Veno-occlusive Research Articles

Prognostic Factors Associated With Increased Mortality in Pediatric Veno-Occlusive Disease Following Hematopoietic Cell Transplantation.

Hepatic veno-occlusive disease (VOD) is a life-threatening complication of hematopoietic cell transplantation (HCT) and is categorized as a transplant-related, systemic endothelial disease. Severe VOD can lead to multi-organ dysfunction (MOF) and is associated with a high mortality rate. To evaluate the incidence of VOD in children after HCT and analyze the outcomes and risk factors associated with increased mortality. A retrospective cohort study of 1243 children with malignant and non-malignant diseases who underwent HCT at two large pediatric centers over 20 years. One hundred one patients (8%) developed VOD post HCT. Most patients developed VOD post allogeneic HCT (76%) versus autologous (24%). The incidence of VOD was twice as high in children with malignant diseases compared to non-malignant (68%vs. 32%). A much higher incidence of VOD occurred in patients after a busulfan-based regimen versus total body irradiation-based and treosulfan-based, 73%, 18%, and 1%, respectively. The 100-day survival rate of HCT patients with VOD was 69%. The overall survival rate of the entire group was 50%, showing improvement over the span of the study years, from 40% between 2000 and 2009 to 63% between 2010 and 2021 (p = 0.022). Factors associated with increased mortality included infections before transplant (p = 0.013), conditioning regimen (p = 0.01), abnormal liver function (p = 0.019), presence of ascites (p = 0.008), MOF (p < 0.001), and the need for admission to a pediatric intensive care unit (p < 0.001). There was no significant difference in survival rates between children treated with defibrotide alone or with those treated with defibrotide and steroids (61% and 65%, respectively; p = 0.685). Severe VOD in pediatric patients following HCT remains a life-threatening complication with a high mortality rate. Early diagnosis and treatment with defibrotide are critical for managing this condition. In our cohort, the addition of steroids to defibrotide was not associated with improved outcomes.

Clinical benefits of partial splenic embolization for cancer patients.

Partial splenic embolization (PSE) has developed as an alternative to surgical splenectomy, mainly to improve hypersplenism and esophagogastric varices in cirrhotic patients. We proposed the novel concept that splenic infarction volume, rather than the splenic infarction ratio, is essential for patients receiving PSE. A splenic infarction volume between 388 and 540mL is suitable for a sufficient increase in platelet count and less severe PSE-related complications. When restricted to patients with massive splenomegaly >700mL, the noninfarcted volume of the spleen plays an important role in increasing platelet counts. Based on the splenic volume concept, PSE or laparoscopic splenectomy should be selected. Partial splenic embolization is effective for cancer patients with hypersplenism. Hypersplenism can occur due to portal vein congestion by thrombosis or tumor thrombosis, and hepatic sinusoidal obstruction syndrome after oxaliplatin-including chemotherapy other than liver cirrhosis. Therefore, PSE has been emphasized as a pretreatment intervention for invasive treatments for cancer patients and is applied synchronously with systemic chemotherapy or chemoembolization for patients with liver malignancies. It was reported that additional PSE on chemoembolization can prolong progression-free survival for patients with hepatocellular carcinoma. Moreover, PSE can improve liver function and fibrosis, promote liver regeneration, and activate host immunity. Partial splenic embolization can result in thrombocytosis (<200×109/L), but this platelet count is unlikely to promote cancer progression. Partial splenic embolization can improve hypersplenism caused by various factors related to the patient's comorbidity and cancer treatment. Our splenic volume concept helps identify appropriate treatment procedures. A proper understanding of PSE and its dissemination is strongly required.

COMPARABLE OUTCOMES AFTER BUSULFAN- OR TREOSULFAN-BASED CONDITIONING FOR ALLO-HSCT IN CHILDREN WITH ALL – RESULTS OF FORUM

The superiority of TBI-based versus chemotherapy-conditioning for allo-HSCT in children with ALL has been established in the international, prospective phase-III FORUM study (#NCT01949129), randomizing 417 patients ≤ 18 years at diagnosis (4-21 years at HSCT) in CR, transplanted from HLA-matched sibling or unrelated donors. Due to the unavailability of TBI in some regions and to accommodate individual contraindications, this study reports the pre-specified comparison of outcomes of patients receiving busulfan-based (BU) or treosulfan-based (TREO) regimens from 2013 to 2018. 180 and 128 patients (median age 9.9 years) received BU/THIO/FLU or TREO/THIO/FLU, respectively. Data were analysed as of 02/2023, with a median follow-up of 4.2 years (range 0.3-9.1). Three-year overall survival was 0.71 (0.64-0.77) (BU/THIO/FLU) and 0.72 (0.63-0.79) (TREO/THIO/FLU), event-free survival was 0.60 (0.53-0.67) (BU/THIO/FLU) and 0.55 (0.46-0.63) (TREO/THIO/FLU), with both p = NS. The 3-year cumulative incidence of relapse (0.31 (0.25-0.38) BU, 0.36 (0.27-0.44) TREO, p = 0.779) and non-relapse mortality (0.08 (0.05-0.13) BU, 0.09 (0.05-0.15) TREO, p = 0.831) were comparable (p = NS). One case of fatal veno-occlusive disease occurred in each group. No significant differences in acute and chronic GvHD or GvHD-free and relapse-free survival (0.48 (0.41-0.55) BU, 0.45 (0.37-0.54) TREO, p = 0.89) were recorded. Outcomes for CR1 or CR2 patients were similar irrespective of the regimen used. In conclusion, BU/THIO/FLU or TREO/THIO/FLU regimens can be an alternative to TBI for ALL patients > 4 years with contraindications or lack of access to TBI.

Long-term follow-up of a phase 2 study of all-trans retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin in acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combinations have produced excellent outcomes in patients with standard-risk acute promyelocytic leukemia (APL). Herein, the authors update their long-term results with the regimen of ATO-ATRA and gemtuzumab ozogamicin (GO) in standard-risk and high-risk APL. This was a phase 2 trial of patients with newly diagnosed APL. Induction comprised ATRA 45 mg/m2 and ATO 0.15 mg/kg daily. GO 6-9 mg/m2 was added for high-risk patients and for standard-risk patients who developed leukocytosis >10×109/L. Consolidation consisted of four courses of ATO-ATRA, with GO for patients who had PML::RARA persistence. One hundred forty-six patients (median age, 53.0 years; range, 19.3-83.9 years) were treated, including 106 patients (72.6%) with standard-risk APL and 40 (27.4%) with high-risk APL. GO was administered to 68 standard-risk patients (64.2%) for leukocytosis. The complete remission rate was 93.8% (95% confidence interval [CI], 92.2%-98.5%). Negative measurable residual disease status was achieved in 97.1% of patients who attained complete remission. At a median follow-up of 61.8 months (95% CI, 4.7-128.4 months), the 5-year event-free survival, disease-free survival, and overall survival rates were 92.4% (95% CI, 87.9%-97.1%), 93.6% (95% CI, 89.5%-97.8%), and 93.1% (95% CI, 88.9%-97.7%), respectively. Induction mortality was 2.7%. The most common severe adverse events were elevated transaminases in 41.0% of patients and infection in 13.7%. There were no cases of veno-occlusive disease. The combination of ATO-ATRA and GO was curative in 94% of patients who had APL with a favorable safety profile (ClinicalTrials.gov identifier NCT01409161).

Adaptive dosing of high-dose busulfan in real-world adult patients undergoing haematopoietic cell transplant conditioning.

To evaluate the effectiveness of a Bayesian adaptive dosing strategy in achieving target busulfan exposure in adult patients undergoing haematopoietic cell transplantation (HCT). This study included 71 adult patients scheduled to receive high-dose busulfan. Busulfan was administered to achieve a cumulative area under the curve (AUC) of 66.0mg/L/h (16 000 μM/min), 82.60 mg/L/h (20 000 μM/min) or 87.6mg/L/h (21 200 μM/min) depending on the regimen. Individual pharmacokinetic (PK) parameters of busulfan were estimated from three blood samples using a one-compartment model and Bayesian estimation after the first standard dose. Individual PK parameters were used to adjust subsequent doses to achieve the target exposure. All patients had their dose adjusted after the first dose administration. The final deviation from the target AUC was significantly improved compared to the initial deviation after standard mg/kg dosing (mean absolute deviation 19.5% vs 11.7%, P< .01). In addition, the proportion of patients with marked deviation from target exposure (ie, >25%) decreased significantly from 31% after standard dosing to 10% after PK-guided dosing (P< .01). Canonical busulfan-related toxicity, specifically veno-occlusive disease, was observed in 5% of patients who achieved successful PK-guided dosing. In contrast, one-third of patients with off-target exposure with poor dosing experienced toxicity. The Bayesian adaptive dosing strategy significantly improves the accuracy of achieving the target busulfan AUC in patients undergoing HCT. This approach not only reduces marked deviations from target exposure, but also reduces the incidence of busulfan-related toxicity, thereby maintaining a favourable toxicity/efficacy ratio.

Rifaximin curative effect and mechanism on monocrotaline-induced hepatic sinusoidal obstruction syndrome in mice

Objective: To investigate the curative effect and possible mechanism of rifaximin treatment on monocrotaline-induced hepatic sinusoidal obstruction syndrome (HSOS) in mice. Methods: Twenty-four male C57BL/6J mice were divided into three groups and treated with solvent control, monocrotaline, and rifaximin, respectively. The histopathological changes of the liver and intestine were observed by hematoxylin-eosin staining. The differences were compared in liver parameters, serum liver enzymes, inflammatory factors, apoptotic factors, gut microbiota, and gut tight junction proteins among three groups of mice. The inter-group comparison was conducted using a t-test and one-way analysis of variance. Results: The rifaximin-treated group had significantly improved liver histopathology. The serological levels of alanine aminotransferase and aspartate aminotransferase were (559.04±89.42) U/L and (676.90±106.25) U/L, respectively, which were significantly lower than those in the PA-HSOS model group [(846.05±148.46) U/L and (953.87±58.10) U/L, P<0.05], and were accompanied by lower levels of apoptotic cells and inflammatory factors. Additionally, the rifaximin-treated mice group gut microbiota had higher diversity compared with the PA-HSOS group (P<0.05), and the Shannon index was 7.77±0.10 and 7.16±0.07, respectively, indicating apparent differences in microbiota among different groups. The abundance of Firmicutes in the rifaximin group was 39.58%±0.56%, which was significantly higher than that in the model group (24.25%±0.64%, P<0.05), while the abundance of Bacteroidetes was 54.7%±0.41%, which was significantly lower than that in the model group (70.92%±0.49%, P<0.05). Simultaneously, the expressions of gut tight junction proteins ZO-1 and Occludin showed an upward trend and validated transcription levels compared to the model group following rifaximin intervention (P<0.05). Conclusion: Rifaximin can alleviate monocrotaline-induced hepatic sinusoidal obstruction syndrome in mice, and its mechanism may be via gut microbiota regulation, which in turn plays a role in improving intestinal barrier function.

Application of artificial intelligence and machine learning for risk stratification acute kidney injury among hematopoietic stem cell transplantation patients: PCRRTICONIC AI Initiative Group Meeting Proceedings.

Acute kidney injury (AKI) is a frequent, severe complication of hematopoietic stem cell transplantation (HSCT) and is associated with an increased risk of morbidity and mortality. Recent advances in artificial intelligence (AI) and machine learning (ML) have showcased their proficiency in predicting AKI, projecting disease progression, and accurately identifying underlying etiologies. This review examines the central aspects of AKI post-HSCT, veno-occlusive disease (VOD) in HSCT recipients, discusses present-day applications of artificial intelligence in AKI, and introduces a proposed ML framework for the early detection of AKI risk.

The benefits of prophylactic defibrotide: Are the tides turning?

Veno-occlusive disease (VOD) is a life-threatening endotheliopathy that can occur after stem cell transplant (SCT). Numerous risk factors contribute to the development of VOD during SCT, and the role of prophylactic defibrotide (DF) in mitigating these risks remains unclear. We compare not only the incidence of VOD development, but also the severity of VOD and survival outcomes between patients who did and did not develop VOD and did or did not receive prophylactic DF. In this single-center retrospective study of 58 pediatric SCT patients from 2008 to 2022, we compare the demographics, risk profiles, and outcomes within three cohorts: Group 1: prophylactic DF and no VOD (n=5), Group 2: prophylactic DF and development of VOD (n=6), and Group 3: treatment DF for patients who developed VOD (n=47). Patients with VOD who did not receive prophylactic DF had higher severity classification of disease at onset (very severe 80.9% vs. 66.7%, p=.592) and at maximum severity (very severe 89.4% vs. 83.3%, p=.532), as opposed to mild, moderate, or severe categorization compared to those who did not receive prophylactic DF. Patients who developed VOD and did not receive prophylactic DF had a lower 1-year survival probability compared to those who received prophylactic DF and still developed VOD (51.1% vs. 75% alive at 1year, excluding the two subjects without adequate follow-up time, p=.266). Although, not statistically significant in our small retrospective study, there is potential overall survival and decreased VOD severity benefits of prophylactic DF.

Potential therapeutic uses of L-citrulline beyond genetic urea cycle disorders.

L-citrulline (referred to hereafter as citrulline), a non-essential amino acid and an intermediate in the urea cycle, is widely recognized for its role in managing genetic urea cycle disorders (UCDs). Recent studies, however, suggest that citrulline's therapeutic potential extends beyond UCDs, particularly in conditions associated with nitric oxide (NO) deficiency, endothelial dysfunction, and oxidative stress. This review explores citrulline's emerging applications in sickle cell disease (SCD), post-operative pulmonary hypertension (PH), hepatic veno-occlusive disease (HVOD), and bronchopulmonary dysplasia (BPD), as well as its speculative use in asthma and acute respiratory distress syndrome (ARDS). In SCD, citrulline may restore NO bioavailability, potentially reducing the incidence and severity of vaso-occlusive crises and preventing complications like pulmonary hypertension. In the context of post-operative PH, citrulline's capacity to enhance NO production can improve pulmonary vascular resistance, decrease right ventricular strain, and reduce the need for mechanical ventilation. Citrulline's protective effects on endothelial function and its ability to mitigate oxidative stress offer promising adjunctive therapy for HVOD, particularly in patients undergoing bone marrow transplantation. In BPD, citrulline could promote alveolar development, reduce inflammation, and improve long-term respiratory outcomes. Despite these promising findings, further research is necessary to determine optimal dosing strategies and to evaluate long-term efficacy and safety. The potential role of citrulline in modulating NO production in conditions like asthma and ARDS also warrants further investigation. This review underscores the versatile therapeutic potential of citrulline and highlights the need for continued research into its applications across various conditions associated with NO deficiency and endothelial dysfunction.

Case report: A finding of PVOD and PAH in first degree relatives suggests shared heritable risk and overlapping features of both pulmonary vascular diseases.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first-degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD.

Elevation of NT-proBNP Levels in Pediatric and Young Adult Hematopoietic Stem Cell Transplant Patients with Endotheliopathy.

Hematopoietic stem cell transplantation (HSCT) in pediatric and young adult (YA) patients can lead to endotheliopathy, such as thrombotic microangiopathy (TMA), sinusoidal obstruction syndrome (SOS), and diffuse alveolar hemorrhage (DAH). Natriuretic peptides have been studied as markers of endotheliopathy and critical illness. We hypothesized that an elevation in NT-proBNP was associated with the development of endotheliopathy (DAH, SOS, or TMA) in the first 100 days following HSCT in pediatric and YA patients. IRB-exempt status was obtained. This retrospective case-control study reviewed HSCT at our institution from 2016 to 2020. Cases were selected based on an endotheliopathy diagnosis in the first 100 days after HSCT. Cases were matched with controls. Baseline and near-event NT-proBNP levels were compared between cases and matched controls. The effect of NT-proBNP levels on developing endotheliopathy was estimated using conditional logistic regression. Sixty-two patients were included (31 cases, 31 controls). Near-event NT-proBNP was significantly higher in cases compared to controls (median: 473 vs. 187 pg/mL, p = 0.03, Wilcoxon rank-sum test), in contrast to comparison in baseline NT-proBNP (median: 86 vs. 86 pg/mL, p = 0.51). After adjusting for covariates, an association between near-event NT-proBNP and odds of developing endotheliopathy did not achieve statistical significance. However, trends from most common transplant indications suggested an association between an elevated near-event NT-proBNP level and endotheliopathy, particularly in acute lymphoblastic leukemia (ALL) patients. NT-proBNP should be studied further as a biomarker for endotheliopathy in pediatric and YA patients undergoing HSCT. This may be particularly relevant for patients undergoing HSCT for ALL.

Safety and feasibility of umbilical cord blood transplantation in children with neuronal ceroid lipofuscinosis: a retrospective study.

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.

Idiopathic pulmonary hypertension in an adult with patent foramen ovale

The article is devoted to the clinical case of combined idiopathic pulmonary hypertension with an open foramen ovale of the atrial septum in a young man of 21 years old with progressive decrease in lung ventilation function. The relationship of pulmonary arterial hypertension with an open foramen ovale of the atrial septum is nearly not described in the literature, as it is rarely found in clinical practice. According to the classification, pulmonary hypertension is divided into idiopathic (primary), secondary and pulmonary hypertension caused by other causes. In the pathogenesis of any PAH, an important role belongs to a complex of vascular changes. Verification of vascular changes is carried out histologically. Variants of idiopathic pulmonary hypertension are plexiform and thrombotic arteriopathy, veno-occlusive disease, capillary hemangiomatosis. An open foramen ovale as a structural anomaly of the adult heart (a vestige of embryonic blood circulation) causes a variety of hemodynamic disorders that can affect the pathogenesis of pulmonary hypertension. Because of this, preclinical observation of a combination of plexiform and thrombotic arteriopathy with a patent foramen ovale of the interatrial septum in a young man of 21 years old and an attempt to determine the role of an open oval window in the progression of pulmonary hypertension and its effect on treatment is of interest. The diagnosis of idiopathic pulmonary hypertension was made based on the clinical picture, laboratory parameters, echocardiography and histological examination of pulmonary vessels. The article discusses the importance of a patent foramen ovale in the pathogenesis of idiopathic pulmonary hypertension.

Genetic testing in pulmonary hypertension in adults and children

Abstract Pathogenic genetic variants have been found in patients with different forms of pulmonary arterial hypertension (PAH). Our aim was to define the genetic background of patients with idiopathic PAH (IPAH), heritable PAH (HPAH), pulmonary veno-occlusive disease (PVOD) and PAH associated with congenital heart disease (PAH-CHD); both in adult and pediatric age. REHAP and REHIPED are Spanish, voluntary, multicenter registries that include patients with PAH. REHAP started in 2007 and includes patients over 18 years of age. REHIPED started in 2009 and collects patients between 2 months and 18 years of age. Patients with IPAH, HPAH, PVOD and PAH-CHD who have undergone a genetic testing were included. 413 adults and 122 children were analyzed. From 2011, Sanger sequencing and multiplex ligation-dependent probe amplification were used to detect genetic variants in the BMPR2, TBX4, and KCNK3 genes. Since 2014, a next generation sequencing (NGS) panel of 21 genes was applied. In 2017 this panel was expanded to cover 35 genes, and in 2019, it was expanded to 37 genes. Since 2020, whole-exome sequencing has been applied for the previously followed-up patients without known pathogenic/likely pathogenic (P/LP) genetic variants, and for each incident case. There was a statistically significant difference (p 0.031) in the etiologies among adults and children. The etiologies in adults were 242 (59%) IPAH, 25 (6%) HPAH, 83 (20%) PAH-CHD, 63 (15%) PVOD. The etiologies in children were 66 (54%) IPAH, 8 (7%) HPAH, 38 (31%) PAH-CHD, and 10 (8%) PVOD. The genetic testing had a variant in 121 (29%) adults (56% pathogenic, 9% likely pathogenic, 32% VUS) and 63 (52%) children (65% pathogenic, 16% LP, 19% VUS) (adults vs children p &amp;lt; 0.001). BMPR2 was the most frequent variant in both populations, followed by EIF2AK4. Patients with HAPH and PVOD are more likely to have a genetic variant, while PAH-CHD are the less likely to have one; both in adults and children (p&amp;lt;0.001). The etiology was reclassified after the genetic testing in 13% adults and 19% children (p 0.08); including 6 adults and 4 children initially classified as IPAH and then diagnosed of PVOD when a P/LP variant was found in EIF2AK4. Also, 5 children were initially diagnosed as IPAH and then reclassified as multisystemic disorders (4 NFU1 and 1 MECP2) In conclusion, a significant number of patients with PAH have a variant in genetic testing, especially if they are diagnosed in pediatric age. BMPR2 is the most frequent variant in our cohort, followed by EIF2AK4. Knowing the genetic background of our patients enables a better classification and understanding of the disease. This is especially important in patients initially diagnosed of PAHI who are then classified as PVOD. Also, knowing the genetic background may help develop new treatments in the future.

Fluid Overload in Children Following Hematopoietic Cell Transplant: A Comprehensive Review.

Fluid overload significantly increases morbidity and mortality in critically ill children. Following hematopoietic cell transplant (HCT), children are at a high risk of fluid accumulation due to essential increased fluid intake for nutrition, blood products, and antimicrobials. In addition, many complications predispose these children to capillary leak and fluid overload (FO), such as sinusoidal obstruction syndrome, engraftment syndrome, sepsis, and acute kidney injury (AKI). FO > 10% occurs in nearly half of children following HCT and is associated with a lower PICU survival rate. In addition, in children with acute respiratory failure post HCT, each 1% increase in cumulative fluid balance on d 3 increases the odds of PICU mortality by 3%. Furthermore, FO worsens AKI. Tools such as the renal angina index and urinary biomarkers such as neutrophil gelatinase-associated lipocalin can help identify patients at risk of AKI and FO. Early detection, prevention, and intervention are crucial to improving outcomes in this population. Management strategies include fluid restriction, diuretics, and continuous kidney replacement therapy (CKRT) when FO exceeds 10% and other measures have failed.

Inotuzumab Ozogamicin and Low-Intensity Chemotherapy in Older Patients With Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22+ Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m2 day 1, 0.5 mg/m2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10-4. Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10-4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. Our results support InO's use in first-line regimens for older patients with CD22+ Ph- BCP-ALL.

Refractory Thrombocytopenia is the Earliest Diagnostic Criterion for Sinusoidal Obstruction Syndrome in Children.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), whose diagnostic criteria changed over time to achieve a timelier diagnosis. Recently, pediatric-specific criteria presented by the European Society for Blood and Marrow Transplantation (pEBMT) incorporated transfusion-refractory thrombocytopenia (RT) as an early indicator of SOS in children. However, a comparison of all individual diagnostic parameters belonging to pEBMT and former SOS diagnostic criteria has never been performed. This retrospective study conducted at a pediatric tertiary care hospital analyzed all pediatric HSCT cases diagnosed with SOS among 170 children transplanted from 2009 to 2023. Eleven patients developed SOS during this period (incidence: 11/170, 6.5%). pEBMT, Seattle, and Baltimore criteria were retrospectively applied to the 11 cases and compared, showing that RT was the earliest fulfilled parameter (median onset: 6d post-HSCT). pEBMT and Seattle criteria identified 11/11 SOS cases, with pEBMT leading to an earlier diagnosis. RT typically manifested before diagnosis, with significantly higher platelet transfusion requirements before diagnosis than after. RT is the earliest satisfied criterion in pediatric SOS and typically occurs in the initial stages of the disease before diagnosis. Further research is needed to identify additional early indicators of pediatric SOS.

Total Marrow and Lymphoid Irradiation (TMLI) Is Associated with Good Early Outcomes in Patients Undergoing Matched Sibling Donor and Haplo-identical Transplants for Acute Lymphoblastic Leukemia

Total marrow and lymphoid irradiation [TMLI] can deliver higher doses of irradiation without increased toxicity. This study evaluated TMLI and Cyclophosphamide in patients undergoing stem cell transplantation for acute lymphoblastic leukemia [ALL] . Fifty-eight patients underwent matched related, unrelated or haplo-identical donor transplant using TMLI. The graft source was PBSC in all while GVHD prophylaxis consisted of cyclosporine with methotrexate or post-transplant cyclophosphamide. The median age was 20 years [range: 5 - 49] and included 20 children. Engraftment occurred in 56 [96.5%] at median of 15 days [range: 12 - 23] with 2 early deaths. Sinusoidal obstruction syndrome [SOS] was seen in 10 patients while hemorrhagic cystitis and cardiac dysfunction occurred in 2 patients each. Cumulative incidence of grade II - IV acute GVHD was 23.6% while grade III - IV was 10.9%. Chronic GVHD was seen in 46.9% while relapse was seen in 10 patients [17.2%]. The 2-year overall survival [OS] was 65.9 ± 6.8% and 2-year disease free survival [DFS] was 59 ± 6.7%. Outcomes were compared with 52 patients who received either Cy/TBI or Flu/Bu4 for conditioning during the same period. Engraftment rates and time to engraftment were similar. Acute GVHD [p = 0.002], regimen related toxicity [p = 0.043] and Day 100 non-relapse mortality [p = 0.020] were significantly lower with TMLI. TMLI was associated with better OS [p = 0.004] and DFS [p = 0.005] for haplo-identical transplants. Better DFS was seen with TMLI in patients with high-risk disease [p = 0.007] and disease status > CR1 [p = 0.041]. The use of TMLI and cyclophosphamide is associated with good outcomes in patients undergoing HSCT for ALL especially with haploidentical stem cell transplants.

S4475 Veno-Occlusive Disease as a Rare Complication of Ipilimumab and Nivolumab

S4475 Veno-Occlusive Disease as a Rare Complication of Ipilimumab and Nivolumab

GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss-of-function mutations.