Early Clinical Predictors of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Myeloablative Stem Cell Transplantation

Abstract

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of hematopoietic stem cell transplantation (HSCT) with mortality in its severe form exceeding 80%. Although the incidence of VOD/SOS has fallen with contemporary transplantation practices, the increasing use of inotuzumab, the return of gemtuzumab, and the popularity of pharmacokinetic-guided high-dose busulfan may impact incidence. Early intervention with defibrotide improves survival, but prompt diagnosis can be difficult. We aimed to identify clinical parameters that could aid in early detection of VOD/SOS in a large, retrospective, cohort study. Of the 1823 adult patients who underwent myeloablative HSCT between 1996 and 2015 in our center, 205 (11%) developed VOD/SOS, with a median onset of day +14. We compared parameters in the 7 days preceding VOD/SOS onset for cases to 447 randomly selected control subjects in an analogous time frame to determine those with predictive value. Between 7 days before and the day of diagnosis, VOD/SOS patients had higher serum creatinine levels and were more likely to develop acute kidney injury (61% versus 33%, P < .0001), more commonly experienced refractoriness to platelet transfusion (48% versus 24%, P < .0001), and had higher trough serum tacrolimus levels (7 days before VOD/SOS onset: median 8.8 versus 7.3, P = .0002; day of onset: median 9.3 versus 7.2, P < .0001) compared with control subjects. Acute renal dysfunction, platelet refractoriness, and elevated or abnormal tacrolimus levels are dynamic clinical markers that should alert clinicians to the development of VOD/SOS before the presence of classical diagnostic criteria. Using these clinical features to recognize VOD/SOS earlier in its clinical course could promote earlier treatment and lead to improved outcomes of this potentially serious complication.

Risk Factors for Development of and Progression of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

“…Studies that evaluated risk factors for VOD/SOS in large HSCT recipient populations over the past 5 to 7 years vary in consistency with previous data and reveal potential risk factors that have not previously been noted [21,23,26,[36][37][38][39] (Table 5). Among 10 such studies identified for this review, with total numbers ranging from 75 to 5072 patients, incidence of VOD/ SOS ranged from 2.0% (lowest incidence was diagnosed with EBMT criteria) to 30.7% (Table 5).…”

“…A post hoc analysis of results from an expanded-access treatment (T-IND) program with defibrotide for post-HSCT patients with VOD/ SOS (with and without MOD; n = 1000) found that earlier postdiagnosis initiation of defibrotide correlated with higher day + 100 survival rates over time (nominal P < .001) [32]. Indeed, based on the apparent value of prompt treatment, some researchers have suggested that consideration of initial pharmacologic treatment should begin at the first signs/symptoms of possible VOD/SOS even if patients have not yet exhibited all criteria for formal diagnosis [21,25]. However, defibrotide is approved only for the treatment of hepatic VOD/SOS post-HSCT in patients with renal or pulmonary dysfunction (in the United States), or severe hepatic VOD/SOS post-HSCT in adults and children age >1 month (in the European Union) [33].…”

“…Transplantation-related factors associated with an increased risk of VOD/SOS in adult HSCT recipients following multivariate analysis included the use of horse antithymocyte globulin [37], oral versus i.v. serum level-adjusted administration of busulfan (adults and adolescents) [38], myeloablative conditioning regimens (total body irradiation-based and busulfan-based) and 2 or more HSCTs [26], use of busulfan-thiotepa conditioning in adults with VOD/SOS requiring pharmacologic treatment with at least analgesics or diuretics [36], and increased trough serum tacrolimus level (above the target range of 5 to 10 ng/mL) [21]. In children, the use of busulfan in conditioning regimens versus nonuse of busulfan was an independent risk factor for VOD/ SOS, diagnosed with the EBMT pediatric criteria in a large study (n = 5072), associated with a cumulative incidence of 5.1% (95% CI, 4.1% to 6.3%; P < .001) [30].…”

“…Patient/hepatic-related VOD/SOS risk factors in adults, identified following multivariate analysis, included Eastern Cooperative Oncology Group Performance Status score 2 to 4 versus 0 to 1, hepatitis C seropositivity, and advanced disease status in 1 study [26]; high pre-HSCT ferritin level (950 ng/mL) in patients with malignant lymphoma in another study [36]; and acute kidney injury, platelet refractoriness, and high international normalized ratio in a 20-year study described as the largest single-center analysis of VOD/SOS incidence following myeloablative conditioning (n = 200) ( Table 5) [21]. In pediatric studies, patient/hepatic-related VOD/SOS risk factors following multivariate analysis included a high pre-HSCT ferritin level (>1000 ng/mL) and post-HSCT sepsis [39], young age and early of neutrophil engraftment [5,22], and female sex, age <2 years, and diagnosis of hemophagocytosis lymphiocytosis [30].…”

“…These advances in VOD/SOS diagnosis and assessment reflect the accumulating evidence that early intervention is associated with improved overall survival. Consequently, they have placed a renewed emphasis on prompt and even preemptive treatment of this condition [20] and have spurred novel perspectives on risk assessment and its role in VOD/SOS management [21][22][23]. A number of widely recognized risk factors for VOD/SOS onset have been established from several decades of study data (Table 4) [17,24].…”