Veno-Occlusive Disease (VOD) after Hematopoietic Stem Cell Transplant (HSCR): Always a Catastrophic Illness?

Introduction

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potential life-threatening complication of conditioning regimens performed for HSCT, is due to an endothelial cell activation/damage and a prothrombotic-hyper-fibrinolytic condition. The clinical diagnosis and grading of VOD/SOS are based on the Seattle, Baltimore and EBMT criteria.

Aims

The aim of our work was to establish the incidence of VOD/SOS in our patient series, the time of clinical diagnosis, the best treatment options in relation to disease severity, the effectiveness of defibrotide treatment for severe/very severe forms, and the incidence of multi-organ failure (MOF).

Methods

Patients

In the period January 2016-June 2019, 146 allogeneic HSCT were performed at our Institution. Patients' median age was 57 years (range 25-72) and 52% of them were males. The primary disease was AML in 82 (56.1%), MDS in 33 (22.6%), ALL in 16 (10.9%), MM in 5 (3.4%), primary or secondary Myelofibrosis in 10 (6.8%). Performance status was good (Karnofsky score ≥90) in 80% of HSCT. At HSCT, 31 patients (21.2%) had either had a previous hepatic disease or increased levels of alanine transaminases (ALT) and 36 (24.6%) had altered pulmonary functional tests. Thirty-five HSCTs were from HLA identical siblings, 55 from MUD and 35 from haplo-identical family donors. Conditioning regimen were either myeloablative or RIC depending on patients' age and co-morbidities. Stem cell source was BM in 36 (24.6%) patients, peripheral hematopoietic stem cells in 109 (74.6%) and cord blood in one. Standard acute GVHD prophyaxis consisted of Cylosporine A (CsA) and short methotrexate or CsA and micofenolate mofetyl in haplo-transplants.

Definition, grading and treatment of VOD

Diagnosis and grading of VOD/SOS were based on the Seattle, Baltimore and EBMT criteria. Renal dysfunction was defined as serum creatinine ≥3x baseline value, creatinine clearance or glomerular filtration rate declined to ≤40% of baseline or dialysis dependence due to VOD/SOS. Pulmonary dysfunction was defined as oxygen saturation ≤90% on room air, requirement for supplemental oxygen to maintain oxygen saturation ≥90%, or ventilator dependence not due to infection. Abdomen echo-tomography was performed in all patients to evaluate the presence of ascites. Patients having a pre-transplant liver disease or increased ALT levels received ursodeoxycholic acid (UDCA) as pharmacological prophylaxis

Results

In our series VOD/SOS occurred in 22/146 patients (15.0%) according to Seattle criteriaand in 13 (8.9%) according to Baltimore criteriaand the recent EBMT scale. Median time to VOD/SOS development was 7 days post-HSCT (range 0-18). Based on the proposed EBMT scale for grading, 9 patients were classified as mild VOD/SOS, one as moderate, 11 as severe and one as very severe. VOD/SOS target organs were the liver in 6 patients, the liver and the lung in 6 and the lung in one. Defibrotide treatment (6.25/kg/day for 21 days) was promptly started in 12 patients including the case with the moderate form of VOD/SOS and delayed by 23 days in one patient. VOD/SOS progression occurred in 7 patients: one evolved from a mild to a severe form and 6 from a severe to a very severe form. Defibrotide treatment induced a response in 10 patients: 8 achieved a complete response and 2 a partial response. However, these last two patients died of a thrombotic microangiopathy syndrome three and four months post-transplant. The remaining 3 patients, including the case with a delayed defibrotide start, experienced a multi-organ failure (MOF) that had been preceded by a liver (one case) and a lung VOD/SOS (two cases). Interestingly, the patient with a liver VOD/SOS had showed a severe liver dysfunction on pre-transplant work-up and the remaining two with a lung VOD/SOS a severe lung dysfunction on pre-transplant work-up.

Conclusions

In our series the incidence of VOD/SOS is similar to that reported by the literature; two organs involvement predicts a high risk of MOF evolution; UDCA is the therapy of choice for mild VOD/SOS; defibrotide, especially if promptly started, is very effective in inducing VOD/SOS resolution.