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Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked ABCD1 gene, resulting in the inability to transport acylated very long chain fatty acids (VLCFAs) into the peroxisome for degradation. VLCFAs subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe progressive demyelinating form of ALD, cerebral ALD, resulting in regions of demyelination observed on brain magnetic resonance imaging that are associated with a “garland ring” of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) has been shown to halt neurologic progression, although the mechanism of disease arrest is unknown. We evaluated imaging- and transplant-related biomarkers in 66 males who underwent HCT. In 77% of patients, gadolinium contrast resolved by 60 days post-HCT. We determined that time to neutrophil recovery and extent of donor chimerism correlated significantly with time to contrast resolution post-HCT. Graft failure was associated with a significantly slower rate of contrast resolution (P < .0001). Time to neutrophil recovery remained significant in multivariate analysis with other biomarkers (P = .03). Our data suggest that robust donor myeloid recovery is necessary for timely repair of the BBB.

Background: Severe organ damage from acute graft-versus-host disease (aGVHD) results in a high risk of morbidity and mortality. Treatments that focus on immunosuppression alone do not consistently improve long-term survival. Modalities that aid in inflammation resolution, immune tolerance, and tissue repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening aGVHD. We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF, Pregnyl®, Organon, USA) to standard aGVHD therapy in a prospective Phase 2 clinical trial (NCT02525029) conducted at the University of Minnesota and Rush University, extending from our previously published Phase 1 study results (Holtan et al, Blood Advances, 2020) showing uhCG/EGF to be safe and preliminarily efficacious as aGVHD therapy. Methods: Patients with new onset Minnesota (MN) high risk aGVHD (N=22) or with aGVHD requiring 2nd line therapy (N=22) received methylprednisolone 48 mg/m2/day plus 2,000 units/m2 of uhCG/EGF subcutaneously (SQ) every other day for 1 week (high risk arm). Patients in need of 2nd line aGVHD therapy received 2,000 - 5,000 units/m2 SQ every other day, with dose depending on organ severity, for 2 weeks plus standard of care immunosuppression (anti-thymocyte globulin (N=4), etanercept (N=1), ruxolitinib (N=5), sirolimus (N=4), steroid boost (N=8)). Patients who achieved a complete or partial response (CR/PR) after their initial course of therapy received twice weekly maintenance doses for the next 5 weeks. Exploratory metabolomic profiling was performed using mass spectrometry. Results: The median age was 61 years (range 2 years - 72 years, 75% male). The majority of patients had stage 3-4 lower GI GVHD (52%) and overall grade III-IV aGVHD (75%) at time of enrollment, with a median baseline albumin of 2.6 g/dl (range 0.9 - 4 g/dl) and median baseline Karnofsky performance status of 50 (range 20-100). The proportion of patients with a response (CR/PR) at day 28 (primary endpoint) was 68% (57% CR, 11% PR, Figure 1A). Among MN high risk patients receiving 1st line steroids, 64% achieved a CR at day 28 (0% PR). Among patients receiving 2nd line therapy, 50% achieved a CR and 23% PR at day 28. The median overall survival for the entire cohort was 1.2 years (Figure 1B), with a 2-year survival of 67% for responders and 12% for non-responders (p Conclusion: Our Phase 2 study demonstrates that uhCG/EGF is a promising addition to systemic therapy in patients with life-threatening aGVHD. The overall survival result is encouraging considering historical median survival of Figure 1 Figure 1. Disclosures Holtan: Incyte: Consultancy, Research Funding; Generon: Consultancy. Ustun: novartis: Honoraria; Blueprint: Honoraria. Arora: Pharmacyclics: Research Funding; Syndax: Research Funding; Kadmom: Research Funding. Bachanova: Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: CSL Behring: Research Funding; Mitobridge, an Astellas Company: Consultancy, Research Funding. Brunstein: GamidaCell: Research Funding; NANT: Research Funding; FATE: Research Funding; BlueRock: Research Funding; AlloVir: Consultancy. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. OffLabel Disclosure: uhCG/EGF has FDA orphan drug designation to treat acute GVHD.

Background: Hematopoietic stem cell transplantation (HCT) is a primary treatment option for various inherited metabolic diseases (IMDs). Successful engraftment is crucial for favorable survival and functional outcomes and correlates with optimal conditioning in these patients with an intact immune system. Traditional regimens have used myeloablative Busulfan and Cyclophosphamide (BuCy) which is associated with significant potential morbidity. Alternate reduced toxicity regimens, like Busulfan and Fludarabine (BuFlu), are often utilized to reduce treatment related toxicities. Objective: To compare outcomes and complications with BuCy and BuFlu based conditioning regimens in patients with IMDs. Methods: This is the largest single institution retrospective analysis of University of Minnesota's transplant database for patients with IMDs who underwent HCT using BuCy + campath or BuFlu + ATG based preparative regimen from March 2008 to September 2017. Incidence of neutrophil and platelet recovery were determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary aplastic graft failure, primary graft failure with autologous recovery, secondary aplastic failure and secondary graft failure with autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined. Results: Total of 99 patients were studied who underwent HCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs transplanted and umbilical cord blood was the most common donor source (74%). One-year overall survival was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with a similar incidence of grade 3-4 acute GVHD (9% in BuCy vs. 6% in BuFlu; p=0.5) and chronic GVHD (9% in BuCy vs. 7% in BuFlu; p=0.67) in the two groups. Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu group (median 21 d vs. 34 d, p = 0.002). The cumulative incidence of graft failure was higher with BuFlu conditioning (29% vs 14%, p= 0.08, Figure 1a). Significantly higher rates of second HCT was noted following BuFlu conditioning (27% vs. 3%, p= 0.001; Figure 1b). The incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were notably higher in the BuCy group. Though donor myeloid engraftment was similar in both groups, donor T-cell engraftment occurred sooner with BuCy conditioning until 1-year post transplant (Figure 2). Conclusions: Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but is associated with a high rate of graft failure in patients with IMD. Alternate immune suppressive agents should be considered to reduce graft failure and minimize toxicities. Alternate donor options, including expanded UCB, should also be considered to improve engraftment in patients with IMDs. Disclosures Shanley: Magenta Therapeutics: Research Funding. Miller:Sangamo Therapeutics: Employment. Orchard:Magenta Therapeutics: Research Funding.

Cerebral leukodystrophy is an X-linked peroxisomal disease characterized by mutations in the ABCD1 gene, resulting in the lack of very long chain fatty acid (VLCFA) transport into peroxisomes. Resultant VLCFA build up in the blood and tissues leads to adrenal gland insufficiency in 95% of boys and a progressive inflammatory cerebral demyelinating process in 40% of patients, which is progressive and most often fatal (cALD). Only hematopoietic stem cell transplant (HSCT) has been shown to halt cerebral disease progression. A key clinical feature of cALD is disruption of the blood brain barrier (BBB) illustrated by gadolinium (gad) contrast enhancement on brain MRI at diagnosis and as an indicator of "active" cerebral disease. Following successful donor neutrophil recovery after HSCT, gad enhancement resolves in the majority of cases by 100 days post HSCT in our experience. A seminal question in the field is how recovery of donor-derived hematopoiesis relates to BBB repair and gad resolution. We evaluated the pre-HSCT characteristics and 1- year post-HSCT outcomes in 78 boys undergoing marrow or umbilical cord blood HSCT for cALD. The median total nucleated cell (TNC) dose was 0.8 x 108cells/kg and CD34+ cell dose was 1.27 x 106cells/kg. Pre-HSCT characteristics included: cALD on MRI quantitated using the Loes scoring system, neurologic disability using the neurologic function scale (NFS), plasma and cerebral spinal fluid (CSF) chitotriosidase level, and intensity of gadolinium on pre-HSCT MRI (gad score). We found 39 boys (59%) had gad resolution by day +28 (early) post-HSCT and 79% had gad resolution by day +100 (later) post-HSCT. Patients with gad resolution by day +28 post-HSCT had lower Loes scores at 1-year (p = 0.008), lower absolute NFS (p = 0.004), and less progression of neurologic symptoms (post-HSCT NFS - pre-HSCT NFS, p = 0.02). Graft failure had occurred in 13% of patients with early gad resolution and in 40% in those without early gad resolution (Fishers exact test p = 0.01). Interestingly, in patients without graft failure we found neutrophil recovery occurred at a mean of 16 days in the early patients compared to 20 days in those without gad resolution (p = 0.02).Factors associated with early gad resolution were: lower Loes score (p = 0.003), lower NFS (p = 0.003), lower plasma chitotriosidase (p = 0.02), lower CSF chitotriosidase (p = 0.02), day of neutrophil recovery post-HSCT (p = 0.008), and lower gad score (p = 0.02). On multivariate analysis, only the day of neutrophil recovery post-HSCT remained significant with p = 0.04). There was no significant difference in cell dose between the groups. This is the first study to link neutrophil recovery following HSCT and early repair of the BBB (gadolinium resolution). This is an important observation, as gad resolution is thought to be an indicator of cerebral disease arrest and activity of neuroinflammation. This observation may also serve as a useful biomarker as new therapies for cALD are being developed, including gene therapy and CD34 expansion. Figure. Figure. Disclosures Lund: Magenta Therapeutics: Research Funding. Miller:Sangamo Therapeutics: Employment. Orchard:Magenta Therapeutics: Research Funding.

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency due to defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in failure of killing intracellular pathogens. Clinical presentation and management of these patients remains heterogeneous. Current management involves non-transplant therapy with interferon-gamma and supportive care, or hematopoietic stem cell transplant (HSCT) in severe cases. There has been limited data on morbidity and outcomes with different treatment options using patient registries. There has been no registry-based study of CGD patients from the United States comparing different treatment options. Methods: We performed a multi-institutional analysis of data from the United States Immunodeficiency Network (USIDNET) registry, comparing morbidity, mortality, and different treatment options. Retrospective review of data from its inception in 1992 through 2016 was performed. We analyzed demographic, co-morbidity and treatment information (HSCT versus non-transplant therapy). Logistic regression was used to compare overall survival (OS), transplant related survival (TRS) and frequency of serious infections and co-morbidities among the treatment groups. Multivariate logistic regression was used to evaluate factors affecting survival. Results: Within the database, 507 CGD patients were identified, with 84% male. X-linked inheritance was most common (73%) with about 78% of patients having gp91 mutation. Of 507 patients, about 10% underwent HSCT (n=50). Overall mortality was 15% with relatively lower incidence in HSCT group (12%). In HSCT cohort, median age at transplant was 13.5 years (0.6-37.3 years), with 74% receiving reduced intensity conditioning (RIC). The most common graft source was peripheral blood stem cells (60%) from a matched-unrelated donor (72%). No mortality was reported in patients who received stem cells from matched siblings and in those who received bone marrow graft with RIC, at median follow-up of 24 months (range 3-402 months). Survival analysis included 302 patients. OS was not significantly different between HSCT and non-transplant groups (p=0.50; Figure 1 a, b). Among patients who underwent HSCT, there was significantly improved TRS in those transplanted before 14 years of age (p= 0.035, HR: 4.51; Figure 1 c, d). The proportion of patients who had >3 infections prior to transplant was significantly reduced by 2-years post-transplant (p < 0.0001, Figure 2). The rate of serious infections prior to transplant was significantly lower in patients transplanted at Conclusion: This is the largest reported American CGD cohort. HSCT at Disclosures No relevant conflicts of interest to declare.

Background:Dyskeratosis congenita (DKC) is a rare genetic bone marrow failure (BMF) syndrome of unknown etiology with a multisystem involvement and predisposition for cancer. It presents as a classic triad of dystrophic nails, oral leukoplakia and skin hyperpigmentation. Hematopoietic stem cell transplant (HSCT) has been tried as a treatment option but there is limited data on outcomes in these patients. Methods:As the disease is rare with high mortality, there have been no prospective studies. Retrospective database analysis is an effective means to evaluate outcomes in this patient population. Our study utilized Pediatric Health Information Systems (PHIS) database, which is an administrative quality-controlled database from 43 not-for-profit children's hospital, to analyze healthcare outcomes in pediatric patients with DKC. ICD-9 code 757.39 was used to identify the disease classification and as the only condition with an indication for stem cell transplant, we isolated the cases that underwent HSCT with that diagnostic code. Results: A total of 40 patients with DKC were identified who underwent transplant. A higher incidence was noted in Caucasian males with no significant difference in mortality across gender and ethnicity. The median length of hospitalization was 48 days (range 8.5 to 160.5 days) with a mean age of hospital admission at 93 months (95% CI: 70, 117). All the transplants were allogeneic with almost 20% umbilical cord (UCT) stem cell transplants. There was 15% mortality noted in this patient population, with all of deaths occurring prior to 2012. The complication rate (including acute and chronic GVHD as well as graft failure) was noted to be 37.5%, with acute GVHD being most common (20%). Fludarabine, Alemtuzumab, Cyclophosphamide, and Melphalan based conditioning regimen were most commonly used. Cyclosporine (65%), steroids (80%), Mycophenolate mofetil (50%) and Tacrolimus (40%) were commonly used for GVHD prophylaxis. Despite small numbers, significantly lower mortality was noted in UCT as compared to the other allogeneic stem cell transplants (p Conclusion: Limited literature is available on pediatric transplant outcome data in DKC. UCT has better transplant outcomes in DKC patients due to longer telomere lengths of donor stem cells. Larger studies are needed for to compare transplant outcomes from different sources. Disclosures No relevant conflicts of interest to declare.

Background: Aplastic anemia (AA) is a rare bone marrow failure (BMF) syndrome of unknown etiology characterized by hypocellular bone marrow and severe persistent pancytopenia. Pediatric AA is more common in adolescent age group with better outcomes as compared to adults. Current treatment modalities include immunosuppressive therapy (IST) or matched related bone marrow transplant, when possible. There is a high risk of disease relapse with IST and clonal evolution into myelodysplastic syndrome. There is limited pediatric data on outcomes with different treatment options. Methods: Retrospective database analysis of Pediatric Health Information Systems (PHIS) database was performed to evaluate healthcare outcomes of pediatric patients (age less than 21 years) with AA from January 1, 2006 to December 31, 2015. PHIS is an administrative quality-controlled database from 43 not-for-profit children's hospitals. ICD-9 code 284.9 was used to identify patients with acquired AA. Appropriate procedure and pharmacy billing codes were used to obtain information regarding transplants and various drugs used. SAS based statistical software was used to perform analysis. Results: A total of 5127 inpatient admissions were noted for AA during the study period. An overall increasing trend of transplant was observed from 2006-2015 (Figure 1). Almost equal inpatient admission rate was noted in males and females, with a slightly higher rate amongst males who underwent transplant (55% vs 45%). Inpatient admission was more common amongst whites in both transplant (n=407, 8%) and non-transplant groups (n=4717, 92%; Table 1). Overall inpatient mortality was about 2% with a similar mortality in those who underwent transplant (5%). Cyclosporine (n= 1785, 38%) and steroids were most common immunosuppressive drugs used in non-transplant group. In the transplant group (Table 2), graft failure (20%) was the most common complication, while Cyclophosphamide (77%), Fludarabine (53%) and anti-thymocyte globulin (31%) based conditioning was most commonly used. Transplant itself was an independent risk factor for mortality (p=0.04) along with graft failure (p=0.02). Steroids (92%) and Cyclosporine (73%) were the most common immunosuppression used. Conclusion: Hematopoietic stem cell transplants have good outcomes in pediatric AA patients. With an increasing trend of HSCT in these patients, successful outcomes with other transplant options such as match unrelated donor transplants should be considered. Treatment algorithm for Pediatric AA needs to be revised to include other transplant sources. Download : Download high-res image (102KB) Download : Download full-size image Download : Download high-res image (231KB) Download : Download full-size image Download : Download high-res image (323KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Abstract 339 Clinical Predictors Of All-Cause In-Hospital Mortality In Patients With Sickle Cell Disease in United States- First Reported Results From A Nationally Representative Sample. Background: Sickle cell disease is the most common monogenic abnormality affecting 70,000–100,000 people in the US, with a reported in-hospital mortality rate of 0.3–0.7%. Predictors of mortality in SCD however remain largely undefined and under-explored. In 2000, data from the Cooperative Study of Sickle Cell Disease had proposed dactylitis, severe anemia and leukocytosis as predictors of adverse events, including death in SCD (Miller et al, NEJM, 2000 13;342(2):83–9). Recently, various demographic predictors of in-hospital mortality including hospital volume, hospital teaching status, and patient socioeconomic status were proposed (McCavit et al Amer Jour Hematology, 2011, 86(4):377–80). However, till date no study has explored the clinical predictors of in-hospital mortality in patients with SCD. Aim: This study aims to explore the various clinical predictors of all cause mortality in hospitalized SCD patients using a nationally representative database. Methods: We used the Nationwide Inpatient Sample (NIS) database for the study. NIS is a stratified probability sample of 20% of all hospital discharges among U.S. community hospitals (n=1,044, sampling universe = 90% of all such discharges) sponsored by the Agency for Health Care Quality and Research. Presence of following ICD-9-CM diagnosis codes were used to define SCD related hospitalizations: 282.41, 282.42, 282.5, 282.60, 282.61, 282.62, 282.63, 282.64, 282.68, and 282.69. ICD-9-CM 99.04, 99.01 were used to identify packed red cell transfusion and exchange transfusion respectively. ICD-9-CM code 517.3 was used to identify ACS and 995.91, 995.92, and 038 were used to identify sepsis as a diagnosis during hospitalization for SCD. Only data on SCD related hospitalizations and mortality were analyzed. Sampling weights were applied to represent all community hospital discharges in the US for the year 2007. Univariate and multivariable logistic regression was performed for statistical analysis. A 2-sided p-value of Results: In 2007, there were a total of 166,084 admissions with a diagnosis of SCD. Of these, 86,318 discharges had SCD as the primary diagnosis upon admission and 79,766 had SCD as one of the secondary diagnoses during the admission. Of these, males represented 37.5% of SCD related hospitalizations. There were a total of 844 deaths reported in the above admissions with an all-cause in-hospital mortality rate of 0.5%. Of these, 420(49.7%) were females. In the multivariable logistic regression model, the following clinical factors were independently associated with statistically significantly higher odds of mortality: Male gender, every ten year increase in age, history of at least one PRBC transfusion, history of exchange transfusion, diagnosis of acute chest syndrome and development of sepsis during the admissions (Table 1). On univariate analysis, history of mechanical ventilation (either non-invasive or invasive) was also a highly significant independent predictor of mortality [estimated OR (95% CI) = 120.9 (82.7–176.9)]. However, we did not include this in the final model as it can be an intermediary for other factors in the pathway leading to mortality and thus potentially introduce confounding in our analysis. Conclusion: This study proposes for the first time, a set of clinical factors which are independent predictors of all –cause mortality in hospitalized patients with SCD. We propose that early and targeted aggressive therapy based on the presence of these factors should guide the management of hospitalized SCD patients for improved mortality. Disclosures: Krishnamurti: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding.

Abstract 2559 Objectives: Thrombotic microangiopathy requires frequent healthcare encounters in the form of frequent hospitalizations. Analysis of trends in disease burden is important to study the changing epidemiology and healthcare utilization. To date, there are no national data on the in- hospital care of Thrombotic Microangiopathy. Aim: The aim of our study was to examine national trends and healthcare utilization for thrombotic microangiopathy related hospital admissions. Methods: Data from the Nationwide Inpatient Sample (NIS), a part of the Healthcare Cost and Utilization Project (HCUP) is used. NIS is the largest all-payer inpatient database in the United States. It is a powerful database which gives a stratified probability sample of 20% of all hospital discharges among U.S. community hospitals (n = 1,044, sampling universe of all discharges). Sampling weights were applied to represent all community hospital discharges in the US for the year 2007. We used the International Classification of Diseases, 9th Revision, Clinical Modification codes to identify thrombotic microangiopathy (ICD-9 code 446.6) related visits. The annualized number of visits was examined from 1997 to 2006, as therapeutic plasmapheresis is not reported as an in-patient procedure by NIS after 2006. Results: There were an estimated annual 1.35 per 100,000 population thrombotic microangiopathy related visits in 1997 which decreased to 0.79 per 100,000 visits in 2006. There was a steady increase in hospitalizations from 1997–2002, followed by a decreasing trend from 2004–2006. Women were significantly more affected than men across all age groups and had a significantly higher rate of hospitalization (p Conclusions: We present the first national data of the burden of in hospital health care utilization of Thrombotic microangiopathies in the United States. These data suggest that there has been a significant increase in cost of in-hospital healthcare utilization in thrombotic microangiopathy related hospital admissions from 1997 to 2006, a significant length of stay and mortality. These data provide a rationale for further study of the health care utilization and burden of care of Thrombotic microangiopathies in order to develop efficient healthcare delivery strategies. Disclosures: No relevant conflicts of interest to declare.