Risk factors for hepatic veno-occlusive disease after bone ... - Nature

Bone Marrow Transplantation, (1997) 20, 397–402  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Risk factors for hepatic veno-occlusive disease after bone marrow transplantation: retrospective analysis of 137 cases at a single institution M Kami, S Mori, S Tanikawa, H Akiyama, Y Onozawa, T Tanaka, R Okamoto, Y Maeda, T Sasaki, H Kaku, Y Matsuura, K Hiruma and H Sakamaki Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

Summary: One hundred and thirty-seven consecutive patients who received bone marrow or peripheral blood stem cell transplantation were studied retrospectively to identify the risk factors for hepatic veno-occlusive disease (VOD). Of the 137 recipients, twenty (14.6%) patients were diagnosed with VOD using the McDonald’s criteria. In these 20 patients with VOD, we analyzed various clinical parameters, including age, sex, HLA status, conditioning regimen, irradiation, immunosuppressive agents, mode of transplantation, history of hepatic dysfunction, pre-transplant hepatic and renal function, infectious episodes, antibiotics use, and serum viral titers. A history of hepatic dysfunction and low levels of pseudocholinesterase before transplantation were found to be statistically significant (P = 0.04 and 0.04). Low levels of pseudocholinesterase were significant by multivariate analysis using the logistic regression model (P = 0.02). These results suggest that pseudocholinesterase levels before transplant are important markers of VOD in patients receiving BMT. Keywords: BMT; VOD; risk factors; pseudocholinesterase

Hepatic veno-occlusive disease (VOD) is one of the serious complications of bone marrow transplantation (BMT), characterized by painful hepatomegaly, ascites and jaundice.1 It occurs in 10–50% of all bone marrow recipients,2 and the mortality rate is high. Various parameters have been reported as risk factors; history of liver dysfunction, elevated AST levels before transplantation, transplantation from an HLA-mismatched or unrelated donor, abdominal irradiation, previous fungal infection, and various chemotherapeutic agents.3–5 We cannot reliably identify a high risk group of VOD before transplantation and reliable therapy and prophylaxis have not been established. The objective of this paper was to determine the risk factors for VOD and to select the high risk patients. We Correspondence: Dr H Sakamaki, Tokyo Metropolitan Komagome Hospital, Bone Marrow Transplantation Team, 3-18-22 Honkomagome, Bunkyoku, Tokyo 113, Japan Received 10 February 1997; accepted 11 May 1997

therefore determined the incidence of VOD using the McDonald’s criteria and analyzed the clinical characteristics of patients with VOD and those without it.

Materials and methods Patients One hundred and thirty-seven consecutive patients (52 males and 85 females) underwent bone marrow transplantation (including peripheral blood transplantation) for hematological malignancies and severe aplastic anemia at our institution between September 1989 and October 1995. The average age of patients was 29.9 (6–51) years old. Conditioning regimens and graft-versus-host disease (GVHD) prophylaxis The primary disease for which transplantation was carried out, transplantation procedures and immunosuppressive agents used are summarized in Table 1. Most of the patients with myeloid malignancies received busulfan (4 mg/kg) for 4 days and cyclophosphamide (CY) (60 mg/kg) for 2 days. Most of the patients with lymphoid malignancies received four doses of 2 g/m2 of cytosine arabinoside over 3 days, 60 mg/kg of CY, for 2 days and 12 Gy of a total body irradiation (TBI) in six fractions over a period of 3 days. Patients with severe aplastic anemia (SAA) received 50 mg/kg of CY for 4 days followed by total lymphoid irradiation (TLI), 7.0 Gy in two fractions. All patients who underwent allogeneic transplantation received acute GVHD prophylaxis as follows: short-term MTX and cyclosporine (CsA) (81 patients), CsA alone (22 patients), FK-506 and short-term MTX (three patients) and FK506 alone (one patient). Diagnosis of VOD Patients were diagnosed as having VOD using the McDonald’s criteria. 1 Patients who satisfied at least two of the following criteria were diagnosed with VOD: jaundice (total bilirubin .2.0 mg/dl), hepatomegaly and upper abdominal pain, ascites and/or body weight gain (at least 5% gain from the baseline body weight, measured just before condition-

Risk factors for hepatic veno-occlusive disease after BMT M Kami et al

398

Table 1

Patient characteristics

Factors No. of patients Sex (male/female) Age (mean, range) Underlying disease CML ALL ANLL SAA MDS NHL myeloma Type of transplant allogeneic autologous syngeneic HLA status match mismatch unrelated Conditioning regimens BU/CY BU/CY/VP-16 Ara-C/CY/TBI CY/TLI Immunosuppressive agents MTX/CSP MTX/FK506 CSP only FK506 only

No. 137 52/85 29.9 (6–51) 42 34 30 11 10 9 1 107 28 2 116 9 12 86 16 18 11 6 81 3 22 1

were defined as having a positive history of hepatic dysfunction. Results of laboratory tests performed around day −30 were defined as the pretransplant levels. Statistical analysis Univariate analysis using the x2 test and the Mann–Whitney U test performed with the pretransplant parameters were used to evaluate the risk of VOD. Multivariate analysis of the risk factors with the multiple logistic regression analysis was then added to the appropriate variables. The Kaplan–Meier survival analysis with the log-rank test was used to determine overall survival rates of each group.

Results Characteristics of patients with VOD Twenty patients (14.6%) were diagnosed with VOD. Patients with VOD had more weight gain, higher levels of maximum total bilirubin and higher rates of upper abdominal pain, ascites and hepatomegaly (Table 2). These were statistically significant. Other variables are also shown in Table 2. The incidence of hepatic failure and early mortality were higher in the VOD group. However, this was not statistically significant. Risk factors for VOD

ing therapy. Hepatomegaly and ascites were diagnosed clinically and/or radiologically. Risk factors Risk factors for VOD were determined by comparing the patients with and without VOD. Risk factors included age, sex, HLA status, conditioning regimen, irradiation, immunosuppressive agents, nature of transplant (allogeneic, autologous or syngeneic, related or unrelated), hepatic and renal function before transplantation, infectious episodes, antibiotics use, serum viral titers (EB virus, herpes simplex virus, cytomegalovirus (CMV), adenovirus). In analyzing viral infection, patients with complement fixation titers higher than ×4 were regarded as positive. The patients who received bone marrow from a onelocus or more mismatched donor or who received it from an unrelated donor were regarded as mismatched recipients. Use of antibiotics was limited to intravenous administration from day −7 to day 30, and oral prophylaxis was omitted from our analysis. We defined both total body irradiation (TBI) and total lymphoid irradiation (TLI) as irradiation, and local irradiation performed to control extramedullary leukemic infiltration was not included in the analysis. Patients with a history of hepatitis, liver dysfunction, positive hepatitis virus antibody, maximum AST and/or ALT level of more than 100 IU/l, or maximum total bilirubin level of more than 1.5 mg/dl during the previous year

Univariate analysis was performed with various parameters. A significant difference was not observed using the variables in our study apart from a history of hepatic dysfunction and low levels of pretransplant pseudocholinesterase (Tables 3 and 4). In our analysis, previously reported risk factors including abdominal irradiation, unrelated BMT, and fungal infection were not statistically significant.2–5 We added the logistic regression analysis for further evaluation. No significant difference was observed except for levels of pseudocholinesterase. This remained a significant risk factor by this evaluation (P = 0.02). The odds ratio was 4.42 per 100 IU/l of pseudocholinesterase. Distribution of pseudocholinesterase levels in patients with or without VOD is shown in Figure 1. This result suggests that patients with low levels of pretransplant pseudocholinesterase have a high risk for VOD. We evaluated long-term survival in patients with VOD. Figure 2 shows the results of the Kaplan–Meier analysis with the log-rank test. It is apparent that the patients with VOD have a poorer prognosis than those without VOD.

Discussion The incidence of VOD was 14.6% by the McDonald’s criteria, comparable to the values previously reported. 6 We excluded four cases which had clinical characteristics of VOD, but with a distinct cause other than VOD: three cases of acute GVHD and one case of congestive heart failure.


Table 2

399

Clinical characteristics

No. Weight gain

number of patients maximal weight gain (%)a

Upper abdominal pain TB .2.0 mg/dl

number of patients number of patients maximal TB level

Hepatomegaly Ascites Liver dysfunction

number of patients number of patients maximal AST level maximal ALT level maximal ALP level

Hepatic failure Renal dysfunctionc

number of patients maximal Cr/pre Cr

Mortalityd

Patients with VOD

Patients without VOD

20 18/20 5.2 (−0.4–17.0) 19/20 16/20 9.2 (0.6–41.6) 13/20 7/20 130.5 (25–487) 233.6 (27–1236) 140.8 (38–256) 3/20 9/20 2.4 (0.7–7.1) 3/20

117 57/117 6.6 (−5.5–13.7) 38/117 11/117 12.6 (0.4–3.8) 5/117 2/114 75.2 (6–385) 134.5 (19–1202) 117.8 (30–437) 1/117 26/117 1.6 (1.2–6.8) 6/117

P value

,0.001b ,0.0001b ,0.0001b ,0.0001b ,0.0001b ,0.0001b ,0.0001b 0.0346b 0.0489b 0.0133b 0.098 0.03b 0.21 0.1257

a

Maximal weight gain post-BMT/basal body weight which was measured at the beginning of conditioning regimen. Statistically significant. c Patients whose maximal creatinine levels post-BMT were more than twice pretransplant creatinine levels were diagnosed as renal dysfunction. d Mortality during the first 100 days after BMT. All causes of death were included. b

One patient presented with hepatomegaly, body weight gain and jaundice after day 20. His clinical features satisfied the McDonald’s criteria for VOD in the absence of other causes of hepatotoxicity. According to the McDonald’s criteria, he was not diagnosed as having VOD; however, the onset of VOD may have been late, a situation which has recently been advocated.7 Our evaluation demonstrated a lower survival rate for patients with VOD than for those without it (Figure 2). Both survival curves showed a plateau. This is probably due to the early mortality in patients with VOD. In analyzing the long-term survival in patients who had survived more than 100 days, the difference in outcome disappeared (data not shown, P = 0.46). In our analysis, seven out of 20 patients with VOD died. Three died of hepatic failure (including VOD). These three patients died at days 87, 122, and 228 after BMT, respectively. Other causes were relapse (two cases), cerebral bleeding and infection (one case of each). Some pilot studies have suggested the effectiveness of heparin8 and ursodiol 9 for prophylaxis of VOD. However, a recent randomized trial denied the efficacy of heparin.10 To make prophylaxis effective, reliable selection of high risk patients is necessary. For this purpose, accurate information about the etiology and risk factors for VOD are required. Univariate analysis showed two parameters to be statistically significant: a history of hepatic dysfunction and low levels of pseudocholinesterase before transplantation (Tables 3 and 4). The former has often been reported as an important risk factor for VOD.1,9,11 However, the definition of hepatic dysfunction has differed in each study, and it is

impossible to evaluate a history of liver dysfunction accurately in a retrospective fashion. Our analysis disclosed one more important risk factor: pseudocholinesterase levels a generic term which includes various enzymes that hydrolyze a cholinester into choline and organic acid.12 This enzyme level correlates with protein synthesis in the liver and with the number of functional hepatocytes. The relation between incidence of VOD and this enzyme level is unknown. However, hepatic VOD may more commonly develop in a liver with latent dysfunction.13,14 For this reason, we added pseudocholinesterase levels to the analysis of risk factors for hepatic VOD. Serum AST, ALT and ALP levels mirror the extent of hepatic injury and are not necessarily proportional to hepatic reserve. This is the first report to demonstrate a correlation between VOD and decreased levels of pseudocholinesterase before BMT. The level of this enzyme differed between the patients with VOD and without it to an extent which was statistically significant on univariate analysis (Table 4). Furthermore, multivariate analysis with logistic regression also revealed levels of this enzyme to be statistically significant (P = 0.02). Figure 1 shows the distribution of pseudocholinesterase levels in patients with or without VOD. This result may indicate that patients with poor hepatic reserve will be even more severely damaged by conditioning therapy and that they will more readily manifest ascites, jaundice and weight gain. Among the various parameters which reflect hepatic function, we consider pseudocholinesterase levels to be the most reliable indicator of hepatic reserve before BMT. Other hepatic enzymes such as AST, ALT and ALP are influenced by transient liver pathology and may correlate


400

Table 3

Univariate analysis of risk factors

Factors Sex

ABO blood types

male female 20. ,19 AML ALL CML SAA high risk normal risk match mismatch unrelated mismatch

Conditioning

Busulfan

Age Diagnosis

Stage a HLA

VP16 AraC Irradiation

TBI TLI

Immunosuppressive agents

MTX CSP FK506

History of hepatic dysfunction Viral infection

HBV HCV CMV HSV VZV EBV

Antibiotics use

total

b lactam aminoglycoside VCMc AMPHc

positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative positive negative

No. of patients with VOD

P value

10/52 10/85 16/117 4/20 2/30 6/34 8/42 2/11 11/81 9/56 14/116 2/9 4/12 8/46 11/91 13/105 7.32 4/16 16/121 5/17 15/120 5/47 15/90 5/19 14/118 15/84 5/53 18/103 2/34 1/4 19/133 10/48 8/94 0/1 19/122 2/7 14/95 15/96 4/20 9/66 7/51 12/79 4/39 13/82 1/16 2/27 18/110 1/20 19/117 2/22 18/115 0/9 20/118 0/2 20/135

0.85 0.69 0.99

0.87 0.22 0.38 0.29 0.25 0.13 0.45 0.23 0.28 0.16 0.47 0.04b 0.99 0.3 0.88 0.99 0.70 0.27 0.36 0.31 0.74 0.35 0.99

a

Patients diagnosed as SAA, ANLL, NHL and ALL in first CR and CML in first CP are regarded as normal risk patients. Others were included in high risk patients. b Statistically significant. c They include intravenous administration only.

poorly with clinical outcome. Other parameters such as coagulation tests, total cholesterol and albumin, which reflect the relatively short term ability of the liver to synthesize protein, had a tendency to be lower in the patients with VOD, but this was not statistically significant.

It is well known that this enzyme decreases transiently during and after chemotherapy. A short interval from the end of previous chemotherapy to the start of conditioning may be a risk factor of VOD. However, among patients with VOD, only one had had chemotherapy during the


Table 4

401

Univariate analysis of risk factors

Factors

AST

(IU/I)

ALT

(IU/I)

Total bilirubin

(mg/dl)

Direct bilirubin

(mg/dl)

ALP

(IU/I)

g GTP

(IU/I)

a

PT

(%)

APTTb

(s)

Fibrinogen

Patients with VOD


P value

28.6 10–151 46.9 7–240 0.62 0.2–1.4 0.11 0.0–0.7 96.5 41–265 59.2 3–501 82.3 61–100 42.3 25–73 255 175–370 232 50–350 4.1 3.5–4.5 168 59–257 0.60 0.3–1.1

26.1 6–180 46.1 3–501 0.56 0.2–1.3 0.14 0.0–0.4 86.2 15–286 42.2 8–238 86.3 34–100 44.3 28–106 265 101–665 293 121–497 4.1 3.1–6.5 157 70–279 0.65 0.1–1.3

0.91

(mg/dl)

Pseudocholinesterase

(IU/I)

Albumin

(g/dl)

Total cholesterol

(mg/dl)

Creatinine

(mg/dl)

0.92 0.90 0.55 0.66 0.48 0.13 0.27 0.08 0.04c 0.91 0.26 0.20

a

Prothrombin time. Partial prothrombin time. c Statistically significant. b

n = 96

1

0.8

n = 20

400

Survival

Pseudocholine esterase (IU/l)

500

300

200

0.6

0.4

Patients with VOD

0.2


100

0 0

0 Negative

Positive

VOD Figure 1 Distribution of pretransplant pseudocholinesterase levels of patients with or without VOD. Patients with low levels of pretransplant pseudocholine are at high risk of VOD. Results are expressed as mean ± 1 s.d.

month prior to BMT, and this patient underwent BMT in relapse. In our analysis, chemotherapy just before BMT seemed to have little effect on pseudocholinesterase levels. For further evaluation of VOD, evaluation of antithrombin III,15 type IV collagen, type III procollagen16,17 and hya-

20

40

60

80

100

120

Time (months) Figure 2 Kaplan–Meier analysis of the overall survival. Log rank (Mantle–Cox) test was performed. The survival rates were different, which was statistically significant (P = 0.01).

luronate acid levels may be appropriate, since these enzymes reflect other aspects of liver function. In conclusion, retrospective analysis revealed that a low level of pseudocholinesterase is a risk factor for VOD. This suggests that poor hepatic reserve plays an important role in the etiology of VOD and that pseudocholinesterase levels reflect it most accurately.


402

References 1 McDonald GB, Sharma P, Matthews DE et al. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122. 2 Rozman C, Carreras E, Qian C et al. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant 1996; 17: 75–80. 3 McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267. 4 Meresse V, Hartmann O, Vassal G et al. Risk factors for hepatic veno-occlusive disease after high-dose busulfan-containing regimens followed by autologous bone marrow transplantation: a study in 136 children. Bone Marrow Transplant 1992; 10: 135–141. 5 Dulley FL, Kanfer EJ, Appelbaum FR et al. Venocclusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation. Transplantation 1987; 43: 870–873. 6 Blostein MD, Paltiel OB, Thibault A, Rybka WB. A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation. Bone Marrow Transplant 1992; 10: 439–443. 7 Naito H, Arioka H, Kobayashi R, Ishikawa Y. Fulminant hepatitis-like veno-occlusive disease of the liver after allogeneic bone marrow transplantation in acute lymphoblastic leukemia. Rinsho Ketsueki J J Clin Hematol 1993; 34: 656– 661. 8 Bearman SI, Hinds MS, Wolford JL et al. A pilot study of continuous infusion heparin for the prevention of hepatic veno-occlusive disease after bone marrow transplantation. Bone Marrow Transplant 1990; 5: 407–411.

9 Essell JH, Thompson JM, Harman GS et al. Pilot trial of prophylactic ursodiol to decrease the incidence of venoocclusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1992; 10: 367–372. 10 Marsa-Vila L, Gorin NC, Laporte JP et al. Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation. Eur J Haematol 1991; 47: 346–354. 11 Jones RJ, Lee KS, Beschorner WE et al. Veno-occlusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783. 12 McQueen MJ. Clinical and analytical considerations in the utilization of cholinesterase measurements. Clin Chim Acta 1995; 237: 91–105. 13 Lemberg A, Macchi MC. Usefulness of serum pseudocholinesterase isoenzymes in acute and chronic liver diseases and neoplasms (experimental and clinical study). Acta Gastroenterol Latinoamericana 1981; 11: 125–132. 14 Gentz HD, Schlicht I, Wiederholt W. Pseudocholinesterase in patients with and without liver diseases (author’s translation). Medizinische Klin 1978; 73: 1422–1426. 15 Catani L, Gugliotta L, Mattioli Belmonte M et al. Hypercoagulability in patients undergoing autologous or allogeneic BMT for hematological malignancies. Bone Marrow Transplant 1993; 12: 253–259. 16 Rio B, Bauduer F, Arrago JP, Zittoun R. N-terminal peptide of type III procollagen: a marker for the development of hepatic veno-occlusive disease after BMt and a basis for determining the timing of prophylactic heparin. Bone Marrow Transplant 1993; 11: 471–472. 17 Heikinheimo M, Halila R, Fasth A. Serum procollagen type III is an early and sensitive marker for veno-occlusive disease of the liver in children undergoing bone marrow transplantation. Blood 1994; 83: 3036–3040.