Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD)

Abstract

Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p < 0.0001). The 100-day transplantation-related mortality was 25.2% in the entire cohort; 8.3% in mild, 8.0% in moderate, 2.7% in severe, and 36.7% in very severe SOS/VOD (p < 0.0001). The very severe grade newly classified by the revised EBMT criteria accounted for the majority of SOS/VOD associated with worse 100-day OS. Therefore, intervention should be applied at the latest for moderate to severe SOS/VOD before deterioration.

Introduction

Hepatic sinusoidal obstruction syndrome or veno-occlusive disease (SOS/VOD) is a lethal complication after hematopoietic cell transplantation (HCT). The incidence of SOS/VOD is variable according to transplant setting and diagnostic criteria [1]. Although it has been reported that the incidence of SOS/VOD has decreased recently with an introduction of reduced intensity conditioning regimen, some data suggest an increased incidence of SOS/VOD in second or tandem transplantation, haploidentical HCT, or addition of more intensive alkylator combinations. Prognosis of SOS/VOD depends upon the extent of hepatic injury, subsequent liver dysfunction, and presence of multiorgan failure (MOF), which occurs in severe grade of SOS/VOD. Severe SOS/VOD is associated with extremely poor survival outcomes with all-cause mortality in excess of 80% at 100 days post-HCT [1,2,3,4,5].

One current problem is there are several diagnostic criteria of SOS/VOD, which have caused different incidences in many trials. In addition, stratification according to the traditional severity criteria has revealed that few patients are included in the mild group, and that many patients in the mild to moderate groups have demonstrated relatively good treatment outcome, while most patients in the severe group have died of SOS/VOD [6,7,8]. According to the traditional criteria, only a small proportion of patients with early elevation of bilirubin and weight gain were estimated for developing severe SOS/VOD [9]. A recent phase III study showed treatment outcomes of defibrotide for patients with severe SOS/VOD, revealing 100-day survival of 38.2% in defibrotide treatment and 25.0% in conservative management [10]. Therefore, based on the traditional severity criteria, it is difficult for physicians to identify patients requiring early therapeutic intervention with defibrotide or other drugs. Thus, intervention may be too early for patients with mild to moderate SOS/VOD or often too late for severe SOS/VOD, leading to rapid progression to MOF despite treatment such as defibrotide [10,11,12,13].

Therefore, the concept of SOS/VOD severity grade based on measurable clinical data has been introduced, and the European Society for Blood and Marrow Transplantation (EBMT) recently proposed new revised criteria. They suggested revised criteria for treatment guidance based on increased level and rate of bilirubin, liver function, renal function, weight gain, and speed of deterioration of all parameters [9, 14]. The revised grading system emphasized the kinetics, which showed the need for early intervention in patients with rapid deterioration. Therefore, for patients with severe SOS/VOD without MOF, early intervention is important according to the new criteria. In the current study, we aimed to validate the revised EBMT severity criteria for SOS/VOD in the context of 100-day survival and transplantation-related mortality (TRM) in patients diagnosed with SOS/VOD according to the traditional criteria.

Materials and methods

Patient enrollment

We retrospectively reviewed records for 235 adult and pediatric patients diagnosed with hepatic SOS/VOD after HCT in six transplantation centers in Korea from 2011 to 2015. For diagnosis and staging of SOS/VOD, modified Seattle criteria [4, 15] and Baltimore criteria [16] were used with clinical evidence and doppler sonograms for identification of portal vein flow. Thirty-two patients who did not fully satisfy at least one of the criteria for SOS/VOD were excluded; thus 203 patients were eligible and selected for analysis. Severity grading was evaluated according to both traditional [6, 17, 18] and revised EBMT guidelines [14]. This research was conducted in accordance with the Institutional Review Board and Ethics Committee guidelines of each institution and the principles of the Declaration of Helsinki.

Prophylaxis and treatment of SOS/VOD

SOS/VOD prophylaxis was given to 178 (87.7%) patients. For SOS/VOD prophylaxis, patients mainly received heparin or prostaglandin E1 with or without ursodeoxycholic acid (UDCA), glutathione, and pentoxyfylline. When SOS/VOD was diagnosed, supportive care including fluid restriction and strict volume control with oral UDCA and glutathione was done in most patients. Defibrotide or recombinant tissue plasminogen activator (rt-PA) was used for thrombolytic purpose according to the center’s policy.

End points and response criteria

The primary endpoint of this study was overall survival (OS) at 100 day post-HCT, and the secondary endpoint was non-relapsed mortality (NRM) including complications such as SOS/VOD after identification of the proportion of patients according to the traditional or revised EBMT severity criteria. As SOS/VOD is a disease showing rapid progression from mild status through MOF to death, the worst grade despite SOS/VOD treatment was used as the severity grade in this study. Complete response (CR) of SOS/VOD was defined when total bilirubin level decreased to normal level (<2.0 mg/dL). In patients without elevation of bilirubin, CR was defined as reduction of elevated transaminase level <50%, normalized creatinine level, disappearance of ascites, no need for oxygen supplement, return to baseline weight, and normalized portal vein flow in doppler findings [3, 10].

Statistical analysis

All categorical variables were compared by Fisher’s exact test and continuous variables were assessed by the Mann–Whitney U-test for comparisons between two groups. OS rates were calculated using the Kaplan–Meier method, and log-rank analysis was used to evaluate differences between subgroups. Cumulative incidence of TRM was calculated by cumulative incidence estimation treating relapsed deaths as a competing risk, and the results were compared using the Gray test [19]. Multivariate analyses by Cox’s proportional regression model were used to calculate the survival hazard ratio including variables with a p-value < 0.10 in antecedent univariate testing. All statistical analyses were performed using “R” software version 2.15.1 (R Foundation for Statistical Computing, 2012). Statistical significance was set at a p-value < 0.05.

Results

Patient characteristics

A total of 203 patients with SOS/VOD fully satisfied at least one diagnostic criteria of the modified Seattle, Baltimore, or revised EBMT criteria. All 203 patients met the modified Seattle criteria. Out of the 203 patients, 125 and 123 patients satisfied the revised EBMT and Baltimore criteria, respectively. As the modified Seattle criteria covered the largest proportion of SOS/VOD diagnosis in this cohort, we analyzed the transplantation outcomes in the 203 patients who satisfied the modified Seattle criteria. Characteristics of enrolled patients with SOS/VOD are summarized in Table 1. Among the 159 patients treated with allogeneic HCT, HLA-mismatched transplant was performed in 72 (45.3%). Among the 87 (54.7%) who received HLA-matched transplants, 46 were from a matched sibling donor and 41 were from a matched unrelated donor. There were 170 (83.8%) patients with malignant diseases and 33 (16.2%) patients with non-malignant diseases. For SOS/VOD prophylaxis, heparin (n = 154) and prostaglandin E1 (n = 113) were mainly used, and UDCA, pentoxifylline, and glutathione were concomitantly used according to the healthcare center’s policy. After diagnosis of SOS/VOD, defibrotide was used in 93 (45.8%), heparin in 84 (41.4%), and rt-PA in 41 (20.2%) patients.

Table 1 Characteristics of 203 patients with SOS/VOD

Severity criteria and patient distribution

As mentioned above, subgroups were identified according to three diagnostic criteria of SOS/VOD with the largest proportion diagnosed according to the modified Seattle criteria. According to traditional severity criteria, no mild SOS/VOD was observed in any diagnostic subgroups. Thus, among the 203 patients diagnosed based on the modified Seattle criteria, 128 (63.1%) were moderate and 75 (36.9%) were severe SOS/VOD. However, according to the revised EBMT severity criteria, which consists of four severity grades (mild, moderate, severe, and very severe), there were 12 (5.8%) mild, 26 (12.8%) moderate, 37 (18.2%) severe, and 128 (63.1%) very severe grade SOS/VOD. Patients with moderate grade SOS/VOD according to the traditional criteria (n = 128) were redistributed into 10 mild, 21 moderate, 34 severe, and 63 very severe grade SOS/VOD in the revised EBMT criteria, while the severe grade SOS/VOD patients according to the traditional criteria (n = 75) were redistributed into 2 mild, 5 moderate, 3 severe, and 65 very severe grade SOS/VOD in the revised EBMT criteria. Also, in two other diagnostic subgroups (Baltimore and EBMT criteria) with lower patient numbers, the distributed proportion was similar in both the traditional and revised EBMT severity criteria (Table 2).

Table 2 Patients distribution according to severity criteria

Transplant outcomes according to severity criteria

The 100-day OS and 1-year OS of the 203 patients were 69.9 and 53.3%, respectively. There were only two grade of subgroups in the traditional criteria—moderate grade (n = 128) and severe grade (n = 75). The 100-day OS of patients with moderate and severe grade SOS/VOD according to the traditional criteria was 92.2% and 32.0% (p < 0.0001), respectively (Fig. 1a). Next, we calculated survival outcomes according to the revised EBMT criteria. The 100-day OS of mild grade (n = 12), moderate grade (n = 26), severe grade (n = 37), and very severe grade SOS/VOD (n = 128) was 83.3%, 84.3%, 94.6%, and 58.6%, respectively (p < 0.0001, Fig. 1b). We also calculated cumulative incidence of TRM caused mainly by SOS/VOD and other infectious complications. The 100-day TRM of mild, moderate, severe, and very severe grade groups was 8.3%, 8.0%, 2.7%, and 36.7%, respectively (p < 0.0001, Fig. 1c). Among 61 patients who died within 100 days post-HCT, 10 died of progression of the primary disease, and 51 died due to graft-versus-host disease (n = 9), sepsis (n = 21), bleeding (n = 3), and multi-organ failure (n = 18) combined with SOS/VOD. After a median follow-up duration of 425 days, the 1-year OS of mild, moderate, severe and very severe grade SOS/VOD was 75.0%, 60.2%, 73.0%, and 44.1% (p = 0.0017), respectively (Fig. 1d). As mild, moderate, and severe grade SOS/VOD according to the revised EBMT criteria showed similar 100-day OS, we grouped them and identified a significantly superior survival outcome compared to very severe grade SOS/VOD (89.3% vs. 58.6%, p < 0.0001, Fig. 2a).

Fig. 1
figure1

a 100-day OS according to the traditional severity criteria. b 100-day OS according to the revised EBMT severity criteria. c 100-day TRM according to the revised EBMT severity criteria. d 1-year OS according to the revised EBMT severity criteria

Fig. 2
figure2

100-day OS according to independent risk factors. a According to the revised EBMT severity criteria (very severe vs. others). b According to the HLA matching (HLA mismatch vs. match). c According to age (18 years or older vs. younger than 18 years)

Risk factors affecting 100-day mortality

We analyzed variables including gender, age, prior transplantation, prior hepatic irradiation, prior history of thrombotic disease, HLA mismatch, donor type, conditioning intensity, stem cell source, time to diagnosis of SOS/VOD, SOS/VOD prophylaxis, total body irradiation, EBMT severity criteria, and ferritin level, disease status, performance status (ECOG), significant comorbidity at the time transplantation. Among them, age (p < 0.001), time to diagnosis of SOS/VOD (p = 0.092), prior transplantation (p = 0.071), HLA mismatch (p = 0.008), significant comorbidity (p = 0.060), ECOG performance status (p < 0.001), and very severe grade based on the revised EBMT criteria (p < 0.001) were revealed as significant variables in univariate analysis. Multivariate analysis showed that very severe grade SOS/VOD based on the revised EBMT criteria (HR = 2.98, 95% CI 1.16–7.62, p = 0.023), HLA-mismatched HCT (HR = 2.39, 95% CI 1.17–4.90, p = 0.017), and older age (HR = 3.26, 95% CI 1.37–7.75, p = 0.007) were independent risk factors for 100-day mortality after diagnosis of SOS/VOD (Table 3, Fig. 2a–c).

Table 3 Multivariate analysis for identification of factors affecting 100-day mortality

Impact of treatment on outcome

Totally 93 patients were treated with defibrotide, 74 (79.6%) of them were classified as very severe grade according to the revised EBMT criteria. The median time to initiation of defibrotide was 3 days (range 0–36 days) after diagnosis of SOS/VOD. Of those 93 patients, 70 (75.3%) received defibrotide within five days (median 1 days, range 0–5 days) after diagnosis of SOS/VOD, while 23 (24.7%) patients received defibrotide in over five days (median 8 days, range 6–36 days). The calculated 100-day OS of patients treated with defibrotide was 65.6%, which was not significantly different compared to 73.5% for patients receiving other treatments (p = 0.190). However, the group with an earlier start of defibrotide within five days after diagnosis showed a better 100-day OS compared to the later defibrotide group (74.5% vs. 43.5%, p = 0.044).

Discussion

To our knowledge, this study is the first effort to validate the revised SOS/VOD guidelines recently suggested by EBMT. Compared to the modified Seattle criteria, the revised EBMT criteria reduced the proportion of patients who satisfied the diagnostic criteria of SOS/VOD, similar to the Baltimore criteria. However, the revised EBMT criteria widely distributed patients into four severity criteria, adding a “very severe grade SOS/VOD” category.

The revised EBMT criteria includes an additional very severe grade category, which requires two or more criteria consisting of total bilirubin ≥8 mg/dl, transaminases level >8× normal range, weight increase ≥10%, creatinine level ≥ 2× baseline at transplant, or other signs suggesting MOF. The very severe grade according to the revised criteria appears similar to the severe grade of the traditional criteria, where both are nearly irreversible MOF status with poor survival outcomes. One major difference is the criteria of renal dysfunction; traditional criteria suggest a 2× upper normal range of creatinine for severe SOS/VOD, while the revised EBMT criteria suggest a 1.5× baseline creatinine level at transplant for severe grade and 2.0× baseline creatinine level at transplant for very severe SOS/VOD, reflecting dynamic renal deterioration from baseline. This difference might contribute to the shift of patients from severe grade in the traditional criteria (75 of 203 [36.9%]) to very severe grade in the revised criteria (128 of 203 [63.1%]) demonstrated by the current study.

According to the traditional severity criteria which consist of three grades (mild, moderate, and severe) [7, 8], most of the previous retrospective data could suggest the worst status during the clinical course, and the prognosis of severe SOS/VOD was very poor with a mortality rate reaching 80–90% [1,2,3]. Our data also showed that significant proportion of patients with severe SOS/VOD (68.0%) died, while most patients with moderate SOS/VOD (92.2%) were alive at 100 days. As SOS/VOD progresses rapidly within several days, the disease course may become disastrous if physicians overlook the appropriate timing for proper treatments. Thus, if SOS/VOD progressed to severe grade despite conservative treatments, the majority of patients died, especially when defibrotide was not available. Even after introducing defibrotide, however, the treatment outcome for severe SOS/VOD remained poor in retrospective studies [10,11,12]. This could be because the timing for interventional therapy using defibrotide or rt-PA might be delayed. Therefore, physician should initiate interventional therapy before progression to severe SOS/VOD and determine the right time for intervention. However, the traditional criteria cannot provide the appropriate information for proper decisions. Based on our study, intervention may be too early for moderate grade SOS/VOD, or too late if the disease status has already progressed to severe grade.

According to the revised EBMT criteria, the 100-day OS of mild, moderate, and severe grade was 83.3%, 84.3%, and 94.6%, respectively, but 58.6% for very severe grade. In addition, the 100-day TRM of mild, moderate, and severe grade was 8.3%, 8.0%, and 2.7%, respectively, but 36.7% for very severe grade. With these results, patients with very severe grade SOS/VOD showed exclusively worse 100-day OS and TRM. In addition, our study validated that 100-day OS of severe SOS/VOD showed a comparable outcome with mild to moderate grade. Therefore, we recommend that SOS/VOD intervention be started from the time of severe grade at the latest before deterioration. The revised criteria provide weight gain ≥ 5% and elevated creatinine level ≥1.5 × baseline at transplant as parameters for severe SOS/VOD. In addition, rapid progression of clinical symptoms within four days and doubling of total bilirubin level within 48 h were also considered criteria for severe SOS/VOD [14].

In addition to the recommended latest severity grade, our data showed that earlier start of defibrotide treatment within five days after diagnosis showed a better 100-day OS compared to later defibrotide treatment (74.5% vs. 43.5%, p = 0.044). This data is supported by a recent trial, which reported that earlier initiation of defibrotide after diagnosis of SOS/VOD improved 100-day OS [12]. Richardson et al. analyzed 573 SOS/VOD patients, of whom 351 (61.3%) had MOF. After SOS/VOD diagnosis, 93.0% of the patients were treated with defibrotide within seven days, while 31.9% of the patients received defibrotide on the day of diagnosis. Even in SOS/VOD with MOF, earlier initiation of defibrotide within seven days was significantly related with better 100-day OS (47.4% vs. 23.3%, p = 0.011), while it was 51.6% in patients without MOF (vs. 32.5%, p = 0.013). In particular, defibrotide after two days from diagnosis for very severe SOS/VOD showed a significantly poorer 100-day OS compared to the earlier group (27.6% vs. 52.2%, p < 0.001). The final extended study also revealed the efficacy of earlier defibrotide initiation from 1000 patients’ data which suggested that defibrotide should not be delayed when SOS/VOD has been diagnosed and emphasized prompt initiation.

It is known that there are three kinds of SOS/VOD risk factors: those directly related to the transplant procedure; those related to the patient’s characteristics and underlying disease; and hepatic-related risk factors [9, 14]. We analyzed the relationship between SOS/VOD risk factors and severity grade in our cohort. None of the risk factors for SOS/VOD, however, has been found to have a direct impact on the severity grade in the current study. We acknowledge that the current analyses were performed retrospectively, and the severity grade was not evaluated at SOS/VOD diagnosis or at the time of treatment initiation. The worst parameters were used for grading during the clinical course, which might distribute patients into the most progressed grade. Also, the treatment strategies and the time of treatment initiation were heterogeneous. Therefore, current treatment outcome results cannot suggest a proper time for intervention. However, we assert that intervention while progressing to very severe SOS/VOD is less effective, and earlier intervention from moderate to severe grade is feasible according to our validation results of the revised EBMT criteria.

After proposal of the revised EBMT guidelines, new pediatrics-specific guidelines for SOS/VOD were recently published [20]. However, this study did not use the pediatrics-specific guidelines. All SOS/VOD of adults and pediatrics was analyzed according to the prior adult guidelines, which were simpler than the pediatric guidelines. We also analyzed 100-day OS of very severe grade versus other grades in adults (49.1% vs. 69.6%, p = 0.054) and children (66.7% vs. 98.1%, p < 0.001) separately. Very severe SOS/VOD showed a significantly poorer 100-day OS compared to mild/moderate/severe grade SOS/VOD in each subgroup analysis.

Here, we retrospectively validated the revised EBMT diagnostic and severity criteria for SOS/VOD from a multicenter cohort including both adults and children. The revised EBMT criteria must be validated by prospective clinical studies in the context of intervention therapy such as defibrotide or other agents, which will allow earlier identification and stratification of SOS/VOD. Finally, further results may provide a guide for selection of patients requiring immediate therapeutic intervention. Although many limitations should be considered, our data firstly demonstrated that the newly developed severity criteria may be helpful for treatment decisions.

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Acknowledgements

The authors acknowledge Yun Jung Choi, PhD., Rph. and Jeonghee Kim, PhD. from HANDOK Inc. for the coordination of data collection and statistical analysis supervised by the investigators.

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J-H.Y. designed the study, enrolled patients, collected and analyzed data, and wrote the manuscript; K.H.Y., K.W.S., C.W.J., J.S.K., S.M.H., H.J.K., J-H.L., H.J.I., H.K., J.-S.A., and B.C., analyzed data, enrolled patients; J.W.L. designed and conducted the study, enrolled patients, analyzed data, and wrote the manuscript; and all authors approved the final version of the manuscript.

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Correspondence to Jong Wook Lee.

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Yoon, J., Yoo, K.H., Sung, K.W. et al. Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). Bone Marrow Transplant 54, 1361–1368 (2019). https://doi.org/10.1038/s41409-019-0492-6

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