Severe Sinusoidal Obstruction Syndrome Research Articles

Diagnosing and Grading of Sinusoidal Obstructive Syndrome after Hematopoietic Stem Cell Transplant of Children, Adolescent and Young Adults treated in a Pediatric Institution with Pediatric Protocols

Sinusoidal obstructive syndrome (SOS), or veno-occlusive disease, of the liver has been recognized as a complex, life-threatening complication in the posthematopoietic stem cell transplant (HSCT) setting. The diagnostic criteria for SOS have evolved over the last several decades with a greater understanding of the underlying pathophysiology, with 2 recent diagnostic criteria introduced in 2018 (European Society of Bone Marrow Transplant [EBMT] criteria) and 2020 (Cairo criteria). We sought out to evaluate the performance characteristics in diagnosing and grading SOS in pediatric patients of the 4 different diagnostic criteria (Baltimore, Modified Seattle, EBMT, and Cairo) and severity grading systems (defined by the EBMT and Cairo criteria). Retrospective chart review of children, adolescent, and young adults who underwent conditioned autologous and allogeneic HSCT between 2017 and 2021 at a single pediatric institution. A total of 250 consecutive patients underwent at least 1 HSCT at UCSF Benioff Children's Hospital San Francisco for a total of 307 HSCT. The day 100 cumulative incidence of SOS was 12.1%, 21.1%, 28.4%, and 28.4% per the Baltimore, Modified Seattle, EBMT, and Cairo criteria, respectively (P < .001). We found that patients diagnosed with grade ≥4 SOS per the Cairo criteria were more likely to be admitted to the Pediatric Intensive Care Unit (92% versus 58%, P = .035) and intubated (85% versus 32%, P = .002) than those diagnosed with grade ≥4 per EBMT criteria. Age <3 years-old (HR 1.76, 95% [1.04 to 2.98], P = .036), an abnormal body mass index (HR 1.69, 95% [1.06 to 2.68], P = .027), and high-risk patients per our institutional guidelines (HR 1.68, 95% [1.02 to 2.76], P = .041) were significantly associated with SOS per the Cairo criteria. We demonstrate that age <3 years, abnormal body mass index, and other high-risk criteria associate strongly with subsequent SOS development. Patients with moderate to severe SOS based on Cairo severity grading system may correlate better with clinical course based on ICU admissions and intubations when compared to the EBMT severity grading system.

Retrospective analysis of veno-occlusive disease/sinusoidal obstruction syndrome in paediatric patients undergoing hematopoietic cell transplantation -a multicentre study

BackgroundSinusoidal obstructive syndrome is a potentially fatal complication following hematopoietic cell transplantation, high-intensity chemotherapies and increasingly seen with calicheamicin based leukaemia therapies. Paediatric specific European Society for Blood and Marrow Transplantation (pEBMT) diagnostic criteria have demonstrated benefit in single centre studies compared to historic criteria. Yet, the extent to which they have been universally implemented remains unclear. MethodsWe conducted a retrospective multi-centre study to examine the potential impact of the Baltimore, modified Seattle and pEBMT criteria on the incidence, severity, and outcomes of sinusoidal obstructive syndrome among paediatric hematopoietic cell transplantation patients. FindingsThe incidence of sinusoidal obstructive syndrome in this cohort (n=488) was higher by pEBMT (21·5%) versus historic modified Seattle (15·6%) and Baltimore (7·0%) criteria (p<0·001). Application of pEBMT criteria identified 44 patients who were not previously diagnosed with sinusoidal obstructive syndrome. Overall, 70·5% of all patients diagnosed with sinusoidal obstructive syndrome ultimately developed severe/very severe disease and almost half of diagnosed patients required critical care support. Overall survival was significantly lower in patients who were diagnosed with sinusoidal obstructive syndrome versus those who were not. InterpretationTaken together, pEBMT criteria may be a sensitive method for prompter diagnosis of patients who subsequently develop severe/very severe sinusoidal obstructive syndrome. To our knowledge, this is the first multi-centre study in the United States (US) to demonstrate that pEBMT guidelines are associated with earlier detection of sinusoidal obstructive syndrome. Since early initiation of definitive treatment for sinusoidal obstructive syndrome has been associated with improved survival in paediatric patients and implementation of pEBMT criteria appears feasible in the US, universal adoption should facilitate prompter diagnosis and lead to improved outcomes of children with sinusoidal obstructive syndrome.Funding: None

Outcomes and Toxicities after Allogeneic Hematopoietic Cell Transplant for Remission Consolidation or Relapse Therapy after CD19 Chimeric Antigen Receptor T Cell Therapy in Children and Young Adults with Acute Lymphoblastic Leukemia

Introduction: CD19-directed chimeric antigen receptor-modified T cells (CART19) induce remarkably high remission rates in relapsed/refractory B-lymphoblastic leukemia (B-ALL), but 50% of children and young adults experience subsequent relapse. Allogeneic hematopoietic cell transplant (HCT) is frequently used after CART19, either for relapse prevention or to treat post-CART19 relapse. However, there is a paucity of safety and outcome data after HCT in this population. This gap is especially relevant because patients often undergo HCT post-CART19 later in their relapsed disease courses (i.e., CR3 or later) than historical patients undergoing HCT for B-ALL. Methods: We conducted a retrospective review of patients aged &amp;lt;30 years with B-ALL who underwent a first HCT for remission consolidation (preemptive cohort) or relapse therapy (relapse cohort) after CART19 at the Children's Hospital of Philadelphia between 2014-2022. The primary outcome was disease-free survival (DFS) from HCT, stratified by cohort. Secondary outcomes included overall survival (OS) and frequency of transplant-related mortality (TRM), graft-versus-host disease (GVHD), sinusoidal obstruction syndrome (SOS), and IgG replacement dependence. Results: The analysis included 41 patients: 19 in the preemptive cohort (pre-planned consolidative HCT, n=5; early loss of B cell aplasia, n=13; positive next-generation sequencing minimal residual disease [MRD], n=1) and 22 in the relapse cohort (morphologic relapse, n=18; detectable flow-based MRD, n=4) (Table 1). With one exception of a patient treated with a CD19/CD28-based product, all patients received investigational or commercial CD19/4-1BB CAR T cells. Median time from CART19 infusion to HCT was 5 months (range, 2-10) for the preemptive and 14 months (range, 5-40) for the relapse cohort. Between CART19 and HCT, 6/19 (32%) preemptive patients received bridging therapy (chemotherapy, n=3; blinatumomab, n=1; inotuzumab, n=2). In the relapse cohort, salvage therapies that successfully induced HCT-acceptable remissions (MRD &amp;lt;0.1%) included inotuzumab (n=11, 50%), cytotoxic chemotherapy (n=5, 23%), blinatumomab (n=2, 9%), CART22 (n=2, 9%), CART19 reinfusion (n=1, 5%), or pembrolizumab (n=1, 5%). At HCT, the majority (79%) of the preemptive cohort was in CR1 or CR2; whereas, the majority (77%) of the relapse cohort was in ≥CR3. All patients received myeloablative conditioning, either total body irradiation-based (n=39) or clofarabine-based (n=2), and 59% received a T cell depleted graft. In the preemptive cohort, with a median follow-up of 36 months, DFS at 1, 2, and 3 years after HCT was 100%, 93% (95% CI, 61-99), and 85% (95% CI, 51-96), respectively (Fig. 1). OS was 100% through 3 years. In the relapse cohort, with a median follow-up of 34 months, DFS was 58% (95% CI, 35-76) and OS was 68% (95% CI, 44-83) by 1 year, and remained the same through 3 years (Fig. 1). When stratified by CD19 immunophenotype at post-CART19 relapse, DFS by 1 year was 67% (95% CI, 34-86) for CD19-positive and 44% (95% CI, 14-72) for CD19-negative disease (p=0.235). Frequently observed toxicities included GVHD and SOS. In the preemptive cohort, 10 patients (53%) developed acute GVHD (3 [16%] were grade ≥3) and 7 (37%) developed chronic GVHD. In the relapse cohort, 11 patients (50%) developed acute GVHD (4 [18%] were grade ≥3) and 6 (27%) developed chronic GVHD. SOS was observed in 1 (5%) preemptive patient and 7 (32%) relapse patients. Four patients (18%), all in the relapse cohort, died of TRM between days +47-65 after HCT. Three had multisystem organ failure in the setting of multiple complications, including severe SOS. One had respiratory failure due to presumed adenoviral pneumonitis. At 1 year post-HCT, 9/18 (50%) preemptive and 8/12 (67%) relapse patients who remained event-free still required IgG replacement. Conclusion: In children receiving their first HCT for post-CART19 remission consolidation, DFS and OS were exceptionally good, without any observed TRM and with comparable rates of GVHD and other major complications to general pediatric HCT populations. For children who were able to undergo HCT following a post-CART19 relapse, of which 77% were in CR3 or later, DFS and OS were also favorable. The majority became long term survivors and all events occurred within 1 year after HCT. However, higher rates of SOS (likely associated with pre-HCT inotuzumab) and TRM were also observed in this cohort.

Analysis of Laboratory Parameters before the Occurrence of Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients after Hematopoietic Stem Cell Transplantation

Introduction: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease of the liver, is a serious complication following hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment with defibrotide can improve patient outcome. The pathogenesis is not fully understood, but it is obvious that some laboratory parameters are already changed before the onset of SOS. The aim of our retrospective study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS. Methods: We analyzed 182 children with a median age of 7.2 years who underwent allogeneic or autologous HSCT for the first time and without defibrotide prophylaxis. Our study population consisted of 126 patients who received allogeneic HSCT (69.2%) and 56 patients who underwent autologous HSCT (30.8%). The stem cell sources were peripheral blood stem cells (50.5%) or bone marrow (49.5%) and the most frequent underlying diseases were solid tumors (34.1%), genetic diseases (19.2%), acute lymphoblastic leukemia (18.1%), and acute myeloid leukemia (13.7%). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation. We investigated the following 15 laboratory parameters after HSCT before the onset of SOS: international normalized ratio (INR), activated partial thromboplastin time (aPTT), reptilase time, factor VIII, factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), fibrinogen, antithrombin III, protein C, protein S, D-dimer, alanine aminotransferase (ALT), bilirubin, and ferritin. The last laboratory values within one week before the onset of SOS were analyzed in the SOS patient group. In the non-SOS patient group, we investigated the parameters for four weeks after transplantation and calculated the median. We selected cut-off values for the continuous parameters based on receiver operating characteristic curves analyses and existing reference values. We performed Mann-Whitney U test, univariate and multivariate analyses to find significant ( P &amp;lt; .05) associations between the values of laboratory parameters and the occurrence of SOS. The probability of developing SOS was calculated using the significant independent variables. Results: The overall incidence of SOS was 14.8% at a median time of 13 days after HSCT. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients. Only 3 out of 27 patients (11.1%) who suffered from very severe SOS died within 100 days after HSCT. In the univariate analysis, we found significant associations between the onset of SOS and the following parameters: INR ≥ 1.3, aPTT ≥ 40 sec, reptilase time ≥ 18.3 sec, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L. In multivariate analysis, we confirmed INR ≥ 1.3 [odds ratio (OR) = 8.104, P = .006], aPTT ≥ 40 sec (OR = 10.174, P = .001), protein C ≤ 48% (OR = 5.215, P = .014), and ferritin ≥ 3100 µg/L (OR = 7.472, P = .004) as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, vWF, vWF activity, protein S, fibrinogen, and ALT were not relevant for the occurrence of SOS. Conclusions: In summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. These four parameters can enable earlier diagnosis and treatment leading to an improved outcome. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.

Sinusoidal Obstruction Syndrome of the Liver Associated With 6-Mercaptopurine During Maintenance in a Child With T-cell Acute Lymphoblastic Leukemia.

Sinusoidal obstruction syndrome (SOS) of the liver is a complication of chemotherapy most often encountered with hematopoietic stem cell transplant due to high-dose conditioning regimens, but it can also occur with regimens outside of the transplant setting. Mild-to-moderate SOS is a well-described 6-thioguanine toxicity; however, it has rarely been reported as secondary to 6-mercaptopurine, a related thiopurine. This report details a case of a 10-year-old male with T-cell acute lymphoblastic leukemia who developed severe SOS during maintenance therapy with 6-mercaptopurine, and a review of the related literature.

P1320: INCIDENCE AND IMPACT OF COMPLICATIONS OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IN PATIENTS OVER 60 YEARS. RETROSPECTIVE EXPERIENCE OF TWO SPANISH CENTERS IN THE 2015-2020 PERIOD

Background: Not fully known if allogeneic HCST complications have a more impact on patients over 60 years and this may limit their access to the procedure. Aims: To describe the incidence of the main complications and to analyze their relationship with age, the transplant modalities, and also their impact on survival and transplant-related mortality (TRM). Methods: Retrospective study of 142 patients over 60 years with hematological neoplasms undergoing allogeneic HSCT. Results: Patient characteristics and survival curves are in Image 1. Graft Versus Host Disease (GVHD) results are presented in the abstract EHA-1952. Post-chemotherapy mucositis was the 2nd complication (60%) after aGVHD and only 5.5% were grade IV. The use of myeloablative conditioning (MAC) (86% vs 57% in reduced intensity (RIC); p-value 0.04) and Methotrexate on the immunosuppression regimen (100%; p-value <0.001) were the two factors with more impact on its appearance. A higher incidence was observed in patients >70 years (82%; p-value 0.19) and it was no impact on survival or TRM. CMV reactivation was the 3rd complication (38%) and it appeared early (median 5 weeks after infusion). Patients with severe aGVRD presented more reactivation (73.5%/p-value 0.005) and also the unrelated transplant with MAC regimen (66.5%) or haploidentical (RIC 63%/MAC 59 %) with a low incidence in related transplant with RIC regimen (19.5%/p-value 0.001). There was also more in seropositive recipients (41%; p-value 0.07), especially if there was a discrepancy recipient +/donor- (46%/p-value 0.3). CMV disease had a lower incidence (7%) and 100% were gut forms. Prior reactivation and aGVHD were the two most important factors related (18% and 100%; p-value <0,001). CMV disease had impact on survival (median OS 6 months vs 40 if no disease; p-value 0.005/HR 0.36 (CI 0.17-0.76)). There were a 20% bacterial sepsis and 11.5% invasive fungal infections (IFI), (90% Aspergillus) and both were early complications (median onset of 2 and 4 months). Once again, severe aGVHD was associated with a higher incidence (60% sepsis; p-value <0.001 and 26.5% IFI; p-value 0.001) and an increase was also observed in patients with graft failure (33,5% sepsis, p-value 0.26 and 22% IFI, p-value 0.04). No differences were observed between the different age groups. Both present an unfavorable impact on survival (median OS of 6 months; p-value<0.001/HR 1.8 (CI 0.63-5.2). Sinusoidal obstruction syndrome (SOS) had an incidence of 7.5%, the median onset was 4 weeks and 72.5% were mild cases. All patients were CMV seropositive and it was more frequent in patients with ALL (16.5%) and in haploidentical transplant recipients (14%). The only case in >70 years was severe (in < 69 years; 90% mild cases; p-value 0.13) and was related to lower survival (median OS of 6 months vs 40 if no SOS; p-value 0.001/HR 0.06 (CI 0.17-0.47) with 100% mortality in patients with severe SOS. Primary graft failure was the least frequent complication (6.5%). Patients with cMPN and those transplanted after to 2 years from diagnosis had a higher incidence (28.5% and 13%; p-value 0.03). No differences were found of older age and other known risk factors. Its impact was very high (mortality of 100% with median OS of 1 month). Although SOS and graft failure were infrequent, they were a very early cause of TRM (80% of deaths before day +100). Image:Summary/Conclusion: Age is not a risk factor for the development of complications, given that an incidence similar to that reported in younger patients and related to known risk factors is observed. However, comparative studies are needed to confirm these results.

Interest of the preventive and curative use of defibrotide on the occurrence and severity of sinusoidal obstruction syndrome after hematopoietic stem cell transplant in children.

Defibrotide (DF) is indicated for the treatment of severe sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT), but its prophylactic use against SOS is not recommended yet. This study describes the impact of the preventive and curative use of DF on reducing the incidence and severity of SOS in children. Patients aged 0–19 years, who received allogenic HSCT after myeloablative conditioning regimen with busulfan or total body irradiation in our comprehensive cancer center, between 2013 and 2017, were included. The Baltimore or modified Seattle criteria were used for SOS diagnosis. SOS was graded using the 2017 European Society for Blood and Marrow Transplantation classification defining severity criteria of SOS in children. SOS occurrence tended to decrease with prophylactic DF, but no significant difference was observed in terms of severity. When not treated with preventive DF, 50% (19/38) of the patients with SOS were graded severe to very severe, but only 37% (7/19) had organ dysfunction. Curative DF was administered at a median of 2 days post‐HSCT, for a median of 6.5 days. The absence of fatal SOS supports the use of early curative DF with acceptable toxicities and questions the optimal duration of DF treatment.

Role of therapeutic drug monitoring of intravenous Busulfan for prevention of sinusoidal obstructive syndrome in children.

Therapeutic drug monitoring (TDM) of intravenous busulfan (Bu) has been recommended for safe engraftment and decreased toxicity in children undergoing hematopoietic stem cell transplantation (HSCT). This study aims to compare HSCT-related outcomes, such as acute or chronic graft-versus-host disease (GvHD), sinusoidal obstructive syndrome (SOS), event-free survival (EFS), and overall survival (OS) in children with and without TDM for busulfan. This retrospective study conducted between February 2012 and February 2021 at our Bone Marrow Transplantation Unit included 172 patients (34% girls) with a median age of 4.70years (IQR 2.41-10.01). Group A consisted of 46 patients whose Bu doses were adjusted according to actual body weight, and group B consisted of 126 patients whose Bu dose adjustments made according to TDM. Totally, 32 patients (19%) developed moderate or severe SOS. The incidence of SOS was significantly higher in the group without TDM (29% vs. 15%, p=.041). A multivariable analysis showed that the presence of acute GvHD and one alkylating drug-containing conditioning regimen compared with two or three were associated with SOS (p=.03 and p=.002, respectively). In patients with TDM, cumulative Bu dose and area under curve also were not associated with SOS. Other HSCT-related outcomes such as acute or chronic GvHD, relapse and graft rejection rates, OS and EFS rates did not differ between the groups. TDM and making dose adjustments with Bayesian forecasting over four days of Bu therapy optimizes exposure and reduces the risk of SOS in children undergoing HSCT.

Impact of Defibrotide in the Prevention of Acute Graft-Versus-Host Disease Following Allogeneic Hematopoietic Cell Transplantation.

Defibrotide is indicated for patients who develop severe sinusoidal obstructive syndrome following allogeneic hematopoietic cell transplantation (allo-HCT). Preclinical data suggested that defibrotide carries a prophylactic effect against acute graft-versus-host disease (aGVHD). The purpose of this study was to investigate the effect of defibrotide on the incidence and severity of aGVHD. This single-center retrospective study included all consecutive transplanted patients between January 2014 and December 2018. A propensity score based on 10 predefined confounders was used to estimate the effect of defibrotide on aGVHD via inverse probability of treatment weighting (IPTW). Of the 482 included patients, 64 received defibrotide (defibrotide group) and 418 did not (control group). Regarding main patient characteristics and transplantation modalities, the two groups were comparable, except for a predominance of men in the defibrotide group. The median age was 55 years (interquartile range [IQR]: 40-62). Patients received allo-HCT from HLA-matched related donor (28.6%), HLA-matched unrelated donor (50.8%), haplo-identical donor (13.4%), or mismatched unrelated donor (7.0%). Stem cell source was either bone marrow (49.6%) or peripheral blood (50.4%). After using IPTW, exposure to defibrotide was not significantly associated with occurrence of aGVHD (HR = 0.97; 95% CI 0.62-1.52; P = .9) or occurrence of severe aGVHD (HR = 1.89, 95% CI: 0.98-3.66; P = .058). Defibrotide does not seem to have a protective effect on aGVHD in patients undergoing allo-HCT. Based on what has been reported to date and on these results, defibrotide should not be considered for the prevention of aGVHD outside clinical trials.

Low Incidence of hepatic sinusoidal obstruction syndrome/veno-occlusive disease in adults undergoing allogenic stem cell transplantation with prophylactic ursodiol and low-dose heparin

Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) is a complication after allogenic hematopoietic stem-cell transplantation (allo-HSCT) with high mortality. The purpose of this study was to assess the incidence and outcome of SOS in patients after allo-HSCT with the impact of ursodeoxycholic acid (UDCA) and low-dose heparin as SOS prophylaxis. Out of 1016 patients, 23 developed SOS, with a cumulative incidence of 2.3% (95% CI 1.3–3.3) 6 months after HSCT. Approximately one quarter of these patients (26.1%) had late-onset SOS. A high proportion were very severe SOS cases (74%), and 83% of the patients were treated with defibrotide (DF). In multivariate analysis, advanced disease (p = 0.003), previous HSCT (p = 0.025) and graft versus host disease (GvHD) prophylaxis by post-transplant cyclophosphamide (PTCy) (p = 0.055) were associated with the development of SOS. The 1-year overall survival (OS) was significantly lower in the SOS group compared to patients without SOS (13% versus 70%, p = 0.0001). In conclusion, we found a low incidence of SOS in patients receiving low-dose heparin and UDCA prophylactically, but among SOS patients, a high mortality. Low-dose heparin and UDCA might be a prophylactic approach for SOS.

Allogeneic hematopoietic stem cell transplantations for relapsed and refractory acute lymphoblastic leukemia following inotuzumab ozogamicin treatment

Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.

“Defibrotide-Free” Regimen As an Alternative Management of Late-Onset Severe Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation Shows Impressive Responses

“Defibrotide-free” regimen as an alternative management oflate-onset severe sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantationshows impressive responsesAbstractBackground. Sinusoidal obstruction syndrome (SOS) ,better known as veno-occlusive disease, is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (HSCT) typically occurs within the first month after HSCT, with limited successful therapeutic options in severe cases. The late-onset of SOS has been described as appearing after day +21 to +30 and up to day+40 to +50. There are no satisfactory therapies for severe SOS, the best current results are with defibrotide. Defibrotide does not currently have Marketing Authorisation in some countries including China, we performed a pilot study using “Defibrotide-free” regimen to treat late-onset severe SOS after allogeneic HSCT.Methods. Eight patients with late-onset severe SOS was enrolled at our institution between Jan 2014 and Jan 2017. Median time of onset was day +42(+26-+53), all 8 patients were subsequently diagnosed with multiorgan failure associated with SOS. “ Defibrotide-free” regimen involved mainly low-dose recombinant human tissue plasmainogen activator (rh TPA) (10mg per dose every 24 hours for 14 doses, intravenously ) and support care, including fluid restriction and diuresis.Results. SOS resolved in all patients ,with median time to resolution of SOS, defined as recovery of all organ function and normalization of bilirubin and portal venous flow, of 11 days. No severe haemorrhage following treatment was observed, the survival rate to day +100 was 100%.Conclusions. “Defibrotide-free” regimen (low-dose rhTPA-based ) seems to be high effective in patients with late-onset severe SOS with acceptable toxicity. It may be adopted as an alternative therapeutic option especially in some hospitals/countries with administrative difficulties to access defibrotide. DisclosuresNo relevant conflicts of interest to declare.

Cyclophosphamide Followed By Intravenous Busulfan (Cy-Bu) As Myeloablative Conditioning: Impact on Venoocclusive Disease and Transplant Outcomes, Real World Experience

Background: Busulfan (BU) followed by Cyclophosphamide (BU-CY)is one of the most commonly used myeloablative conditioning(MAC) regimens in allogenic Hematopoietic Stem Cell Transplant (HSCT).BU is not inherently hepatotoxic but decreases the levels of glutathione which is critical in the metabolism of toxic CY metabolites.This has been implicated in the higher rates of Sinusoidal Obstruction Syndrome (SOS) with this protocol due to increased sinusoidal endothelial cell injury. Reversal of the protocol i.e cyclophosphamide followed by Busulfan (CY-BU) has been shown to reduce the rates of SOS, especially in myelofibrosis patients.Aim: We retrospectively analysed 25 patients who were given CY-BU as MAC from Jan 2015 to June 2017 for effect on SOS and overall D100 mortality and morbidity in these patients.Patients and methods: Since Jan 2015 we adopted protocol of CY-BU conditioning for all matched sbling donor (MSD) myeloablative transplants at our bone marrow transplant (BMT)center, which included patients of thalassemia major. Briefly CY-BUprotocol consists of CY 60mg/kg on days -7 and -6 followed by intravenous BU 3.2 mg/kg on days -5 to -2 (total 04 days). In patients of thalassemia anti thymocyte globulin (ATG) was administered on day-1 as part of conditioning. All patients received cyclosporine and methotrexate as graft versus host disease (GVHD) prophylaxis. All patients were monitored daily from D-7 to D+30 post HSCT for development of SOS. SOS was defined as per Baltimore criteria and patients meeting criteria for SOS were classified as mild, moderate or severe SOS. All patients were monitored every week after D+30 for presence of GVHD or any other complications till D +100.Results:Twenty five patients underwent HSCT with a CY-BU myeloablative conditioning protocol from Jan 2015 to June 2017. They were compared with 56 controls that underwent HSCT with BU-CY as the conditioning protocol during the period immediately before we switched to CY-BU. The median (IQR) age of patients was 17.5 (6.75 - 35.25) years for BU-CY and 14.00 (6.00 - 27.00) years for CY-BU. There were 38 (68%) males in BU-CY and 16 (64%) males in CY-BU group. The diagnosis in both the groups combined were 13 (16%) ALL, 23 (28%) AML, 14 (17%) CML and 31 (38%) Thalassemia and others. The median peak serum bilirubin in the CY-BU cohort was 1.4mg/dl as compared to 2.45mg/dl in the BU-CY cohort (p = 0.006) (Fig-1) and there was also a trend towards lesser transaminitis in the CY-BU group. 12% patients in the CY-BU group developed mild SOS in comparison to 25% in the BU-CY cohort. The incidence of severe SOS was 20% in the BU-CY group as compared to 4% in the CY-BU group. Overall 72% in the CY-BU cohort did not develop SOS as compared to 45% in the BU-CY cohort. The p value for chi square test for overall difference in VOD between both the groups was 0.082. There was no difference in occurrence of GVHD or other regimen related toxicity like hemorrhagic cystitis in the two groups. There was no difference in the D+100 mortality in the two groups (14% (BU-CY) vs 8% (CY-BU), p = 0.517). CY-BU conditioning appears to reduce the rates of SOS in all transplants including Thalassemia patients, in comparision to BU-CY. A larger study in Thalassemia patients is required to confirm our findings.Conclusions: Reversing the order of administration to cyclophosphamide followed by busulfan (CY-BU) is well tolerated MAC regimen and is associated with significantly less hepatotoxicity. This study limited by smaller number of patients, shows trend towards significantly less incidence of severe SOS and mortality due to SOS with CY-BU regimen. We are aware that our limited number of patients could have effected statistical analysis as far as GVHD and other transplant related mortality issues are concerned. However significant less hepatotoxicity as shown by our study is very important for patients of thalassemia major who due to hepatic iron overload have higher incidence of SOS. There is a need for prospectively studying CY-BU in a larger cohort of patients and comparing with other novel MAC regimens like treosulfan and thiotepa to develop a more effective and safe conditioning regimen.Figure 1: Box-plot comparing maximum serum bilirubin (max_bil) in peritransplant period in two groups (see text) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study.

131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility. Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%). This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.

Inotuzumab Ozogamicin Monotherapy as an Outpatient Salvage Treatment in Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia: Compassionate Access

AbstractRelapsed and refractory (RR) acute lymphoblastic leukemia (ALL) poses unique and difficult challenges to a practicing clinician in India where access to novel immunotherapies is limited. Between 2017 and 2020, eight patients with B-cell ALL at our center received inotuzumab ozogamicin (IO) monotherapy on compassionate access, as salvage therapy after at least two lines of conventional therapy failure, and most often as outpatient infusion. Eight patients (21–60 years, three females) received IO. Three patients had morphologic relapse and five patients reported persistent measurable residual disease (MRD). The best response on IO therapy achieved was negative MRD in six of seven patients and complete response (CR) with persistent MRD in one. One patient died (intracranial hemorrhage) before completion of first cycle. All responding patients were transplant eligible and four patients (57%) underwent allogeneic hematopoietic cell transplantation (Allo-HCT). Median follow-up of this cohort is 9 months (4–29.6 months), four patients (57%) are alive as stable with negative MRD. No significant infusion reactions occurred during therapy. Three patients developed grades III and IV neutropenia, two patients showed grade III transaminitis, and two patients developed post-HCT severe sinusoidal obstruction syndrome (SOS). IO is a feasible outpatient based salvage therapy to improve the remission status in RR B-cell ALL.

Refined ultrasonographic criteria for sinusoidal obstruction syndrome after hematopoietic stem cell transplantation.

Hepatic sinusoidal obstruction syndrome (SOS)/veno-occlusive disease is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). We previously reported the efficacy of the Hokkaido Ultrasonography (US)-based scoring system (HokUS-10) for US findings. To establish easier-to-use criteria, we retrospectively evaluated US findings from 441 patients, including 30 patients with SOS using the HokUS-10 scoring system. Using logistic regression analysis, we established the novel diagnostic criteria HokUS-6. In the presence of ascites, US diagnosis was made in the presence of two of the following 6 parameters: moderate amount of ascites, the appearance of a paraumbilical vein blood flow signal, gallbladder wall thickening, portal vein dilatation, portal vein velocity decrease, and hepatic artery resistive index increase. The AUC, sensitivity, and specificity of HokUS-6 were 0.974 (95% confidence interval 0.962-0.990), 95.2%, and 96.9%, respectively. The scores were significantly higher in patients with severe SOS than in those with non-severe SOS (p = 0.013). Furthermore, the scores before HSCT were significantly higher in patients who developed SOS than in controls (p = 0.001). The HokUS-6 is an easy and useful way to diagnose and identify the risk of SOS.

Myeloablative Busulfan/Melphalan Consolidation following Induction Chemotherapy for Patients with Newly Diagnosed High-Risk Neuroblastoma: Children's Oncology Group Trial ANBL12P1

Consolidation using high-dose chemotherapy with autologous stem cell transplantation (ASCT) is an important component of frontline therapy for children with high-risk neuroblastoma. The optimal preparative regimen is uncertain, although recent data support a role for busulfan/melphalan (BuMel). The Children's Oncology Group (COG) conducted a trial (ANBL12P1) to assess the tolerability and feasibility of BuMel ASCT following a COG induction. Patients with newly diagnosed high-risk neuroblastoma who did not progress during induction therapy and met organ function requirements received i.v. busulfan (every 24 hours for 4 doses based on age and weight) and melphalan (140 mg/m2 for 1 dose), followed by ASCT. Busulfan doses were adjusted to achieve to an average daily area under the curve (AUC) <5500 µM×minute. The primary endpoint was the occurrence of severe sinusoidal obstruction syndrome (SOS) or grade ≥4 pulmonary complications within the first 28 days after completion of consolidation therapy. A total of 146 eligible patients were enrolled, of whom 101 underwent BuMel ASCT. The overall incidence of protocol-defined unacceptable toxicity during consolidation was 6.9% (7 of 101). Six patients (5.9%) developed SOS, with 4 (4%) meeting the criteria for severe SOS. An additional 3 patients (3%) experienced grade ≥4 pulmonary complications during consolidation. The median busulfan AUC was 4558 µM×min (range, 3462 to 5189 µM×minute) for patients with SOS and 3512 µM×min (2360 to 5455 µM×minute) (P=.0142). No patients died during consolidation. From the time of study enrollment, the mean 3-year event-free survival for all 146 eligible patients was 55.6 ± 4.2%, and the mean 3-year overall survival was 74.5 ± 3.7%. The BuMel myeloablative regimen following COG induction was well tolerated, with acceptable pulmonary and hepatic toxicity.

Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

Targeted-dose of busulfan: Higher risk of sinusoidal obstructive syndrome observed with systemic exposure dose above 5000 µMol⸱min. A historically controlled clinical trial.

Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.

The Impact of Modern Chemotherapy and Chemotherapy-Associated Liver Injuries (CALI) on Liver Function: Value of 99mTc-Labelled-Mebrofenin SPECT-Hepatobiliary Scintigraphy.

Chemotherapy is increasingly used before hepatic resection, with controversial impact regarding liver function. This study aimed to assess the capacity of 99mTc-labelled-mebrofenin SPECT-hepatobiliary scintigraphy (HBS) to predict liver dysfunction due to chemotherapy and/or chemotherapeutic-associated liver injuries (CALI), such as sinusoidal obstruction syndrome (SOS) and nonalcoholic steatohepatitis (NASH) activity score (NAS). From 2011 to 2015, all consecutive noncirrhotic patients scheduled for a major hepatectomy (≥ 3 segments) gave informed consent for preoperative SPECT-HBS allowing measurements of segmental liver function. As primary endpoint, HBS results were compared between patients with versus without (1) preoperative chemotherapy (≤ 3months); and (2) CALI, mainly steatosis, NAS (Kleiner), or SOS (Rubbia-Brandt). Secondary endpoints were (1) other factors impairing function; and (2) impact of chemotherapy, and/or CALI on hepatocyte isolation outcome via liver tissues. Among 115 patients, 55 (47.8%) received chemotherapy. Sixteen developed SOS and 35 NAS, with worse postoperative outcome. Overall, chemotherapy had no impact on liver function, except above 12 cycles. In patients with CALI, a steatosis ≥ 30% significantly compromised function, as well as NAS, especially grades 2-5. Conversely, SOS had no impact, although subjected to very low patients number with severe SOS. Other factors impairing function were diabetes, overweight/obesity, or fibrosis. Similarly, chemotherapy in 73 of 164 patients had no effect on hepatocytes isolation outcome; regarding CALI, steatosis ≥ 30% and NAS impaired the yield and/or viability of hepatocytes, but not SOS. In this first large, prospective study, HBS appeared to be a valuable tool to select heavily treated patients at risk of liver dysfunction through steatosis or NAS.