Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study – Bone Marrow Transplantation

Seventy-one centers from 20 countries participated in this study, 24% of all eligible centers (Supplementary Table 2). The total number of allogeneic transplantations in adult patients at these centers in the year 2018 was 2886. Among these patients, 93 cases of VOD/SOS had been diagnosed. Additional VOD/SOS -related data was received of 70 patients; these cases were analyzed in detail. In three of these patients, the EBMT criteria for classical VOD/SOS were not fulfilled and there were no findings indicating late-onset VOD/SOS. In two cases the Seattle criteria had been used. These three patients were excluded, and 67 patients remained for the analysis.

A summary of the patient material and the main results is presented in Table 2.

Incidence

The cumulative incidence of VOD/SOS at day 21 was 1.8 (95% CI 1.4–2.4) % and at day 100 2.4 (1.9–3.0) %. As the details of the diagnostic criteria were not available for all patients, this incidence analysis includes all 93 patients with reported VOD/SOS, independent of the criteria used.

Risk factors

All VOD/SOS patients had risk factors. Two patients had one risk factor, four patients 2, eight patients 3, eight patients 4, and forty-five more than 4 risk factors. The median number of risk factors was 5, range 1–8.

Prophylaxis

Forty patients (60%) had received VOD/SOS prophylaxis. Defibrotide had been given to 7 patients, either alone (4) or together with ursodeoxycholic acid (3) and/or heparin (1). Ursodeoxycholic acid had been given to 22 patients, heparin to 15 patients either alone (9 patients) or in combination with ursodeoxycholic acid (5) or defibrotide (1).

Conditioning

The pretransplant conditioning given to the patients who later developed VOD/SOS was MAC in 51.5% and RIC in 48.5% of the cases; in one case the intensity was lacking. Among the whole population of 2886 patients transplantated during the time of the study at the participating centers the conditioning was MAC in 51.9% and RIC in 48.1%.

In the whole patient population, the cumulative incidence of VOD/SOS at 100 days among the patients given MAC was 2.4% and among those given RIC 2.3%.

Diagnosis of VOD/SOS

Classical VOD/SOS according to the EBMT (Baltimore) criteria (in the first 21 days after HSCT) was diagnosed in 52 patients, late-onset VOD/SOS (>21 days) according to the EBMT criteria in 15 patients. The timing of the onset of VOD/SOS is shown in Fig. 1.

According to the EBMT criteria, late-onset VOD/SOS can be diagnosed in three situations: 1. The findings of classical VOD/SOS occur after day 21; 2. VOD/SOS is proven histopathologically; or 3. two or more of the following findings are present: bilirubin ≥34 µmol/L, painful hepatomegaly, weight gain >5%, ascites, and in addition there is hemodynamical or/and ultrasound evidence of VOD/SOS. In all but one late-onset case, the criteria of classical VOD/SOS were fulfilled after day 21. In the remaining case the diagnosis was based on the third alternative. Histological evidence for VOD/SOS was obtained in four cases but the diagnosis of late-onset VOD/SOS was not based solely on this criterion in any case.

Overall, in classical and late-onset VOD/SOS, imaging was used to support the diagnosis in 59 of the 67 patients. Ultrasound was used in 58 and CT in 6 cases. A decrease in velocity or reversal of portal flow was demonstrated in 12 patients. Hepatic venous pressure gradient was measured in 3 cases. Liver biopsy was carried out in 5 cases.

Severity grading

Table 1 shows the EBMT severity grading. In the present patient population, the severity grades of the 67 cases of VOD/SOS were: mild 0, moderate 3, severe 29, and very severe 35. It should be noted that according to the grading patients with mild or moderate VOD/SOS and two or more risk factors must be graded one grade higher. All but two patients had two or more risk factors, and the two with only one risk factor had already originally severe grade VOD/SOS. Therefore in all the three patients with originally mild VOD/SOS the grade was revised to moderate, and all 13 moderate cases became severe.

The grade was classified as very severe in all but one patient based on multiorgan dysfunction/ failure (MOD/MOF). In the remaining case, the criteria were high bilirubin and >10% weight increase.

Treatment

Sixty of the 67 patients received VOD/SOS-targeted treatment. This was defibrotide in 54 cases. Other VOD/SOS-targeted treatments mentioned in single cases were corticosteroids (2 patients), acetylcysteine, ursodeoxycholic acid, eculizumab, low molecular weight heparin, and transjugular intrahepatic portosystemic shunt.

Three patients with severe and four with very severe VOD/SOS were not given VOD/SOS- targeted treatment.

The severity grade did not affect the VOD/SOS-targeted treatment. Defibrotide was given to 3/3 patients with moderate, 23/26 with severe and 28/31 patients with very severe VOD/SOS.

Without the modification of grade based on risk factors, 3 patients would have had mild and 13 moderate grade VOD/SOS. Defibrotide treatment was given to all these patients with mild and 12/13 patients with moderate grade.

Resolution of VOD/SOS

Resolution was defined as maintained normalization of the symptoms and signs of VOD/SOS. The complication resolved in 37 of 64 patients (58%), in 3/3 with moderate, 22/28 (79%) with severe, and 12/33 (36%) with very severe VOD/SOS (p < 0.001). The information was lacking of one patient with severe and two with very severe VOD/SOS.

If the effect of risk factors is omitted, VOD/SOS resolved in 3/3 patients with mild, 10/12 with moderate, 12/16 with severe, and 12/33 with very severe grade complication.

Survival

The median follow-up of the VOD/SOS patients from the transplantation was 19.1 (95% CI 15.5–21.0) months. Thirty-eight of the 67 patients (57%) survived by day 100 post transplantation, 3/3 in moderate, 22/29 (76%) in severe, and 13/35 (37%) in very severe VOD/SOS (p = 0.002). The survival of patients with severe vs. very severe grade VOD/SOS is shown in Fig. 2. The survival at six months was 58.9% and 37.1% (p = 0.093) in the severe and very severe grade, respectively.

Overall survival of patients with severe and very severe VOD/SOS.

Of 40 deceased patients, the causes of death were reported in 36 cases. All deaths were due to non-relapse causes. VOD/SOS was listed among the causes of death in 20, MOD/MOF in 21 cases.

If the effect of risk factors is omitted, the survival by day 100 according to the severity grade was 3/3 in mild, 11/13 in moderate, 11/16 in severe, and 13/35 in very severe VOD/SOS.