Veno-occlusive Research Articles

Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission

AbstractThe detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10−4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome–positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10−3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061.

Incidence and Role of Recipient-Specific Antibodies in Allogeneic Hematopoietic Cell Transplantation from Mismatched Related Donors

High titer of donor-specific antibodies (DSAs) increases the risk of graft rejection after mismatched related hematopoietic cell transplantation (HCT). There are no data regarding the incidence of anti-HLA recipient-specific antibodies (RSAs) and their role after transplantation. Here we aimed to identify the incidence of RSAs in a mismatched related hematopoietic cell donor population and their possible impact on immune-mediated complications, such as acute graft-versus-host disease (aGVHD), and complications resulting from endothelial injury, such as transplantation-associated thrombotic microangiopathy (TA-TMA) and veno-occlusive disease (VOD). We prospectively analyzed the incidence of anti-HLA antibodies in 28 mismatched related pairs of recipients and their donors who underwent HCT at our center between 2020 and 2022. In positive samples screened for anti-HLA class I and/or II antibodies, the specificity of the HLA antibodies was analyzed. All recipients had a hematologic malignancy and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were tested for TA-TMA and aGVHD development during routine post-transplantation visits up to 100 days post-transplantation. We used modified Jodele criteria for TA-TMA diagnosis, and based aGVHD grading on the MAGIC criteria. VOD was assessed using the European Society for Blood and Marrow Transplantation. Anti-HLA antibodies were detected in 12 donors (43%) and in 9 recipients (32%). There were no significant differences between donors and recipients according to age (median, 42 years [range, 17 to 69 years] versus 39 years [range, 8 to 68 years]), sex, or pregnancy history. No transfusion history was noted in the donor group (P < .05). RSA antibodies were present more often than DSAs and were detected in 9 out of 12 (75%) anti-HLA-positive donors and in only 2 out of 9 (22%) recipients, respectively (P < .05). During the follow-up, 11 patients (39%) developed aGVHD, including grade I-II in 9 (32%) and grade III-IV in 2 (7%). Twelve patients (43%) met the criteria for TA-TMA, and only 1 patient (3.5%) was diagnosed with VOD by day 100 post-HCT. RSAs were detected significantly more often in the TA-TMA group; among 12 patients diagnosed with TA-TMA, 7 (58%) had RSAs (P < .05). We did not find a correlation between RSAs and aGVHD. The patient with VOD did not have an RSA-positive donor. There was no difference in membrane attack complex (MAC) concentration in the RSA-positive group on day 30 and day 60 post-HCT; however, there was a trend toward higher MAC concentration in the RSA-positive group on day 100 (median, 912 ng/mL [range, 788 to 1120 ng/mL] versus 616 ng/mL [range, 352 to 1244 ng/mL]; P=.055). Patients with RSA suffered more often from platelet and red blood cell decreases or transfusion refractoriness, and increased lactate dehydrogenase activity was observed in all RSA-positive cases. The donor immune status and the presence of RSA may be associated with higher rates of TA-TMA in mismatched HCT recipients. Antibody-mediated complement activation might be an additional factor influencing TA-TMA occurrence.

HokUS-10 scoring system predicts the treatment outcome for sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation

Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a multi-center retrospective study to evaluate the utility of our ultrasonographic scoring system for the diagnosis of SOS (HokUS-10) in predicting SOS-related mortality (SOS-RM). We analyzed a total of 42 patients who developed SOS after HSCT. The cumulative incidences of SOS-RM, non-relapse mortality (NRM), and overall survival at day 180 after the diagnosis of SOS were 26.4%, 28.8% and 54.5%, respectively. The area under the receiver operating characteristic curve analysis showed that the optimal cut-off value of HokUS-10 total score to predict SOS-RM was 8 points after the treatment of SOS. In the individual HokUS-10 score, ascites and portal vein flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS were shown as significant risk factors for SOS-RM. Our study suggested that US findings after the treatment can predict the treatment outcomes for SOS.

Hepatobiliary disease after bone marrow transplant: A cross-sectional study of 377 patients.

Bone marrow transplantation (BMT) is a standard treatment for several haematologic conditions. Following BMT, patients may develop hepatobiliary complications that impact morbidity and mortality. The differential diagnosis may include drug-induced liver injury (DILI), sepsis-associated liver injury (SALI), sinusoidal obstruction syndrome (SOS), graft-versus-host disease (GVHD), viral hepatitis, ischaemic hepatitis, and fulminant hepatitis. To evaluate the frequency, clinical characteristics, and outcomes of patients with hepatobiliary alterations associated with BMT in a tertiary referral centre. This was a cross-sectional study with data collected from the medical records of patients undergoing BMT between January 2017 and June 2022. We diagnosed hepatobiliary complications based on established criteria. We included 377 patients; 55.7% had hepatobiliary complications. Female gender, pre-BMT hepatobiliary alteration, and haploidentical allogeneic transplantation were associated with increased risk with odds ratios (OR) of 1.8 (p = 0.005), 1.72 (p = 0.013) and 3.25 (p = 0.003), respectively. Patients with hepatobiliary complications spent longer in the hospital than those without (27.7 × 19.3 days, respectively; p < 0.001). Among 210 patients with hepatobiliary complications, 28 died compared to 5 of 167 without complications (OR 4.98; p = 0.001). Hepatobiliary complications are frequent in patients undergoing BMT. There is a greater risk of their occurrence in women, people with pre-BMT liver alterations, and in haploidentical transplants. The occurrence of these complications increases the length of stay and is associated with a higher risk of death.

Andrographolide attenuated MCT-induced HSOS via regulating NRF2-initiated mitochondrial biogenesis and antioxidant response.

Hepatic sinusoidal obstruction syndrome (HSOS) is a death-dealing liver disease with a fatality rate of up to 67%. In the study present, we explored the efficacy of andrographolide (Andro), a diterpene lactone from Andrographis Herba, in ameliorating the monocrotaline (MCT)-induced HSOS and the underlying mechanism. The alleviation of Andro on MCT-induced rats HSOS was proved by biochemical index detection, electron microscope observation, and liver histological evaluation. Detection of hepatic ATP content, mitochondrial DNA (mtDNA) copy number, and protein expression of nuclear respiratory factor-1 (NRF1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) demonstrated that Andro strengthened mitochondrial biogenesis in livers from MCT-treated rats. Chromatin immunoprecipitation assay exhibited that Andro enhanced the occupation of nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) in the promoter regions of both PPARGC1A and NRF1. Andro also activated the NRF2-dependent anti-oxidative response and alleviated liver oxidative injury. In Nrf2 knock-out mice, MCT induced more severe liver damage, and Andro showed no alleviation in it. Furthermore, the Andro-activated mitochondrial biogenesis and anti-oxidative response were reduced in Nrf2 knock-out mice. Contrastingly, knocking out Kelch-like ECH-associated protein 1 (Keap1), a NRF2 repressor, reduced MCT-induced liver damage. Results from co-immunoprecipitation, molecular docking analysis, biotin-Andro pull-down, cellular thermal shift assay, and surface plasmon resonance assay showed that Andro hindered the NRF2-KEAP1 interaction via directly binding to KEAP1. In conclusion, our results revealed that NRF2-dependent liver mitochondrial biogenesis and anti-oxidative response were essential for the Andro-provided alleviation of the MCT-induced HSOS. Graphical Headlights: 1. Andro alleviated MCT-induced HSOS via activating antioxidative response and promoting mitochondrial biogenesis. 2. Andro-activated antioxidative response and mitochondrial biogenesis were NRF2-dependent. 3. Andro activated NRF2 via binding to KEAP1.

Risk Factors for Acute Kidney Injury after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Aims: The aim of this study was to identify risk factors associated with acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) by systematically reviewing the relevant literature. Methods: This meta-analysis surveyed relevant articles published in PubMed, Embase, and the Cochrane Library up to December 2022 to identify the reliable risk factors for AKI after HSCT, calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: Twenty studies with 4,378 patients were included. Umbilical cord blood transplantation (OR = 2.36; 95% CI: 1.77–3.15; p < 0.00001), calcineurin inhibitors (CNIs) (OR = 1.97; 95% CI: 1.06–3.67; p = 0.03), sinusoidal obstruction syndrome (SOS) (OR = 5.80; 95% CI: 3.96–8.51; p < 0.00001), allogeneic transplantation (OR = 4.27; 95% CI: 1.83–9.95; p = 0.0008), hypertension (OR = 2.07; 95% CI: 1.16–3.69; p = 0.01), amphotericin B (OR = 4.03; 95% CI: 2.54–6.40; p < 0.00001), vancomycin (OR = 2.19; 95% CI: 1.24–3.87; p = 0.007), and total body irradiation (TBI) (OR = 1.81; 95% CI: 1.27–2.57; p = 0.001) were risk factors for AKI. Conclusion: Umbilical cord blood transplantation, CNIs, SOS, allogeneic transplantation, hypertension, amphotericin B, vancomycin, and TBI were risk factors for AKI. It is important for clinical staff to be aware of these risk factors in their treatment planning with patients undergoing HSCT.

Allogeneic Hematopoietic Cell Transplantation for Juvenile Myelomonocytic Leukemia with a Busulfan, Fludarabine, and Melphalan Regimen: JPLSG JMML-11

Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU)+fludarabine (FLU)+melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m2/day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m2/day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0×109/L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m2, spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n=6; TMA, n=2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML.

Improvement in survival of acute myeloid leukemia and myelodysplastic syndrome patients following allogeneic transplant: a long-term institutional experience

BackgroundAllogeneic stem cell transplant (allo-SCT) plays a key role in the treatment of patients with both acute myeloid leukemia (AML) and myelodysplastic (MDS). Outcomes of allo-SCT have improved with optimization of transplant practices. We sought to evaluate trends in survival in AML and MDS patients undergoing allo-SCT at our institution from 1984 to 2018.MethodsA retrospective analysis of 900 consecutive AML and MDS patients undergoing allo-SCT was performed. Patients were divided by year of transplant for analysis. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints included non-relapse mortality (NRM), graft-versus-host disease (GVHD), GVHD-free relapse free survival (GRFS), and transplant complications.ResultsWe found a significant improvement in survival from 1984 to 2018 with 5-year PFS and OS improving from 17% to 49% and 17% to 53%, respectively (statistically significant difference since 2004; p&amp;lt;0.001). There was a significant difference in rates of grade II-IV aGVHD (p&amp;lt;0.001) and chronic GVHD at day +365 with cumulative incidence of both highest from 2014-2018, however, NRM improved across the years with 5- year NRM decreasing from 45% to 21%. Rates of pulmonary infections, hemorrhagic cystitis, veno-occlusive disease, and fungal infections also decreased across the years (p&amp;lt;0.001).ConclusionsWe found a significant improvement in survival of AML and MDS patients undergoing allo-HCT over the past several decades. This likely reflects improvements in transplant practices and general supportive care. Post-transplant relapse remains the leading cause of transplant failure in this group.

Echocardiographic Study of Ventricular Septal Defect in 1- to 12-Year-Old Children Visiting a Tertiary Care Center in Patna, India.

Background Symptoms of serious heart problems present at birthoften appear during the first few days, weeks, or months of a child's life. Shunt formation between the left and right ventricle is a crucial component of the pathophysiology of ventral septal defects. Objectives We aim to determine the most frequent types of ventricular septal defect (VSD) by echocardiography and whether there is any gender variation in the type of ventricular septal defect. Material and methods A total of 100 children who were clinically suspected of or diagnosed with VSD at the age of 1-12 years were enrolled in this study. The septum of the atrioventricular (AV) canal, the muscular septum, and the parietal band of the distal conal septum were evaluated by color Doppler. Ventricular septal defect (VSD) size and kind are similarly impacted by the 2D echo mode. The size and site of the VSD, associated congenital anomaly, and significant morphological changes in ventricular cavities, gender discrimination, and relation-specific types of ventricular septal defect were observed. Results A total of 100 VSD children presentedwith clinical symptoms of fast breathing, retraction of the chest, cough, cyanosis, fever, difficulty during feeding, cyanotic spell, chest pain, and edema at 65%, 62%, 54%, 52%, 54%, 29%, 9%, 11%, and 4%, respectively. Conclusion Early diagnosis is essential for effective medical care of diseases such as infective endocarditis (IE), which is present in some cases of VSD, and the avoidance of persistent pulmonary veno-occlusive disease (PVOD).

Select Toxicologic Pathology Case Studies of the Hepatobiliary System.

This case study session of the hepatobiliary system was held during the 42nd Annual Society of Toxicologic Pathology Symposium in Summerlin, Nevada. The case studies highlighed potential hepatic and biliary toxicity liabilities. This article comprises several of the case studies that were presented during the session which included copper-associated hepatitis in a dog, sinusoidal obstruction syndrome in non-human primates, hepatic cytoplasmic alteration in mice and rats, and Kupffer cell hyperplasia/granulomatous inflammation in rats. Presenters, when applicable, provided case signalment, anatomic/clinical pathology data, and diagnoses and discussed potential pathogeneses.

Connective tissue disease-associated pulmonary hypertension: A comprehensive review.

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease, pulmonary venous hypertension, interstitial lung disease-associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%-12%. The most recent European Society of Cardiology/European Respiratory Societyguidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD-PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD-PAH are inferior to those of idiopathic PAH, with those of SSc-PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD-PAH, particularly SSc-PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD-PAH. Ultimately, a better understanding of the pathogenesis of CTD-PAH will be required to develop targeted therapies for this morbid condition.

The Role of Whole Abdomen and Pelvis Radiation Therapy in Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a rare entity that typically presents in adolescent and young adult men with widespread abdominopelvic disease. The benefit of whole abdomen and pelvis radiation therapy (WAPRT) after chemotherapy and maximal surgical resection is unknown. Our objective was to evaluate the oncologic benefit and toxicity of WAPRT in this rare and aggressive disease. We conducteda retrospective review of patients with DSRCT treated at our institution primarily between 2018-2021. The cumulative incidence (CI) of intra-abdominopelvic failure was compared among those who received WAPRT after chemotherapy and surgery vs those who received chemotherapy and surgery alone without WAPRT utilizing Gray's method. Progression-free survival (PFS) and overall survival (OS) were also compared among patients who did and did not receive WAPRT using the Kaplan-Meier method from the date of surgery. Toxicity was graded per CTCAE v5.0 criteria. Twenty-eight patients were included (median age 17.5 years; range 6-38 years; 78% male, 22% female). All patients received chemotherapy with VDC/IE, all but one underwent extensive tumor resection, and all but two received HIPEC at time of resection. Nineteen patients (median age 13 years) received WAPRT after surgery, while 9 patients (median age 24 years) were treated with systemic therapy and surgery alone. Patients who received WAPRT were generally treated to 30 Gy in 20 fractions utilizing intensity-modulated radiation therapy (IMRT), with a boost to gross disease to a total dose of 45-50 Gy in 9 patients. Median follow up was 20 months. The CI of intra-abdominopelvic failure at 12 and 24 months was 16% and 50% with WAPRT vs 74% and 87% without WAPRT (p = 0.003), with a median time from surgery to intra-abdominopelvic failure of 15 months after WAPRT vs 5 months without. PFS was also improved with WAP-RT (94% and 83% at 12 and 24 months) vs without WAPRT (67% and 0% at 12 and 24 months), p = 0.001. Among those who received WAPRT, patients who received a boost to gross disease had similar intra-abdominopelvic control as those who had no gross disease to boost and received WAPRT only (CI at 24 months 50% without boost vs 48% with, p = 0.95). OS did not differ between those who did and did not receive WAPRT (OS at 24 months, 88% vs 83%, p = 0.89). Most toxicities after WAPRT were mild, including grade 1-2 fatigue, nausea, and vomiting, with the exception of one patient who developed veno-occlusive disease. Although limited by selection bias and short follow up, our study shows durable intra-abdominopelvic control and an improvement in PFS after WAPRT with IMRT, without an effect on OS. Additional larger, prospective investigations evaluating the value and toxicity of WAPRT for DSRCT are warranted.

Tacrolimus-associated sinusoidal obstruction syndrome after living-related liver transplantation

Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease, is manifested by obliterating inflammation of the terminal hepatic veins, characterized by hepatomegaly, right upper quadrant pain, jaundice and ascites, and most often occurs in patients after hematopoietic stem cell transplantation and usually in those who received platinum-based drugs. Cases of SOS development in patients after transplantation of solid organs (lungs, pancreas, liver) are also reported in the world literature. These incidents are rare, and isolated and poorly studied after living-related liver lobe transplantation. The diagnosis is based on clinical signs, imaging techniques (according to ultrasound and radiological methods of examination), histological assessment of liver biopsy. Tacrolimus has been reported to be a causative agent that potentially plays a role in the pathophysiological mechanism of SOS. Aim. To study the relationship between the use of prolonged-release tacrolimus and the development of SOS in patients after living-related liver transplantation. Clinical case. In this article, we present a case of SOS after living-related liver transplantation which was associated with a toxic effect of prolonged-release tacrolimus (“Envarsus”). In a 55-year-old man, after living-related liver transplantation, high blood concentrations of tacrolimus associated with uncontrolled drug intake were detected. When performing a number of laboratory and instrumental methods of examination due to a massive ascites manifestation, the diagnosis of SOS was made. The study was carried out in accordance with the principles of the Helsinki Declaration. The informed consent was obtained from the patient for conducting the studies. Conclusions. By ruling out other possible contributing factors, including an acute rejection crisis, it was concluded that prolonged-release tacrolimus (“Envarsus”) was the cause of SOS.

The Effect of Granulocyte Colony-Stimulating Factor (G-CSF) on Early Complications and Graft-Versus-Host Disease (GVHD) in Allogeneic Stem Cell Transplantation (ASCT) Recipients.

Objectives Granulocyte colony-stimulating factor (G-CSF) is commonly used to accelerate neutrophil recovery after allogeneic stem cell transplantation (ASCT) in most transplant centers. There was no consensus on the optimal use of G-CSF after ASCT. Although we useG-CSF to minimize morbidity and mortality, G-CSF can increase the risk of graft-versus-host disease (GVHD). In our study, we want to show the effect of prophylactic G-CSF on infection frequency, neutrophil and platelet engraftment, the duration of neutropenia, the development of GVHD, hospitalization time, and transplant-related mortality (TRM) after ASCT. Materials and methods One hundred (71 males and 29 females) patients who did not receive G-CSF and 100 (58 males and 42 females) patients who received prophylactic G-CSF were included in the study. Results Age, diagnosis, the time between diagnosis and transplantation, preparation regimen, donor type, and the number of infused cluster of differentiation (CD) 34+ cells were not different in both groups (p>0.05). The frequency of female patients was higher in the group receiving G-CSF. Febrile neutropeniawas more frequent in patients who did not receive G-CSF. Neutrophil engraftment and platelet engraftment were detected longer in patients not receiving G-CSF. The frequency of veno-occlusive disease (VOD) and hyperacute, chronic, andacute GVHD was not different in both groups (p>0.05). One hundred-day TRMand five-year overall survival (OS) were similar in the two groups (p>0.05). Conclusions Our study supports that G-CSF usage does not cause an increase in the frequency of GVHD and has a positive effect on the process by accelerating myeloid engraftment. In light of the data in our study, we can say that the use of G-CSF should be investigated in a randomized controlled clinical trial.

B-054 Potential of Autotaxin in the Early Diagnosis of Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Cell Transplantation

Abstract Background Sinusoidal obstruction syndrome (SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Early intervention leads to a good prognosis, but it is often difficult to differentiate SOS from other hepatobiliary complications. Liver biopsy is the gold standard for diagnosing SOS, but it is difficult to perform invasive testing early in the transplant process, and no specific biomarker for SOS has been established. Autotaxin (ATX) is useful as a liver fibrosis marker, the serum levels of which are elevated by metabolic inhibition of liver sinusoidal endothelial cells. Considering the pathophysiology of SOS, which begins with injury of liver sinusoidal endothelial cells, serum ATX levels may be elevated early in the onset of SOS. Methods A retrospective study was conducted of 247 patients who had received allo-HCT, including 11 patients who developed SOS and met the EBMT criteria (male, 7; female, 4). Of 11 patients with SOS, 9 had pathologically proven SOS. The median time from allo-HCT to SOS diagnosis was 31 days (range, 8–141 days [male], 16–31 days [female]). This cohort included 39 patients with hepatobiliary complications without SOS (total bilirubin &amp;gt; 2 mg/dL; male, 23; female, 16). Serum ATX levels were measured in stored samples before conditioning and at days 1, 3, 5, 7, 14, 28, 60, 90, 180, and 365 after allo-HCT by a two-site enzyme immunoassay with an AIA-2000 analyzer. The area under the receiver operating characteristic (AUROC) of serum ATX levels for the diagnosis of SOS was analyzed. Results We first investigated the variability of serum ATX levels during the allo-HCT period. Serum ATX levels fluctuated as follows: decreased on day 1, increased and peaked on days 7–14, and then decreased again on days 28–60. A variety of factors associated with allo-HCT such as the conditioning regimen and administration of steroids affected serum ATX levels. Serum ATX levels before and after allo-HCT tended to be higher in patients with SOS. In male patients, the AUROCs of serum ATX levels on day 3 after allo-HCT were 0.75 (in all patients; 95% confidence interval [95%CI], 0.49–1.00) and 0.75 (in patients with hepatobiliary complications; 95%CI, 0.48–1.00). In female patients, the AUROCs of serum ATX levels on day 14 after allo-HCT were 0.88 (in all patients; 95%CI, 0.77–0.98) and 0.94 (in patients with hepatobiliary complications; 95%CI, 0.82–1.00). These findings indicated that serum ATX levels before the diagnosis of SOS had a diagnostic capacity. In addition, focusing on severe SOS cases, three of six patients had serum ATX levels above the upper reference limit before conditioning (a total of 18 patients exceeded the upper reference limit in this cohort). Of the remaining three patients, two had elevated post-transplant ATX levels near or above the upper reference limit prior to diagnosis of SOS. Conclusion Although validation by further studies with larger numbers of SOS cases is needed, the serum ATX level may be a useful biomarker for early diagnosis of SOS after allo-HCT.

The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis.

Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.

Pulmonary veno-occlusive disease with vanished pulmonary consolidation.

Pulmonary veno-occlusive disease (PVOD) is an extremely rare cause of pulmonary hypertension. Previously reported computed tomography (CT) findings of PVOD included centrilobular ground-glass opacities, a mosaic pattern, and septal lines; however, chest CT revealing pulmonary consolidation disappearance with repositioning has not been reported.

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug-induced liver injury.

The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.

POSTER: ALL-471 Veno-Occlusive Disease Risk and Other Outcomes in Patients With B-Cell Precursor Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin and Proceeding to Hematopoietic Stem Cell Transplantation

POSTER: ALL-471 Veno-Occlusive Disease Risk and Other Outcomes in Patients With B-Cell Precursor Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin and Proceeding to Hematopoietic Stem Cell Transplantation

ALL-471 Veno-Occlusive Disease Risk and Other Outcomes in Patients With B-Cell Precursor Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin and Proceeding to Hematopoietic Stem Cell Transplantation

ALL-471 Veno-Occlusive Disease Risk and Other Outcomes in Patients With B-Cell Precursor Acute Lymphoblastic Leukemia Receiving Inotuzumab Ozogamicin and Proceeding to Hematopoietic Stem Cell Transplantation