Abstract: Background: The indications for treating children with immune thrombocytopenia (ITP) remain controversial. A valid and reliable bleeding assessment tool could assist in objectively quantifying bleeding and influence treatment decisions. Both the ITP Bleeding Score (IBLS) and the ITP-Bleeding Assessment Tool (BAT) have been developed to assess bleeding severity in ITP. The IBLS scores bleeding severity using an 11-item tool with grading from 0 to 2 and the 18-item BAT grades from 0 to 3 or 4. The BAT includes some types of bleeding not represented on the IBLS, such has intramuscular hematomas. To date, no data describe how these two measures compare when measuring bleeding associated with ITP. Objective: To describe and compare bleeding as assessed by both the IBLS and BAT and to correlate bleeding severity with platelet counts in a cohort of children with ITP. Methods: A longitudinal observational cohort of children ages 〉 1 and 〈 18 years with ITP, were enrolled from 2013-2015 in the Pediatric ITP Consortium of North America ICON1 trial. All children were enrolled prior to starting a new second line monotherapy (not IVIG, steroids or anti-D). At enrollment, bleeding was assessed using the IBLS in all children. A subset of children also underwent a BAT assessment. Grades of bleeding were described and compared between tools and agreement in grading was assessed. Severity was correlated with platelet count using Spearman's correlation calculation. Results: 118 children were enrolled from 21 ICON centers. 54% had chronic ITP and the median age was 11.4y (range 1.2-17.8). The mean platelet count was 28 x 109/l (SD 57) and 88% had a baseline platelet count of 〈 30 x 109/l. The burden of skin and oral bleeding was high. Table 1 compares bleeding scores for the 78 patients with both measures. Agreement for grades 0, 1, and 2 between the measures was highest for urinary bleeding (97%), gastrointestinal (95%), subconjunctival (95%), and epistaxis (91%). Agreement between IBLS oral bleeding by historyand BAT gum bleeding was 78% and with BAT oral cavity bleeding was 79%. IBLS oral bleeding by physical examination and BAT gum bleeding was 73% and BAT oral cavity bleeding was 79%. The lowest agreement was seen for skin manifestations. IBLS skin bleeding by history showed only 54% and 62% agreement with the BAT ecchymoses and petechiae items respectively. IBLS skin bleeding by physical examination showed 59% agreement with both the BAT ecchymoses and petechiae items. Grades 3 and 4 scores from the BAT did not provide additional information beyond the IBLS for most sites of bleeding. For sites included on the BAT but not represented on the IBLS, only 1 child had an intramuscular hematoma, 1 suffered an ocular bleed, and none experienced hemarthrosis. Bleeding from minor wounds and bleeding with tooth loss captured additional bleeding symptoms in 9 and 4 children, respectively. There were no episodes of pulmonary or intracranial hemorrhage in the cohort. Table 2 shows the correlation between bleeding severity and platelet count for all items on each measure. Conclusion: The IBLS and BAT were similarly effective at identifying bleeding symptoms, although neither tool showed strong correlation with the platelet count. There were moderate correlations noted between skin bleeding scores and platelet counts for both tools. A major limitation of this comparison is the different definitions of bleeding severity between the two measures. For sites where the items were more detailed, agreement declined (i.e. adding specificity reduced generalizability). While no patients in our cohort exhibited significant grade 3 or 4 bleeding outside of skin findings, we conclude that in the setting of clinical trials, the ability to capture very severe bleeding might be an important distinction that supports using the more complicated BAT, but for clinical practice, a simplified assessment such as the IBLS may suffice. Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Neufeld:Novartis: Consultancy. Bussel:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immunomedics: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; BiologicTx: Research Funding. Haley:CSL Behring: Honoraria; Baxalta: Membership on an entity's Board of Directors or advisory committees. Thompson:Celgene: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta (now part of Shire): Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Consultancy, Research Funding; Mast: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lily: Research Funding; Eli Lily: Research Funding.

Abstract: 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)

Abstract: Background: The impact of second line therapies on health related quality of life (HRQoL) and fatigue in pediatric patients with ITP is not well studied. Objective: To describe the impact of second line therapies on HRQoL and fatigue in North American pediatric patients with ITP. Methods: A longitudinal observational cohort of 120 children with ITP starting second line treatments was enrolled from 2013-2015 at 21 ICON centers. Enrollment requirements included age 1-17y and starting a second line treatment (not IVIG, corticosteroids or anti-D immunoglobulin) as monotherapy. HRQoL (Kids ITP Tool - KIT) and fatigue (Hockenberry Fatigue Scale - FS) surveys were completed prior to starting treatment (baseline) and 1 and 12 months after starting treatment by patient/caregiver. KIT is scored from 0 (worst) to 100 (best), and the FS scores were re-scaled so that 0 is no fatigue and 100 is highest fatigue. At the same time points as the patient/caregiver surveys, physicians assessed the perceived effect of treatment on patient HRQoL using a 7-point scale. ANOVA was used to compare the baseline means of the treatment groups. This study specifically compared change from baseline to 1 month in the KIT and FS using paired t-tests within each treatment group. The 12 month timepoint was not used in the paired analysis of individual treatments due to attrition between 1 and 12 months. Results: The median age at enrollment was 11.3 y (1.2-17.8), and 16% (19/120) had newly diagnosed ITP, 31% (37/120) had persistent ITP, and 53% (64/120) had chronic ITP. The median number of prior treatments was 3 (range: 1-9). Fifty-eight (48%) patients had received at least one prior second line treatment. Treatments selected for second line treatment included: rituximab (n=43), romiplostim (n=31), eltrombopag (n=20), oral immunosuppressants (n=19), splenectomy (n=4), and dapsone (n=3). The child and parent proxy KIT scores significantly improved on rituximab (p & lt;0.001 for both), oral immunosuppressants (p=0.02, p=0.001), and eltrombopag (p=0.01 for both). Child KIT scores also significantly improved on romiplostim (p=0.003); however, there was no significant change in the parent proxy score (p=0.29). The parent impact KIT scores significantly improved from baseline to 1 month on all treatments (p & lt;0.001), although the scores were not significantly different between treatment types (p=0.67). Child, parent proxy, and parent impact KIT scores significantly increased between 1 month and 12 months in paired analysis combining treatments (p & lt;0.001). As previously described, at enrollment, physicians reported that ITP had impacted the patients' HRQoL severely in 15%, significantly in 45%, moderately in 38%, and almost not at all in 3%. Physicians reported that HRQoL improved in 68% (range: 64-75%) of patients while on treatment from baseline to 1 month with no significant difference by treatment group (p=0.46). The physician's assessment of the patient's baseline HRQoL significantly correlated with the child and parent proxy KIT report (p & lt;0.0001); however, after 1 month of treatment, the physician's assessment no longer correlated with the child (p=0.26) or parent proxy KIT report (p=0.11). At enrollment, the median FS-Child score (n=54) was 18.5 (range 0-85), the median FS-Adolescent score (n=42) was 20.2 (0-73), and the median FS-Parent (n= 100) score was 35 (7-81). One month FS-Child improved for those who were treated with rituximab (p=0.03); there was no significant change in fatigue on the other treatments. One month FS-Parent significantly improved for those treated with rituximab (p=0.015) and eltrombopag (p=0.009). Conclusions: In this pediatric cohort, all second line treatments appear to significantly improve HRQoL in ITP. Rituximab had the greatest impact in decreasing fatigue at one month. Physician assessment of patient HRQoL did not correlate well with patient assessment after treatment was started, suggesting there may be challenges in ascertaining the effect of treatment on HRQoL. Future analysis of ICON1 will consider the impact of treatment on HRQoL and fatigue while also accounting for the treatment effect on bleeding and platelet count. Disclosures Grace: Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klaassen: Amgen: Consultancy; Hoffman-La Roche LTD: Consultancy; Octapharma: Honoraria; Baxalta: Honoraria; Biogen Canada LTD: Consultancy; Agios Pharmaceuticals: Consultancy. Despotovic: Sanofi: Consultancy; Schell Cooley LLP: Other: Expert witness. Bussel: Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rothman: Pfizer: Consultancy; Agios Pharmaceuticals: Honoraria. Haley: Genentech: Honoraria; Baxalta: Honoraria; CSL Behring: Honoraria. Neufeld: Octapharma: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lambert: Educational Concepts in Medicine: Honoraria; Novartis: Honoraria; AstraZeneca: Research Funding.

Abstract: Introduction A 4-year-old child presented with neck pain for several months which progressed to jaw pain and limitation in opening of the jaw. Eventual diagnosis of Kaposiform hemangioendothelioma is notable for the later age of presentation, the involvement of bone and soft tissue and the response to therapy. Case In March of 2020 child first developed sore throat and pain in his neck which led to limitation in neck movements. An enlarged tonsil was noted and treated. Symptoms improved only to recur and worsen by August 2020. Child was waking up with pain at night. Tonsils were removed in September to address this. Shortly thereafter, his mouth wouldn't open well. They saw several physicians without a definitive diagnosis for this including pediatrician, ENT and audiology. In late February 2021 ENT was re-consulted. A lytic lesion was discovered on X-ray. MRI further elucidated this as a destructive mass within the right mandibular ramus with soft tissue extension. A biopsy then characterized it as a Kaposiform Hemangioendothelioma. The biopsy showed a cellular vascular neoplasm forming variable small lobules with intervening fibrous tissue. The cells were monotonous and flat to spindled. Slit-like spaces and glomeruloid structures were seen. CD31 and D2-40 stains highlighted the endothelial cells and SMA stain pericytes. HHV8 stain was negative. No laboratory evidence of consumptive coagulopathy was noted. there was no evidence of Kasabach Merritt syndrome (KMP) Management Given the location of tumor and risks and morbidity of surgery, child was initiated on oral sirolimus aiming for a trough between 10 and 15 ng/ml and prednisone therapy with rapid taper in 4 weeks. Significant reduction in size of tumor was noted on serial scans. It measured 3.9 cm in craniocaudal, 2.8 cm in transverse, and 3.5 cm in AP dimension at diagnosis and reduced to 3.5 x 1.9 x 2.8 cm within 6 weeks. Child had improved mobility of jaw and improved speech. Nocturnal pain resolved on steroids but recurred off steroids. Aspirin was added to the treatment when steroids were weaned and helped resolve the pain. Hypercholesterolemia was noted on sirolimus, but otherwise very well tolerated at this dose. Clinical exam and serial MRIs have shown continued response to therapy. Summary We present this case as a rare presentation in an older child with the mandibular bone as the primary site. Kaposiform hemangioendotheliomas are very rare, and usually seen in the newborn or early infancy. The occurrence later in life with bone and adjacent soft tissue primary and cervicofacial location is more rare. Although 70% of KHE are complicated by Kassabach Merritt phenomenon, the older age and location in bone are features that have been associated with lack of KMP in larger series. In many cases surgical management would be preferred, but given the location of this tumor, we opted for medical therapy with sirolimus and prednisone. The impressive response to therapy is encouraging and makes us hopeful that we may decrease size such that surgery is less morbid or avoid surgery entirely. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Gorham–Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications, including pain and pathologic fractures. As with other vascular anomalies, somatic mosaic mutations in oncogenes are often present, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggests additional targeted therapies could be effective.

Abstract: Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype–genotype correlation and have expanded medical therapy for this group of unique disorders.

Abstract: Transplant‐associated thrombotic microangiopathy (TA‐TMA) is an endothelial injury complication of hematopoietic stem cell transplant (HSCT) leading to end‐organ damage and high morbidity and mortality. Defibrotide is an anti‐inflammatory and antithrombotic agent that may protect the endothelium during conditioning. Procedure We hypothesized that prophylactic use of defibrotide during HSCT conditioning and acute recovery could prevent TA‐TMA. A pilot single‐arm phase II trial (NCT#03384693) evaluated the safety and feasibility of administering prophylactic defibrotide to high‐risk pediatric patients during HSCT and assessed if prophylactic defibrotide prevented TA‐TMA compared to historic controls. Patients received defibrotide 6.25 mg/kg IV q6h the day prior to the start of conditioning through day +21. Patients were prospectively monitored for TA‐TMA from admission through week 24 post transplant. Potential biomarkers of endothelial injury (suppression of tumorigenicity 2 [ST2], angiopoietin‐2 [ANG‐2] , plasminogen activator inhibitor‐1 [PAI‐1], and free hemoglobin) were analyzed. Results Twenty‐five patients were enrolled, 14 undergoing tandem autologous HSCT for neuroblastoma and 11 undergoing allogeneic HSCT. Defibrotide was discontinued early due to possibly related clinically significant bleeding in 12% (3/25) of patients; no other severe adverse events occurred due to the study intervention. The other 22 patients missed a median of 0.7% of doses (0%–5.2%). One patient developed nonsevere TA‐TMA 12 days post HSCT. This observed TA‐TMA incidence of 4% was below the historic rate of 18%–40% in a similar population of allogeneic and autologous patients. Conclusions Our study provides evidence that defibrotide prophylaxis is feasible in pediatric patients undergoing HSCT at high risk for TA‐TMA and preliminary data indicating that defibrotide may reduce the risk of TA‐TMA.