Sinusoidal Obstruction Syndrome/veno-occlusive Disease Research Articles

Utility of the refined EBMT diagnostic and severity criteria 2023 for sinusoidal obstruction syndrome/veno-occlusive disease

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis of SOS/VOD is associated with improved clinical outcomes. In 2023, the refined European Society for Blood and Marrow Transplantation diagnostic and severity criteria (refined EBMT criteria 2023) have been advocated. The revision has introduced new diagnostic categories, namely; probable, clinical, and proven SOS/VOD. In addition, the Sequential Organ Failure Assessment (SOFA) score has been newly incorporated into the SOS/VOD severity grading. We performed a retrospective analysis to evaluate the utility of these criteria. We analyzed 161 cases who underwent allogeneic HSCT. We identified 53 probable, 23 clinical, and 4 proven SOS/VOD cases. Probable SOS/VOD was diagnosed a median of 5.0 days earlier (interquartile range: 2–13 days, P < 0.001) than that of clinical SOS/VOD. The development of probable SOS/VOD alone was associated with a significantly inferior survival proportion compared to non-SOS/VOD (100-day survival, 86.2% vs. 94.3%, P = 0.012). The SOFA score contributed to the prediction of prognosis. Consequently, the refined EBMT criteria 2023 demonstrated the utility of SOS/VOD diagnosis and severity grading. Further investigations and improvements in these criteria are warranted.

Effect of Ursodeoxycholic Acid for Sars-Cov-2 Prevention in Hematological Malignancies: An Observational Real-World Study

Introduction: Disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).After the adjustments and optimizations of Chinese control strategies and policies for COVID-19 on December of 2022, clinical exposure increased rapidly.There are greater concerns for patients with hematological malignancies, particularly those who have undergone hematopoietic stem cell transplantation (HSCT). One promising preventive measure that has recently gained attention is ursodeoxycholic acid (UDCA). This drug is mainly used to treat biliary tract disease and other hepatobiliary disorders, particularly primary biliary cholangitis (Hirschfield GM, et al. Gut 2018); and also has been widely used at a higher dosage to prevent sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) after HSCT in the clinical setting. Recently, Brevini et al. demonstrated that UDCA downregulated ACE2 expression by reducing farnesoid X receptor signaling, resulting in reduced SARS-Cov-2 infection (Brevini T, et al. Nature 2022), indicating that pharmacological prophylaxis using UDCA against COVID-19 in vulnerable groups was feasible, but the clinical data to support this practice is limited. Therefore, we aim to present epidemiological data for Chinese patients with hematological malignancies during this epidemic wave, and investigate the protection effects offered by UDCA against COVID-19 in these patients. Methods: This investigation was a single-center, observational real-world study, and was granted by the ethics committee of the Institute of Hematology &amp; Blood Diseases [No. QTJ2023012-EC-1]. The transplant patients were included in the “NICHE-SKIRT” project (Cao Y, et al. Am J Hematol 2023). Informed consent for the acquisition and the use of patient samples was obtained. Data for hospitalized patients at the Institute of Hematology &amp; Blood Diseases Hospital (Tianjin, China) was reviewed between December 2022 and January 2023. COVID 19 status was assessed using hospital-reported PCR and/or antigen tests for twice a week. We analyzed follow-up records up to 14th February 2023. The primary end-point was the rate of COVID -19 infection. Results: We enrolled 393 patients with a median age of 38 years old. At the cutoff date, 297 patients (75.6%) had confirmed COVID-19 infection (72.5% in the allo-HSCT cohort). Among the 273 evaluable patients, the majority (64.8%) had asymptomatic/mild disease. The severe/critical patients accounted for only 15.8%. Seven hospitalized patients had died from COVID-19 by the last follow-up date. The median period between COVID-19 diagnosis and death was 15 days (range: 2-32 days). Lower proportion of CD3+CD4+T cells associated with more severe COVID-19 clinical spectrum (Asymptomatic/mild [n = 97] moderate [n = 46], adjusted P = 0.001; Asymptomatic/mild vs. severe/critical [n = 25], adjusted P = 0.036). Among these patients, 163 received UDCA (UDCA group) while 230 did not (non-UDCA group). The COVID-19 infection rate was lower in the UDCA group (69.9% vs. 79.6%; P= 0.039). However, patients in the UDCA group had a higher ECOG score and Charlson Comorbidity Index (Table 1), suggesting that they were more likely to have underlying health conditions. To account for this potential bias, we performed PSM, which confirmed that the UDCA group had a significantly lower rate of COVID-19 infection compared to the non-UDCA group (69.0% vs. 81.0%; P = 0.049) in the validated cohort. Univariate logistic regression analysis showed that only UDCA administration was associated with COVID-19 infection (OR: 0.598; P = 0.029). To further investigate the effect of UDCA in specific populations, we carried out an exploratory analysis. Our results suggest that males, patients with a CCI ≥ 2, a history of smoking, and those with acute lymphoblastic leukemia (ALL) may benefit the most from the protective effect of UDCA against COVID-19. Conclusion: This study aimed to investigate the prevalence and clinical outcomes of SARS-CoV-2 infections in Chinese patients with hematologic disorders during the COVID-19 epidemic that began at the end of 2022. Our findings provide support for preclinical studies suggesting that UDCA may have marginal benefit in protecting against COVID-19. However, prospective studies with a higher dose of UDCA need to be performed.

Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.

Molecular Advances in Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) detected in the liver has been considered a severe complication of hematopoietic stem cell transplantation (HSCT). SOS/VOD is characterized by hepatomegaly, right upper quadrant pain, jaundice, and ascites. The severe forms of the disease may result in multi-organ dysfunction (MOD) with a high mortality rate (>80%). The development of SOS/VOD can be rapid and unpredictable. Therefore, early identification and severity assessment is crucial in facilitating prompt diagnosis and timely treatment. Effective treatment and potential prophylaxis with defibrotide highlight the need for characterizing a sub-group of patients at high risk for SOS/VOD. Moreover, antibodies that are conjugated with calicheamicin, gemtuzumab, and inotuzumab ozogamicin, have led to renewed interest in this syndrome. Evaluation and management of serious adverse events associated with gemtuzumab and inotuzumab ozogamicin are recommended. We review hepatic-, transplant- and patient-related risk factors, criteria for diagnosis and grading classification, and SOS/VOD potential biomarkers. Furthermore, we examine pathogenesis, clinical presentation, diagnostic criteria, risk factors, prophylaxis, and treatment of SOS/VOD occurring post HSCT. Moreover, we aim to provide an up-to-date summary of molecular advances in the diagnosis and management of SOS/VOD. We performed a comprehensive review of the literature and examined the recently available data, mostly using the PubMed and Medline search engines for original articles published over the last decade. In the era of precision medicine, our review provides up-to-date knowledge of genetic or sera markers for SOS/VOD with the goal of identifying a subset of high-risk patients.

Endothelial Dysfunction Syndromes after Allogeneic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapy with a curative potential for a variety of malignant and non-malignant diseases. The major limitation of the procedure is the significant morbidity and mortality mainly associated with the development of graft versus host disease (GVHD) as well as with a series of complications related to endothelial injury, such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Endothelial cells (ECs) are key players in the maintenance of vascular homeostasis and during allo-HSCT are confronted by multiple challenges, such as the toxicity from conditioning, the administration of calcineurin inhibitors, the immunosuppression associated infections, and the donor alloreactivity against host tissues. The early diagnosis of endothelial dysfunction syndromes is of paramount importance for the development of effective prophylactic and therapeutic strategies. There is an urgent need for the better understanding of the pathogenetic mechanisms as well as for the identification of novel biomarkers for the early diagnosis of endothelial damage. This review summarizes the current knowledge on the biology of the endothelial dysfunction syndromes after allo-HSCT, along with the respective therapeutic approaches, and discusses the strengths and weaknesses of possible biomarkers of endothelial damage and dysfunction.

Handheld Ultrasound or Conventional Ultrasound Devices in Patients Undergoing HCT: A Validation Study.

Abdominal ultrasound exams play a major role in the diagnosis of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD). The development of portable hand-held ultrasound devices (HHUS) has been shown to facilitate the diagnosis of many diseases, but little data on the value of HHUS in the diagnosis of SOS/VOD are available. We performed a study aimed at validating portable ultrasound (US) devices in the setting of hematopoietic stem cell transplant (HCT). Sixteen evaluable patients undergoing allogeneic HCT were studied using conventional US and HHUS during the first 3 weeks after transplant. The results obtained demonstrate that there is a close correlation between conventional and handheld ultrasound examination in the measurement of the right hepatic lobe (r = 0.912, p &lt; 0.0001), the left hepatic lobe (r = 0.843, p &lt; 0.0001), the portal vein (PV) (r = 0.724, p &lt; 0.0001), and the spleen (r = 0.983, p &lt; 0.0001) based on Pearson's correlation. The same data, analyzed through Lin's concordance correlation coefficient, evidenced a substantial level of agreement in the comparison of the spleen and right hepatic lobe, while a lower grade of agreement in the measurement of the portal vein and left hepatic lobe. Moreover, there was good agreement between results obtained by the two types of ultrasound devices in assessing ascites (p &lt; 0.0001), gallbladder thickening (p &lt; 0.0001), and the direction of PV flow (p &lt; 0.0001). HHUS device allows the study of HokUs-10 parameters with an excellent agreement with conventional US, and may contribute to SOS/VOD diagnosis.

Immune-related generalised oedema – A new category of adverse events with immune checkpoint inhibitors

BackgroundGeneralised oedema was occasionally reported associated with immune checkpoint inhibitors (ICPIs). The purpose of this study is to investigate immune-related generalised oedema (ir-GE) drug related to ICPI, through frequency, clinical and pathological characteristics, and patient's outcome. Patients and methodsObjectives of the study were to report on ir-GE associated with ICPI to define frequency, associated signs and symptoms, pathological characteristics, severity, and response to corticosteroids. To be included in the study, adult patients had to have ir-GE related to ICPI with certain or likely link, without any other known causes of generalised oedema. The study design was observational, over the period 2014–2020, from pharmacovigilance databases in France, including the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry. Calculation of the frequency of ir-GE was restricted to the prospective REISAMIC registry. ResultsOver 6633 screened patients, 20 had ir-GE confirmed drug related to ICPI. Based on the prospective REISAMIC registry, the frequency of ir-GE was 0.19% of ICPI-treated patients (3 cases out of 1598 screened patients). The 20 patients with ir-GE had a median (range) age of 62 (26–81) years, most frequent tumour types were melanoma (n = 9; 45%) and lung cancer (n = 6; 30%). The most frequent localisations of oedema were peripheral (n = 17; 85%), pleural (n = 13; 65%), and peritoneal (n = 10; 50%). Polyserositis was observed in 11 (55%) patients. The median (range) weight gain per patient was 9 (2–30) kg. Associated signs and symptoms met criteria for capillary leak syndrome (n = 4; 20%), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) (n = 3; 15%), or subcutaneous autoimmune syndrome (n = 2; 10%). Corticosteroids were administered to 15 patients; of them, 10 (67%) improved clinically after corticosteroids. Based on CTCAEV5.0, the highest severity of ir-GE was grade ≥4 in 11 (55%) patients and four (20%) patients died due to ir-GE. ConclusionsGeneralised immune system-related oedema is a new category of adverse event with immune checkpoint inhibitors and is often associated with a life-threatening condition. The pathophysiology may in some cases be related to endothelial dysfunctions, such as SOS/VOD or capillary leak syndrome.

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology.

Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease after hematopoietic cell transplantation: historical and current considerations in Korea.

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a rare but severe complication of hematopoietic cell transplantation (HCT) showing high mortality. Multiple risk factors for SOS/VOD were identified, but it is often confused with other hepatic complications due to nonspecific clinical features. Therefore, diagnostic and severity criteria have been revised several times. The European Society of Blood and Marrow Transplantation suggested a new guideline that excludes the standard duration of development within 21 days, emphasizes late-onset SOS/VOD, and suggests the importance of Doppler ultrasonography. The severity criteria were further subdivided for guidance to begin active treatment using defibrotide which was approved in Korea since 2016. In a phase 3 trial, defibrotide had superior 100-day survival, compared to best available treatments (38.2% vs. 25.0%). Although several studies of SOS/VOD in Korean patients have been performed after the implementation of HCT, most involved small number of pediatric patients. Recently, the Korean Society of Blood and Marrow Transplantation investigated the incidence of SOS/VOD in the Korean population, and several influential studies of adult patients were published. Here, we summarize recent issues regarding the mechanism, diagnosis, severity criteria, prevention, and treatments of SOS/VOD in Korean patients, as well as recent analyses of nationwide incidence.

Retrospective Application of Sinusoidal Obstruction Syndrome/Veno-occlusive Disease Diagnostic Criteria in a Pediatric Hematopoietic Stem Cell Transplant Cohort.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) posthematopoietic stem cell transplantation (HSCT) is often diagnosed using the modified Seattle (MS) or European Society for Blood and Marrow Transplantation (EBMT) criteria. We hypothesized that strict application of these criteria could affect the timing of diagnosis and incidence of SOS/VOD. We collected data on 215 transplants performed in 184 patients at a single pediatric hematopoietic stem cell transplantation center, which were divided into 3 cohorts. Clinical diagnosis and treatment of SOS/VOD was documented in 13% of transplants (cohort 1). On retrospective review, 49% of transplant events met either MS and/or EBMT criteria, however, were not diagnosed with SOS/VOD (cohort 2); remaining 38% of transplant events did not meet MS or EBMT criteria and were not diagnosed with SOS/VOD (cohort 3). Day+100 overall survival was significantly inferior for cohort 1 (78%) compared with cohorts 2 or 3 (92% and 95%, P=0.01) with no difference between cohorts 2 and 3 (P=0.5). Patients diagnosed with SOS/VOD >day+13 had worse day+100 overall survival when compared with those diagnosed ≤day13 (64.3% and 100%, respectively, P=0.02). This study highlights the value of careful clinical assessment to guide diagnosis and the need to refine diagnostic criteria for SOS/VOD in children.

Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel.

No biomarker panel has been established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD clinical risk score of the Center for International Blood and Marrow Transplant Research (CIBMTR) to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (P<0.0001), overall survival (OS), and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (Heidelberg, 2010-2015, n=359, P<0.0001) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (P<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk.

Adjuvant recombinant thrombomodulin therapy for hepatopathy induced by vincristine, actinomycin D, and cyclophosphamide in pediatric rhabdomyosarcoma: A case report.

Hepatopathy induced by vincristine, actinomycin D and cyclophosphamide (VAC) is a potentially lethal complication of VAC chemotherapy for pediatric malignancy, which is managed by conventional anticoagulation and liver-supporting treatment alone. We report a case of VAC-induced hepatopathy with coagulopathy and severe inflammation. A 15-year-old male with rhabdomyosarcoma receiving adjuvant chemotherapy presented with refractory thrombocytopenia, followed by abdominal tenderness and non-neutropenic fever. Hepatic dysfunction and coagulopathy subsequently emerged with persistent fever. This condition indicated disseminated intravascular coagulation. A diagnosis of 'very severe' sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was established in accordance with the European Society for Blood and Marrow Transplantation diagnostic criteria for hepatic SOS/VOD in children. Early administration of recombinant thrombomodulin (rTM) (380 U/kg/day) and prednisolone (1.8 mg/kg/day) successfully controlled the condition. Serum concentrations of pro-inflammatory cytokines increased with hepatopathy development but immediately decreased after drug initiation. rTM administration may be promising for the control of inflammatory VAC-induced hepatopathy.

Validation of treatment outcomes according to revised severity criteria from European Society for Blood and Marrow Transplantation (EBMT) for sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD).

Traditional severity criteria of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) were determined retrospectively but found inappropriate for therapeutic decisions. Data of 203 patients with SOS/VOD were collected according to the modified Seattle diagnostic criteria and were analyzed for validation of the revised severity criteria recently proposed from European Society for Blood and Marrow Transplantation (EBMT). According to the traditional severity criteria, none of the patients were mild grade, while 63.1% were moderate and 36.9% were severe grade. However, according to the revised EBMT criteria, the majority of patients (63.1%) were very severe, 18.2% were severe, 12.8% were moderate, and 5.9% were mild grade. The 100-day overall survival (OS) of mild, moderate, severe and very severe groups was 83.3, 84.3, 94.6, and 58.6%, respectively. Very severe SOS/VOD showed a significantly lower OS than the others (58.6 vs. 89.3%, p < 0.0001). The 100-day transplantation-related mortality was 25.2% in the entire cohort; 8.3% in mild, 8.0% in moderate, 2.7% in severe, and 36.7% in very severe SOS/VOD (p < 0.0001). The very severe grade newly classified by the revised EBMT criteria accounted for the majority of SOS/VOD associated with worse 100-day OS. Therefore, intervention should be applied at the latest for moderate to severe SOS/VOD before deterioration.

Sinusoidal obstruction syndrome/veno-occlusive disease after high-dose intravenous busulfan/melphalan conditioning therapy in high-risk Ewing Sarcoma.

This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p = 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p = 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.

Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease

Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUCmax) rather than with the average cumulative AUC (AUCavg). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L—higher than that achieved by current standard busulfan regimens—was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.