As an attempt to prevent the development of SOS/VOD, different therapeutic strategies have been tested. Ursodeoxycholic acid (UDCA) was shown to enhance biliary secretion of bile acids and bilirubin glucuronides through post-transcriptional up-regulation of export pumps. This agent also exerts anti-apoptotic effects in cholestatic hepatocytes (through a decrease in mitochondrial release of cytochrome C) and enhances bicarbonate secretion in cholangiocytes (employing an increase in cytosolic calcium that stimulates chloride/bicarbonate antiporter channel). Interestingly, UDCA displays an immunomodulatory role by decreasing both the expression of MHC (major histocompatibility complex) classes I and II in hepatocytes (the former by a non-selective binding to glucocorticoid receptor that suppresses IFN-γ pathway) (30). Unfractionated heparin, on the other hand, acts by binding and activation of antithrombin that ultimately inactivates factor Xa activity and thrombin, as well as the thrombin-dependent platelet activation and factors V and VIII release (31). Concerning the microvascular prothrombotic status and clot formation in hepatic sinusoids and venules (4), heparin may play a role in primary prophylaxis, yet at the expense of an increased bleeding risk. Defibrotide, in another spectrum, is an orphan-drug, known for its profibrinolytic activities on the dependence of an increased expression and activity of tissue plasminogen activator, tissue factor pathway inhibitor, and thrombomodulin; coupled with its antithrombotic properties on the dependence of the reduced expression of plasminogen activator inhibitor, platelet-activating factor, and thrombin; ultimately decreasing platelet activation and secondary hemostasis. Defibrotide was also shown to downregulate MHC-I and II expression (the former induced by prostaglandins E2 and I2 increased expression) (32). Given its master player role in hemostasis, vascular biology, and immune-modulatory properties, defibrotide has been explored not only in the treatment but also as a prophylactic strategy in patients with a higher risk of developing an SOS/VOD. Lastly, and considering the tested strategies in former trials, N-acetyl-L-cysteine was explored given its role as a scavenger of reactive oxygen species and glutathione precursor (33). To date, there is still no consensus on the demand and efficacy of primary prophylactic strategies in SOS/VOD, as well as the target population that could benefit most from this strategy.
In this analysis, we report an aggregated overview of the role of primary prophylaxis of SOS/VOD in patients undergoing hematopoietic stem cell transplantation. Considering all patients undergoing cell-based therapies, UDCA scored higher. However, when only allotransplanted patients were analyzed, defibrotide marginally outcasted UDCA in this subset of patients. This observation, beyond being related to the nature of the procedure (autologous or allogeneic), potentially reflects patient and disease intrinsic characteristics, that vary across those two therapeutic procedures. Allotransplanted patients are typically diagnosed with more aggressive neoplasms (acute leukemias, for example) (34); and during induction and consolidation therapies are exposed to significant cumulative doses of cytotoxic agents, exhibiting a higher need for blood transfusions that otherwise induce hemosiderosis and increase iron deposits in liver (35). The conditioning regimens vary widely across studies (and even over time), being well known that, for example, liver irradiation may potentiate SOS/VOD incidence as shown in a previous analysis where the incidence of this complication was increased in patients exposed to single-dose versus hyperfractioned regimens (36). In our analysis, the distribution of allotransplanted patients whose conditioning regimens were dependent upon total body radiation was not uniformly distributed across different trials (neither the pre-transplantation needs for irradiation of the abdominal compartment), and this circumstance may impose a milder heterogeneity in the findings. Immune reconstitution following allogeneic transplantation of hematopoietic progenitors will also induce cellular damage, depending on the degree of HLA (human leukocyte antigen) matching (37), another observation that may impose an undetermined heterogeneity in the pooled population.
In light of the current knowledge, it is fair to hypothesize that the minimal advantage of primary prophylaxis with defibrotide in allotransplanted patients may arise from its immunomodulatory and iron chelation properties (32) that secondarily reduce oxidative stress and inflammation associated with the iron-induced liver disease. In fact, elevated serum ferritin levels before hematopoietic stem cell transplantation are regarded as an important risk factor for SOS/VOD development (38). Pre-transplantation transfusion dependency (associated with hemosiderosis) was associated with lower overall survivals, a higher burden of graft-versus-host disease, and an increased non-relapse mortality in patients undergoing myeloablative conditioning regimens (39); with therapeutic strategies to deplete iron stores in historical cohorts even showing an increase in liver function tests of patients after bone marrow transplantation (40).
Beyond the patient, disease, and therapeutic measures intrinsic properties that may influence the hazard of SOS/VOD development, observational bias in clinical trials may also limit the extrapolation of general conclusions emanated from them. For instance, recent trials were pivotal by showing that there was a disagreement in SOS/VOD diagnosis between local physicians (thoroughly accompanying the patient journey) and the ones responsible for centrally and blindly revising clinical and analytical data (27). The dependence of the diagnosis of this entity on clinical and analytical criteria (both dynamic) may undoubtedly influence its diagnosis and reported incidence.
Overall, when considering the pharmacological agents assessed in our analysis, ursodeoxycholic acid, beyond highly affordable, displays a pleiotropic pharmacological action, modulating both liver bile acids secretion, hepatocyte resistance to apoptosis and decreasing the potential for immune-mediated injury by downregulating MHC expression in liver cells surface (30). For these reasons, evidence prompts its use as a beneficial prophylactic strategy in patients undergoing hematopoietic stem cell transplantation.
When considering only patients undergoing allogeneic bone marrow transplantation, we systematize and report, for the first time, an aggregated overview of the primary prophylactic strategies for SOS/VOD. Despite the population heterogeneity that cannot be avoided in the pooled analysis, taking into consideration our findings, the pharmacological principles of the different therapeutic strategies, and the immune (dis)regulation associated with each particular transplant, we open doors to a more rationale critical thinking and decision making in the clinical practice, by proposing a hierarchization of therapeutic strategies.