Nationwide Survey of Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, and Outcome: On Behalf of Complications Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)
Authors: Yakushijin Kimikazu , Atsuta Yoshiko , Noriko Doki , Yokota Akira , Kanamori Heiwa , Miyamoto Toshihiro , Sakamaki Hisashi , Yabe Hiromasa , Morishima Yasuo , Kato Koji , Suzuki Ritsuro , Fukuda Takahiro 
Published: October 2019

Abstract

Background
Sinusoidal obstruction syndrome (SOS) is well known as one of potentially lethal complications after hematopoietic stem cell transplantation (HSCT). To determine the incidence, risk factors and outcomes of SOS after allogeneic HSCT, we conducted a retrospective study among registering centers for the Japan Society for Hematopoietic Cell Transplantation (JSHCT).

Patients and Methods
One hundred and seventeen centers of the JSHCT participated in this study. A total of 4171 patients (4290 transplants) who underwent HSCT performed in those 117 centers between 1999 and 2010 were retrospectively analyzed. Additional data on the diagnosis, clinical presentation, and update of follow-up of 618 cases who developed SOS were collected. Median age of patients at transplant was 41 years (range, 0-76). The diagnosis included AML (n=1575), ALL (n=943), MDS (n=433), lymphoid malignancy (n=493), plasmacytic malignancy (n=54), CML/MPN (n=365), bone marrow failure (n=157), and others (n=270). 1166 patients were transplanted from a related donor (BM, n=501, PB, n=664, CB, n=1), and 3124 were transplanted from an unrelated donor (BM, n=2100, CB, n=1024). Conditioning regimen consisted of myeloablative regimen (MAC, n=2809) and reduced-intensity regimen (RIC, n=1367). The diagnosis of SOS was established clinically based on the Seattle criteria (presence before day 30 after HSCT, of at least two of the following features: (1) jaundice (2) hepatomegaly and right upper quadrant pain and (3) ascites and/or unexplained weight gain (≥ 2%)) or on the Baltimore criteria (hyperbilirubinemia ≥ 2 mg/dl before day 21 after HSCT and at least, two of the following features: (1) hepatomegaly (2) ascites and (3) weight gain (≥ 5%)). Complete response for SOS (CR) was defined as resolution of all the signs and symptoms of SOS diagnostic criteria.

Results
A total of 462 patients developed SOS fulfilling the Seattle criteria (cumulative incidence 11.0% [95% confidence interval [CI], 10.1-12.0]), and 161 out of 462 patients met the Baltimore criteria. The median time from the day of transplant to diagnosis of SOS was 12 days (range, -2-30). The signs and symptoms at diagnosis were weight gain (91%), jaundice (69%), hepatomegaly (61%), right upper abdominal pain (58%), ascites (48%), respiratory failure (25%), renal failure (23%), and encephalopathy (12%). CR rate was 45% in all SOS patients (52% and 30% in patients with SOS diagnosed by the Seattle but did not fulfill the Baltimore criteria and in patients who fulfilled the Baltimore criteria, respectively (P<0.001, Fisher’s exact test)). The main causes of death for SOS patients were SOS-related mortality (49%), disease progression (18%), and others (33%). Probabilities of overall survival calculated by using Kaplan-Meier method with SOS treated as time-dependent variable at day 100 and 2 years after HSCT were 40% and 24% in patients with SOS and 76% and 44% in patients without SOS, respectively (P<0.001, logrank-test) Multivariate analyses showed the number of HSCT (≥ 2; relative risk [RR] 1.35, 95%CI, 1.06-1.73, P=0.02), age (16-39 y; RR 0.67, 95%CI, 0.50-0.90, P=0.008 and >40; RR 0.95, 95%CI, 0.72-1.25, P=0.70, reference 0-15 y), PS 2-4 (RR 2.00, 95%CI, 1.57-2.54, P<0.001), HCV-Ab positive (RR 2.19, 95%CI, 1.13-4.26, P=0.02), advanced disease status (RR 1.73, 95%CI, 1.37-2.20, P<0.001), MAC (TBI-based; RR 1.69, 95%CI, 1.30-2.20, P<0.001, Bu-based; RR 2.38, 95%CI, 1.79-3.16, P<0.001, and other; RR 1.83, 95%CI, 1.03-3.26, P=0.04, reference RIC) were independent risk factors for SOS. Multivariate analysis adjusted with other significant variables affecting survival (SOS was treated as time-dependent variable) revealed that SOS was highly associated with overall mortality (hazard ratio [HR] 2.09, 95%CI, 1.84-2.36, P<0.001). The risk of overall mortality was higher in patients who fulfilled the Baltimore criteria (HR 1.78, 95%CI, 1.53-2.07, P<0.001 for patients who did not fulfill the Baltimore criteria, and HR 2.66, 95%CI, 2.20-3.22, P<0.001 for patients who fulfilled the Baltimore criteria).

Conclusions
This retrospective survey showed that the cumulative incidence of SOS was 11.0% in Japanese population, which was similar to previous reports from western countries. Patients with SOS had significantly poor prognosis. Therefore, we should establish strategies for SOS prevention and treatment for high risk patients in order to improve overall survival.

Disclosures:
No relevant conflicts of interest to declare.