Initial Hematopoietic Stem Cell Transplantation Research Articles

The impact of ageing on the distribution of preformed anti-HLA and anti-MICA antibody specificities in recipients from eastern China prior to initial HSCT

BackgroundWith the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA.ResultsThere were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA.ConclusionsThe prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

Suitability of Hemophagocytic Syndrome who had a graft rejection for repeat transplantation

Background: Hematopoietic stem cell transplantation (HSCT) is a crucial treatment for hemophagocytic lymphohistiocytosis, with reduced-intensity conditioning transplantation (RIC) being a superior strategy. Aim: Engraftment failure is a significant challenge, necessitating additional HSCT so a case study involved ten patients who experienced engraftment failure and hemophagocytic syndrome after initial HSCT. Place & duration of study: Chughtai Institute of Pathology, Lahore from March 2018 and January2023 Results: The study found that all five subjects who underwent a second allo-HSCT achieved rapid hematopoietic restoration, with ANC levels above 0.5 108 /L for granulocytes and 20 108 /L for platelets. After transplantation, three individuals experienced acute graft-versus-host disease (aGVHD) of varying severity, with a 60% prevalence and a median onset time of 26 days. Two patients managed their conditions with methylprednisolone, while two patients underwent treatment with second-line anti-GVHD medicine. Implication: A study reveals that second allogeneic hematopoietic stem cell transplantation (allo-HSCT) can restore hematopoietic tissue in failed engraftment patients, particularly those with acute Graft-Versus-Host Disease (aGVHD). Conclusion: A trial evaluating allogeneic hematopoietic stem cell transplantation (allo-HSCT) for engraftment failure in liver and heart failure patients showed a 80% success rate. Further studies are needed to predict success factors for a second allo-HSCT treatment, but the consensus is strong for its potential in treating hemophagocytic disorders. Keywords Implantation failure, hematopoietic stem cell transplantation, Second allogeneic, Hemophagocytic syndrome

Effect of Early Cytomegalovirus Reactivation on Relapse in Adult Patients with Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: A Registry Study from the Japan Society for Transplantation and Cellular Therapy (JSTCT)

Background Cytomegalovirus reactivation (CMVR) is a well-known complication contributing to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have demonstrated that CMVR is associated with poor clinical outcomes following HSCT. However, some studies have shown that CMVR following HSCT may have a recurrence-suppressing effect on hematological diseases, including acute myeloid leukemia and acute lymphoblastic leukemia. Conversely, data on the relevance between CMVR and relapse in patients with myelodysplastic syndromes (MDS) following HSCT remain limited and inconclusive. This nationwide retrospective study aimed to examine the association between CMVR and MDS relapse following HSCT. Methods This study was conducted by the Adult Myelodysplastic Syndromes Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT). Clinical data were collected by the JSTCT and the Japanese Data Center for Hematopoietic Cell Transplantation employing the Transplant Registry Unified Management Program (TRUMP). Overall, 1,082 patients aged ≥16 years who were diagnosed with de novo MDS, underwent initial allogeneic HSCT between 2010 and 2018, and survived until 100 days post-transplant without disease relapse were examined. Patients who received cord blood transplantation, in vivo T-cell depletion, and prophylactic anti-CMV treatment were excluded. CMVR was defined as the initiation of CMV preemptive or definitive therapy within 100 days post-transplant. Patients underwent pp65 antigenemia monitoring commencing at the time of neutrophil engraftment after HSCT. Preemptive therapy was typically instituted upon the detection of a minimum of 2 CMV pp65 antigen-positive cells per 50,000 white blood cells. In analysis, CMVR and acute/chronic graft-versus-host disease (GVHD) were evaluated as time dependent covariates. This retrospective study was approved by the Data Management Committee of the JSTCT and the ethics committee of the Ehime University School of Medicine. Results Of the 1,082 patients, 622 (57.5%) experienced CMVR. The median time from HSCT to the onset of CMVR was 46 (range, 4-97) days. In contrast, reactivation beyond 100 days after HSCT was observed in 20 patients (1.8%). End-organ disease due to CMV infection was detected in 79 (7.3%) patients with a median of 61 (range, 19-385) days. CMV infections included enteritis (n = 65), retinitis (n = 5), pneumonitis (n = 4), hepatitis (n = 3), and others (n = 3). Of the whole cohort, the 5-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), disease-free survival, and overall survival (OS) were 15.6%, 26.7%, 57.7%, and 60.5%, respectively. The OS of patients with CMVR was significantly lower than that of patients without CMVR (P = 0.047). A total of 423 patients died at the time of analysis, and no difference in the cause of death was found between patients with and without CMVR. Then, the effect of CMVR on relapse after HSCT was analyzed by patient, disease, and transplant characteristics. Interestingly, in patients with <5% bone marrow blast count at the time of HSCT, CMVR was significantly associated with a lower CIR (5-year CIR, 7.6% vs. 16.4%; P = 0.002). On the contrary, no difference in the CIR was found between patients with and without CMVR in the group with ≥5% bone marrow blast count (5-year CIR, 19.4% vs. 18.0%; P = 0.72). Moreover, the OS of patients with CMVR was significantly lower than that of patients without CMVR in the group with ≥5% bone marrow blast count (P = 0.009). However, the OS of patients with <5% bone marrow blast count was similar between with and without CMVR (P = 0.82). In the multivariate analysis, CMVR was significantly associated with a lower CIR in the group with <5% bone marrow blast count (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23-0.70; P = 0.001). Furthermore, in the analysis excluding patients with grade II-IV acute GVHD, CMVR was similarly associated with a lower CIR in the group with <5% bone marrow blast count (HR, 0.38; 95% CI, 0.18-0.80; P = 0.011). Conclusion This study presents that CMVR may have different effects on MDS relapse depending on the bone marrow blast count at the time of HSCT. Although more studies are needed to understand the underlying mechanisms of this association, these findings may serve as a basis for devising effective CMV prophylaxis after HSCT.

Prognostic Factors in Children with Acute Myeloid Leukemia Receiving the First Hematopoietic Stem Cell Transplantation in Second Remission

Introduction In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) is generally restricted to patients with a high risk of relapse. However, 30-40% of children with AML receiving chemotherapy will eventually relapse; these patients often undergo initial HSCT after achieving second CR (CR2) with re-induction chemotherapy. Previous studies have reported favorable prognostic factors in children with relapsed AML: no prior history of HSCT, longer duration of CR1, and achieving CR2 before HSCT. The identification of prognostic factors in children who received initial HSCT in CR2 may facilitate the refinement of risk stratification in first-line therapy, but they remain largely unknown. In this study, we explored the prognostic factors of pediatric patients with AML who received initial HSCT in CR2. Methods Data from 234 patients were collected from the Transplant Registry Unified Management Program sponsored by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. The patients were selected according to the following criteria: (1) de novo AML, (2) age < 16 years and CR2 at the time of receiving HSCT, (3) no prior HSCT, and (4) HSCT performed between 2000 and 2019. Patients without information on survival and disease recurrence or those with Down syndrome (DS) were excluded. A myeloablative conditioning (MAC) regimen was defined as total-body irradiation (TBI) at > 8 Gy, melphalan > 140 mg/m2, or busulfan ≥ 9 mg/kg. All other regimens were analyzed as reduced-intensity conditioning regimens. High-risk (HR) cytogenetics/genetics were defined as either 7-/7q-, 5q-, complex karyotype (three or more chromosomal abnormalities in the absence of one of the recurring translocations or inversions), t(6;11)(q27;q23), t(6;9)(p23;q34), t(16;21)(p11;q22), t(9:22)(q34;q11.2), or fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD). Results The median age at HSCT was 7 years (range, 1-15), and the median follow-up period for survivors was 7.7 years (range, 0.2-19.2). The 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) rates were 63.5% (95% CI, 56.6-69.5%) and 66.9% (95% CI, 60.0-72.8%), respectively (Figure 1). The 5-year cumulative incidence of relapse was 24.7% (95% CI, 19.2-30.6%), whereas the 5-year cumulative incidence of non-relapse mortality was 11.8% (95% CI, 7.9-16.6%). The 5y-EFS was 72.6% (95% CI, 61.1-81.2%) for patients with core binding factor AML and 100% (95% CI unavailable owing to small patient number) for patients with t(15;17)(q22;q21). Patients with 11q23/KMT2A rearrangement and HR cytogenetics/genetics showed worse outcomes, with 5y-EFS rates of only 43.8% (95% CI, 21.4-64.3%) and 36.4% (95% CI, 17.8-55.3%), respectively. Among the French American British classification subtypes, patients with M7 AML showed inferior outcomes with a 5y-EFS of 18.8% (95% CI, 4.6-40.2%). For the conditioning regimens, aside from "other MAC,” which included only three patients, melphalan-based non-TBI MAC was associated with the most favorable outcomes, with a 5y-EFS of 77.1% (95% CI, 64.2-85.9%). Multivariate analysis identified duration of CR1 > 1 year and melphalan-based non-TBI MAC regimen as independent favorable prognostic factors, while M7 was identified as an independent adverse prognostic factor (hazard ratio 2.62, p = 0.033, Table 1). Conclusion In the present study, approximately two-thirds of children who experienced relapse after chemotherapy remained in remission after HSCT in CR2. Melphalan-based non-TBI MAC is recommended as a conditioning regimen for this select population. Patients with t(15;17)(q22;q21) showed particularly excellent outcomes after initial HSCT in CR2, whereas those with HR cytogenetics/genetics or non-DS M7 were scarcely rescued with HSCT even after attaining CR2. Precise identification of high-risk populations among them with poor early treatment response and/or unfavorable genetic alterations will contribute to refining the risk stratification and indications for HSCT in CR1. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A New Risk Assessment Tool for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:Allogeneic hematopoietic stem cell transplantation (HSCT), can be curative for many hematologic disorders. However, HSCT is still associated with significant risks. HSCT outcomes are dependent on patient, disease and transplant related factors. There are a number of assessment tools being used to predict outcomes. Some use patient related variables such as the hematopoietic cell transplantation specific comorbidity index (HCT-CI), some use disease-related variables such as the disease-risk index (DRI) and some others incorporate combined variables. We aimed to incorporate disease, patient comorbidities, donor, and transplant characteristics into one comprehensive prognostic model to predict 2 year disease-free survival (DFS).Methods:273 consecutive patients (162 males, 111 females) receiving an initial HSCT from 2010 and 2016 were identified and retrospectively analyzed. Median age was 56 years (range 18-76 years) and a broad representation of hematologic disorders (119 AML, 46 ALL, 60 MDS, 18 NHL, 30 other) were included. All pts received peripheral blood as graft source. The majority received an unrelated donor transplant (166) and were conditioned with a myeloablative regimen (199).The dataset was randomly split in a 2:1 ratio to create training and testing dataset prior to data analysis. Variables under consideration as predictors of 2 year disease-free survival included: patient (age, sex, blood type, CMV status, Karnofsky Performance Status, HCT-CI), donor (age, sex, blood type, CMV status), disease (type, time since diagnosis, Disease Risk Index), and transplant (prep regimen, year of transplant, related/unrelated, match/mismatch) characteristics. Using the training dataset, a lasso penalized Cox regression was applied with the penalty parameter being derived as the mean of 1,000 iterations of 10-fold cross-validation. Patient risk scores was computed from the model and used to stratify patients based on a median split of risk scores; survival differences were evaluated using the log-rank test. Model performance was evaluated in the training and testing datasets by deriving time-dependent AUC curves, evaluating survival differences by risk strata, and comparing predicted to observed survival probabilities at 2 years.Results:Karnofsky Performance Status (<90, 90+), Disease Risk Index (Low, Intermediate/High), HCT-CI (Low, Intermediate/High), prep regimen (RIC/Non-myeloablative, myeloablative), and donor age (<30, 30+) were selected by the model. More specifically, lower performance status (HR 1.3), higher Disease Risk Index (HR 1.4), higher HCT-CI (HR 1.3), RIC/non-myeloablative prep regimen (HR 1.1), older donor age (HR 1.1) were associated with poorer disease-free survival. The prognostic model derived from the training dataset demonstrated good discrimination for the prediction of 2 year DFS with a median AUC value of 0.72 (IQR 0.69-0.73). When applied to the testing dataset, an AUC value of 0.73 was obtained. Across time, results were relatively consistent between 1 and 2 years post-transplant. A significant difference between the two risk strata was evidenced in the training and testing dataset (Figure 1, p<0.01). Comparison of predicted and observed survival probabilities at 2 years demonstrated agreement in both datasets.Conclusion:This comprehensive prognostic model is able to stratify patients into high risk and low risk groups with significantly different outcome. The inclusion of additional variables in the model increased accuracy (higher AUC) relative to existing models, which highlights the importance of taking into consideration additional constructs when trying to predict DFS. Further independent validation of our findings is necessary. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Economic Burden of Hematopoietic Stem Cell Transplantation (HSCT) in Patients with Acute Lymphoblastic Leukemia (ALL) in the US

IntroductionAcute lymphoblastic leukemia (ALL) is a rare disease that affects lymphoblasts derived from lymphoid stem cells and due to the acute nature of this cancer, it is rapidly fatal without treatment (National Cancer Institute, 2016). The average 5-year overall survival (OS) rate was 35% for adult ALL and over 90% of the relapsed or refractory patients eventually die with a median OS of 3-6 months (Kantarjian HM et al. 2010, Bassan and Hoelzer 2011, Forman and Rowe 2013). Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with B-cell ALL. Previous studies find that HSCT is associated with high costs and healthcare resource use. However, there is no study examining the allogeneic HSCT costs specifically for the adult ALL patients.ObjectiveThe aim of this study is to quantify the economic burden of allogeneic HSCT for adult B-cell ALL patients and relapsed adult B-cell ALL patients in the US.MethodsThis was a retrospective cohort study using Truven Health MarketScan® Commercial and Medicare Supplemental Databases. 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, have ≥1 allogeneic HSCT hospitalization (index date is the admission date for the initial HSCT hospitalization), are ≥18 years old on index date, and have ≥6 months of continuous enrollment prior to index date. Patients with medications for T-Cell ALL during the study period were excluded. Relapsed ALL patients were required to have ≥1 inpatient claims or ≥2 non-diagnostic outpatient claims at least 30 days apart for relapsed ALL diagnosis (ICD9: 204.02, ICD10: C91.02). Patients were followed until the earliest of inpatient death, end of continuous enrollment, or end of the study period (10/31/2016). Outcomes included all-cause and HSCT-related costs and total hospital length of stay (LOS) observed during the index hospitalization, and during 100, 180, or 365 days post-index periods (for the subset of patients with at least 100, 180, or 365 days of continuous enrollment after index date or an inpatient death during that follow-up). The costs for the HSCT-related complications such as graft versus host disease (both acute and chronic), hepatic veno-occlusive disease (VOD), graft failure, serious infections, bronchiolitis obliterans, secondary malignancies, and inpatient death were included, as well as the costs for transplant conditioning regimens during the 14 days before HSCT. Costs were sum of the plan paid amount and out-of-pocket amount in 2016 dollars. All descriptive analyses were conducted for patients with ALL (including both frontline and relapsed ALL) and relapsed ALL, separately.ResultsA total of 692 ALL patients (mean age: 45.6; male: 56.1%; mean Charlson comorbidity index: 3.2) were identified. Among all the ALL patients, 123 had relapsed ALL. Among ALL patients, mean (SD; median) costs were $275,642 ($316,109; $212,742) and mean (SD) LOS was 31.1 (20.9) days during the initial HSCT hospitalization (Table 1). During the first year post index, mean (SD; median) all-cause and HSCT-related costs were $543,146 ($416,148; $455,245) and $394,069 ($378,893; $301,977), respectively, with all-cause and HSCT-related mean (SD) LOS of 52.5 (41.5) and 49.2 (40.3) days. Among relapsed ALL patients, mean (SD; median) costs were $319,643 ($310,479; $255,545) during the initial HSCT hospitalization (Table 2). Mean (SD; median) all-cause and HSCT-related costs were $680,503 ($651,399; $556,244) and $535,245 ($577,152; $395,031) during the first year post index. Mean (SD) LOS was 33.9 (18.0) days during the initial HSCT hospitalization and 61.5 (46.4) and 59.1 (45.8) days during the first year post index for all-cause and HSCT-related hospital stays, respectively. The initial HSCT hospitalization accounts for about 47% and 51% of the total costs in the first year after HSCT for ALL and relapsed ALL patients, respectively.ConclusionsAllogeneic HSCT in ALL is associated with substantial economic burden, especially among relapsed ALL patients. During the first year post HSCT, about half of the total costs occurred during the initial HSCT hospitalization. [Display omitted] DisclosuresZhang:Amgen Inc.: Employment, Equity Ownership. Cong:Amgen Inc.: Employment, Equity Ownership.

Disparities in the Use of Allogeneic Hematopoietic Stem Cell Transplant Among Children, Adolescents, and Young Adults with Acute Leukemia in California

Introduction: Previous literature suggests that allogeneic hematopoietic stem cell transplant (HCT) utilization rates are lower amongst Hispanic and Black compared to non-Hispanic White (NHW) cancer patients. However, no previous studies have focused explicitly on the pediatric and adolescent young adult (AYA) population. We sought to examine utilization of HCT by race/ethnicity using the California Cancer Registry (CCR) and the Office of Statewide Health Planning and Development (OSHPD) hospitalization database. We hypothesized that Black and Hispanic patients with acute leukemia less frequently receive HCT than NHW patients. Methods: Using population-based data from California, a retrospective cohort of patients aged 0-39 years with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) diagnosed between 2000 and 2015 was assembled. The primary exposure was a composite of race/ethnicity with NHW patients as the reference group. The primary outcome was receipt of first HCT, defined by diagnosis codes in OSHPD or treatment in the CCR. Logistic regression analyses were used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI). Multivariable models were adjusted for race/ethnicity, age, sex, year of diagnosis, leukemia type, insurance type at diagnosis, rurality, and neighborhood socioeconomic status at diagnosis (SES). Results: Among 7,183 patients (4,790 with ALL and 2,393 with AML), 21% (16% of ALL patients and 31% of AML patients) underwent HCT. Distributions of insurance type and neighborhood SES differed by race/ethnicity with a higher proportion of Black and Hispanic patients having Medicaid insurance and living in lower SES neighborhoods. In univariate analyses, Black and Hispanic race/ethnicity were associated with decreased likelihood of receiving HCT (OR 0.70 95% CI 0.53, 0.94 and OR 0.77 95% CI 0.68, 0.88, respectively) and Asian race was associated with increased likelihood of HCT (OR 1.29 95% CI 1.07, 1.56) compared to NHW patients. In the multivariable model, there was no statistically significant difference in receipt of HCT among Hispanic patients, but disparities persisted among Black patients (Table 1). Uninsured patients and those in the lowest SES quintile were also less likely to receive HCT, while older age and AML were associated with HCT receipt. In analyses stratified by age and leukemia type, we found that the disparities in receipt of HCT among Black patients was largely driven by patients &amp;gt;20 years old (adjusted OR 0.50 95% CI 0.33, 0.78). These analyses also revealed that the increased likelihood of HCT among Asian/PI patients was driven by patients &amp;lt;21 years old with ALL (adjusted OR 1.59 95% CI 1.07, 2.38). Among those who did undergo HCT, Hispanic patients had a longer initial HCT admission (39 v. 35 days, p&amp;lt; 0.0001) and more frequent readmissions (32% with &amp;gt;2 readmissions in the first year post-HCT v. 25%, p=0.005) compared to NHW patients. Conclusions: HCT is a potentially curative treatment for high-risk acute leukemia; thus the observed racial and SES disparities in receipt of HCT may contribute to disparities in leukemia survival. More detailed disease, treatment, and relapse data would provide a better understanding of the etiology of our findings and allow for reduction of existing disparities through improved access to HCT. Disclosures Muffly: Servier: Research Funding; Amgen: Consultancy; Adaptive: Research Funding. Wun:Glycomimetics, Inc.: Consultancy.

Microbiology and Risk Factors for Hospital-Associated Bloodstream Infections Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

BackgroundChildren undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients.MethodsWe performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997–2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI.ResultsOf 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI (P = .021) and, specifically, fungal HA-BSIs (P = .002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01–1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19–2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21–2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%; P = .002).ConclusionsOver the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT.

Sustained Hematopoietic Recovery after Salvage Autologous Stem Cell Transplants after Long Term Storage of Cryopreserved Hematopoietic Progenitor Stem Cells (HPSC)

Sustained Hematopoietic Recovery after Salvage Autologous Stem Cell Transplants after Long Term Storage of Cryopreserved Hematopoietic Progenitor Stem Cells (HPSC)

Morbidity, Mortality, and Healthcare Utilization in a National Cohort of Pediatric Patients with Hemophagocytic Lymphohistiocytosis Who Received Hematopoietic Stem Cell Transplant

Background Hemophagocytic lymphohistiocytosis (HLH) is a severe life threatening hyper-inflammatory syndrome of abnormal immune activation and dysregulation if untreated. The 5-year probability of survival (pSu) obtained from HLH registries and treatment protocols HLH-94 and HLH-2004 ranges from 21%-64%, with improved 5-year pSu of up to 70% following hematopoietic stem cell transplant (HSCT) (Arico et al., Trottestam et al., Bergsten et al.). Despite significant advances in the management of HLH over time, survival remains low and the extent of disease morbidity and healthcare utilization is poorly characterized. In this study, we sought to investigate morbidity, mortality, and the healthcare burden in children and adolescents with HLH who underwent HSCT. Methods Using the Pediatric Health Information System (PHIS) database, we identified patients under the age of 21 years admitted between 01/01/2004 and 09/30/2018 with a primary or secondary ICD-9 or ICD-10 diagnosis codes for HLH, as well as concurrent medication charges for both dexamethasone and etoposide in the same encounter. We then identified the patients who underwent HSCT to further analyze them. We abstracted data on demographics, hospitalizations, HSCT related complications, mortality, resource utilization and costs. Results were summarized using descriptive statistics. Time to HSCT was calculated as elapsed time from the admission date of the initial encounter to the date of the encounter in which there was a procedure code for HSCT. Time to mortality event was calculated as elapsed time from the admission date of the initial encounter to the discharge date of the encounter in which mortality occurred. The PHIS database provides an encrypted patient medical record number; thus, we were able to follow patients over time. This allowed for a better visualization of the patient's hospitalizations trend over 14 years. Results A total of 493 patients met inclusion criteria for HLH during the study period from 52 children's hospitals. The majority of patients (n = 284, 58%) were less than 5 years of age. Of these, 136 patients (28%) underwent HSCT with 155 hospital encounters, including readmissions. The median age at the time HSCT was 2 years (IQR; 0-9 years) and there were 82 males (60%). The median time to HSCT was 126 days (IQR: 75-193 days) and the average length of stay for the initial HSCT hospitalization was 61.1 days. Median initial HSCT hospitalization cost was $463,630 (IQR; 230,795 - 558,533). ICU care was required for 71 (46%) of patients. Overall, 91 (67%) patients developed transplant-related complications, which included infections, sinusoidal obstruction syndrome or graft versus host disease (Table 1). Mortality after HSCT was 22% (n=30) with an increased mortality observed with advanced age at the time of HSCT (Figure 1). The median time to death after the initial HSCT admission was 65 days (IQR; 56-94 days). Conclusion This is a large in-patient cohort of pediatric patients with HLH who underwent HSCT in the US. We observed an improved overall mortality after HSCT in this population compared to previous studies. However, morbidity (particularly from infections) and heath care resource utilization remain high. This stresses the importance of novel therapeutic approaches to improve not only patient survival but also long-term quality of life. Planned future analysis of this database will be aimed at assessing treatment variability; morbidity and mortality by treatment regimen, time to HSCT, and HSCT preparative regimen; and risk factors associated with mortality in pediatric patients with HLH who do and do not undergo HSCT. Disclosures No relevant conflicts of interest to declare.

Successful Bone Marrow Transplantation Using an Immunomyelosuppressive Conditioning in Patients with Severe Congenital Neutropenia: The Results of a Single-Institute

Severe congenital neutropenia (SCN) is a rare heterogeneous genetic disorder characterized by recurrent bacterial infections from early infancy due to severe chronic neutropenia. Majority of SCN patients have benefitted by the treatment with granulocyte colony-stimulating factor (G-CSF). However, patients on long-term G-CSF therapy have a relative risk of developing myelodysplastic syndrome/acute myeloid leukemia. The only curable treatment for SCN patients is hematopoietic stem cell transplantation (HSCT). Recently, HSCTs with reduced intensity conditioning regimens have been applied to the treatment for SCN patients prior to malignant transformation. However, the optimal conditioning of HSCT for SCN patients has not been established. In this study, we conducted bone marrow cell transplantations (BMT) in 16 patients with SCN using an immunomyelosuppressive conditioning regimen to minimize early and late transplant-related morbidity in Hiroshima University Hospital. A total of 17 BMT procedures were performed in 16 patients with SCN from 2008 to 2019. Five of 16 patients had experienced the engraftment failure of initial HSCT and 4 of them were referred to our hospital for re-transplantation. Fifteen of 16 patients had a heterozygous mutation in the ELANE gene. Bone marrow cells (BM) were obtained from 6 HLA-matched related, 3 HLA-matched unrelated, and 8 HLA-mismatched unrelated (7/8 antigens) donors, respectively. Conditioning regimen consisted of fludarabine, cyclophosphamide, melphalan, total body irradiation (3.6 Gy) with or without antithymocyte globulin. Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft-versus-host disease (GVHD). Engraftment of neutrophils was observed within post-transplant 24 days in all patients. Two patients developed graft failure on day 40 and day 90, respectively, after the temporal engraftment. However, both patients were rescued by second BMT from different HLA-matched unrelated donors receiving the same conditioning regimen. Four patients who received BMT from HLA-matched related donors developed stable mixed chimerism without neutropenia in peripheral blood for 3 to 10 years. Although one patient who received donor lymphocyte infusion due to mixed chimerism developed grade II acute GVHD and limited chronic GVHD, the others did not develop severe GVHD. All patients are alive for 6 months to 11 years after BMT with no signs of severe infections or transplantation-related morbidity. Similar conditioning regimen has been applied to BMT for 35 patients with chronic granulomatous disease (CGD) in our hospital. In that study 4 male adulthood patients with CGD already fathered each child by their wives through spontaneous pregnancy, implying the successful preservation of patients' fertility. Collectively, our results demonstrate that BMT with a sufficient immunosuppressive conditioning regimen may be a feasible and effective treatment for SCN patients, irrespective of initial engraftment failure. The excellent results in our cohort suggest that indications for proceeding to HSCT could be extended to patients without malignant transformation.The further analyses of accumulated cases are necessary to assess the efficacy, safety, and less late adverse effects related to HSCT including fertility. Disclosures No relevant conflicts of interest to declare.

Hematopoietic Stem Cell Transplant Utilization in Relapsed/Refractory Hodgkin Lymphoma: A Population Level Analysis of Statewide Claims Data

Introduction: In the era of novel therapies, the first and subsequent lines of therapies are rapidly evolving in the treatment of patients with Hodgkin lymphoma (HL) in order to optimize disease control and reduce long term health risks. Hematopoietic stem cell transplant (HSCT) is often used following treatment failure. While utilization of HSCT can be ascertained from transplant-specific registries, the treatment path for patients with relapsed/refractory HL leading up to HSCT is largely unknown. We developed an algorithm to define a cohort of commercially insured patients with HL from 2009-2013 in the Massachusetts All Payer Claims Database (MA APCD) who received HSCT. Further, we describe treatment characteristics of this cohort.Methods: The Patient Protection and Affordable Care Act of 2010 established requirements for states to assess healthcare outcomes which resulted in at least 16 states establishing All Payer Claims Databases. The MA APCD provides detailed medical claims data, physician provider data, and pharmacy data for all commercially insured patients in the state, regardless of site of care. Moreover, each patient is assigned a unique identifier, which allows us to follow patients even if they change insurer (“insurance churning”). To our knowledge, no studies exist using APCD for HL from any state.We identified a cohort with HL who underwent HSCT during the study period from among 7,613 cases with ICD-9 diagnostic codes for HL and of those, 695 had ICD-9 codes for both HL and HSCT. To identify incident HSCT cases during our study period, we developed and iteratively refined an algorithm using ICD-9 diagnostic and procedure codes, dates of service, and length of stay which narrowed the cohort to 178 patients. After review of the medical and pharmacy claims databases by an oncologist (AW), 113 patients were identified as part of the final cohort who underwent autologous and/or allogeneic HSCT. Reasons for exclusion include not HL (34), not HSCT (8), and prevalent (i.e. “history of”) HSCT only (23). We then summarized initial treatment, salvage treatment, and HSCT where data were available.Results: Among this commercially insured cohort of 113 patients who received HSCT, the median age was 39.0 years and 51.3% were female. Initial therapy data were identified for 65 of the 113 patients (58%); 58 (89.2%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Of the 60 people for whom salvage therapy data could be discerned, 32 (53.3%) received ifosfamide, carboplatin, etoposide (ICE), 11 (18.3%) received gemcitabine, vinorelbine, liposomal doxorubicin (GVD), 11 (18.3%) received other chemotherapy, and 6 (10%) received brentuximab vedotin. Notably, 92 (81.4%) of all transplants were autologous, 10 (8.9%) were allogeneic transplant, and 9 (8.0%) were autologous followed by allogeneic transplant. Of the 64 patients with initial therapy data, median time to HSCT after completion of initial treatment was 238.5 days (25th-75th percentile, 151.5-428.0). Additionally, 25 HSCT were performed during the year 2009 and 20 of these had unknown initial chemotherapy regimens. Our dataset was limited to the years 2009-2013 and this missing chemotherapy information is most likely due to initial treatment prior to 2009.Conclusion: We successfully developed and refined an algorithm to help identify HSCT among patients with HL within a large statewide claims database. We characterized a cohort of patients with relapsed/refractory HL, including patterns of initial and salvage treatments in a sizeable subset of patients. Median time to HSCT demonstrates that the majority of patients undergo transplant for relapsed/refractory disease within a year of completing initial treatment. Future directions include determining reasons for incomplete information on initial and salvage therapy, such as insurance product or type, different sites of care within community and academic practices, and potential referral patterns into the state for HSCT care. As less than 5% of cancer patients are enrolled onto clinical trials, partnerships between clinical experts and data science are a powerful way to use large claims databases to study more representative patient populations. DisclosuresRodday:Seattle Genetics: Research Funding. Kumar:Seattle Genetics: Research Funding. Parsons:Seattle Genetics: Research Funding.

Risk factors for healthcare-associated Clostridium difficile infection in pediatric hematopoietic stem cell transplant recipients

BackgroundLimited published literature exists to identify unique risk factors for Clostridium difficile infection (CDI) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. Our objective was to describe the epidemiology of CDI in pediatric patients undergoing HSCT and to identify potential risk factors for CDI.MethodsThis IRB-waived, single-center retrospective review included Duke University Hospital (DUH) patients 12 months of age or older admitted to pediatrics between March 1, 2012 and August 23, 2016 undergoing initial HSCT during the index hospitalization. The primary endpoint (PCR-confirmed CDI within 100 days post-transplantation) was characterized using descriptive statistics. Transplant type, prior CDI history, days of total parenteral nutrition (TPN), and antibiotic use intensity scores were compared between occurrence groups using Pearson’s chi-square, Wilcoxon rank-sum or Student’s t tests as appropriate.Results207 subjects (most Caucasian [55%] and male [61%]) were included, and 15 (7.2%) died. CDI occurred in 24 (12%) within a median (interquartile range) of 35 (9, 47) days since HSCT, and most (92%) were hospital-onset. All cases were healthcare-associated and mild-moderate in severity. None of the patients experienced CDI-related complications. CDI-positive and CDI-negative patients were similar with regards to demographics. Higher median (adjusted) days of TPN (80.6 vs. 29, P < 0.0001) and antibiotic use intensity scores (382.8 vs. 191.0, P < 0.0001), respectively, were associated with CDI. No significant differences between these groups were observed with regard to transplant type (P = 0.28) and prior CDI history (P = 0.10).ConclusionCDI occurred in 12% of pediatric patients within 100 days of undergoing initial HSCT. Onset of this mild-moderate, uncomplicated disease occurred within a median of 35 days and commonly during hospitalization. Patients with CDI were more likely to have increased use of TPN and a higher antibiotic use intensity score.Disclosures All authors: No reported disclosures.

Successful Hematopoietic Stem Cell Transplantation Using an Immunosuppressive Conditioning Regimen in Ten Patients with Severe Congenital Neutropenia: A Single-Institute Experience

Severe congenital neutropenia (SCN) is a rare heterogeneous genetic disorder characterized by severe chronic neutropenia, with absolute neutrophil counts below 0.5×109/L, and by recurrent bacterial infections from early infancy. Granulocyte colony-stimulating factor (G-CSF) is widely used for the treatment of neutropenia in patients with SCN. However, the long-term G-CSF therapy has a relative risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The only curative treatment available for SCN patients is hematopoietic stem cell transplantation (HSCT). Recently, HSCTs with reduced intensity conditioning (RIC) regimens have been applied to the treatment of SCN patients without malignant transformation who have become G-CSF refractory. However, the optimal conditions of HSCT for SCN patients have not been established. In this study, we conducted bone marrow cell transplantations (BMT) in ten patients with SCN using an immunosuppressive conditioning regimen to minimize early and late transplant-related morbidity in Hiroshima University Hospital.Ten patients with a total of 11 HSCT procedures in our institution (performed from 2007 to 2015) were enrolled in this study. Four of the ten patients had experienced engraftment failure of the initial HSCT and three of them were referred to our hospital for re-transplantation. Heterozygous mutation inthe ELANE gene was identified in nine of ten patients. These nine patients received BMT less than 10 years of age. All ten patients had recurrently experienced moderate to severe bacterial or fungal infection before HSCT and received temporal or regular administration of G-CSF. Bone marrow cells (BM) were obtained from five HLA-matched related (MRD), three HLA-matched unrelated (MUD), and three HLA-mismatched unrelated (7/8) donors (MMUD), respectively. The conditioning regimen basically consisted of fludarabine (100 to 125 mg/m2), cyclophosphamide (100 to 150 mg/kg), melphalan (70 to 90 mg/m2), total body irradiation (3 to 3.6 Gy), and/or anti-thymocyte globulin (10 to 12 mg/kg). Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft-versus-host disease (GVHD). Engraftment of neutrophils was successfully observed within 24 days of post-transplantation in all patients. All patients achieved complete chimerism at the time of engraftment. Two patients who underwent BMT from MRD and one patient who underwent BMT from MUD showed the gradual decrease of donor-derived cells. Donor lymphocyte infusion treatment successfully achieved the complete chimerism or stable mixed chimerism in these 3 patients. Although 3 patients experienced the acute GVHD (Grade I-II), the addition of glucocorticoids to tacrolimus prevented the extension of acute GVHD. Only one patient developed mild chronic GVHD presenting limited type of skin involvement. All patients are alive for 9 months to 9 years after HSCT with no signs of severe infections or transplantation-related morbidity.Our results demonstrate that BMT together with a sufficient immunosuppressive conditioning regimen may be a feasible and effective treatment for SCN patients, irrespective of initial engraftment failure. Although our results through the small number of cohort is limited to conclude, the BMT with the optimal donors may lead to the increased opportunity for lower risk of SCN patients especially at younger age as a curative treatment. The further analyses of accumulated cases are necessary to assess the efficacy, safety, and less late adverse effects related to HSCT including fertility. DisclosuresNo relevant conflicts of interest to declare.

Association Between Multiple Mismatches at the HLA-DPB1 and DRB3/4/5 Genes and Adverse Outcomes in HLA-a, -B, -C, -DRB1 and -DQB1 Identical Hematopoietic Stem Cell Transplantation: A Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC) and the Francophone Society for Histocompatibility and Immunogenetics (SFHI)

Background: Matching for all alleles of the HLA-A, -B, -C, and -DRB1 loci (8/8 match) is associated with the highest overall survival (OS) rates after unrelated donor (URD) hematopoietic stem cell transplantation (HSCT). In Europe, patients (pts) are also matched at the HLA-DQB1 loci (10/10 match) with no overall evidence of improved OS. HLA-DPB1 mismatching has been associated with a higher risk of acute graft-versus-host disease (aGvHD) and a decreased risk of relapse. A detrimental role of additional HLA-DQB1, HLA-DPB1 and HLA-DRB3/4/5 mismatches (MM) has been recently identified on OS but only in 7/8 HLA-A, -B, -C, and -DRB1 loci URDs HSCT. We investigated the impact of HLA-DPB1 and HLA-DRB3/4/5 MM on outcomes in a large cohort of 10/10 matched URD HSCTs.Patients and methods: 2,393 pts who received an initial HSCT from a 10/10 matched URD in 35 French centers were included between January 2000 and October 2012. Informed consent was obtained in accordance with the Declaration of Helsinki. High-resolution typing was performed for HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 and -DRB3/4/5 loci for all donor/recipient pairs. Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. Impact of HLA-DRB3/4/5 and -DPB1 MM was quantitatively and qualitatively evaluated. For quantitative evaluation, patients were classified into 5 different groups according to their global matching level for the 7 considered loci (14/14, 13/14, 12/14, 11/14, 10/14). For qualitative evaluation, MM type and directionality (GvH and host versus graft (HvG) directions) were evaluated. HLA-DPB1 MM were classified as permissive or non-permissive (K Fleischhauer, Lancet Oncol. 2012). The primary composite endpoint for the analysis was GvHD-free and relapse-free survival (GRFS). We defined early GRFS as being alive at 3 months after HSCT with no previous grade III-IV aGvHD and no relapse and late GRFS as being alive >3 months with no previous grade III-IV aGvH, no relapse and no moderate or severe chronic GvHD (cGvHD). Late GRFS was evaluated at months 6, 12, 24 and 36 after HSCT. Acute GvHD, cGvHD, relapse and OS were also studied. Models were adjusted for HSCT period, disease risk, age, sex matching, stem cell source, and conditioning regimen.Results: Table 1showspopulation characteristics and distribution of cumulative MM. The median follow-up was 59 months. Compared to 14/14 pairs, quantitative evaluation showed a significantly lower early GRFS for pts who received a 10-11/14 (Hazard Ratio HR 2.0, 95% CI 1.4 to 2.9, p=0.0003) or a 12/14 URD HSCT (HR 1.4, 95% CI 1.1 to 1.8, p=0.01). This was related to a significantly increased risk of grade III-IV aGVHD associated with 10-11/14 (HR 2.3, 95% CI 1.5 to 3.7, p=0.0004) and 12/14 pairs (HR 1.7, 95% CI 1.2 to 2.4, p=0.003). 10-11/14 pairs were also associated with a higher risk of death at 3 months (HR 2, 95% CI 1.1 to 3.6, p=0.024). Qualitatively, in pts matched for HLA-DRB3/4/5 but MM for HLA-DPB1 (n=1846, 77.1%), 2 HLA-DPB1 MM and non-permissive HLA-DPB1 MM were associated with a lower early GRFS (HR 1.4, 95% CI 1.1 to 1.9, p=0.01 and HR 1.3, 95% CI 1.0 to 1.7, p=0.02 respectively) due to an increased risk of aGvHD (HR 1.7, 95% CI 1.2 to 2.5, p=0.002 and HR 1.50, 95% CI 1.08 to 2.08, p= 0.017 respectively). Outcomes were not influenced by either GvHD or HvG mismatch directions. Late GRFS analyses once adjusted were not significantly different according to MM numbers, type and directions. Only 19 pairs (0.8%) were DPB1 matched and DRB3/4/5 mismatched (high linkage disequilibrium between DRB3/4/5 and DRB1); HLA-DRB3/4/5 MM could thus not be qualitatively analyzed.Conclusion: MultipleHLA-DPB1 and HLA-DRB3/4/5 MM have an early impact after 10/10 matched URDs HSCT. The best outcomes are seen in 13 and 14/14 pairs. Early GRFS is significantly impacted by 10-11/14, 12/14, 2 DPB1 MM as well as non-permissive HLA-DPB1 MM URD HSCT which is related to an increased risk of grade III-IV aGvHD. There is a significantly increased risk of mortality for 10-11/14 pairs at 3 months. Prospective evaluation of matching for HLA-DPB1 and HLA-DRB3/4/5 is warranted to reduce early post-HSCT toxicity in donor-recipient 10/10 matched pairs. [Display omitted] DisclosuresMichallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Peffault De Latour:Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Incident cancers and late mortality in Australian children treated by allogeneic stem cell transplantation for non-malignant diseases.

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a variety of non-malignant conditions. However, these children face an increased risk of late death and incident cancers after HSCT, which may occur many years after their initial HSCT. We examined cancer occurrence and late mortality in a population-based cohort of 318 Australian children who underwent allogeneic HSCT for non-malignant disease. Standardized incident ratios (SIRs) and standardized mortality ratios (SMRs) were calculated and compared with population controls. We identified six (1.9%) cancers at a median 9.2 years post-HSCT. Cancer occurred 15 times more frequently than in the general population (SIR 15.4, 95% CI = 6.9-34.2). Of the 198 patients who survived for at least 2 years post-HSCT, 11 (5.6%) died at a median 7.5 years post-HSCT. The mortality rate was 17 times higher than in the general population (SMR 17.5, 95% CI = 9.7-31.2). Children transplanted for non-malignant conditions require evidence-based survivorship programs to reduce excess morbidity and mortality.

Hospital Cost Associated with Veno-Occlusive Disease (VOD) in Patients with Hematopoietic Stem Cell Transplant (HSCT)

Introduction: VOD (also known as Sinusoidal Obstruction Syndrome) is a potentially life threatening complication of hematopoietic stem-cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction (MOD), leads to high morbidity and mortality in HSCT patients. This study assessed healthcare utilization and costs associated with VOD in patients undergoing HSCT. Methods: A retrospective cohort study was conducted using the Premier research database and had a starting population of all patients with inpatient HSCT between January 1, 2009 and May 31, 2014. The VOD cohort (all-VOD) included those who also had at least one discharge diagnosis indicating liver injury or at least two diagnoses for VOD symptoms, such as hyperbilirubinemia and/or hepatomegaly, during the study period. sVOD patients were identified using diagnoses for multi-organ dysfunction and were a subset of the VOD cohort. The non-VOD cohort was all patients from the starting cohort who did not have evidence of VOD. Primary outcomes were total hospitalization costs, hospital length of stay (LOS), and inpatient mortality. Secondary outcomes were intensive care unit (ICU) costs, ICU LOS, 30-day all-cause readmission rates and associated costs. Unadjusted descriptive analysis included Chi-squared or Wilcoxon Rank Sum tests for comparisons between cohorts, with non-VOD as the reference group. Multivariable analysis estimated the association between VOD status and primary outcomes, adjusting for differences in demographic, hospital, and clinical characteristics. Generalized linear models (GLM) were applied for total costs and LOS, and logistic regression was used for inpatient mortality. Recycled prediction was used to calculate the adjusted outcomes by VOD status. Results: A total of 5,418 patients had inpatient HSCT during the study period. The study included 291 all-VOD patients (134 sVOD and 157 non-severe VOD), in addition to 5,127 patients without evidence of VOD. Unadjusted descriptive analysis found that the all-VOD cohort had higher hospital costs (Median: $119,594, IQR: $59,793-$220,461) and longer LOS (Median: 28 days, IQR: 20-41) than the non-VOD cohort (Median cost: $62,747, IQR: $40,590-$120,974, p Discussion: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through the codes most likely to be related to VOD/sVOD. Notably, the 40% mortality in the sVOD group is considerably lower than the approximately 80% mortality reported in the literature. One important reason for this difference is that our analysis measured mortality during initial HSCT hospitalization, while the higher rates in the literature are based on 100-day mortality. Additionally, our algorithm may have yielded less severe disease compared to the literature. Conclusions: VOD and sVOD were associated with increased healthcare utilization and costs compared with the HSCT patients without VOD. sVOD patients also had almost 6 times higher odds of inpatient mortality compared with patients without VOD. Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy. Nejadnik: Jazz Pharmaceuticals: Employment, Equity Ownership. Cao: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Lipkin: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Robinson: Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Villa: Jazz Pharmaceuticals: Employment, Equity Ownership.

Venous Thromboembolism Is Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

▪Introduction: Although venous thromboembolism (VTE) after allogeneic hematopoietic stem cell transplantation (HSCT) is known to occur, there are currently limited data on its incidence, risk factors and outcomes. Studies that have examined VTE after HSCT have been small and not adequately able to address clinical risk factors including graft-versus-host disease (GVHD). We describe VTE incidence, characteristics, risk factors and outcomes in a large cohort of patients undergoing allogeneic HSCT.Methods: We identified all patients who underwent allogeneic HSCT between January 1, 2002 and December 31, 2013 at Dana Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH). Using pharmacy records and medical chart review, patients who received systemic anticoagulation (low-molecular weight heparin, warfarin, fondaparinux, and dabigatran) for VTE were identified. All VTE events were confirmed by radiologic imaging (ultrasound, CT, MRI or V/Q scan). VTE was defined as catheter-associated, pulmonary embolism (PE), lower extremity deep vein thrombosis (DVT), upper extremity DVT, superior vena cava (SVC) thrombosis or other (pelvic, abdominal, or ventricular thrombosis).Results: 2276 patients who underwent initial allogeneic HSCT at DFCI/BWH were identified, with a median follow-up time of 50 months (range 4-146) among survivors. 190 patients (8.3%) developed VTE. The 1 and 2-year cumulative incidence of all VTE were 5.5% (95% CI 4.6-6.5%) and 7.1% (95% CI 6.1-8.2%) respectively. There was no difference in age, gender, body mass index, diagnosis, disease status at time of HSCT, conditioning regimen intensity, donor type (HLA matched/mismatched, related/unrelated, or cord blood), or graft source (bone marrow or peripheral blood) between HSCT recipients with and without VTE.Amongst the 190 patients who developed VTE, 65 (34.2%) were lower extremity DVT, 48 (25.3%) were catheter-associated, 45 (23.7%) were PE, 10 (5.3%) were PE and DVT, 9 (4.7%) were upper extremity DVT, 9 (4.7%) were other DVT, and 4 (2.1%) were SVC thrombosis. Catheter-associated DVT occurred at a median of 1.1 months (range 0.1-41.1) after HSCT, which was significantly shorter than other types of VTE (figure, p<0.0001). Only 9 patients (4.7%) were not on systemic immune suppression at time of VTE. 98 patients (51.6%) had active GVHD at time of VTE, while 28 (14.7%) had a history of GVHD, still on immune suppression at time of VTE. For patients with active or previous GVHD, the most prevalent organ involvement was skin (38.4%).In a multivariable Cox model treating VTE and GVHD as time-dependent variables, VTE was associated with increased non-relapse mortality (HR=1.47; 95% CI 1.07-1.98), but not relapse (HR=0.98, 95% CI 0.69-1.34), progression-free survival (HR=1.21, 95% CI 0.94-1.57) or overall survival (HR=1.07, 95% CI 0.86-1.34). Non-relapse mortality remained as a significant association with VTE when catheter-associated VTE were excluded (HR=1.67; 95% CI 1.14-2.37). In a multivariable model to identify potential risk factors for VTE, both acute and chronic GVHD were independently associated with developing VTE (see table). In patients who developed GVHD, 8% had a subsequent VTE: 7% non-catheter-associated and 1% catheter-associated.Conclusion: Venous thromboembolism is a prevalent complication of allogeneic HSCT that increases non-relapse mortality risk. Both acute and chronic GVHD are associated with an increased risk of developing VTE. Further analysis is needed to identify HSCT patients with the highest risk for VTE who might benefit from VTE prophylaxis.TableMultivariable Cox model stratified by conditioning intensity for identification of potential risk factors for VTEPrognostic FactorHR (95% CI)p-valueAge: >=70 years vs <70 years0.26 (0.04-1.85)0.18Male vs Female0.97 (0.72-1.29)0.81BMI: >=30 vs <301.07 (0.79-1.46)0.65Matched related vs unrelated donor1.09 (0.79-1.49)0.61Mismatched vs matched donor0.99 (0.62-1.59)0.96Myeloid diagnosis0.81 (0.60-1.10)0.18GVHD prophylaxis: Sirolimus vs No Sirolimus0.91 (0.68, 1.24)0.56Prior acute GVHD2.02 (1.47-2.77)<0.0001Prior chronic GVHD2.30 (1.52-3.48)<0.0001Median time to VTE: Catheter-associated=1.1 mos, PE=13 mos, lower extremity DVT=9 mos, upper extremity DVT=2.7 mos, PE and DVT=7.5 mos, SVC=37.3 mos and other DVT=7.8 mos (p<0.0001). [Display omitted] DisclosuresArmand:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy.

Hospital Cost Associated with Veno-Occlusive Disease (VOD) in Patients with Hematopoietic Stem Cell Transplant (HSCT)

Introduction: VOD (also known as Sinusoidal Obstruction Syndrome) is a potentially life threatening complication of hematopoietic stem-cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction (MOD), leads to high morbidity and mortality in HSCT patients. This study assessed healthcare utilization and costs associated with VOD in patients undergoing HSCT.Methods: A retrospective cohort study was conducted using the Premier research database and had a starting population of all patients with inpatient HSCT between January 1, 2009 and May 31, 2014. The VOD cohort ("all-VOD") included those who also had at least one discharge diagnosis indicating liver injury or at least two diagnoses for VOD symptoms, such as hyperbilirubinemia and/or hepatomegaly, during the study period. sVOD patients were identified using diagnoses for multi-organ dysfunction and were a subset of the VOD cohort. The non-VOD cohort was all patients from the starting cohort who did not have evidence of VOD. Primary outcomes were total hospitalization costs, hospital length of stay (LOS), and inpatient mortality. Secondary outcomes were intensive care unit (ICU) costs, ICU LOS, 30-day all-cause readmission rates and associated costs. Unadjusted descriptive analysis included Chi-squared or Wilcoxon Rank Sum tests for comparisons between cohorts, with non-VOD as the reference group. Multivariable analysis estimated the association between VOD status and primary outcomes, adjusting for differences in demographic, hospital, and clinical characteristics. Generalized linear models (GLM) were applied for total costs and LOS, and logistic regression was used for inpatient mortality. Recycled prediction was used to calculate the adjusted outcomes by VOD status.Results: A total of 5,418 patients had inpatient HSCT during the study period. The study included 291 all-VOD patients (134 sVOD and 157 non-severe VOD), in addition to 5,127 patients without evidence of VOD. Unadjusted descriptive analysis found that the all-VOD cohort had higher hospital costs (Median: $119,594, IQR: $59,793-$220,461) and longer LOS (Median: 28 days, IQR: 20-41) than the non-VOD cohort (Median cost: $62,747, IQR: $40,590-$120,974, p<0.001; Median LOS: 21 days, IQR: 16-27; p <0.001). The sVOD sub-cohort had much higher costs and LOS (Median cost: $198,436, IQR: $102,027-$406,683, p<0.001; Median LOS: 37.5 days, IQR: 27-66; p<0.001). Inpatient mortality rates in the all-VOD and sVOD groups were significantly higher than the non-VOD group (non-VOD: 3.0% vs VOD: 18.6%, p<0.001; sVOD: 39.6%, p<0.001). In multivariable regressions, the adjusted hospital costs for non-severe VOD was $8,988 higher than the non-VOD group (p=0.037), and sVOD was $41,703 higher than the non-VOD group (p<0.001). The adjusted hospital LOS for non-severe VOD was 0.90 days longer than the non-VOD group (p=0.023) and for the sVOD group was 7.02 days longer than the non-VOD group (p<0.001). The sVOD group had significantly higher inpatient mortality (10.6%) compared with non-VOD group (3.4%, Adjusted Odds Ratio=5.88, p<0.001), although the mortality difference between non-severe VOD and non-VOD groups was not significant.Discussion: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through the codes most likely to be related to VOD/sVOD. Notably, the 40% mortality in the sVOD group is considerably lower than the approximately 80% mortality reported in the literature. One important reason for this difference is that our analysis measured mortality during initial HSCT hospitalization, while the higher rates in the literature are based on 100-day mortality. Additionally, our algorithm may have yielded less severe disease compared to the literature.Conclusions: VOD and sVOD were associated with increased healthcare utilization and costs compared with the HSCT patients without VOD. sVOD patients also had almost 6 times higher odds of inpatient mortality compared with patients without VOD. [Display omitted] [Display omitted] DisclosuresDvorak:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Lipkin:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Robinson:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

Successful Retransplantation of Bone Marrow Cells Following Failure of Initial Engraftment in 4 Patients with SCN

Severe congenital neutropenia (SCN) is characterized by severe chronic neutropenia with a absolute neutrophil count of less than 0.5×109/L, maturation arrest of myeloid precursors at the promyelocyts/myelocyte stage, and the recurrent bacterial infections from early infancy. The induction of G-CSF therapy dramatically improved the prognosis of most patients with SCN. Analysis on patients on the Severe Chronic Neutropenia International Registry has demonstrated that the patients with SCN on long-term G-CSF treatment are at a risk of developing myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). Recently, hematopoietic stem cell transplantation (HSCT) has been applied for a curative treatment in SCN patients without malignant transformation. However, the optimal conditions of HSCT for SCN have not been established. The failure of engraftment has been reported in some of SCN patients receiving HSCT with reduced intensity conditioning (RIC) or using cord blood as a donor source. Here, we tried to undergo retransplantation of bone marrow cells for 4 SCN patients with ELANE mutation who referred to our hospital because of the engraftment failure of initial HSCT. The summary of initial HSCT is shown in Table. The source of stem cells and the conditioning regimen were heterogenous in four patients. In this study we used bone marrow cells as stem cell source for all patients to transfuse the sufficiently total nucleated cells. Bone marrow cells were obtained from an HLA-matched related, an HLA-matched unrelated, and two HLA-mismatched unrelated (7/8) donors, respectively. Conditioning regimen consisted of fludarabine (125 mg/m2), cyclophosphamide (140 mg/kg), anti-thymocyte globulin (ATG, 10-12 mg/kg), melpharan (90 mg/m2), and TLI (3.6 Gy). Short-term methotrexate and tacrolimus were administered for the prophylaxis of graft versus host disease (GVHD). Engraftment of neutrophils was observed within post-transplant 21 days in all patients. Three of 4 patients have achieved complete engraftment without any signs of GVHD during their course. One patient required additional donor-lymphocyte infusion to sustain the stable engraftment. All patients are alive for 1 to 5 years after HSCT with no signs of infections or transplantation-related morbidity. Furthermore, we observed successful BMT using similar conditioning regimen in other 4 SCN patients without prior transplantation. In our cohort, sufficient administration of ATG is thought to be critical for preventing both engraftment failure and acute GVHD. These results suggest that bone marrow transplantation using fludarabine-based conditioning regimen with a sufficient dose of ATG may be a feasible and effective treatment for SCN patients irrespective of initial engraftment failure. Indications for proceeding to HSCT have been under discussion in patients with SCN. Accumulation of cases and further analysis are necessary to assess the efficacy and safety of this regimen including late complication related to HSCT.TableHSCT characterictecs at the initial transplantationCase1234EtiologyELANE G185RELANE V72MELANE 4501-4503 delELANE V72MAge at the time of HSCT10 months2 years3 years 9 months15 monthsStem cell sourcecord bloodbone marrowcord bloodbone marrowHLA disparitymismatched unrelated donor (5/6)matched unrelated donor (6/6)matched related donor (6/6)mismatched unrelated donor (6/8)Transfused NCC (108/kg)0.71.90.491Transfused CD34 cells (106/kg)0.6991.90.071.07Conditioning regimenBU 16, CY 120, Flu 120CY 140, Flu 125, L-PAM 90 TBI 3, ATG 2.5CY 100, Flu 120 TBI 3, ALG 40Flu 125, L-PAM 140 TBI 2, ATG 5Posttransplant day of rejection72 days55 days after 4 times of DLI14 daysone year after mixed chimerismDLI (times)0430Busulfan (BU, mg/kg), Cyclophophamide (CY, mg/kg), Fludarabine (Flu, mg/m2), Melpharan (L-PAM, mg/m2), Total body irradiation(TBI, Gy), Anti-thymoglobulin (ATG, mg/kg), Anti-lymphoglobulin (ALG, mg/kg), donor lymphocyte infusion (DLI) DisclosuresNo relevant conflicts of interest to declare.