Impact of oral eicosapentaenoic acid on veno-occlusive disease/sinusoidal obstruction syndrome onset prevention: Single-center retrospective analysis Free

Introduction Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), marked by painful hepatomegaly, jaundice, and weight gain due to fluid retention. While defibrotide has improved outcomes, the mortality rate in severe cases remains high. Although the overall incidence of VOD/SOS has declined to 2–3% due to reduced-intensity conditioning and better patient selection, younger individuals receiving high-intensity treatment still face elevated risk. Prophylactic agents such as ursodeoxycholic acid and defibrotide have shown preventive benefits, though their efficacy remains limited.

Eicosapentaenoic acid (EPA) is an omega-3 fatty acid that possesses numerous beneficial effects, including the reduction of triglyceride levels. A previous study reported that oral EPA administration following bone marrow transplantation reduced cytokine levels and prolonged survival. Given its low toxicity profile, our institution adopted EPA as a standard post-transplant regimen beginning in 2009. Since then, despite the prevalence of intensive conditioning and second transplants, no cases occurred in patients who received EPA. This study retrospectively investigates whether EPA can prevent VOD/SOS after allo-HSCT.

Methods We retrospectively reviewed all allo-HSCT cases performed at Ehime University Hospital from April 2008 to June 2024 for hematological malignancies or immune deficiencies. Conditioning regimens and GVHD prophylaxis were tailored to each patient based on age, disease status, organ function, HCT-CI, KPS, donor compatibility, and other clinical factors. This study was approved by the institutional ethics committee (approval no. 2408006).

Oral EPA (1800 mg/day in divided doses) was introduced in 2009 but temporarily halted in 2010 after a cerebral hemorrhage incident, which was later deemed unrelated to EPA. Administration resumed in August 2013 and continued thereafter. Patients who received at least 10 days of EPA were grouped as the EPA group, while others—due to mucosal disorders or non-prescription—were placed in the no-EPA group.

VOD/SOS diagnosis was based on EBMT 2016 criteria, but the 2023 update was also applied to identify cases lacking hyperbilirubinemia. Conditioning regimens were classified as myeloablative or reduced-intensity using accepted definitions. Risk stratification at transplantation followed standard clinical parameters. Neutrophil engraftment was defined as three consecutive days of ≥500 cells/mm³. Acute GVHD was diagnosed per standard criteria. Statistical analyses included Kaplan-Meier method for overall survival (OS), Gray's method for competing risks, and log-rank or Fisher's exact tests, with significance set at P < 0.05.

Results A total of 138 transplants from 123 patients were included. Of these, 91 patients received EPA, while 47 did not. Both groups had a median age of 51 years, with a median survival of 815 days in the EPA group versus 4376 days in the no-EPA group. KPS was significantly lower in the no-EPA group, but other baseline characteristics were comparable. Most EPA-treated patients received the supplement for ≥31 days. All patients were concurrently treated with ursodeoxycholic acid.

Three cases of VOD/SOS (6.5%) occurred exclusively in the no-EPA group, with none reported in the EPA group (P = 0.014). VOD/SOS was diagnosed day 28, 10 and 4 after transplant. One patient met the EBMT 2023 criteria without bilirubin elevation but showed ultrasound-confirmed signs of VOD/SOS. Defibrotide was not approved, so all three patients received alternative care including recombinant thrombomodulin. One patient recovered and survived; two died from disease progression. Multivariate analysis could not be performed due to the limited number of cases.

No significant differences were observed between EPA and no-EPA groups for 100-day outcomes including neutrophil engraftment (median 19 vs 16 days, P = 0.077), OS, relapse, NRM, or acute GVHD. Each group had one death from cerebral hemorrhage. Thirteen deaths occurred in the EPA group and ten in the no-EPA group within 100 days.

ConclusionsIn summary, the findings of our study suggest that oral EPA administration can safely prevent the onset of VOD/SOS after allo-HSCT. To validate this hypothesis, a prospective multicenter clinical trial is required.