Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan‐Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990–2015. Patients' supportive care was changed in order to reduce the regimen‐related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N‐acetyl‐L‐cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995–1999 (16.2%) compared with 2.3% during 2010–2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P < 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.

Impact of busulfan pharmacokinetics on outcome in adult patients receiving an allogeneic hematopoietic cell transplantation

“…About 60% of all patients transplanted between 2013 and 2020 were conditioned with Bu, almost all of them to treat myeloid neoplasms (i.e., 95%). Bu PK dosing started in the 2000’s and introduced as TDM in the following years, allowing an important reduction of hepatic toxicity and the SOS, as the incidence of SOS has been reduced from about 15 to 3% in <10 years [ 4 , 18 ]. Our target-AUC was reached in only 46% of the time, but we used narrower target limits than others (i.e., 800–1500 μmol/l*min [ 23 ], 900–1520 μmol/l*min [ 26 ]).…”

“…Bu pharmacokinetics (Bu-PK) after intravenous Bu administration is performed since 2013 in Basel as standard therapeutic drug monitoring (TDM), permitting a dose individualization for each patient according to the calculated area-under-the-curve (AUC) [ 17 ]. TDM has permitted to decrease mainly hepatic toxicity and especially the incidence of SOS, which plays an important role in non-relapse mortality (NRM) [ 4 , 18 ]. Since April 2019, Bu infusion was switched from 4 times daily (Bu-4) to once daily (Bu-1) in Basel, as this is more comfortable for application without showing an increase prevalence in toxicity or end-organ damage [ 19 , 20 ].…”

Análise dos fatores associados ao retransplante de células-tronco hematopoiéticas: estudo caso-controle

“…The use of ursodeoxycholic acid is considered useful in the prophylaxis and treatment of some liver conditions, especially from DECH for being one of the reasons that may lead to the need for HSCR according to the results presented by this study. A retrospective study investigated the use of ursodeoxycholic acid and found a decreased incidence of sinusoidal obstruction syndrome and other liver complications 21 .…”

Busulfan-cyclophosphamide versus cyclophosphamide-busulfan as conditioning regimen before allogeneic hematopoietic cell transplantation: a prospective randomized trial

“…The hepatotoxicity of BuCy regimen is well described [12][13][14]26]; one of the pathomechanism of the hepatotoxicity of Bu and Cy is the depletion in glutathione levels, which plays a central role in the metabolism of the toxic metabolites of Cy in hepatocytes [9,10]. Glutathione depletion as a mechanism of hepatic toxicity had been studied extensively [27][28][29].…”

“…It is known that inter-individual discrepancy of pharmacokinetics of busulfan impacts on toxicity outcomes [ 31 – 33 ]. The introduction of busulfan therapeutic drug monitoring between 2000 and 2010 led to a reduction in adverse outcomes regarding liver toxicity, highlighted by a reduction in the VOD incidence from 15% in the late 1990s to 3% after 2010 after dose adjustment of busulfan during this time period [ 26 , 31 ]. In our trial, the incidence of severe VOD is 1.4% (one case in 70 patients) and this is comparable to the literature, where incidence of 2-5% has been described [ 26 , 34 ].…”