Hepatic veno-occlusive disease (VOD) remains one of the most severe complications of hematopoietic SCT (HSCT). Anticoagulation and thrombolytic therapies using tissue-plasminogen activator (t-PA) have been used, but are reported to be ineffective and are associated with significant bleeding complications. We analyzed 56 moderate-to-severe post HSCT hepatic VOD cases treated with t-PA. We analyzed clinical outcomes according to the maximal daily dose of t-PA (t-PAmax) and the severity of VOD. Patients were stratified by t-PAmax⩽10 mg (n=37) vs t-PAmax>10 mg (n=19). A higher t-PAmax was associated with increased mortality. Bleeding complications were more likely at higher t-PAmax in both moderate and severe VOD (P=0.036, 0.063), especially if patients had concomitant use of anticoagulants (36.4% vs 13.3%). In moderate VOD, the response rate was 86.4% for t-PAmax⩽10 mg/day and 80% for t-PAmax>10 mg compared with 33.3% and 7.1%, respectively, for severe VOD (P=0.106). The 5-year OS in moderate and severe VOD was 49% and 7%, respectively, and it was 32% for t-PAmax⩽10 mg and 18% for t-PAmax>10 mg. Our data demonstrate that lower bleeding complications and bleeding-related deaths may result from strict limitations on the t-PAmax without concomitant use of anticoagulation therapy. However, the overall response and survival outcomes should be re-evaluated by a well-validated study in the future.
Hepatic veno-occlusive disease (VOD) represents a spectrum of organ injury that occurs after the administration of high-dose chemotherapy used for hematopoietic SCT (HSCT). Although it has been reported that the incidence of VOD has decreased recently, some data suggest an increased incidence of VOD in cases of second or tandem transplantation or after the addition of more intensive alkylator combinations.1, 2 The prognosis of VOD depends upon the extent of hepatic injury, subsequent liver dysfunction, and presence of multiorgan failure. Severe VOD is associated with extremely poor survival outcomes, with all-cause mortality in excess of 98% by day 100 post HSCT. In moderate VOD, the mortality is about 20%.3
Standard therapy for VOD is mainly supportive care, and includes diuresis, transfusion support and renal replacement therapy concomitant with ursodeoxycholic acid (UDCA) and glutathione maintenance. However, supportive care alone still results in very poor outcomes, especially in moderate-to-severe VOD. Therefore, several studies using systemic anticoagulation or thrombolytic therapies using tissue-plasminogen activator (t-PA) have been performed. However, those studies found that major bleeding complications adversely affected the OS.4, 5, 6 Defibrotide is a polydisperse oligonucleotide that binds to the vascular endothelium and has pleiotropic properties on microvasculature and the extracellular matrix. Recent studies of its use in VOD have demonstrated complete response (CR) rates between 36–60% with consistent OS at post-HSCT day 100 of 35–50% with the added benefit of reduced toxicity.7, 8, 9
At the present time, the difficulties associated with t-PA prohibit its use, and defibrotide is not available in routine practice because of its high cost. Thus, in the case of moderate-to-severe hepatic VOD, the only available treatment option is supportive care. We investigated our experiences using t-PA with or without concomitant use of anticoagulants for moderate-to-severe VOD in an effort to find an effective and the safest treatment protocol that can improve survival outcomes for this group of patients.
Patients and Methods
Patients and prior disease status
After approval from the Catholic Medical Center Institutional Review Board, 63 patients from our database (from 2000–2011) were identified as hepatic VOD cases treated with t-PA with or without anticoagulation therapy. Seven patients with mild VOD were excluded, leaving 56 patients for analysis. The median age was 35.5 years (range: 15–58), and there were 32 male patients (57.1%). Twenty-six patients had AML), 18 had ALL, 5 had CML, 4 had myelodysplastic syndrome and 3 patients suffered severe aplastic anemia. They all underwent HSCT after pre-conditioning based on the protocol set by the Catholic Blood and Marrow Transplantation Center in Korea. Among patients with AML and ALL, five were receiving their second HSCT (three were in second remission and two were refractory). Twenty-nine patients (65.9%) were in their first remission, 3 (6.8%) were in their second remission, and 7 (15.9%) were refractory. For CML, three patients were in the chronic phase, one patient had a complete hematologic response and the last was in the blastic phase. For myelodysplastic syndrome, three patients were in RAEB2 and one patient was in RCMD.
Details in HSCT
Thirty-two patients (57.1%) received stem cells from matched sibling donors, and the remaining 24 patients received transplants from suitably matched unrelated donors (matched (n=13), <2 allele-mismatched (n=11)). Forty-three patients (76.8%) received BM and 13 (23.2%) received peripheral blood stem cells. All CML patients were pre-conditioned with TBI of 1200cGy plus CY 60 mg/kg for 2 days (TBI1200cGy/CY). For ALL, nine patients were pre-conditioned with TBI of 1320cGy plus CY 60 mg/kg for 2 days, six received a TAM regimen consisting of 1200 cGy of TBI, ARA-C 3 g/m2 for 3 days and melphalan (MEL) 100 mg/m2 for 1 day10 and three were treated with FLU/MEL consisting of fludarabine (FLU) 30 mg/m2/day for 5 days and MEL 70 mg/m2/day for 2 days. For AML, eight patients were treated with TBI1320cGy/CY, three received TAM and one patient was treated with the FLU/MEL regimen. Seven patients were treated with a BU/CY regimen consisting of BU 3.2 mg/kg for 4 days plus CY 60 mg/kg for 2 days, three were treated with BU/TBI consisting of BU 3.2 mg/kg for 2 days plus TBI 1320cGy and four were treated with FLU/BU/TBI400cGy consisting of FLU 30 mg/m2/day for 5 days and BU 3.2 mg/kg for 2 days plus TBI 400 cGy. For myelodysplastic syndrome, three patients were treated with TBI1320 cGy/CY and one patient was treated with FLU/BU/TBI400cGy. All severe aplastic anemia patients were treated with PCB/CY/ATG consisting of oral procarbazine (PCB) 6.25 mg/kg for 6 days plus CY 50 mg/kg for 4 days. On the basis of definition of conditioning intensity,11, 12 45 were pre-conditioned with a myeloablative conditioning regimen, and the other 11 received a reduced-intensity conditioning regimen.
We administered oral UDCA and glutathione pills in all patients, but i.v. VOD prophylaxis was given to only 39 (69.6%) patients. For i.v. VOD prophylaxis, 22 patients received heparin 100 IU/kg/day and 17 received prostaglandin E1 (PGE1) 1 μg/kg/day infusion continuously from the day before the start of conditioning to D+21 after HSCT. GVHD prophylaxis was administered using a calcineurin inhibitor plus a short course of MTX on D1, D3, D6 and D11. Anti-thymocyte globulin (ATG, 2.5 mg/kg) was administered for 2 days (D-2∼D-1, total 5 mg/kg) to the patients who received allele-mismatched unrelated donor grafts. In patients with severe aplastic anemia, ATG was administered for 3 days without regard to donor type.
Diagnosis and management of VOD
The median time from HSCT to the diagnosis of VOD was 21 days (range: 5–92). For the diagnosis and staging of VOD, both the Seattle criteria3, 13 and the Baltimore criteria14 were utilized along with clinical evidence and additional Doppler sonograms. Although we performed Doppler sonogram in 42 patients (21 in moderate VOD, 21 in severe VOD), the diagnostic relevance was not consistent for which we only used the results additionally to the diagnostic criteria of VOD. No VOD cases were confirmed by the liver biopsy in this study. The stage of VOD was evaluated according to previous studies. Precisely, moderate VOD (n=27) was diagnosed according to at least one of the following: increase in total bilirubin level to over 6 mg/dL or weight gain >5%, or the presence of ascites. Severe VOD (n=29) was diagnosed in patients with renal failure (creatinine >twice above baseline), respiratory failure or bilirubin levels >20 mg/dL.15, 16 Among 27 patients with moderate VOD, three patients were diagnosed with weight gain >5% only, without increased bilirubin level over 6 mg/dL and ascites. For these three patients, we additionally checked reduced portal vein flow with a Doppler sonogram compared with the pre-HSCT data.
When VOD was diagnosed, the i.v. infusion of t-PA was immediately started at a variable initial dose (range: 5–20 mg) mixed in 200 mL normal saline for 6 h. Ten milligrams t-PA was started in 42 patients, 5 mg in 7 patients and 15∼20 mg in 7 patients, and we then cautiously maintained or elevated the dose of t-PA depending on the response. Repeated infusion was completed every 24 h. Response evaluation for dose adjustment was based on the continuous decrement of TB levels over at least two consecutive days with no evidence of bleeding. If there was no response, the t-PA dose was increased by 5–10 mg/day and the maximal daily dose was increased to 50 mg/day. There were 19 patients (33.9%) with a maximal t-PA dose >10 mg/day and 10 (17.8%) with a maximal t-PA dose >20 mg/day. The median number of days of t-PA infusion was 6 (range: 1–36), and a calculated cumulative dose of >50 mg was administered to 29 patients (51.8%). A CR was defined as a decrease in TB levels to <2 mg/dL with normalization of other laboratory findings (that is, creatinine) and recovery of the patient’s weight and abdominal circumference to the baseline level.
Additional treatment included fluid restriction and I/O control with oral UDCA and glutathione in all 56 patients. Eleven (19.6%) patients were treated with concomitant anticoagulation therapy, with low-dose heparin in seven and PGE1 in four patients. Steroid was administered to 27 (48.2%), and a renal replacement device was required for 15 (26.7%) patients. In the case of steroid, 16 patients with previous acute skin and gut GVHD received steroid at the time of diagnosis of VOD, and 11 patients received additional steroid treatment after diagnosis of VOD.
Definitions and statistical analysis
We divided patients into two groups according to whether their maximal daily infusion dose of t-PA was more or less than 10 mg. For each group, clinical information, including t-PA dose, number of days of administration and parameters associated with HSCT, and laboratory findings during t-PA treatment were obtained. All categorical variables were compared using Chi-squared analysis and Fisher’s exact test. Continuous variables were assessed with the Student’s t-test or the Wilcoxon rank-sum test. OS was calculated using Kaplan–Meier analysis, and log-rank analysis was used to evaluate differences between subgroups. OS represented the proportion of people who were alive at a specified time from the date of diagnosis of VOD. The cumulative incidence of CR and death due to bleeding complications after t-PA treatment was calculated by the Gray test.17 Hazard ratio associated with survival, death and response was calculated using Cox’s proportional hazard model. All statistical analyses were performed using SAS 9.2 software (SAS Institute, Inc., Cary, NC, USA) and R software (version 2.15.1, R foundation for statistical Computing, 2012). A P-value <0.05 was deemed statistically significant.
Fifty-six patients were divided into two groups according to whether their maximal daily dose of t-PA was ⩽10 mg or >10 mg. There were 37 patients in the t-PA⩽10 mg/day (range 5–10 mg) group and 19 patients in the t-PA>10 mg/day (range 12.5–50 mg) group. We analyzed the clinical parameters between the two groups and found that in the higher t-PA group there were more cases of severe VOD (73.7% vs 40.5%, P=0.019), and the median cumulative dose was observed to be higher (55 vs 240 mg, P<0.001). There were 29 patients (51.7%) with a cumulative t-PA dose of ⩽50 mg. Among them, 24 were in t-PA⩽10 mg/day group and 5 were in the >10 mg/day group. Otherwise, variables such as gender, age and the length of time from HSCT to diagnosis were not different, and laboratory parameters, including total bilirubin, platelet count and prothrombin time levels, were also similar between the two groups. Distributions of prior disease status, detailed information associated with HSCT, and additional treatments are presented in Table 1.
Clinical outcomes of t-PA treatment according to the maximal daily dose
With a median follow-up duration of 79 months (range: 16–119), OS for all patients with moderate-to-severe VOD was 18% at 5 years, and CR was achieved in 29 patients (51.8%), Twenty-three patients (41.1%) with moderate VOD and six patients (20.7%) with severe VOD. We performed a follow-up Doppler sonogram in 15 patients with clinical CR, and all of them (10 moderate VOD and 5 severe VOD) were identified to be recovered to a normal portal vein flow compared with a reduced flow at diagnosis of VOD. Death due to a complication of VOD was identified in a total of 27 cases, 10 of which were related to bleeding complications. Figure 1 shows a comparison of clinical outcomes according to the maximal daily dose of t-PA. Patients receiving t-PA ⩽10 mg/day showed a significantly higher response rate (P=0.029) and lower mortality due to bleeding complications (P=0.003), but patients were more likely to have severe VOD in the t-PA>10 mg/day group as presented above. Some patients with multiorgan failure also achieved a good response with t-PA. Among 25 patients with creatinine levels higher than 2 mg/dL (renal replacement therapy was performed in 14 of these patients), five patients (20%) achieved a CR and one patient (6.7%) stopped renal replacement therapy. Although t-PA⩽10 mg/day group showed a higher response rate, the difference in OS was not statistically significant between the two groups (P=0.08, Figure 2a). However, t-PA⩽10 mg/day group showed a relatively favorable OS at 6 months (65% vs 37%), at 1 year (51% vs 25%) and at 5 years (20% vs 15%). As shown in Figure 2b, the estimated OS rates between moderate vs severe VOD were, respectively, 93% vs 21% at 6 months, 77% vs 10% at 1 year and 37% vs 2% at 5 years (P<0.001). However, subgroup analysis between moderate (Figure 2c) and severe (Figure 2d) VOD showed no difference in OS according to the maximal daily dose of t-PA.
Table 2 shows the bleeding complications in moderate-to-severe VOD after administering t-PA. For all bleeding events (n=23), there were significantly more cases in the t-PA>10 mg/day group (63.2% vs 29.7%, P=0.016). For major bleeding events, there were also more cases both in the t-PA>10 mg/day group (47.4% vs 16.2%, P=0.013) and in the anticoagulation combination subgroup (54.5% vs 20%, P=0.02). In both the t-PA>10 mg/day and >20 mg/day subgroup, more deaths were attributed to bleeding complications. Major bleeding (n=15) sites included seven cases of brain, five cases of lung, and five cases of gastrointestinal hemorrhages. Most of the brain and lung hemorrhages were identified as the major cause of death (n=10).
Hazard ratios for OS, response rate, death due to all-cause of VOD and death due to bleeding complications were calculated in Table 3. Severe VOD was the most influential factor for all clinical outcomes. Although there were more severe VOD cases in the t-PA>10 mg/day group and in the cumulative dose >50 mg subgroup, adjusted results show that rates of death due to all causes of VOD were significantly lower in the cumulative dose ⩽50 mg subgroup and that death due to bleeding complications was significantly lower in the t-PA⩽10 mg/day group.
Subgroup analysis according to severity of VOD
In the moderate vs severe VOD subgroup, the response rate to t-PA treatment was 88% vs 27%, respectively. The response rate was not significantly different according to the daily t-PA dose in either VOD subgroup. A lower daily dose of t-PA just showed a trend toward a better response rate in severe VOD (P=0.106). Patients with moderate VOD treated with t-PA⩽10 mg/day (n=22) showed significantly fewer bleeding events (9.1% vs 80%, P=0.006) with no bleeding-related death (Figure 3a). Patients with severe VOD treated with t-PA⩽10 mg/day also showed lower rate of bleeding-related death, but the data lacked statistical significance (P=0.063, Figure 3b). In both VOD subgroups, the rates of death due to all causes of VOD were similar according to the maximal daily t-PA dose (P=0.695, 0.230). Hazard ratios for OS, response rate, death due to any cause of VOD and bleeding-related death were calculated in the severe VOD subgroup (Table 4). In both the higher maximal daily t-PA group and the subgroup of cumulative dose >50 mg, multivariately adjusted results show that the rate of death due to all causes of VOD and bleeding-related death were significantly higher. Patients who received concomitant anticoagulation therapy also revealed more bleeding-related death.
There have been numerous reports in the literature of patients treated with t-PA with or without anticoagulation, but only a few series have showcased a sample number >10 patients.4, 5, 6, 18, 19 Our study included 56 patients with moderate-to-severe VOD who were mainly treated with t-PA infusion, which makes it one of the largest retrospective analyses.
Among previous reports, Bearman et al.4 analyzed the largest number of patients (n=42) with established VOD treated with t-PA with unfractionated heparin. They reported 12 patients (29%) showed clinical improvement with at least a 50% reduction in pre-treatment bilirubin. However, OS was poor, and no patients with multiorgan failure responded. Further, 10 patients (24%) developed severe bleeding, of which a significant number (n=9) proved fatal. They concluded that t-PA with or without anticoagulation should be administered only in severe VOD with multiorgan failure. In contrast to previous studies, we analyzed outcomes after dividing patients into multiple subgroups according to the maximal daily t-PA infusion dose, cumulative total dose and concomitant anticoagulation use. Subsequently, we found that, in some situations, a more favorable clinical outcome could be obtained than would be suggested by previous reports.
First, our data showed that the maximal daily dose of t-PA should be strictly limited to avoid fatal bleeding complications. Similarly, a higher t-PA dose is ineffective, and physicians should avoid t-PA dose-escalating protocols for moderate-to-severe VOD. Further, a higher cumulative total dose of t-PA showed higher all-cause mortality because of complications of VOD with more bleeding events. Our findings may be valuable because there have been no prospective dose-dependency studies of t-PA, probably because of the low incidence of VOD and the risk of bleeding complications. Researchers in previous studies have started t-PA minimally at 2–5 mg/day and maximally at 30–40 mg/day. The duration of treatment was generally from 2 to 21 days with a cumulative dose of 10 to 800 mg.4, 5, 19 We treated patients with a starting dose at the level of 5 to 20 mg, and the dose was increased to a maximal daily infusion dose of up to 50 mg according to the treatment response of VOD. The duration of treatment with t-PA was from 1 to 36 days, and the cumulative dose ranged from 20 to 1000 mg. In practice, the t-PA dose was increased in the non-responding group, and one would expect the disease course to be worse in the higher t-PA group. Thus, we attempted to determine the t-PA dose-associated bleeding complication and death due to bleeding rates as primary end points, and the OS and response rate as secondary end points. Our data demonstrated that higher daily maximal dose of t-PA was significantly associated with more overall bleeding complications, major bleeding events and death due to bleeding complications at the level of >10 mg/day.
The concomitant use of anticoagulation is not suggested based on our results. Previous studies failed to compare the risk and response of concomitant use of anticoagulation treatments. However, a few reports showed that concomitant use did not increase bleeding risk in a selected small patient population.19, 20 We used low-dose heparin (100 IU/kg/day) or PGE1 (1 μg/kg/day) as an i.v. VOD prophylactic regimen. However, after the diagnosis of VOD, the maintenance of anticoagulants with t-PA infusion is a difficult decision between increased bleeding risk or a poor disease response. Eleven patients were treated with concomitant use of t-PA and anticoagulation (heparin (n=7), PGE1 (n=4)), and six patients showed major bleeding complications (54.5%) compared with non-concomitant use (20.0%, P=0.020). For death due to bleeding complications, concomitant treatment was also associated with higher rates of death (36.4%) than non-concomitant use (13.3%, P=0.074).
Our study had several limitations. Retrospective analysis of a heterogeneity of treatments, a small number of patients and the imbalance of VOD staging between the compared subgroups could introduce bias, preventing proper analysis. Further, we do not have an untreated comparison group, and we cannot definitively establish the efficacy of t-PA. However, on the basis of these results, a prospective study is warranted using limited daily dosageof t-PA without concomitant anticoagulation therapy when the alternative is supportive care only.
In conclusion, using t-PA in moderate-to-severe VOD should be re-considered, as long as doses are limited and patients are not also taking anticoagulation treatment. A prospective study should be done to evaluate appropriate dosage, duration of treatment, indication, efficacy and strategies for minimizing the risk of bleeding complications.
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This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1020370).
The authors declare no conflict of interest
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Cite this article
Yoon, J., Min, W., Kim, H. et al. Experiences of t-PA use in moderate-to-severe hepatic veno-occlusive disease after hematopoietic SCT: is it still reasonable to use t-PA?. Bone Marrow Transplant 48, 1562–1568 (2013). https://doi.org/10.1038/bmt.2013.101
- veno-occlusive disease
- hematopoietic SCT
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