Safety and Efficacy of Dose Escalation of Defibrotide in Hematopoietic Stem Cell Transplantation (HSCT) Recipients with Sinusoidal Obstructive Syndrome (SOS) Refractory to Standard Treatment Doses of Defibrotide

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1002/pbc.29735

Journal Title

Pediatric Blood and Cancer

Department

Pediatrics

Second Department

Medicine

Abstract

Background: SOS is a lethal complication (84% mortality) of HSCT, resulting in multi-organ failure (MOF) (Cairo/Cooke et al, Richardson et al, BJH 2020). Endothelial damage within the sinusoids of the liver progresses to a cascade of fibrosis, sclerosis, inflammation, thrombosis, and ischemia, culminating in SOS (Cooke et al, BBMT, 2008). Defibrotide stabilizes endothelial cells in microvascular beds and is FDA approved for the treatment of SOS with renal and/or pulmonary dysfunction (Cairo, et al, BJH 2020). However, only 40-60% of HSCT recipients with SOS survive to Day+100 despite defibrotide treatment (Richardson et al, Blood, 2016). Importantly, patients post HSCT with SOS who obtained a CR following defibrotide have a higher Day +100 OS and median survival vs those who did not obtain a CR (93% vs 37%) 796 vs 68 days (Richardson et al, TCT, 2021). Tripleff et al. (BBMT, 2018) demonstrated the safety of dose escalation of defibrotide to 25 mg/kg/dose (100 mg/kg/day) without evidence of toxicity in HSCT recipients with refractory SOS following standard defibrotide dosing. Objective: To evaluate the safety and efficacy of defibrotide dose escalation in HSCT patients who had progressive disease or were refractory (non-CR) to standard defibrotide dosing. Design/Methods: Dose escalation of defibrotide proceeded from 6.25 mg/kg/dose to 10, 15, 25 mg/kg/dose q6h in HSCT recipients until CR or DLT. SOS grading were per Cairo/Cooke, et al., BJH, 2020. Response criteria were defined as: CR is Grade 1 or less, partial response is improvement in 1 grade or more in ≥3/6 SOS grading criteria, progressive disease (PD) is progression one grade or more in ≥ 3/6 SOS grading criteria, and stable disease (SD) includes all other patients. Patients also received antithrombin III replacement to maintain activity between 100-120% (Haussmann et al. Haematologica 2006). Results: Eight HSCT recipients with refractory/progressive post-HSCT SOS following defibrotide (6.25mg/kg q6hrs): age 8 mo-18y (median 18mo), M/F 3/5, 6 malignant, 2 non-malignant disease. Seven of the eight patients received MAC. All patients had grade 4 SOS prior to initiation of defibrotide dose escalation. Seven patients received hemodialysis during defibrotide. No patient developed hemorrhage during the dose escalation of defibrotide. CR was 62.5%, 12.5% SD and 25% PD. The probability at Day 100 OS in this patient group was 87.5% (CI95: 38.7-98.1). Conclusions: Dose escalation of defibrotide to maximum of 100mg/kg/day (25mg/kg q6hrs) was well tolerated in defibrotide refractory HSCT related SOS with improved day 100 OS. A larger cohort will be evaluated to confirm these findings.

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