Sinusoidal Obstruction Syndrom (SOS): Warning about Autologous Stem Cell Transplantation (ASCT) Preceded By Regimens Containing Oxaliplatin
Authors: Debureaux Pierre-Edouard , Le Febvre de Nailly Delphine , Tavernier Emmanuelle , Bedoui Manel , Kuhnowski Frederique , Tamburini Jerome , Fornecker Luc Mathieu , Tilly Herve , Sibon David , Moles Marie-Pierre , Glaisner Sylvie , Richardet Jean Philippe , Mule Sebastien , Calderaro Julien , Haioun Corinne , Dupuis Jehan 
Published: October 2019

Abstract
Introduction
ASCT is a cornerstone in lymphoma therapeutics, especially in the relapse setting. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most widely used conditioning regimen with a low rate of transplant mortality. Bendamustine has occasionally been used in France as a substitute for carmustine during a period of shortage ("BendaEAM"). SOS is a potentially life-threatening complication, rarely observed in ASCT. In an EBMT study of 1010 ASCT, SOS occurred in less than 1% after BEAM in patients who had a normal level of AST before conditioning1. After having observed 5 cases of SOS in our institution during a 3 year period and numerous cases in other centers, we did perform a retrospective study in order to try to understand the apparent increase in incidence of this complication.
Methods
After a national alert spread through our cooperative group (LYSA) and the French health agency (ANSM), we collected history of lymphoma, hepatic disease, chemotherapy, SOS risks factor, conditioning of ASCT, diagnostic criteria for SOS (based on the EBMT classification2 or liver biopsy), treatment and outcomes. We did determine the incidence in 2 centers (Henri Mondor University Hospital and Curie Institute) where the total number of ASCT was available.
Results
We observed 6 cases of SOS after ASCT in Henri Mondor University Hospital during the last 10 years (incidence 4.1% on 145 ASCT for lymphoma) among which the 5 most recent cases had oxaliplatin exposure before ASCT. Oxaliplatin exposition tended to be associated with SOS (p=0.09). In Curie Institute, a SOS incidence of 3/46 (6.5%) was reported during a 6 year-period, and all three patients had received oxaliplatin before ASCT.
A national query permitted to find 22 cases of SOS in 10 centers during the last 6 years. Twenty had a history of oxaliplatine exposure before ASCT. Principal characteristics are presented in table 1. No patient had a history of cirrhosis or significant hepatic pathology. Two patients had liver infiltration due to the lymphoma before treatment by oxaliplatin. The majority of patients didn't present with any of the known risk factors for SOS. One patient had liver anomalies (AST > 2 ULN and cholestasis) after 4 cycles of an oxaliplatin-containing regimen for relapsing diffuse large B-cell lymphoma. Biopsy of liver showed early sinusoidal lesions. Despite these results, he proceeded to ASCT with BEAM conditioning and experimented a moderate form of SOS. Five patients received fluconazole and aprepitant during conditioning.
Discussion
During the last decade, cisplatin was often substituted by oxaliplatin inside the DHAP protocol in order to avoid renal impairment. Pre-operative oxaliplatin in hepatic metastases of colorectal cancer leads to asymptomatic damage of sinusoidal endothelial cells (SEC) in half of the patients3. Our principal hypothesis is that oxaliplatin provokes a frailty of liver and conditioning of ASCT and co-factors (peg-filgrastim and cytochromes inhibitors- fluconazole and aprepitant) lead to SOS. SEC had a receptor for G-CSF and activation of this receptor lead to inflammatory state4. Peg-filgrastim administered at a fixed dose in the early time of ASCT (Day+1 or +3) with low concurrence increases the inflammatory state of SEC. Fluconazole and aprepitant are inhibitors of cytochromes 3A4 which metabolize etoposide. Each inhibitor could increase exposition to etoposide. Five patients received both inhibitors during conditioning which might have increased liver toxicity which led to SOS.
Conclusion
We want to warn about the probable association of oxaliplatin before ASCT and SOS. In some French centers, this led to switch oxaliplatin by carboplatin for patients eligible to ASCT.
BibliographyCarreras E et al. Incidence and outcome of hepatic VOD after blood or marrow transplantation: a prospective cohort study of the EBMT. Blood. 1998;92(10):3599-3604.Mohty M et al. Revised diagnosis and severity criteria for SOS/VOD in adult patients: a new classification from the EBMT. Bone Marrow Transplant. 2016;51(7):906-912.Rubbia-Brandt L et al. Severe SOS associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460-466.Fusté B et al. GSF factor increases expression of adhesion receptors on endothelial cells through activation of p38 MAPK. Haematologica, 2004;8.
Table 1. Table 1.

Disclosures
Tilly: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria.