Severe fluid retention is a life-threatening feature of SOS due to the induction of ascites and pleural effusion. As standard treatments for fluid retention, fluid restriction, sodium management, and administration of diuretics such as furosemide and spironolactone are recommended [2, 6]. However, the management of severe cases refractory to standard treatment remains clinically challenging. In the present report, we describe the successful control of severe fluid retention and CHF due to post-HSCT SOS using TSP in combination with defibrotide. Considering several risk factors in the present case, including HSCT from an unrelated donor, large donor/recipient HLA disparity, high-dose TBI-based conditioning, and prior exposure to InO [2], we administered UDCA, heparin, and lipo-PGE1 to prevent SOS. However, the patient developed SOS, and his fluid retention progressed rapidly despite the early initiation of defibrotide therapy and standard supportive care, including fluid restriction and daily intravenous furosemide. A recent retrospective study of post-HSCT SOS showed that SOS-related mortality was approximately 60% in the cases with a higher HokUS-10 score (≥ 8 points) after initiation of SOS treatment [12]. In our case, the highest HokUS-10 score was 10 points on day 22, despite the initiation of defibrotide therapy on day 13 with standard supportive care, suggesting a poor prognosis. Of clinical importance, although it took approximately 8 weeks to resolve SOS completely, TSP administration resulted in sustained urine output and rapid improvement of fluid retention, which could causally contribute to overcoming severe SOS.

To the best of our knowledge, this is the first case report on the utility of TSP for severe post-HSCT SOS. However, a previous single case report suggested the efficacy of oral tolvaptan for post-HSCT SOS with cardiopulmonary failure [8]. In this previous case, oral administration of tolvaptan for 2 days (3.75 mg and 7.5 mg) effectively controlled ascites and edema. As a minor adverse event, although hypernatremia gradually developed from 135 to 159 mEq/L within 3 days after the last administration of oral tolvaptan, it was reportedly controlled with dextrose infusion. Despite the recovery of the reverse PV flow, as indicated on echography, the patient reportedly died of lymphoma progression on day 55. Thus, although the long-term outcome was inconclusive, this report suggests the possible efficacy of aquaretic agents for severe fluid retention associated with post-HSCT SOS.

Compared to oral tolvaptan, intravenous TSP has several advantages, including rapid onset of action, flexibility in dose adjustment, and utility in cases of impaired oral intake [9, 10, 13, 14]. Of note, the time to maximum plasma concentration of active tolvaptan in intravenous administration of TSP is reportedly approximately 1.5 h, while that in oral administration of tolvaptan itself is 4 h [9]. As a result, in CHF patients with refractory fluid retention, TSP reportedly exerts a diuretic effect within 1 h after administration and reaches a peak effect within 1 or 2 h [15]. Consistently, in our case, although his urine output was only 920 mL/day 1 day before TSP administration, it reached 1900 mL within 6 h after the first dose of TSP, resulting in rapid clinical improvement of fluid retention.

In the present case, TSP appeared to effectively relieve severe fluid retention primarily through its diuretic effect. Although the rapid diuresis induced by TSP improved hemodynamic parameters, TSP might not directly improve the sinusoidal endothelial damage and inflammatory cascades associated with SOS. Further pathophysiological studies are necessary to clarify the pharmacological effects of TSP in SOS.

Electrolyte abnormalities are a known adverse effect of TSP due to hemoconcentration caused by excessive aquaresis. In the OPTION-HF study, the incidence of hypernatremia in the TSP-treated cases (2.7%) was almost similar to that in the oral tolvaptan-treated cases (2.1%) [10]. In contrast, the incidence of hyperkalemia and dehydration was higher in the TSP-treated cases (6.0% and 10.1%, respectively) than in the oral tolvaptan-treated cases (2.1% and 4.1%, respectively) [10]. In this context, it is noteworthy that nearly half of the cases that developed hyperkalemia after TSP treatment had underlying renal dysfunction, suggesting a requirement for careful monitoring, particularly in cases with renal dysfunction. In our case, although mild hypernatremia developed after an initial dose of TSP, it resolved the next day without any therapeutic intervention. Ultimately, no other adverse effects were observed during 5 weeks of TSP administration.

In the post-HSCT setting, potential interactions between TSP and other drugs are an important clinical issue. TSP is rapidly converted to tolvaptan, which is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3 A4 (CYP3 A4) [16, 17]. Although no significant dose adjustments of tacrolimus were necessary during TSP therapy in the present case, further accumulation of clinical data is needed to evaluate potential interactions with other drugs such as tacrolimus, a substrate of P-gp and CYP3 A4 [18, 19], and cyclosporine, a potent inhibitor of P-gp and CYP3 A4 [20].

In conclusion, our case report demonstrates the potential utility of TSP in controlling severe and refractory fluid retention due to post-HSCT SOS, although further clinical studies are required to verify its efficacy and safety.