Sinusoidal obstruction syndrome or hepatic veno-occlusive disease (SOS/VOD) occurs either as early or late onset (i. e. within 21 days or beyond day 21, respectively) complication after hematopoietic stem cell transplantation (HSCT) and is characterized by hyperbilirubinemia, ascites or weight gain, right upper quadrant pain of liver origin, and tender hepatomegaly . SOS/VOD may be a self-limited disease. However, in severe SOS/VOD cases >80% of patients die due to multiorgan failure (MOF) as well as other complications . Defibrotide is the only therapeutic agent approved for the treatment of severe SOS. High-dose methylprednisolone (HDMP) showed encouraging response rates in patients with SOS, but defibrotide and some other concomitant medications (alteplase, streptokinase, PGE1, etc.) have also been used in a number of reports [3, 4] making the HDMP clinical value less clear. Here we describe our results of treating adult SOS/VOD after HSCT with HDMP and without the use of defibrotide or any other concomitant therapy.
We retrospectively reviewed all patients who received SCT at our institution during a 10-year period (2007–2016). During this period, defibrotide was periodically not available and HDMP was the treatment of choice. We identified 11 patients who fulfilled the recently published EBMT diagnostic criteria for SOS  and were treated with HDMP, without the concomitant use of defibrotide at any time point during their disease course. No other agents such as TPA in addition to HDPM were used due to possible risk of treatment-related toxicity. Patient characteristics are shown in Table 1. SOS/VOD was diagnosed on the median 22 (7–81) days after HSCT. The median bilirubin at diagnosis of SOS/VOD was 70.7 (11.1–137) µmol/L for the entire study population. One patient had normal bilirubin value but similarly to the remaining patients fulfilled the EBMT criteria for SOS/VOD and displayed signs such as ascites and weight gain, right upper quadrant pain of liver origin, and tender hepatomegaly. A response was defined as a decrease in total serum bilirubin concentration by 50% from the baseline and resolution of all SOS/VOD related clinical symptoms within 1 month from the start of HDMP. For patients with normal serum bilirubin values, a response was defined as regression of symptoms associated with SOS/VOD. The patients had no signs of aGvHD and hepatitis of infectious origin was ruled out at the time of SOS/VOD diagnosis.
All 11 patients were treated with HDMP 500 mg/m2 every 12 h for 3 days starting on the day of SOS/VOD diagnosis. All patients received standard supportive care according to HSCT protocols. Seven (64%) patients responded to treatment with HDMP. 4 patients responded early, within 7 days after the start of therapy. Median serum bilirubin value at the start of therapy was 70.7 (11.1–137.0) µmol/L and it was 25.1 (15.8–33.6) µmol/L on day 5 for patients who responded within 7 days. The remaining three patients who ultimately responded had increased levels of serum bilirubin (median 130.2 (37.5–152.2) µmol/L) 7 days after HDMP therapy, but subsequently without any additional therapy had decrease in concentration of bilirubin to median of 51.8 (19.5–53.4), 44.2 (14.8–46.9), and 24.3 (10.9–30.6) on days 14, 21, and 28, respectively. Anicteric patient diagnosed with SOS/VOD responded early with the resolution of all symptoms within 7 days of therapy. The median serum bilirubin value for non-responders at the start of HDMP therapy was 67.4 (44.4–80.2) µmol/L and it was 111.4 (62.6–437.8) µmol/L 14 days after therapy. All responders showed a reduction of serum bilirubin in comparison to baseline value on day +14 while all 4 non-responding patients had higher than baseline serum bilirubin values on day +14. Patients with early-onset SOS/VOD had a tendency to respond more rapidly with three of four patients responding within 5 days. In contrast, two out of three patients with late-onset disease had a delayed response to therapy (+21 and +31 days). All non-responders developed MOF and died of SOS/VOD. Among the responders, one patient died due to GVHD (day +232 after HDMP therapy), one patient died from acute coronary syndrome (day +22 after HDMP therapy) and the cause of death (day +847 after HDMP) in one patient remains unknown. Using Kaplan–Meier survival analysis, overall survival (OS) for the entire cohort was 64% at +100 days and 36% two years after HSCT. For patients who responded to HDMP therapy, OS was 57% two years after HSCT. Overall survival by disease severity (EBMT criteria ) is shown in Fig. 1. There were no serious adverse reactions during treatment period with HDMP. All surviving patients had normal liver function at the last follow-up.
The treatment of severe SOS/VOD remains a therapeutic challenge, where a significant number of patients die despite treatment. Four multicenter, prospective trials reported results of severe SOS/VOD treatment with defibrotide resulting in +100-day OS ranging from 38 to 50% and leading to the approval of this treatment modality as frontline therapy for severe SOS/VOD [5,6,7,8]. The four studies also included pediatric patients who may have a better outcome. In contrast, we included only adult (>18 years of age) patients. Importantly, patients with normal serum bilirubin were also eligible. Notably, defibrotide trials used Baltimore criteria which allow the identification of early-onset SOS/VOD only. Our patients were selected using the EBMT criteria  allowing the separation between early and late-onset SOS/VOD as well as prospective disease severity assessment. These factors may have affected the outcomes in our cohort.
In a compassionate-use study by Corbacioglu et al. severe SOS/VOD accounted for 48% of cases . Our findings are similar to Corbacioglu et al. in terms of disease severity and response. In all, 5/11(45%) of our patients had severe SOS and 2/5 (40%) responded to therapy.
Defibrotide therapy-related adverse reactions leading to discontinuation of treatment (major bleeding, hypotension) occurred in 4% of cases in the randomized study . In a defibrotide compassionate-use program, the most serious and dose-dependent adverse event was major bleeding leading to discontinuation of treatment in 9% of cases . Richardson, et al. produced valuable data on the largest number of patients treated with defibrotide to date. Though, adverse events occurred in up to 60% of patients, severe adverse events, like hemorrhage and hypotension were reported in only up to 4% of the cases .
A number of case series of a total of 109 patients who received HDMP therapy have been published in both pediatric and adult populations [3, 4, 9, 10]. Response rates ranging from 33 to 67% were demonstrated in cases of severe disease, with overall survival rates of 58% in adults  and 78% in children . Notably, defibrotide was also used concomitantly in some of these cases. Hennenfent et al.  demonstrated that early administration of HDMP resulted in response rates of only 33%, though among SOS/VOD patients, cases of liver disease of uncertain etiology were also treated in parallel. Here, the study population might have contributed to a lower response rate, despite early treatment. The most commonly observed side effects of HDMP were hyperglycemia well controlled with insulin alone and hypertension. The rate of infectious complications—sepsis, CMV reactivation or fungal infections did not differ from other HSCT patients not on HDMP .
Our patient outcomes are in line with the results of the reported HDMP studies. We observed a comparable response rate of 64% and an overall survival of 57% in responding patients at 2 years, but without the use of defibrotide. We found that HDMP therapy was effective in both early and late-onset SOS/VOD, with 4 (57%) and 3 (43%) responders, respectively (Table 1). Treatment was initiated without therapeutic delays at the time of diagnosis.
Studies on the treatment of SOS/VOD usually define a patient response as a reduction of serum bilirubin by 50%, 10 days after the start of therapy. Our study shows that some patients might respond later, with a consistent reduction of bilirubinemia and disappearance of all signs of SOS.
In summary, with the caveat of retrospective nature and small sample size of our study, HDMP appears to be well tolerated and may have a role in the treatment of patients with SOS/VOD. These findings warrant prospective studies incorporating combination approaches including approved agents such as defibrotide in rigorously selected SOS/VOD patient populations.
Mohty M, Malard F, Abecassis M, Aerts E, Alaskar AS, Aljurf M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016;51:906–12.
Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2010;16:157–68.
Myers KC, Lawrence J, Marsh RA, Davies SM, Jodele S. High-dose methylprednisolone for veno-occlusive disease of the liver in pediatric hematopoietic stem cell transplantation recipients. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2013;19:500–3.
Khoury H, Adkins D, Brown R, Trinkaus K, Vij R, Miller G, et al. Does early treatment with high-dose methylprednisolone alter the course of hepatic regimen-related toxicity? Bone Marrow Transplant. 2000;25:737–43.
Richardson PG, Smith AR, Triplett BM, Kernan NA, Grupp SA, Antin JH, et al. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome: interim results from a treatment IND study. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2017;23:997–1004.
Corbacioglu S, Carreras E, Mohty M, Pagliuca A, Boelens JJ, Damaj G, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the international compassionate-use program. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2016;22:1874–82.
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127:1656–65.
Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant: J Am Soc Blood Marrow Transplant. 2010;16:1005–17.
Hennenfent KL, Augustin KM, Dipersio JF, Khoury H. Is there a role for high-dose methylprednisolone in the treatment of hepatic regimen-related toxicity? Bone Marrow Transplant. 2006;37:229.
Al Beihany A, Al Omar H, Sahovic E, Chaudhri N, Al Mohareb F, Al Sharif F, et al. Successful treatment of hepatic veno-occlusive disease after myeloablative allogeneic hematopoietic stem cell transplantation by early administration of a short course of methylprednisolone. Bone Marrow Transplant. 2008;41:287–91.
Conflict of interest
The authors declare that they have no conflict of interest.
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Vaisvilas, M., Buseckaite, S., Mickeviciute, O. et al. High-dose methylprednisolone for the treatment of sinusoidal obstruction syndrome in adults. Bone Marrow Transplant 53, 923–925 (2018). https://doi.org/10.1038/s41409-018-0087-7