the univariate analysis on SOS development seemed to confirm this. However, the multivariate analysis showed that cyclophosphamide 200 mg/kg was not a risk factor for developing SOS (HR = 2.995, 95% CI 0.708–12.663, p = 0.136). Therefore, either cyclophosphamide itself, or a reduced cyclophosphamide dose, cannot clearly explain the reduced rate of SOS in this study. It is possible that there are not only inter-patient but also racial variabilities in Cy metabolism. One report found a relationship between Cy metabolism and liver damage in Asian patients [21]. The study suggested that Cy-induced liver damage was mainly dose-dependent. There is a need for more studies on the dose/toxicity relationship and racial differences in Cy metabolism, including single-nucleotide polymorphisms, in Asian patients. Frequency of SOS was significantly higher in the horse ATG (18.9%) group and lower in the rabbit ATG (3.8%) group in this study. A high incidence and low SOS mortality was found for horse ATG whereas the reverse was found for rabbit ATG. Although horse ATG was a risk factor for developing SOS, rabbit ATG was a risk factor for poor overall survival. This does not mean that SOS after rabbit ATG was more aggressive, despite the low incidence of SOS. Overall, the SOS-specific mortality among all rabbit ATG patients was no higher than that among all horse ATG patients. The SOS-specific mortality and SOS-specific survival rates in the rabbit ATG group, even in those who developed SOS, were no worse than in the horse ATG group. Rather, rabbit ATG seemed to confer some protective effect against SOS. Hence, the incidence of SOS seemed to be lower after rabbit ATG conditioning, although severe cases could not be prevented. Horse ATG has been unavailable in Korea since 2004 and has been replaced by rabbit ATG. This timescale corresponds with the rapid drop in the incidence of SOS in Korea in this study. The different features of the two ATGs could explain these results. An increase in the frequency of regulatory T cells has been observed with rabbit ATG but not with horse ATG, and a marked difference has been shown in the gene-expression profiles of human cells cultured with horse and rabbit ATG [22]. More prolonged lymphopenia follows rabbit ATG administration, and patterns of viral reactivation have been shown to differ between these two ATGs [23]. Horse and rabbit ATGs lead to a similar depletion of CD8+ cytotoxic T cells, but there was a more profound depletion of CD4+ T cells after the use of rabbit ATG [24]. It is not clear whether these different features between the two ATGs could explain the preventive effect of rabbit ATG on SOS development. The patients who developed SOS had poorer survival than those who did not, and the mortality rate in the SOS group was very high under supportive care. In this regard, more effort should be put into prevention and early intervention after selecting high risk SOS. The treatment strategy for SOS is complex because although some patients can recover with supportive care, some patients require specific therapy such as recombinant tissue plasminogen activator or defibrotide to avoid fatality [25,26]. Doppler sonogram or certain
biomarkers can identify early cases, and preventive drugs can be helpful [27–30]. The current definition of severity is based on the final clinical outcome, which does not help to identify candidates for specific therapies. This study revealed that either rabbit ATG or weight gain of more than 10% were risk factors for poor overall survival in the SOS group. Therefore, patients with SOS following rabbit ATG conditioning or weight gain of more than 10% should be considered as candidates for more active therapy in AA. The retrospective data collected in this study have some limitations. First, the diagnosis of SOS was wholly based on the attending physician’s diagnosis according to the clinical criteria, and there was no need for supportive current imaging modalities. Hence, the frequency of SOS could be overestimated because other similar conditions such as hyperacute GVHD or drug-liver injury could not be clearly ruled out. Another problem is the heterogeneity in the use of prophylactic drugs for SOS, although most patients had received heparin for this purpose. In conclusion, SOS is a relatively rare acute complication of alloHSCT in AA (7.3%). Nevertheless, the mortality of SOS is still high (21.1%) under supportive care [30]. The use of a horse ATG conditioning regimen was a significant risk factor for developing SOS, whereas a rabbit ATG conditioning regimen and weight gain >10% were significant risk factors for survival in SOS patients.
Conflict of interest statement All authors have no conflict of interest to declare.
Acknowledgements We thank Mi Young Kim for assisting data collection and management. This work was supported by Priority Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0094050). Contributions: H. K. and S.-S. Y. developed the study concept. H. K., K-H. L., S.-K. S., C.-W. J., Y.-D. J., S.-H. K., B.-S. K., J.-H. C., J.Y. K., M.-S. H., S.-H. B., H.-J. S., J.-H. W., S. O., W.-S. L., J.-H. P., S.-S. Y. performed study. H. K. wrote the manuscript. S.-S. Y. critically reviewed the manuscript.
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