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Prophylactic, Preemptive, and Curative Treatment for Sinusoidal Obstruction

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Prophylactic, Preemptive, and Curative Treatment for Sinusoidal Obstruction Bone Marrow Transplantation (2020) 55:485–495 https://doi.org/10.1038/s41409-019-0705-z FEATURE Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a position statement from an international expert group 1 1 2 3 4 5 Mohamad Mohty ● Florent Malard ● Manuel Abecasis ● Erik Aerts ● Ahmed S. Alaskar ● Mahmoud Aljurf ● 6 7 8 9 10 11 12 Mutlu Arat ● Peter Bader ● Frederic Baron ● Grzegorz Basak ● Ali Bazarbachi ● Didier Blaise ● Fabio Ciceri ● 13 14 15 16 17 18 Selim Corbacioglu ● Jean-Hugues Dalle ● Fiona Dignan ● Takahiro Fukuda ● Anne Huynh ● Jurgen Kuball ● 19 20 21 22 23 Silvy Lachance ● Hillard Lazarus ● Tamas Masszi ● Mauricette Michallet ● Arnon Nagler ● 24 25 26 27 28 Mairead NiChonghaile ● Shinichiro Okamoto ● Antonio Pagliuca ● Christina Peters ● Finn B. Petersen ● 29 30 31 32 33 34 Paul G. Richardson ● Tapani Ruutu ● Wael Saber ● Bipin N. Savani ● Robert Soiffer ● Jan Styczynski ● 35 36 37 38 Elisabeth Wallhult ● Ibrahim Yakoub-Agha ● Rafael F. Duarte ● Enric Carreras Received: 8 May 2019 / Accepted: 6 June 2019 / Published online: 1 October 2019 © The Author(s) 2019. This article is published with open access Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening 1234567890();,: 1234567890();,: complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group. Introduction ischemia in zone 3 of the acinus, and concomitant hepato- cellular damage; all of which results in the clinical symp- Sinusoidal obstruction syndrome (SOS), formerly called toms of SOS/VOD and an associated hepato-renal veno-occlusive disease (VOD; referred to as SOS/VOD syndrome, namely fluid retention, ascites, weight gain, hereafter), is a life-threatening complication that can occur painful hepatomegaly, and jaundice [3–5]. In the most after hematopoietic stem cell transplantation (HCT) [1]. The severe cases, patients may develop multiorgan dysfunction conditioning regimen and immune-mediated injury follow- (MOD) with pulmonary and renal involvement, encepha- ing allogeneic HCT (allo-HCT) generate toxic metabolites lopathy and, ultimately, death. Despite the incidence of that damage sinusoidal endothelial cells. The expression of SOS/VOD being limited, around 10–15% after myeloa- tissue and von Willebrand factors contribute to the clothing blative allo-HCT and up to 5% after reduced-intensity cascade activation, perpetuate the endothelial cell injury conditioning (RIC) allo-HCT, particular attention must be leading to the formation of gaps in the hepatic sinusoidal paid to permit its early detection and treatment and to pre- endothelium [2]. Red blood cells penetrate through those vent the development of the most severe forms, which are in gaps in the perisinusoidal space, beneath the endothelial turn associated with a very high mortality rate (>80%) cells, and subsequently dissect off the endothelial lining, all [1, 5]. In an effort to improve early diagnosis, the European of which embolize as part of the sinusoid flow and in turn Group for Blood and Marrow Transplantation (EBMT) obstruct the sinusoid [1]. This process reduce hepatic out- revise the modified Seattle [6] and Baltimore [4] criteria, flow, produces postsinusoidal hypertension with tissue and recently published revised diagnosis and severity cri- teria for adults [7]. The next step was to provide treatment recommendation * Mohamad Mohty for SOS/VOD in adult patients. Commissioned by the [email protected] EBMT, a global SOS/VOD Task Force was developed to Extended author information available on the last page of the article help identify and address the key challenges in the 486 M. Mohty et al. prophylactic, preemptive, and curative treatment for SOS/ contrast, beyond day 21, hyperbilirubinemia is less con- VOD in adult patients. The Task Force committee met in sistent [8, 11, 12]. Therefore, hyperbilirubinemia is not 2018 and identified five key clinical practice questions (risk mandatory for the diagnosis of late SOS/VOD, provided factors, how to treat, when to treat, supportive care, and patients present with at least two other clinical manifesta- preventive therapy) relevant to clinical hematologists and tions (painful hepatomegaly, weight gain >5%, and/or allied health practitioners. Practice guidelines from this ascites) as well as hemodynamic and/or ultrasound evidence initiative for each particular question forms the basis of this of SOS/VOD. In adult patients, thrombocytopenia with article and lays out a roadmap of common issues encoun- platelet transfusion refractoriness was not retained as a tered with prophylactic, preemptive, and curative treatment criterion, given the frequency and the lack of specificity of for SOS/VOD in adult patients with reference to the com- this symptom in the pancytopenic phase after allo-HCT [7]. mercially available products and on clinical trials. Simultaneously, the EBMT proposed criteria for severity grading of SOS/VOD once the diagnosis is made [7]. SOS/ VOD is graded in four stages of severity (mild, moderate, EBMT diagnosis and severity criteria for SOS/ severe, and very severe), based on five parameters: time VOD since first clinical manifestation of SOS/VOD, bilirubin level and kinetics, transaminase level, weight gain, and In adult patients, Baltimore criteria have been reported to be renal function (Table 2). Importantly, in the presence of two more specific than the Seattle one for SOS/VOD diagnosis: or more risk factors, patients are classified in the upper specifically, while hemodynamic studies could not confirm grade. Yoon et al. have validated these criteria in 203 the diagnosis in 42% of patients assessed by the Seattle patients with SOS/VOD [13]: 5.9% were in the mild, 12.8% criteria, such lack of confirmation was seen in only 9% of moderate, 18.2% severe, and the majority (63.1%) was in patients using the Baltimore criteria, a finding further vali- the very severe grade. The day 100 overall survival (OS) of dated by corroboration with histopathology [8, 9]. Coppell mild, moderate, severe, and very severe groups was 83.3, et al.’s meta-analysis yielded an almost 100% discrepancy 84.3, 94.6, and 58.6%, respectively, and very severe SOS/ in the incidence of SOS/VOD (Baltimore 9.6% vs. Seattle VOD showed a significantly lower OS than the others (58.6 17.3%) [5] and Yakushijin et al. report an even higher vs. 89.3%, p < 0.0001). Similarly, the day 100 transplant- difference of 2.5% with the Baltimore criteria vs. 10.8% related mortality was significantly higher in very severe with the modified Seattle criteria [10]. This discrepancy SOS/VOD, being 36.7, vs. 8.3% in mild, 8.0% in moderate, between both classifications was related to hyperbilir- and 2.7% in severe (p < 0.0001). This study confirms the ubinemia, mandatory in the Baltimore, but not in the Seattle worse outcome of very severe SOS/VOD, while severe criteria. However, hyperbilirubinemia and jaundice are SOS/VOD seems to have similar outcome to mild and almost invariably present in classic SOS/VOD in adult moderate SOS/VOD. Overall further validation might be patients [8]. Therefore, it was decided to keep the Baltimore required with careful evaluation of therapeutic intervention criteria for diagnosis of classical SOS/VOD (within 21 days to evaluate the prognosis of severe SOS/VOD in the defi- after HCT) in the revised EBMT criteria (Table 1)[7]. In brotide (DF) era. Table 1 EBMT criteria for SOS/VOD diagnosis in adults Risk factors Classical SOS/VOD Late-onset SOS/VOD In the first 21 days after HSCT >21 days after HSCT Given the role of risk factors in the severity grading of SOS/ fi Bilirubin ≥ 2 mg/dL and two of Classical VOD/SOS VOD (patients with two or more risk factors are classi ed in the following criteria must be beyond day 21 the upper grade), an accurate identification of these high- present: OR risk factors must be performed, as previously discussed - Painful hepatomegaly Histologically proven SOS/VOD (Table 3)[7]. Here, we highlight several important issues - Weight gain > 5% OR - Ascites Two or more of the following regarding risk factor evaluation. For haploidentical donors, criteria must be present: studies using the Baltimore RIC regimen and posttransplant - Bilirubin ≥ 2 mg/dL (or 34 μmol/ cyclophosphamide protocol showed no increased incidence L) of SOS/VOD [14, 15]. However, this may not be the case in - Painful hepatomegaly - Weight gain > 5% the context of haploidentical allo-HCT with other con- - Ascites ditioning regimens incorporating one or more alkylating AND hemodynamical or/and agents and posttransplant cyclophosphamide. We therefore ultrasound evidence of SOS/VOD maintain the previous recommendation to consider haploi- These symptoms/signs should not be attributable to others causes dentical donor as a risk factor as any HLA-mismatched Prophylactic, preemptive, and curative treatment for sinusoidal obstruction syndrome/veno-occlusive. 487 Table 2 EBMT criteria for severity grading of a suspected SOS/VOD in adults Milda Moderatea Severe Very severe MOD/MOFb Time since first clinical symptoms >7 days 5–7 days ≤4 days Any time of SOS/VODc Bilirubin (mg/dL) ≥2 and <3 ≥3 and <5 ≥5 and <8 ≥8 Bilirubin (μmol/L) ≥34 and <51 ≥51 and <85 ≥85 and <136 ≥136 Bilirubin kinetics Doubling within 48 h Transaminases ≤2 × normal >2 and ≤5 × normal >5 and ≤8 × normal >8 × normal Weight increase <5% ≥5% and <10% ≥5 % and <10% ≥10% Renal function <1.2 × baseline at ≥1.2 and <1.5 × baseline ≥1.5 and <2 × baseline ≥2 × baseline at transplant or transplant at transplant at transplant others signs of MOD/MOF Patients belong to the category that fulfills two or more criteria.
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