Severe Veno-occlusive Disease Research Articles

6-Mercaptopurine-Associated Sinusoidal Obstructive Syndrome During Interim Maintenance I: A Case Report.

Thiopurine-methyltransferase (TPMT) and nudix-hydrolase-15 (NUDT15) are enzymes relevant to the metabolism of thiopurine medications, used to treat immunologic disorders and malignancies. Standard dosing administered in the setting of TPMT/NUDT15 dysfunction can cause excessive cytotoxic metabolites and life-threatening complications. We describe an adolescent with high-risk B-cell acute lymphoblastic leukemia (ALL) whose TPMT/NUDT15 status was unknown due to lack of insurance approval for genetic testing. He subsequently developed myelosuppression and severe veno-occlusive disease (VOD) after receiving 6-mercaptopurine (6-MP). Our patient provides an example of a very rare 6-MP-related toxicity and the potential benefit of TPMT/NUDT15 screening before initiating thiopurine therapy.

Real-World Tisagenlecleucel Outcomes in Richter-Transformed Chronic Lymphocytic Leukemia: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Background: Richter transformation (RT) is a rare but serious transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly large B-cell lymphoma (LBCL). There is currently no standard therapy for RT lymphoma and median overall survival (OS) is estimated to be only 8-12 months. Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T cell therapy approved for the treatment of r/r LBCL in patients who have received ≥2 lines of prior therapy. Here, we describe the efficacy and safety of tisagenlecleucel in patients with RT in a real-world setting with a median follow-up (infusion to data cutoff) of 31 months. Methods: Data were collected as part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. All patients were treated in the United States, Canada, or Israel. Efficacy outcomes analyzed included overall response rate (ORR), progression-free survival (PFS), and OS. Safety outcomes included the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 4, 2023, 48 patients with RT received a single tisagenlecleucel infusion. The median age at infusion was 68 years (range, 39-83). Fifty-eight percent of patients were ≥65 years old. The median number of all prior lines of therapy was 3 (range, 1-8); 42% of patients received ibrutinib as a prior therapy. No information confirming clonal relation of LBCL to CLL in evaluated patients was available. Fifty percent of patients had primary refractory disease. Prior to infusion, 46% of patients were reported to have elevated lactate dehydrogenase (LDH). Two patients who received tisagenlecleucel infusion, and were alive at data cutoff, had not yet reached 100 days post-infusion and were therefore not evaluable for efficacy and safety. Among the 46 patients evaluated for efficacy and safety, the ORR (complete response [CR] + partial response) was 63% (95% CI, 47.5-76.8) and CR rate was 50% (n=23). In total, 23 patients (23/46, 50%) experienced disease relapse, 17 within 6 months of infusion (Figure). Twelve- and 24-month PFS were 43% and 39%, respectively; 12- and 24-month OS rates were 51% and 44%, respectively. Among 23 patients with a best overall response of CR, 57% remained in remission at data cutoff. The most common adverse events of any grade were CRS (78%), hypogammaglobinemia (46%), and ICANS (35%). Grade 3/4 CRS was reported in 11% of patients. No patient experienced grade 5 CRS. CRS was managed with tocilizumab in 81% of cases. Grade 3 ICANS was reported in 9% of patients. No grade 4/5 ICANS events were observed. Two patients went on to receive a stem cell transplant following tisagenlecleucel infusion. In total, 25 deaths were reported. The most common cause of death was progressive disease (13/48, 27%). Twelve patients (12/48, 25%) died in the absence of disease progression. Causes of non-relapse-related mortality included infection (including COVID-19, n=5), respiratory failure (n=2), malignant neoplasm (n=2), prior malignancy (n=1), multiorgan dysfunction (n=1), and severe veno-occlusive disease (n=1). Conclusions: In the largest cohort of patients with RT receiving treatment in a real-world setting, tisagenlecleucel resulted in a high overall response rate and durable survival. The incidences of CRS and ICANS were similar to other real-world reports of tisagenlecleucel for patients with LBCL. Overall, these findings demonstrate that tisagenlecleucel could be considered a potential treatment option for patients with RT who have a high unmet medical need.

Clinical Characteristics, Management, and Allogeneic Hematopoietic Cell Transplantation of Patients with Toll-like Receptor 8 Gain-of-Function Mutations

Toll-like receptor 8 gain-of-function (TLR8 GOF) is a recently described inborn error of immunity due to germline or somatic mutations in the TLR8 gene and characterized by severe neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases, bone marrow failure. Treatment of TLR8 GOF has been challenging to date, and guidance for optimal therapy is lacking. We describe the clinical characteristics and management of 10 patients with TLR8 GOF variants, including the first female patient and further clinical outcome on the 6 patients initially reported with this disease with a focus on the role of allogeneic hematopoietic cell transplantation (HCT). All but one patient were male ranging from 0.5 months to 28 years at age of symptom onset. Eight patients had somatic mutations with variant allele frequencies of 7-26%; two patients had germline mutations. The 9 male patients all had severe neutropenia and varying degrees of anemia and/or thrombocytopenia. Oral ulcers, recurrent infections, hepatosplenomegaly, and hypogammaglobulinemia were common. Immune phenotype was variable, ranging from severe lymphopenia to marked T cell lymphoproliferation. Several patients had an inverted CD4:CD8 T cell ratio and skewing of T cell subsets to the terminal effector memory phenotype. Increased double-negative T cells were also observed. All patients had low class switched memory B cells. Bone marrows were hypo- to hypercellular with marked myeloid hypoplasia, and in most cases, with increased T cells, large granular lymphocytes, and/or lymphoid aggregates. Neutropenia was initially responsive to granulocyte colony stimulating factor (GCSF) +/- steroids in several patients but ultimately become refractory to therapy. Immunomodulatory agents and chemotherapy were unsuccessful. Six patients underwent allogeneic HCT; two patients died at 8 and 18 years without definitive therapy; and one patient was lost to follow-up. The female patient had germline disease and presented with pure red blood cell aplasia at 2 weeks of life and is scheduled to undergo HCT. Transplant data were available for 5 of 6 patients who underwent HCT. Age at transplant was 3 to 21 years. One patient who received a graft from a 7/8 HLA-matched unrelated donor developed severe veno-occlusive disease and secondary graft failure. The patient underwent a second transplant and ultimately died. Another patient received a matched sibling donor HCT while critically ill from Candida lusitaniae and mucormycosis infection with associated multisystem organ failure. The patient engrafted with 100% donor chimerism but died on day +15 post-HCT. The remaining 3 patients are alive and well 8 months to 2 years post-HCT. Two patients received grafts from HLA-matched donors (1 sibling and 1 unrelated) with reduced intensity conditioning and cyclophosphamide, mycophenolate mofetil and vorinostat for graft-versus-host disease (GVHD) prophylaxis. The third patient underwent a haploidentical HCT with myeloablative conditioning and post-transplant cyclophosphamide. Post-HCT complications included acute skin and/or gastrointestinal GVHD that was responsive to therapy in all patients, and severe lung GVHD in one patient. There were no major infectious complications. All three patients had full donor chimerism in myeloid and T cells with complete resolution of disease phenotype at last follow-up. The patient for whom detailed transplant data is not available received a haploidentical HCT. He developed mixed myeloid chimerism for which he received multiple donor lymphocyte infusions and was alive at last contact >3 years post-HCT. TLR8 GOF should be considered in male and female patients with severe, unexplained neutropenia refractory to GCSF, and particular care should be taken when investigating for mutations given the disease-causing variant allele frequencies as low as 7%. Neutropenia and immune dysregulation were refractory to all therapies in our cohort, and TLR8 GOF was fatal in two patients who did not receive definitive therapy. Allogeneic HCT is curative and should be considered without delay for medically suitable patients.

Peritoneal and Pleural Drains in Pediatric Hematopoietic Cell Transplant Recipients with Veno-Occlusive Disease are Safe and Do Not Adversely Impact Clinical Outcomes.

There is a lack of data on the safety and efficacy of peritoneal drain (PD) and chest tube (CT) in the management of effusions in stem cell transplant recipients with veno-occlusive disease (VOD). In this retrospective pediatric study, clinical outcomes and health resource utilization (HRU) were compared in 32 patients with VOD who had a PD (PD+) post-HCT versus 27 patients who did not (PD-). Nine patients also had a CT (7 PD+ and 2 PD-). PD + patients were more likely than PD-patients to have received myeloablative conditioning (100% vs. 85.2%; p = 0.04) and have severe or very severe VOD (100% vs. 56% p < 0.01). Mechanical obstruction (38%) and hypotension (38%) were common complications, and 13% developed peritonitis. While the frequencies of cardiac dysfunction and acute kidney injury were comparable between both groups, respiratory support and its median duration were higher in PD + patients. The hospital and intensive care unit length of stay, albumin use, and the duration of defibrotide and albumin therapy was significantly longer in PD + patients. At a median follow-up of 1.04 years (range:0.03-14.6), the 2-year overall survival was similar in both groups (53.8% vs. 51.5%; p = 0.73). Although PD use was similar between 1995 and 2007 vs. 2008-2021; (47% vs. 58%; p = 0.65), day+100 mortality was improved in recent years (53.3% vs. 17.8%; p = 0.01), coinciding with the use of defibrotide (0% vs. 84%; p < 0.01). PD in pediatric patients with VOD post-HCT, although associated with increased HRU, was safe when clinically indicated and did not adversely impact clinical outcomes.

Cardiovascular Causes of Death in Patients Treated for Localized Prostate Cancer

<h3>Purpose/Objective(s)</h3> From two trials in localized prostate cancer, cardiovascular disease represented the second cause of death. Based on our own data, we retrieved and reviewed the clinical information on those patients labelled by investigators as dying from cardiovascular disease (CVD) aiming to confirm and precisely define the cause/diagnosis of their cardiovascular death. <h3>Materials/Methods</h3> From October 2000 to September 2010, 1230 patients were randomized into two prostate cancer trials. Causes of death compiled up to January 2022, were based on data from clinical records, death certificates, obituaries, family members, and family physicians. Patients who were reported dying from CVD were classified into 2 groups: cardiac events proper and vascular events outside the heart. <h3>Results</h3> With a median follow up of 13.4 years, 663/1230 (53.9%) patients had died, 274 in IRPC and 389 in HRPC. 6 of the 136 patients reported dead from CVD were excluded: 3 pulmonary embolisms, 1 thrombosis, 1 severe veno-occlusive disease and 1 aorto-thoracic dissection. A total of 130/663 (19.6%) patients died from CVD. No significant differences were seen in the group of cardiac events proper [47/274 (17.2%) vs 56/389 (14.4%), p=0.4], or in vascular events outside the heart [15/274 (5.5%) vs 12/389 (3.1%), p=0.2] between IRPC and HRPC patients, respectively. The group of CVD deaths from cardiac events accounted for 79.2% (103/130) of all deaths. Many different diagnoses were attributed as potential cause of cardiac death; coronary heart disease was the most frequent 70.8%, followed by heart rhythm disorders 5.4% and heart valve disease 3.1%. The second group of CVD deaths made of vascular events outside the heart represented 20.8% (27/130) of all CVD deaths. <h3>Conclusion</h3> In localized prostate cancer, deaths from CVD represented almost 20% of all causes of death as per original definition from investigators. Of these, deaths linked to a truly cardiac event occurred in 79.2% of the cohort with the remaining deaths attributed to vascular events outside the heart. Notwithstanding potential caveats related to the retrospective nature of this review, this differentiation seems appropriate and may aid in better assessing the possible relationship between ADT and its real impact on the heart.

181 - Final Long-Term Results from the Defifrance Registry Study: Efficacy and Safety of Defibrotide (DF) for the Treatment of Severe/Very Severe Veno-Occlusive Disease/ Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT)

181 - Final Long-Term Results from the Defifrance Registry Study: Efficacy and Safety of Defibrotide (DF) for the Treatment of Severe/Very Severe Veno-Occlusive Disease/ Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Cell Transplantation (HCT)

Successful Treatment with ALVR105 for Disseminated Adenovirus Infection in an Infant after Allogeneic Hematopoietic Cell Transplantation: A Case Report

Background: Adenovirus (AdV) disease is one of the most difficult-to-manage complications in infants and children who have received allogeneic hematopoietic cell transplantation (HCT). Cidofovir has been used off-label as preemptive anti-adenoviral therapy. It is the current standard of care treatment, but data supporting its therapeutic value are lacking, and its use is limited by severe renal toxicity.Case: A 10-month-old male with infantile osteopetrosis underwent a single-unit umbilical cord blood transplant (TNC = 21.78 × 10 7/kg, CD34 = 10.5 × 10 5/kg) after myeloablative conditioning (busulfan, cyclophosphamide, and anti-thymocyte globulin). Cyclosporine and mycophenolate mofetil (MMF) were used for graft versus host disease (GVHD) prophylaxis. A positive test for adenovirus from a respiratory viral panel pre-transplant delayed conditioning for six weeks until the patient had two negative tests, one week apart. His post-transplant course was complicated by severe veno-occlusive disease starting on day +3, with secondary respiratory and renal failure. The patient was started on continuous renal replacement therapy along with intravenous defibrotide and high-dose steroids. Neutrophil engraftment did not occur until day +38. Post-engraftment, the patient developed a skin rash diagnosed as GVHD by biopsy, which was treated with corticosteroids at 2 mg/kg/day. As part of viral infection surveillance, the patient received a weekly blood PCR test for adenovirus; on day +25 it was noted he had reactivated adenovirus. He had been demonstrating overall clinical improvement, including declining hepatic transaminases and bilirubin, and reduced respiratory support requirements until day +39, when he developed fever with an increased need for respiratory support and rising transaminases. The respiratory viral panel showed that the patient was positive for adenovirus. Further workup also showed adenovirus PCR positive in stool and increase in quantitative adenoviremia, all consistent with disseminated adenoviral infection. The use of cidofovir was contraindicated in this patient due to renal toxicity.ALVR105 (Viralym-M), an allogeneic, off-the-shelf, multivirus-specific T-cell therapy (VST) that can target AdV, BKV, CMV, EBV, HHV-6, and JCV, was provided by AlloVir on a compassionate-use basis. A cell line that was HLA matched to the patient at 2 out of 8 HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was identified. After emergency IND approval, institutional review board approval, and family consent, one ALVR105 dose of 0.7 × 10 7 cells was infused on day +48. The dosage was calculated based on the patient's age, weight (8.5 kg), body surface area (0.35 m 2), and the dosing regimen used in a previous phase 2 trial. The patient developed fever and low blood pressure around 30 hours post-infusion, requiring an increase in his existing inotropic support and stress dose hydrocortisone. This was likely associated with underlying post-transplant complications, but a possible association with ALVR105 infusion could not be ruled out.The patient's viral load decreased substantially in the following weeks (Table 1). Concurrently, his liver enzymes, pulmonary secretions, and respiratory support requirements all improved. His respiratory secretions became negative for adenovirus PCR at day +28 post-infusion of ALVR105.At the time of writing, the patient was day +100 post-transplant (day +56 post-infusion of ALVR105), and his veno-occlusive disease had improved. Supplemental oxygen was no longer required, but volume-assured pressure was still in use, likely due to hepatosplenomegaly. The patient had detectable adenovirus viremia but below the threshold of quantitative measurement (<190 copies/ ml). The patient remains well-engrafted with evidence of persistent ALVR105 (Viralym-M) as illustrated in Table-2, but the % of Allovir cells are below our lab's 5% validation threshold. The patient's GVHD has resolved. MMF dosing was stopped on day + 31 from transplant, and the patient is receiving only cyclosporine and physiologic doses of hydrocortisone.Conclusion: In this infant with post allogeneic HCT disseminated adenovirus infection, ALVR105 appeared to be safe and was temporally associated with marked clinical improvement, suggesting VSTs may be of value in very young patients with adenovirus infection. This represents the first use of ALVR105 in an infant (< 1-year-old) patient. [Display omitted] DisclosuresMoon: Allovir: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure:Virus specific cell therapy, used against adenovirus infection in post-transplant setting.

Economic Burden of Veno-Occlusive Disease (VOD) in Patients with Acute Lymphoblastic Leukemia (ALL) in the US

IntroductionHepatic Veno-occlusive disease (VOD) is a potential life threatening complication of hematopoietic cell transplantation (HSCT) and may also occur after chemotherapy (Negrin et al. 2017). Severe VOD characterized by multi-organ failure (MOF) is fatal and associated with high mortality (Coppell et al. 2010). The economic burden of VOD in ALL patients has not been reported in the published literature.ObjectiveTo investigate the incidence, inpatient mortality and economic burden of VOD among adult B-cell ALL patients in the US.MethodsThis was a retrospective cohort study using Truven Health MarketScan® Commercial and Medicare Supplemental Databases. We first identified the adult B-cell ALL patients. Patients with ≥1 inpatient claims or ≥2 non-diagnostic outpatient claims at least 30 days apart for any ALL diagnosis (ICD-9-CM 204.00-204.02, ICD-10-CM C91.00-C91.02) during 4/1/2009 - 10/31/2016 were extracted. All patients were required to have ≥1 hospitalization with diagnosis-related group in 834-839 on or after the first ALL diagnosis, be ≥18 years old, and have ≥6 months of continuous enrollment prior to the first ALL diagnosis date. Patients with medications for T-Cell ALL during the study period were excluded. VOD patients were then identified based on clinical criteria (Coppell et al. 2010) and expert opinions. VOD patients must have one of the following: 1) a ICD-10-CM code specifically for VOD diagnosis (K76.5), 2) prescription for defibrotide sodium that is indicated for treatment of VOD in the US, 3) at least two VOD symptoms from either Baltimore or Seattle criteria for VOD (ascites, abnormal weight gain, hyperbilirubinemia, or hepatomegaly) within 60 days post HSCT admission, or 4) multi-organ failure (MOF) with liver failure within 60 days post HSCT admission. The VOD index date was the first observed VOD diagnosis date, defibrotide sodium prescription date, or HSCT admission date. HSCT patients were excluded if they had evidence of chronic graft-versus-host disease (GVHD) any time before or 100 days after the VOD index date or if they had acute GVHD or total parenteral nutrition cholestasis during 60 days before or 100 days after the VOD index date. Severe VOD patients were defined as VOD patients with MOF. Patients were followed until the earliest of inpatient death, end of continuous enrollment, end of the study period (10/31/2016), and capped at 100 days. Outcomes included incidence rates of VOD in ALL patients, inpatient mortality of the VOD patients, and VOD-related costs and hospital length of stay during the 100 days post-index period. Costs were sum of the plan paid amount and out-of-pocket amount in 2016 US dollars. Descriptive analyses were conducted for all VOD patients, severe VOD patients and non-severe VOD patients, respectively.ResultsA total of 2,571 ALL patients were identified and 3.4% of them had VOD. Severe VOD patients accounted for 52% of the VOD patients. All VOD patients had HSCT before the VOD event. VOD patients were younger (mean age: 44.2 vs. 50.1), more likely to be male (male: 62.5% vs 55.0%) but sicker (mean Charlson comorbidity index: 2.1 vs. 1.9) compared with the average ALL patients. Inpatient mortality was higher among severe VOD patients (37.0%) when compared to both non-severe VOD (14.3%) and average VOD patients (26.1%). Mean (SD) VOD-related costs were $55,975 ($160,335) for All VOD patients, $86,953 ($206,906) for severe VOD patients and $22,047 ($72,847) for non-severe VOD patients (Figure 1). Mean (SD) VOD-related length of stay was 39.3 (33.0) days among all VOD patients, 49.2 (36.8) days for severe VOD patients and 28.5 (24.3) days for non-severe VOD patients.ConclusionsThe incidence of VOD is low in adult B-cell ALL patients. The diagnosis of VOD is clinical and as such might be underdiagnosed within the current study. Approximately half of the VOD events among ALL patients are severe involving MOFs. VOD events are associated with considerable economic burden and high inpatient mortality, with greater economic burden and inpatient mortality rate among severe VOD patients. These results may potentially underestimate the burden of VOD in ALL patients due to the fact that the HCPCS code specific for defibrotide sodium was not available given its recent approval in the US (2016). Future studies with more recent data are needed to accurately quantify the economic burden of VOD in the US. [Display omitted] DisclosuresZhang:Amgen Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership. Cong:Amgen Inc.: Employment, Equity Ownership.

Prophylactic Effects of Recombinant Thrombomodulin Against Sclerodermatous Chronic Graft-Versus-Host Disease in a Rodent Model

Graft-versus-host disease (GVHD) is the one of the most serious complications of the allogenic stem cell transplantation (SCT). Especially, chronic GVHD has complex pathologies including the aspects of autoimmune diseases and microangiopathies. Recombinant thrombomoduin (rTM), which shows anticoagulant activity independent of antithrombin through binding to thrombin to activate protein C, has been used for disseminated intravascular coagulation (DIC). Recent studies have also demonstrated that rTM suppresses inflammatory response through various pathways including activated protein C (APC), degradation of HMGB1, inhibiting inflammatory cytokine and increasing regulatory T-cells (Treg), leading to attenuate tissue damages in animal models such as acute respiratory distress syndrome and liver injury by heatstroke. In acute GVHD mice model, rTM is reported to have therapeutic effect with contribution of Treg and blockade of HMGB1. In addition, rTM protects endothelial cells from calcineurin inhibitor-induced cytotoxicity in vitro using human umbilical vein endothelial cells. Thus, rTM is expected to show beneficial effects for post transplant complications. Actually, rTM has been sometimes used for severe veno-occlusive disease, DIC and thrombotic microangiopathy after SCT in clinical settings, but it is not clear whether rTM could have impact on acute or chronic GVHD themselves. In this study, we investigated the role of rTM especially focusing on preventing chronic GVHD in a rodent model.Bone marrow and splenocyte from donor mice (B10.D2) were transplanted into irradiated host mice (Balb/c) to induce sclerodermatous chronic GVHD (Scl-cGVHD). First, to demonstrate whether rTM could ameliorate the Scl-cGVHD, irradiated host mice were given splenocytes with rTM. Compared with the control group, rTM significantly improved chronic skin GVHD. However, rTM did not improve survival rate when increased dose of splenocytes was given to induce lethal intestinal GVHD together with Scl-cGVHD. In addition using another mice strain combination mimicking acute GVHD, rTM did not show any impact on ameliorating GVHD. Collectively, these results suggested that rTM had a beneficial effect on skin sclerodermatous lesions, not systemically. Next, to test whether rTM has therapeutic effects against skin lesions, rTM was started from 3 weeks after transplantation when Scl-cGVHD had already appeared. rTM did not improved Scl-cGVHD anymore. Next, to clarify whether the prophylactic mechanism of rTM to Scl-cGVHD is due to anticoagulant activity alone and/or complicated immure regulations by APC and rTM, Scl-GVHD mice was given dalteparin, APC and rTM, respectively. As shown in figure below, only rTM attenuated Scl-cGVHD with retaining normal skin structure and less inflammatory cell invasion compared to other groups, suggesting that rTM related immune regulation was a significant contributor to skin prophylactic effect, not anticoagulant activity. Though skin lesions were dramatically different among groups, in splenocytes there were no significant difference of cell subpopulation, T-cell activation and inflammatory cytokines (TNFα, IFNγ, IL17A). There was also no significant difference in regulatory B-cell, which was known to have a suppressive role in Scl-cGVHD model, and Treg. Moreover to confirm that rTM dose not influence these properties in vivo and in vitro, we analyzed splenocytes after repetitive administration of rTM to non-treated mice and short-term culture of splenocytes mixed with rTM. As expected, there was no significant difference by adding rTM in cell subpopulation including Treg, Breg and cytokine production in vivo and in vitro. From these findings, prophylactic mechanism of rTM in Scl-cGVHD was not due to anticoagulant activity nor APC related anti-inflammatory effects, but more likely to rTM related immune regulation. HMGB1 is one of the targets that rTM acts on as an immune modulator, but a previous report demonstrated that HMGB1 blockade attenuated GVHD systemically including skin, intestine and liver. In contrast to our findings that rTM worked mainly at skin lesions, unknown mechanisms of immune regulation by rTM might exist. In conclusion, rTM would be a promising drug for preventing sclerodermatous skin GVHD in addition to improving various complications associated with coagulation abnormalities. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence and Outcome of Hepatic Veno-Occlusive Disease After Blood or Marrow Transplantation: A Prospective Cohort Study of the European Group for Blood and Marrow Transplantation

AbstractTo determine the incidence and outcome of hepatic veno-occlusive disease (VOD) after blood or marrow transplantation (BMT), we prospectively evaluated all consecutive patients receiving a BMT during a 6-month period in participating EBMT centers. All of them were evaluated for occurrence of VOD according to previously defined clinical criteria. The clinical course, outcome, value of prophylactic and therapeutic interventions, and the influence of previously described risk factors were analyzed. During the study period, 1,652 BMT were performed in 73 centers. VOD was diagnosed in 87 patients (5.3%; 95% confidence interval [CI], 4.2% to 6.4%). Fifty-six of 631 allogeneic BMT (8.9%) and 31 of 1,010 autologous BMT (3.1%) developed this complication (P < .0001). VOD was classified as mild in 7 (8%), moderate in 56 (64.4%), and severe in 24 (27.6%) cases. Sixteen patients died of VOD (corresponding to 1% of the whole series, 18.4% of VOD patients, and 66.7% of severe VOD). The use of unfractionated heparin did not significantly decrease the incidence of VOD. Independent variables associated with an increased risk of VOD were allogeneic BMT (relative risk [RR], 2.8; P< .001), pre-BMT elevation of serum aspartate aminotransferase (RR, 2.4; P = .001), high-dose cytoreductive therapy (RR, 2.3;P = .003), Karnofsky performance score less than 90% (RR, 2.7; P = .006), and prior abdominal radiation (RR, 2.9;P = .03). In conclusion, this prospective study shows that (1) the incidence of VOD is lower than that reported in smaller studies from single centers, (2) about one fourth of cases of VOD progress to severe disease, (3) main risk factors have a major impact on incidence of VOD, and (4) the use of prophylactic unfractionated heparin does not seem to reduce the incidence of VOD.

A Pilot Trial of Pre-Transplant Risk Stratification and Prophylactic Defibrotide to Prevent Serious Thrombotic Microangiopathy in High-Risk Pediatric Hematopoietic Stem Cell Transplant Patients

Background: Transplant associated thrombotic microangiopathy (TA-TMA) is a known complication of hematopoietic stem cell transplant (HSCT) associated with endothelial injury that leads to end organ damage and high morbidity and mortality. No proven method for prevention of TA-TMA exists. One strategy is to decrease or even prevent the initial endothelial injury during conditioning. Defibrotide is an anti-inflammatory and anti-thrombotic agent that has been shown to protect the endothelium from damage and treat TA-TMA. We hypothesize that prophylactic use of defibrotide during HSCT conditioning and acute recovery may potentially prevent TA-TMA. Methods: We initiated a pilot single-arm phase II trial (NCT#03384693) to evaluate the safety and feasibility of administering prophylactic defibrotide to pediatric patients at high risk for the development of TA-TMA following HSCT. Additionally, we sought to determine if administration of prophylactic defibrotide would prevent the development of TA-TMA in clinically high-risk patients compared to historic controls. High-risk patients were defined as either patients with high-risk neuroblastoma whose treatment plan included autologous tandem transplants conditioned with cyclophosphamide/thiotepa (Cy/TT) and carboplatin/etoposide/melphalan (CEM), or allogeneic transplant patients undergoing myeloablative conditioning, with at least three of the following: age ≥10 years old, race/ethnicity other than Caucasian, ABO minor incompatibility, or haploidentical donor. Based on prior analysis at our center, we anticipated an incidence of TA-TMA of 28% in the high-risk patients undergoing allogeneic transplants and 40% in the neuroblastoma patients. Patients received defibrotide 6.25mg/kg IV q6h the day prior to the start of conditioning through day +21 and received supportive care per institution guidelines, including maintaining platelets above 30 x10^9/L. Patients were prospectively monitored for TA-TMA from admission through week 24. Results: Twenty-five patients were enrolled, 14 with neuroblastoma and 11 undergoing allogeneic HSCT. The median age was 3.45 (2.1-10.1) and 15.7 (0.8-27.4) years for autologous and allogeneic patients, respectively. Ten of the allogenic transplants were with an alpha-beta T-cell depleted haploidentical HSCT, while one was with a matched unrelated HSCT. Follow-up is complete on all patients. Defibrotide was stopped early due to clinically significant bleeding in 3 patients (day +3, +6 and +10, respectively). Bleeding episodes were excessive bleeding from oral hematoma, diffuse alveolar hemorrhage, and melanic stools and epistaxis and were classified as "possibly related" to the study drug. The other 22 patients missed a median of 0.7% of doses (0-5.2%), most often due to concomitant medication infusions. There were no allergic or hypersensitivity reactions. One patient with acute lymphoblastic leukemia (ALL) in CR4 died during the study period from respiratory failure in the setting of disseminated aspergillus and veno-occlusive disease (VOD), leading to a TRM of 0% and 9.1% in the autologous and allogeneic patients, respectively. Of the neuroblastoma patients, 4 did not go on to receive a second transplant; three due to development of moderate to severe VOD and one per parental preference. Five of the 14 neuroblastoma patients developed VOD, 4 after Cy/TT (1 mild, 2 moderate, 1 severe) and 1 after CEM (mild); all of which resolved. One patient developed non-severe TA-TMA, diagnosed 12 days post-HSCT (4% incidence). She received an alpha-beta T-cell depleted peripheral blood HSCT from her mother for ALL after conditioning with total body irradiation, cyclophosphamide, thiotepa, and ATG. Her course was complicated by diffuse alveolar hemorrhage on day +6 for which defibrotide was stopped. Her TA-TMA was treated with eculizumab and resolved without sequelae. Conclusions: 12% (3/25) patients required early discontinuation of defibrotide due to clinically significant bleeding; no other severe adverse events occurred due to the study intervention. The observed TA-TMA incidence of 4% was far below the anticipated rate of 28-40%. Our study provides preliminary evidence that defibrotide prophylaxis is safe and feasible in children and adolescents undergoing HSCT at high risk for TA-TMA and may reduce the risk of TA-TMA. Future larger randomized studies are needed to verify these findings. Disclosures Higham: Jazz Pharmaceuticals: Research Funding. Shimano:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding. OffLabel Disclosure: Defibrotide- off label use as prophylaxis for transplant associated thrombotic microangiopathy (TA-TMA)

A case report of severe veno-occlusive disease following autologous stem cell transplantation successfully treated with Defibrotide

Veno-occlusive disease (VOD) is one of the complications of hematopoietic stem cell transplantation that can also be caused by high-dose chemotherapy. This complication can lead to high mortality following bone marrow transplantation. It is more common after allogeneic stem cell transplantation, and is rare after autologous stem cell transplantation. While mild cases of VOD may reduce over a period of a few weeks, very severe cases can cause multi-organ damage, which has a high mortality. is therefore required with early diagnosis and treatment of this complication. In this paper, we present a sever VOD case after autologous stem cell transplantation, that was treated successfully with Defibrotide. The patient was a 14-month-old girl who has neuroblastoma with bone metastasis. VOD should be considered in the differential diagnosis of haematopoietic stem cell transplantation recipients who present with unexplained liver injuries, ascites and/or multi organ failure. Recipients of haematopoeitic stem cell transplantation who present with unexplained liver injuries, ascites and/or multi organ failure should have VOD considered in their differential diagnosis. If there is severe VOD diagnosed, then Defibrotide could be an option for treatment.

A case report of severe veno-occlusive disease following autologous stem cell transplantation successfully treated with Defibrotide.

Veno-occlusive disease (VOD) is one of the complications of hematopoietic stem cell transplantation that can also be caused by high-dose chemotherapy. This complication can lead to high mortality following bone marrow transplantation. It is more common after allogeneic stem cell transplantation, and is rare after autologous stem cell transplantation. While mild cases of VOD may reduce over a period of a few weeks, very severe cases can cause multi-organ damage, which has a high mortality. is therefore required with early diagnosis and treatment of this complication. In this paper, we present a sever VOD case after autologous stem cell transplantation, that was treated successfully with Defibrotide. The patient was a 14-month-old girl who has neuroblastoma with bone metastasis. VOD should be considered in the differential diagnosis of haematopoietic stem cell transplantation recipients who present with unexplained liver injuries, ascites and/or multi organ failure. Recipients of haematopoeitic stem cell transplantation who present with unexplained liver injuries, ascites and/or multi organ failure should have VOD considered in their differential diagnosis. If there is severe VOD diagnosed, then Defibrotide could be an option for treatment.

Incidence of Breakthrough Invasive Fungal Infections While on Micafungin for Antifungal Prophylaxis in Pediatric Hematopoietic Cell Transplant Patients

Introduction Pediatric hematopoietic cell transplant (HCT) patients are at significant risk for invasive fungal infections (IFIs). IFIs are life threatening for HCT patients. Due to its tolerability and lack of drug interactions, micafungin is utilized as primary antifungal prophylaxis (PAP) in the peri-transplant period. In 2012, we created a micafungin dosing protocol for pediatric patients based on the most current literature at that time. Objectives Our primary endpoint was to determine the prevalence of breakthrough IFIs in pediatric HCT patients after initiating PAP according to this institutional micafungin dosing protocol. The secondary endpoint was to evaluate the incidence of adverse effects (AEs). Methods Retrospective analyses of our institution's electronic records were performed to quantify the incidence of breakthrough IFIs in pediatric HCT patients who received micafungin for PAP according to institutional protocol between July 2012 and Dec 2017. Micafungin Pediatric Dosing Guidelines. PAP for HCT Results A total of 300 pediatric HCT patients were included in the analysis. All patients were neutrophil engrafted by Day +30. All patients started micafungin PAP prior to conditioning and continued through Day +100. Of the 300 patients, 50% converted to voriconazole, 30% remained on micafungin, 20% converted to fluconazole and 10% received amphotericin B. Per the European Organization for Research and Treatment of Cancer (EORTC) IFI Criteria Classification, 10 patients (3.1%) developed an IFI. Eight cases (2.6%) were classified as proven and 2 cases (0.7%) were probable. Pathogens identified were Candida parapsilosis (5/8 cases), Rhizopus (1 case), Candida krusei (1 case) and one case had both Mucormycosis and Rhizopus. The infection source was blood in 6/8 cases, wound (1 case) and sinuses/brain (1 case). Seven of eight patients with ‘proven' IFI died. Two deaths were directly associated with IFI (C. parapsilosis and mucormycosis); other deaths were attributed to bacterial infection (3), pulmonary hemorrhage or underlying disease. For the entire study group, approximately 8%, 5.7% and 1.7% had Grade 2, 3 and 4 hepatotoxicity, respectively (CTCAE grading criteria). Most patients with Grade 3 or 4 were noted to have moderate to severe Veno-Occlusive Disease or other primary disease processes so the events were likely not related to micafungin. Conclusions The micafungin dosing protocol for pediatric HCT patients has shown to be efficacious with very few documented breakthrough IFI over a five year study period. Additionally, micafungin was well tolerated at these doses with few treatment-related and/or low grade AEs.

Refractory Thrombocytopenia Is a Valid Early Diagnostic Criteria for Hepatic Veno-Occlusive Disease in Children.

We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed veno-occlusive disease (VOD) with 35 matched control subjects who underwent hematopoietic stem cell transplant but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared with 71.5% of the control group. VOD patients required more platelet transfusions than control subjects (median PTR, 6.9 mL/kg [range, .57 to 17.59] versus 3.57 mL/kg [range, 0 to 14.63], respectively) with a statistically significant difference (P < .0001). The number of days with platelet requirements was significantly higher for VOD patients as compared with control subjects (median 68% versus 39%, P =< .0001). The PTR peaked at ~12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value of developing VOD was 88.9% (95% confidence interval, 66.5% to 97%) in patients who were given >7 mL/kg/day of platelets during the at-risk period of days +3 to +13 after transplant. For patients who received >8 mL/kg/day of platelets, the positive predictive value of developing VOD was 86.7% (95% confidence interval, 61.2% to 96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared with severe VOD; however, the PTR was higher in patients whose VOD did not resolve. The median daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared with those who did not get defibrotide was 6.04 mL/kg and 5.72 mL/kg, respectively, but the difference was not statistically significant (P=.56). On univariate and multivariate analysis use of intravenous immunoglobulin was significantly associated with VOD (P=.0088) but was not significantly associated with fatal VOD. In conclusion, RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia, especially if they require >7 mL/kg/day of platelets.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) for Very Severe Veno-Occlusive Disease after Unmanipulated Haploidentical HSCT with Post-Transplant Cyclophosphamide

Background: The use of unmanipulated Haploidentical HSCT (Haplo-HSCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Veno-occlusive disease (VOD) is a threatening complication after both autologous and allogeneic HSCT, with high mortality rates despite early medical treatment, including the use of defibrotide. The objective of this study was to describe characteristics and outcomes of patients with refractory very severe VOD after Haplo-HSCT with PT-Cy, treated with TIPS as salvage procedure. Methods: We retrospectively analysed 176 Haplo-HSCT with Cy-post consecutively performed between 2011 and May 2019 in a single centre. VOD was defined according to modified Seattle, Baltimore or revised EBMT criteria. Severity was retrospectively graded according to revised EBMT severity criteria into four categories: mild, moderate, severe and very severe. Complete response (CR) was defined as a normal total bilirubin level (&lt;2 mg/dL) or, in patients with normal bilirubin or alternative causes of hyperbilirubinemia, as normalized renal function, reduction of elevated transaminase level &lt;50%, tense ascites resolution, and no need for oxygen supplement in the absence of alternative hypoxemia causes. Results: Sixteen patients (9.1%) met the modified Seattle, Baltimore or revised EBMT diagnostic criteria for VOD. Ultrasound with Doppler ultrasonography was performed in all patients, and at least indirect signs of VOD were found in all cases. Based on revised EBMT severity criteria, there were 2 mild (12.5%), 2 moderate (12.5%), 2 severe (12.5%) and 10 very severe (62.5%) grade VOD. Twelve patients (75%) were treated with defibrotide, including all patients with very severe VOD, except one with CNS hemorrhage (Patient 1). Six patients with very severe VOD, were treated with TIPS due to rapid clinical or analytical deterioration or refractory hepatorenal syndrome, despite medical treatment including defibrotide (Table 1). All were male patients, with a median age of 31 years (range 22-36), all transplanted with myeloablative conditioning regimen. TIPS insertion was performed on a median time since VOD diagnosis of 5 days (range 1-28) without technical complications in any case. Median total bilirubin, ALT, creatinine and INR the day of procedure were 3 mg/dL (range 2.2-11.2), 1120 UI/L (range 10-2595), 2.45 mg/dL (range 2.06-3.58) and 1.96 (range 1.1-4) respectively. Median hepatic venous pressure gradient (HVPG) prior to and after TIPS was 22.5 (range 14-29) and 6.5 (range 2-10) mmHg respectively, with a median drop of 16.5 mmHg (range 9-19). Following TIPS, all patients showed clinical improvement with hepatomegaly, ascites and renal failure resolution, and all showed analytical improvement with bilirubin, creatinine and ALT values reduction, except for patient 2, whose TIPS indication was refractory hepatorenal syndrome with normal ALT levels (Figure 1). The 5 patients who had iniciated defibrotide before TIPS, completed 21 days of treatment. All patients met criteria for CR in a median of 8 days after TIPS insertion (range 2-82). The 100-day overall survival (OS) was 100%. Five patients were alive with normal liver and renal function at last follow up, and one patient died due to infection 7 months after Haplo-HSCT, with VOD in complete resolution. Conclusions: Incidence of VOD after Haplo-HSCT with PT-Cy is comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe VOD according to revised EBMT severity criteria. For patients with rapid progressive VOD, early TIPS insertion allowed completion of defibrotide therapy. The use of TIPS together with defibrotide resulted in complete response and no associated complications with a 0% of VOD associated mortality in spite of high severity. ALT values may be the best predictor of CR after TIPS procedure. In our experience, timely and individualized use of TIPS significantly improves outcome of very severe VOD after Haplo-HSCT. Therefore, TIPS should be promptly considered in rapid progressive cases. Disclosures No relevant conflicts of interest to declare.

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Role of Initiating Supportive Care Preceding Veno-occlusive Disease Diagnosis Following Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Severe veno-occlusive disease (VOD) following hematopoietic stem cell transplantation has a high mortality rate. The clinical course of VOD, role of preemptive and aggressive supportive care, and outcomes were investigated in a retrospective study from 2007 to 2014. Defibrotide was not available in all but one case with VOD at our center during the study. Forty-nine allogeneic transplants with intravenous busulfan-based or total body irradiation-based myeloablative conditioning were included. The median after hematopoietic stem cell transplantation day for suspicion of developing VOD (pre-VOD phase) was 6 due to weight gain, hepatomegaly, and/or mild increase in total bilirubin without fulfilling the modified Seattle criteria in 22 cases (45%). Despite fluid restriction, aggressive diuresis, and fresh frozen plasma infusions, 16 patients (33%) developed VOD by +10 days. Five cases (31%) had severe, 9 (56%) moderate, and 2 (13%) mild VOD. Eight cases (50%) required transfer to intensive care. One patient was given defibrotide, which was later discontinued due to concerns of adverse effects. Day +100 survival was 100% with complete resolution of VOD. Preemptive and aggressive supportive care could help achieve favorable outcomes in VOD and may have ameliorated the severity. This approach may be combined with other measures in the prevention/treatment of VOD.

Economic Burden of Veno-occlusive Disease in Patients With B-cell Acute Lymphoblastic Leukemia in the United States

PurposeThe goal of this study was to evaluate the incidence, inpatient mortality, and economic burden of hepatic veno-occlusive disease (VOD) in adults with B-cell acute lymphoblastic leukemia (ALL) in the United States. MethodsUsing MarketScan Commercial Claims and Encounters Database and Medicare Supplemental and Coordination of Benefits Database, data for patients with B-cell ALL from April 1, 2009, to October 31, 2016, were extracted by using diagnosis codes. VOD was identified based on clinical criteria and expert opinions. Patients with VOD were followed up from diagnosis of VOD until the earliest occurrence of inpatient death, end of continuous enrollment, end of study period, or for a maximum of 100 days. The incidence of VOD and VOD-associated inpatient mortality were calculated. VOD-related health care costs based on paid adjudicated claims were calculated. FindingsOf the 2571 adults with B-cell ALL, the overall incidence of VOD was low at 3.4% (88 of 2571). Of these patients with VOD, 52% (46 of 88) experienced multiorgan failure and were identified as having severe VOD. VOD was only identified in patients having undergone hematopoietic stem cell transplantation (5.4% [88 of 1624]). The inpatient mortality rate of those with any VOD over the 100-day postindex period was 26.1%, and the inpatient mortality was even higher for patients with severe VOD (37.0%). Total mean (SD) medical costs per patient during the 100 days’ post-VOD diagnosis were $55,975 ($160,335); mean (SD) costs per patient were ∼4-fold higher for severe ($86,953 [$206,906]) versus nonsevere ($22,047 [$72,847]) VOD. ImplicationsClinical criteria were used to identify VOD events and thus VOD might be underdiagnosed. The mortality of VOD also might be underestimated because only inpatient deaths are captured in the data. The incidence and mortality of VOD could also be underestimated because we focused on adult patients who might receive reduced-intensity treatment. The economic burden of VOD may be underestimated because the Healthcare Common Procedure Coding System code specific for defibrotide was not available, and thus the cost for defibrotide might not be included. Finally, as the study population consisted of patients with commercial or Medicare supplemental insurance, results may not be generalizable to all patients with VOD in the United States. Although VOD occurred infrequently in adults with B-cell ALL, it was associated with high inpatient mortality and substantial costs. Patients with severe VOD were associated with highest mortality and highest costs. Given the clinical and economic burden associated with VOD, it is important that patients at high risk for VOD be identified and treated to minimize this risk.

PSY112 - Healthcare Resource Use (HRU) Associated with Severe Adverse Events (AES) Of Interest in Adults With Relapsed or Refractory (R/R) B-Precursor Acute Lymphoblastic Leukemia (All) In Eu-4 Countries

To estimate HRU associated with severe AEs of interest in adults with R/R B-precursor ALL in EU-4 countries (France, Italy, Spain and UK). A Delphi-based methodology was employed which comprised two phases: a questionnaire administered to clinicians (phase 1) and a country-specific panel to discuss the phase 1 results to generate robust point estimates (phase 2). Physicians must be board certified and have at least 5-years’ experience with R/R ALL. Four types of grade 3/4 AEs (vascular events, infections, cytopenia and gastrointestinal events) were evaluated. Outcomes included number of outpatient day visits, length of stay (LOS) in hospital and LOS in intense care unit (ICU) (in days). Four clinicians from UK, and three clinicians from Spain, France, and Italy were enrolled with a median of 10 years’ experience treating R/R ALL. In France, average number of outpatient day visits was highest for diarrhea (2.5), while veno-occlusive disease (VOD) and septic shock (SS) led to longest average LOS in hospital (17.5). SS also required longest LOS in ICU (4.5). In Italy, viral infection needed highest number of outpatient day visits (7.3) and VOD had longest inpatient LOS (22.5). SS had longest LOS in ICU (13.7). In Spain, thrombocytopenia incurred highest number of outpatient day visits (3.3) and VOD had longest inpatient LOS (16.0). SS led to highest LOS in ICU (9). In the UK, fungal infection incurred highest average number of outpatient day visits (3.8) while VOD led to longest inpatient LOS (16.8). Again, SS needed longest LOS in ICU (7.5). In the EU-4 countries, severe VOD universally incurred the highest LOS in hospital (16~22.5 days) and severe SS had highest LOS in ICU (4~13.7 days) among adults with R/R B-precursor ALL. Novel therapies that can improve outcomes while reducing the incidence of these AEs are needed.