Usefulness of Liver Stiffness Measurement in Predicting Hepatic Veno-Occlusive Disease Development in Patients Who Undergo HSCT

LETTER TO THE EDITOR Usefulness of liver stiffness measurement in predicting hepatic veno-occlusive disease development in patients who undergo HSCT

Bone Marrow Transplantation (2017) 52, 494–497; doi:10.1038/ The diagnosis of VOD is primarily based on established clinical – bmt.2016.320; published online 12 December 2016 criteria (modified Seattle or Baltimore criteria);6 9 ultrasound imaging may be helpful in the exclusion of other disorders in patients with suspected VOD. Liver biopsy should be reserved for Hepatic veno-occlusive disease (VOD), or sinusoidal obstructive patients in whom the diagnosis of VOD is unclear and other syndrome (SOS), is a clinical syndrome characterized by hepato- diagnoses need to be excluded.10 megaly, ascites, weight gain and jaundice, which can develop Liver stiffness (LS) measurement using Fibroscan is a new more frequently in the first 30 days after hematopoietic stem cell safe, accurate and non-invasive method used to better identify 11,12 transplantation (HSCT).1,2 Its incidence, although influenced liver fibrosis and degree of portal hypertension in chronic liver by diagnostic criteria, has been estimated to be 13.7% (range disease patients. LS measurement was carried out using FibroScan 0–62.3%) and, in untreated hepatic severe VOD/SOS, it is (Echosens, Paris, France) after at least 6 h of fasting, as previously associated with 480% mortality.3 In this syndrome, sinusoidal described.13 Briefly, the FibroScan device consists of a 3.5 MHz endothelial cells and hepatocytes in zone 3 of the hepatic ultrasound transducer probe mounted on the axis of a vibrator. acinus are damaged by toxic metabolites generated during the Mild amplitude and low-frequency vibrations (50 Hz) are trans- conditioning regimen.4 The classic VOD pathway develops by the mitted to the liver tissue, inducing an elastic shear wave, which narrowing of the sinusoids, embolization of endothelial cells and propagates through the underlying tissue. Transient elastography increased clot formation, leading to obstruction of the sinusoids, (TE) measurement assesses the stiffness of the liver, which is used subendothelial and centro-acinar fibrosis and then to portal- as an indirect marker of liver fibrosis. Furthermore, its measure- central fibrosis resulting in post-sinusoidal portal hypertension, ment is useful in predicting the degree of portal hypertension. which dominates the clinical picture.5 For each patient, the physician carried out at least 10 valid

Table 1. Demographic and clinical characteristics of patients enrolled

Subject Sex Age Diagnosis Conditioning regimen Type of SCT VOD Day after VOD tp number (years) HSCT

1 M 5.7 AML BU-MEL-CPM-ATG MUD No 2 F 12.2 ALL BU-THIO-CPM-ATG MUD Yes 22 Defibrotide 3 M 5 ALL FLUDA-TREO-MEL-ATG MUD No 4 F 20.4 ALL BU-THIO-CPM Sibling Yes 25 Paracentesis 5 M 8.4 Ewing sarcoma BU-MEL Autologous Yes 24 Diuretics+UDCA 6 M 4.5 ALL BU-THIO-CPM+ ATG PMUD Liver Diuretics+UDCA toxicity 7 M 9.4 Beta-thalassemia THIO-FLUDA-TREO-ATG Sibling No 8 F 14.5 Severe aplastic FLUDA-CPM-ATG PMUD Liver 11 Diuretics+UDCA anemia toxicity 9 M 15.8 Severe aplastic THIO-FLUDA-TREO-ATG Sibling No anemia 10 M 6 Beta-thalassemia BU-THIO-FLUDA-ATG PMUD No 11 M 19 AML TREO-THIO-FLUDA Sibling No 12 M 15.8 AML TREO-THIO-FLUDA+ATG PMUD No 13 M 13.2 AML TREO-THIO-FLUDA Haploidentical No 14 F 11.4 ALL TREO-THIO-CPM MFD No 15 M 16.5 LH REC FLUDA+ MEL Sibling No 16 F 9.3 Beta-thalassemia BU+FLUDA+THIO MUD No 17 M 10.6 AML FLUDA+TREO+THIO MUD Yes 19 Defibrotide+ Diuretics 18 F 16.9 Severe aplastic FLUDA-CPM-ATG MUD No anemia 19 M 5.4 ALL (relapse) TREO-THIO-FLUDA Haploidentical GvHD Defibrotide 20 M 8.7 Ewing sarcoma BU-MEL Autologous No 21 M 14.8 ALL (relapse) BU-THIO-FLUDA-ATG Haploidentical No 22 M 13.6 Ewing sarcoma BU-MEL Autologous No Abbreviations: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; ATG = anti thymocyte globulin; BU = busulphan; CPM = cyclopho- sphamide; CPMpost = CPM after HSCT; F = female; FLUDA = fludarabine; GvHD = graft-vs-host disease; M = male; MEL = melphalan; MFD = matched family donor; MUD = HLA matched unrelated donor; PMUD = HLA partially unrelated matched; THIO = thiotepa; TREO = treosulfan; UDCA = Ursodeoxycoholic acid. Letter to the Editor 495 measurements or a maximum of 20 attempts at measurement transplantation. All examinations were conducted at bedside to with an ‘M’ probe. The examinations were considered valid if the minimize the risk of infection. success rate was 460%, and the interquartile range was o30% of The study was carried out in accordance with the ethical the median value (See Supplementary Material). guidelines of the Helsinki Declaration and was approved by the A recent paper has shown that LS measurement using ARFI local ethics committee. All study participants provided written (Acoustic Radiation Force Impulse) and Fibroscan could represent informed consent. an additional diagnostic parameter for adult patients with GvHD was diagnosed using the Glucksberg et al.15 criteria; drug- suspected post-transplant hepatic injury; in fact, LS pretransplant related hepatotoxicity was diagnosed according to the recent values using ARFIo1.25 m/s were correlated with the absence of Meeting Report by Fontana et al.,16 for example, patients who severe complications after allo-HSCT.14 developed severe direct hyperbilirubinemia in an extremely early The aim of our study was to verify the role of LS measurement phase of post transplant (on days +2 and +5) without other clinical in predicting VOD development in a pediatric population who VOD manifestations or any other causes, such as infections, GvHD underwent HSCT using Fibroscan. and biliary obstructive causes were also excluded. The data presented herein are interim data from a prospective The VOD was diagnosed according to the modified Seattle or Baltimore criteria.7,8 The severity of the VOD was assessed single-center study, which is currently in progress. All consecutive 17 18 patients referred to the Hemato-Oncologic Pediatric Unit of according to Carreras et al. and McDonald et al. Sant’Orsola Hospital, from November 2014 to May 2016, with During the study period, 22 (16 males, 6 females, mean age: hemato-oncologic disease with indications for allo- and auto-SCT 140 months, min 54, max 245) out of 30 patients who had undergone HSCT were enrolled according to the previously were enrolled. Of the patients having indications for auto-SCT, defined inclusion criteria. The indication for HSCT, and the those who underwent TBI or a busulfan-based conditioning baseline clinical and demographic characteristics of the patients regimen were enrolled. The inclusion criteria were: informed – enrolled are shown in Table 1. consent, age 4 70 years and patients affected by hemato- With the exception of patients 5, 20 and 22 who had Ewing’s oncologic disease with any indications for allo-SCT or with sarcoma and had undergone autologous transplantation, all indications for auto-SCT after TBI or busulfan-based chemother- patients underwent allogeneic transplantation. Table 1 also 4 apy. The exclusion criteria were obesity (body mass index 40), reports the pre-HSCT conditioning regimens. Patients 2, 4, 5 and pacemakers or implantable defibrillators and the presence of 17 developed VOD; according to the diagnostic criteria,7,8 our ascites. patients were classified as moderate VOD (all required treatment, The baseline demographic and clinical characteristics of the no one died from VOD). Patients 6 and 8 developed a clinical patients were recorded. At enrollment (before pre-HSCT che- picture suggestive of liver toxicity; patient 19 developed GvHD. motherapy), all patients underwent laboratory tests, routine The TE measurement was successful in all patients; none had abdomen ultrasonography examination and LS measurement. ascites during TE assessment, as documented by the preliminary Laboratory tests and LS measurement were subsequently carried ultrasonographic examination. The LS value for each assessment out at 7–10 days (T1), 17–20 days (T2) and 27–30 days (T3) after and the VOD diagnosis are shown in Figure 1; no evident

20.0 VOD +6 days VOD +3 days

18.0

16.0

VOD +4 days 14.0

12.0 VOD +5 days

LS (kPa) 10.0

8.0

6.0

4.0

2.0 T0 T1 T2 T3

Legend:

VOD

Liver toxicity

No liver complication

Figure 1. Variation of LS values at each determination for all patients; at T2 in patient 2, LS suddenly increased 4 days before VOD; in patient 4, LS suddenly increased 5 days before VOD; in patient 5, LS suddenly increased 6 days before VOD and in patient 17, LS suddenly increased 3 days before VOD (continuous lines). The early LS values which progressively increased in patients who developed liver toxicity (dashed lines). The LS values in patients without liver complications (dotted lines).

© 2017 Macmillan Publishers Limited, part of Springer Nature. Bone Marrow Transplantation (2017) 494 – 497 Letter to the Editor 496 differences were observed at baseline LS values between patients A Colecchia1, G Marasco1, F Ravaioli1, K Kleinschmidt2, R Masetti2, who developed VOD and those who did not. Of the patients who A Prete2, A Pession2 and D Festi1 developed VOD, patient 2 had an increase in LS 18 days after 1Department of Medical and Surgical Sciences, University of Bologna, HSCT, developing VOD 4 days later; patient 4 had an increase in LS Bologna, Italy and 2 17 days after HSCT, developing VOD 5 days later; patient 5 had an Pediatric Oncology and Hematology Unit, University of Bologna increase in LS 18 days after HSCT, developing VOD 6 days later Sant’Orsola-Malpighi Hospital, Bologna, Italy and patient 17 had an increase in LS 16 days after HSCT, E-mail: [email protected] developing VOD 3 days later. The LS values increased in the measurement carried out before VOD diagnosis, and these values were different from the baseline and the from previous values. REFERENCES In the two patients who developed liver toxicity, there was a 1 Baglin TP. Veno-occlusive disease of the liver complicating bone marrow trans- gradual and early increase in LS, starting from the fifth day after plantation. Bone Marrow Transplant 1994; 13:1–4. HSCT. Of these patients, the first one had spontaneous resolution 2 Dalle J-H, Giralt SA. Hepatic Veno-occlusive disease after hematopoietic stem cell fi of the liver toxicity and the second one developed multi-organ transplantation: risk factors and strati cation, prophylaxis, and treatment. Biol Blood Marrow Transplant 2016; 22:400–409. failure and died on day 44 after HSCT. 3 Coppell JA, Richardson PG, Soiffer R, Martin PL, Kernan NA, Chen A et al. 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