Allogeneic Hematopoietic Stem Cell Transplantation Patients Research Articles

Real World Experience of Etanercept in Steroid Refractory Acute Graft Versus Host Disease from a Tertiary Cancer Centre in India

Introduction Acute graft versus host disease (aGVHD) is an important complication of allogeneic hematopoietic stem cell transplant (AHSCT). Steroid refractory (SR) aGVHD is seen in about 40- 50% of patients with no recommended standard of care. We report our experience with etanercept (ETA) as the initial agent in SR aGVHD. Materials and Methods We retrospectively analysed 43 AHSCT patients from 2010 to 2019 who received ETA as initial agent for SR aGVHD amongst 311 patients who underwent AHSCT in the same period. Patients received myeloablative (MAC) or reduced intensity conditioning (RIC). The transplants were from matched sibling donor (MSD), matched unrelated donor (MUD) and haploidentical donor (Haplo). GVHD prophylaxis was calcineurin inhibitor (CNI) plus methotrexate (MTX)/ mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide (PTCy) with CNI and MMF. aGVHD was graded as per the modified Glucksberg criteria. Additionally, all aGVHD episodes were also classified as per the Minnesota Scoring into High Risk (HR) and Standard Risk (sr) GVHD. First line treatment of aGVHD Grade II-IV was systemic steroids with methylprednisolone 1-2 mg/kg/day. SR aGVHD was defined as per standard criteria. ETA was started as 25 mg (0.4 mg/kg in children) subcutaneously every 72 hours initially and was tapered gradually depending on response. Response of SR aGVHD to ETA was defined as follows:Complete response (CR) was the complete resolution of aGVHD manifestations in all organs. Partial response (PR) was improvement in GVHD stage in at least 1 of the initially involved organs without CR and worsening in any other organs. Very good partial response (VGPR) was improvement in GVHD in all initial organs, with maximum stage I involvement in 1 or more organs (except upper gut). No response (NR)/Progression/Failure of therapy was defined as same grade or progression of GVHD in any organ or the addition of further GVHD therapy beyond ETA. Death prior to 1st response assessment was taken as NR. Response assessment was done at 3 time points - Day 14, Day 28 and Day 56 after initiation of ETA. Reduction of initial systemic steroid dose by ≥30% from baseline on day 28 after start of ETA was analysed as a subgroup to assess outcomes of patients. Results The characteristics of all 43 patients are shown in Table 1. ETA was required in a total of 45 episodes in 43 patients. The overall grade of GVHD and organs involved at the start of first line treatment are as in Table 2. The median day of onset of acute GVHD was 58 days (range 8-738 days). The median day of start of ETA was 86 days (range 16-74 days). The median number of days steroid was given prior to start of ETA was 7 days. The median number of ETA doses given were 11 (range 2-25). Response assessment on the predetermined time points are as in Table 2. The response rates (CR+VGPR+PR) at Day 14, Day 28 and Day 56 were 62%, 69% and 64% respectively. The organ specific response rates (CR+VGPR+PR) were 70% for lower gut, 67% for skin and 50% for liver. A third line agent for aGVHD was added in 10 patients, which included ruxolitinib, cyclosporine, mycophenolate mofetil, basiliximab or low dose weekly cyclophosphamide. The median OS of the whole cohort of SR aGVHD was 5.2 months. The median OS of the responders (CR+PR+VGPR) at Day 28 from ETA start was 6.8 months versus 2.8 months (p=0.0003) in non-responders (Fig 1). The median OS of sr group of Minnesota Grading was 24 months versus 10 months in HR group (p=0.085) (Fig 2). Patients, in whom reduction in the systemic steroid dose ≥ 30% at Day 28 from start of ETA was possible, had a significantly better median OS (9.5 months versus 3.5 months; p=0.000021) (Fig 3). In multivariate analysis, steroid dose reduction on day 28 of start of ETA was the most significant factor (p=0.008; hazard ratio 3.33; CI 1.3-8.1) CMV reactivation was seen in 64% of the patients. Fungal infections in 51% and bacterial infections in 78% patients after start of ETA. The causes of death were infection in 25 (58%) patients, refractory GVHD in 8 (18%), combination of GVHD and infection in 2 (5%) and relapse in 4 (9%) patients. Conclusion ETA used as initial agent has shown acceptable response rates for SR aGVHD in our cohort, especially for lower gut and skin. However, infections were the major cause for mortality for this cohort and early tapering of systemic steroids may be the key to improving outcomes. Disclosures No relevant conflicts of interest to declare.

Plasma levels of norepinephrine and expression levels of ß2-adrenergic receptor gene correlate with the incidence of acute graft-versus-host disease

Background: Acute graft-versus-host disease is a major complication in allogeneic hematopoietic stem-cell transplantation. Epinephrine and norepinephrine are stress hormones which affect many cells, including immune cells through interaction with adrenergic receptors, mainly β2-adrenergic receptor. The immunomodulatory effects of epinephrine, norepinephrine, and signaling of the adrenergic receptor have been shown to decrease the probability of the acute graft-versus-host disease in animal models. The aim of our study was to investigate the possible correlations between the serum levels of epinephrine and norepinephrine and also leukocytic expression levels of β2-adrenergic receptor with the incidence of acute graft-versus-host disease in patients undergoing allogeneic hematopoietic stem-cell transplantation. Methods: In this study, the plasma levels of epinephrine and norepinephrine and the leukocytic expression of β2-adrenergic receptor gene were measured and compared in allogeneic hematopoietic stem-cell transplantation patients with and without acute graft-versus-host disease. Data were analyzed and illustrated using SPSS 19 and GraphPad Prism 6. The student T-test, Pearson, and Spearman's tests were performed and p<0.05 was considered as significant. Results: We showed that the plasma levels of norepinephrine and the relative amount of the mRNA of β2-adrenergic receptor at 7 and 21 days after allogeneic hematopoietic stem-cell transplantation were significantly lower in patients with acute graft-versus-host disease than recipients without acute graft-versus-host disease. There were also negative correlations between the plasma levels of norepinephrine, leukocytic levels of the mRNA of β2-adrenergic receptor, and the incidence of acute graft-versus-host disease. Conclusion: Our results suggest that stress hormones and their receptor might have a role in preventing acute graft-versus-host disease and could be promising factors in controlling the outcome of allogeneic hematopoietic stem-cell transplantation.

The Transplant Evaluation Rating Scale predicts overall survival after allogeneic hematopoietic stem cell transplantation

AbstractTo evaluate the impact of psychosocial risks on post–hematopoietic stem cell transplantation (HSCT) outcomes, we prospectively conducted psychosocial assessment of 556 consecutive allogeneic HSCT patients who received their first allogeneic transplant at our center between 2003 and 2017. The Transplant Evaluation Rating Scale (TERS) score was prospectively assessed by a psychologist before transplantation, and patients were categorized as low, intermediate, or high risk based on their TERS score. Patients in the high-risk TERS group had significantly longer hospital stays during the first 180 days and 1 year post–allogeneic HSCT compared with the low-risk group (16 vs 13 and 21 vs 16 days; P = .05 and .02, respectively). The survival estimates for low-, intermediate-, and high-risk TERS groups at 3 year were as follows: overall survival (OS), 73%, 60%, and 65%; disease-free survival (DFS), 63%, 55%, and 60%; nonrelapse mortality (NRM), 11%, 20%, and 17%; and relapse, 26%, 25%, and 23%, respectively. In a multivariable analysis, intermediate- and high-risk TERS scores predicted for inferior OS, similar DFS, and higher NRM compared with low-risk TERS score. In a subset analysis of patients with low/intermediate risk per Disease Risk Index, multivariable analysis showed that high- and intermediate-risk TERS scores predicted for significantly worse OS, worse DFS, higher NRM, and similar relapse rates compared with low-risk TERS score. Our findings show that psychosocial factors as measured by TERS score are strong predictors of morbidity and mortality after HSCT among patients with low/intermediate disease risk.

Study protocol of a pilot study evaluating feasibility and acceptability of a psychosexual intervention for couples postallogeneic haematopoietic stem cell transplantation

IntroductionSexual dysfunction is one of the most common side effects of allogeneic haematopoietic stem cell transplantation (HSCT) for haematological cancers. Problems can persist between 5 and 10 years post-transplant and...

Clinical and Neuroimaging Correlates of Post-Transplant Delirium

Delirium is common among adults undergoing hematopoietic stem cell transplantation (HCT), although the clinical and neuroimaging correlates of post-HCT delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-transplant delirium in a retrospective cohort of 115 adults undergoing neuroimaging after allogeneic HCT. Delirium was established using previously validated methods for retrospective identification of chart-assessed postprocedural delirium. Chart reviews were independently conducted by a multidisciplinary team with expertise in HCT, psychiatry, and psychology on consecutive allogeneic HCT patients who underwent neuroimaging assessments and transplantation at a single center between January 2009 and December 2016. Neuroimaging markers of white matter damage and brain volume loss were also recorded. In total, 115 patients were included, ranging in age from 20 to 74 years (mean [SD] age, 49 [13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (odds ratio [OR], 1.92 [1.28, 2.87] per decade, P=.002), greater severity of white matter hyperintensities (OR, 1.95 [1.06, 3.57], P=.031), and conditioning intensity (OR, 6.37 [2.20, 18.45], P < .001) but was unrelated to cortical atrophy (P=.777). Delirium was associated with fewer hospital-free days (P=.023) but was not associated with overall survival (hazard ratio, 0.95 [0.56, 1.61], P=.844). Greater incidence of delirium following HCT was associated with greater age, microvascular burden, and conditioning intensity. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted.

Impact of Educational Interventions on Psychological Distress During Allogeneic Hematopoietic Stem Cell Transplantation: A Randomised Study.

BackgroundPhysical and psychological factors, like wrong attitudes and behaviours, can negatively influence the health outcomes of the patients receiving allogeneic hematopoietic stem cell transplantation (AHSCT). Educational interventions aiming to improve knowledge on side effects, risks, complications and preventive behaviour can reduce psychological distress, and improve quality of life (QoL). We aimed to compare a standard approach with therapeutic patient education (TPE) to analyse the impact on AHSCT patients’ QoL, psychological distress and knowledge of AHSCT side effects, risks complications and preventive behaviour.Material and methodsA prospective interventional study was conducted analysing data of 36 patients who received one of two different educational approaches, which were a standard approach (not-exposed) or TPE (exposed).ResultsIn the exposed group QoL improved 14 days after transplantation (42.2 vs 25.6; p<0.03) and at time of discharge (36.6 vs 54.4; p<0.005). Anxiety and depression were better controlled in the exposed group, both at hospitalisation and discharge (anxiety: 48.1 vs 53.2; 46.4 vs 51.6. p<0.04; depression: 49 vs 55.3; 48 vs 54.3, p<0.03). Knowledge of AHSCT risks and complications improved in exposed patients, both at admission (10.1/15 vs 8/15 correct answers; p<0.01) and discharge (10.7/15 vs 8.8/15 correct answer; p<0.03).ConclusionsThe TPE for AHSCT patients improved knowledge, reduced anxiety and depression, which consequently increasing QoL. Therefore, we recommend our approach to further engage patients in the treatment plan, which should specifically take place prior to AHSCT initiation.

Glycemic variability is associated with poor outcomes in pediatric hematopoietic stem cell transplant patients.

Among pediatric hematopoietic stem cell transplant (HSCT) recipients, abnormal glycemic control is shown to be associated with increased risk of transplant-related mortality, death from any cause, risk of infection, increased hospitalized, and intensive care days. Independent effects of higher glycemic variability, a component of glycemic control, have not been described. This study aimed to characterize risk factors for, and consequences of, higher glycemic variability in HSCT patients. Medical records for a cohort of 344 patients, age 0-30 years, who underwent first HSCT from 2007 to 2016 at Children's Hospital Colorado were retrospectively reviewed. Glucose coefficients of variation (CV) were analyzed for HSCT days -14 to 0 and 0-30, and patients were assessed for potential risk factors and outcomes. Roughly one-third of patients had pre-HSCT and day 0-30 glucose CV above the reported healthy adult range. Independent of HSCT type, doubling of pre-HSCT glucose CV was associated with a 4.91-fold (95% confidence interval [CI], 1.40-17.24) increased hazard of infection, as well as increased risk for intensive care hospitalization for allogenic HSCT patients. Multivariable analysis demonstrated that allogeneic HSCT patients had a 1.40- and 1.38-fold (95% CI, 0.98-1.99 and 1.00-1.91) increased hazard of death for every doubling of pre-HSCT and day 0-30 glucose CV, respectively. Just as with higher mean glucose, higher glycemic variability in the pediatric HSCT population is independently associated with significantly increased morbidity. Additional research is required to evaluate the utility of glucose control to mitigate these relationships and improve HSCT outcomes.

Outcome of peripheral blood allogeneic hematopoietic stem cell transplantation as a treatment option in patients with severe aplastic anemia between 40 and 50 years

The frontline treatment for patients younger than 40 years with severe aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-identical sibling donor. However, in patients with severe AA who are older than 40 years, allogeneic HSCT has been found to be associated with increased treatment-related mortality and toxicity, even when matched sibling donors are used. We report our institutional experience with allogeneic HSCT in patients with severe AA between 40 and 50 years. A total of 19 patients with severe AA were included in the study. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method. The mean age of patients at the time of transplant was 43.79 years, and 57.9% were male. The mortality rate was 36.8%, attributed to infection (10.5%), relapse (15.8%), and renal failure (5.3%) in all cases. Acute graft-versus-host disease (GVHD) occurred in five patients (26.3%), and chronic GVHD occurred in two patients (10.5%). The 5-year OS was 62% and the 5-year DFS was 52%. We found that the patient's age, platelet level prior to transplantation, and the number of CD3 cells infused for each transplant were independent prognostic factors for OS, and the age and sex of the patient, graft rejection, and platelet level prior to transplantation were significant prognostic factors associated with DFS. We recommend that immunosuppressive therapy be considered as a first-line treatment in patients with severe AA who are older than 40 years. Allogeneic HSCT can be considered a valid alternative option in patients whose suppression therapy fails.

Pre-transplant thrombocytopenia predicts engraftment time and blood products requirement in allogeneic hematopoietic stem cell transplantation patients

IntroductionThrombocytopenia is a common consequence of leukemia that affects the outcome of hematopoietic stem cell transplantation (HSCT). The stromal damage of bone marrow following pre-HSCT conditioning regimens can delay the hematopoietic engraftment and increased blood product transfusions. We tried to define threshold based on pre-transplant platelet count as a biomarker to predict engraftment time and blood product requirements in allogeneic HSCT patients. MethodsThis retrospective study was performed on 194 patients who received allogeneic HSCT. The median for platelet (PLT) count of patients at the admission day was considered as a cut off value. The association of platelet count with white blood cell (WBC) and PLT engraftment time and also the requirement of packed red blood cell or PLT transfusions as outcomes of interest were investigated. Results164 patients (84.5 %) had successful WBC engraftment, and PLT engraftment was seen in 155 patients (79.9 %) in 30 and 50 days after HSCT, respectively. The patients with PLT count higher than 154,000/μL had better PLT engraftment (P = 0.060), and WBC engraftment (P = 0.014) than those with PLT count lower than this cut off. The pre-transplant PLT count had negative relations with SD platelet requests after HSCT (P = 0.008). ConclusionThe thrombocytopenia before HSCT might delay the platelet and WBC engraftment time, which should be taken into account before transplantation. Since the blood product transfusion is one of the factors associated with engraftment, the pre-transplant platelet count can be used as a predictive biomarker to manage the blood product requirement during the HSCT until engraftment occurs.

The role of serum uric acid in the prediction of graft‐versus‐host disease in allogeneic hematopoietic stem cell transplantation

BackgroundUric acid (UA) level is of the valuable signs of inflammation. However, the role of UA in the outcomes of hematopoietic stem cell transplantation (HSCT) such as GVHD and patients’ overall survival is still a matter of debate. In this study, we aimed to evaluate the relationship between UA levels and GVHD incidence and overall survival in allogeneic HSCT patients.MethodsA total of 201 patients who were admitted for allogeneic transplantation at Taleghani hospital, Tehran, Iran, were considered for retrospective analysis. Serum UA levels from 1 week before transplantation until 2 weeks after transplantation were used to determine thresholds and find out the association of serum UA levels with GVHD and overall survival.ResultsWe showed that the determined thresholds using receiver operating characteristic curves have poor predictive value for GVHD and overall survival. The patients with serum UA higher than 3.4 mg/dL had 37% lower odds of GVHD incidence and 35% lower hazard of death than patients with UA lower than 3.4 mg/dL.ConclusionOur results indicated that serum UA levels lower than 3.4 mg/dL could significantly increase the incidence of GVHD and hazard of death. The antioxidant functions of UA could explain the lower incidence of GVHD in hyperuricemic patients. However, the inconsistencies of the previous studies require further investigation to elucidate the role of UA in the prediction of GVHD.

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients’ characteristics were: median age, 61 (34–72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.

Enteral Vancomycin Is Effective Clostridium Difficile prophylaxis in Pediatric, Adolescent, and Young Adult Hematopoietic Stem Cell Transplant Recipients

Background Clostridium difficile infection (CDI) is a major source of morbidity for patients undergoing autologous and allogeneic hematopoietic stem cell transplantation (HSCT). CDI can complicate gastrointestinal mucositis, lead to mucosal barrier infections or sepsis, and compromise nutrition after HSCT. CDI may contribute to acute gastrointestinal graft-versus-host disease (GI aGVHD) and reduce overall survival in allogeneic HSCT patients. Use of enteral vancomycin as CDI prophylaxis may reduce morbidity and improve outcomes in HSCT recipients. Methods As a quality improvement initiative, enteral vancomycin was instituted as CDI prophylaxis in all autologous and allogeneic HSCT recipients at Methodist Children's Hospital beginning 02/13/19. Patients were prescribed vancomycin 125 mg oral/enteral twice daily (Ganetsky et al. Clin Infect Disease 2019; 68 (12):2003-2009) from HSCT admission to discharge home. Patients readmitted during the first 100 days after HSCT resumed enteral vancomycin while hospitalized. Physicians, advanced practice providers, and pharmacists monitored enteral vancomycin administration. The infectious disease and prevention team monitored CDI and weekly vancomycin resistant enterococcus (VRE) stool testing per institutional policy. Pre- and post-implementation data was retrospectively reviewed (number of HSCT patients, CDI, VRE, adverse events of enteral vancomycin, and GI aGVHD). Two-sided Fisher's exact test was used to compare CDI before and after institution of enteral vancomycin prophylaxis. Results Between 01/05/2018 and 02/12/2019, the rate of CDI was 29% (n=9/31). After implementation of CDI prophylaxis (02/13/19 to 09/16/19), the rate of CDI was 0% (n=0/23). Enteral vancomycin resulted in a significant reduction in the number of CDI cases (p=0.0068). Prior to implementation of CDI prophylaxis, 26% (n=7/27) of allogeneic HSCT recipients developed GI aGVHD. Of the 7 patients that developed GI aGVHD, 6 had a history of CDI. After implementation of CDI prophylaxis, 7% (n=1/14) of allogeneic HSCT recipients developed GI aGVHD. There were no VRE positive screens or infections. There were no adverse events related to enteral vancomycin. Conclusions Enteral vancomycin appears to be safe and effective CDI prophylaxis in pediatric, adolescent, and young adult HSCT recipients. Since institution of enteral vancomycin prophylaxis, there has been a significant reduction of CDI in our HSCT patients. This quality improvement project is ongoing and future analyses will compare GI aGVHD and overall survival with CDI pre- and post-implementation of enteral vancomycin prophylaxis.

Optimization of Antimicrobial Prophylaxis in Patients Undergoing Hematopoietic Stem Cell Transplantation Utilizing an Absolute Neutrophil Count Driven Approach

Background Hematopoietic stem cell transplantation (HSCT) recipients often develop profound neutropenia and are ultimately at an increased risk of developing life-threatening infections peri-engraftment. There is discordance in the current guidelines for antibacterial prophylaxis (AP) in patients undergoing HSCT. While ASTCT, formerly ASBMT, guidelines suggest beginning antibacterial prophylaxis on the day of stem cell infusion, NCCN and ASCO/IDSA guidelines recommend beginning at time of neutropenia. These recommendations for timing of antimicrobials are unsubstantiated by any comparative analyses. Methods A retrospective study was conducted across two cohorts over a two-year period (November 2016-2018). The pre-intervention cohort called for initiation of AP on Day -1 while the post-intervention cohort initiated AP when patients' absolute neutrophil count (ANC) was ≤500 cells/mm3. The preferred AP agent used was levofloxacin, which was discontinued in both cohorts when patients attained a post-nadir ANC of ≥500 cells/mm3. The primary outcome was frequency of febrile occurrences, defined as a temperature of ≥38°C. Secondary outcomes included days of AP, positive blood cultures, all-cause mortality, length of stay (LOS), acute graft-versus-host disease (GvHD) through Day +100, and Clostridiodies difficile infection rates. Patients were excluded if they received a haploidentical transplant or inappropriately initiated AP per cohort approach. Results A total of 248 patients were included in the final analysis with 130 and 118 patients in the pre- and post-intervention cohorts, respectively. The majority of patients included were male (60%) and autologous transplant recipients (83%), with no clinically significant difference in major patient characteristics between both cohorts. There were lower rates of fever occurrences for autologous HSCT recipients (83 pre- vs 69% post-intervention; p=0.019), but no difference in allogeneic (64 vs 73%; p=0.542) HSCT patients. A significant reduction in the mean AP days per patient was identified (10.3 vs 4.9 days; p Conclusion Delaying AP until severe neutropenia showed a reduction in primary outcome of fever in autologous patients, and no difference in allogeneic patients or other significant clinical outcomes regarding patient safety. This approach is associated with a drastic reduction in antimicrobial exposure.

Clinical and Neuroimaging Predictors of Post-Transplant Delirium

<h3>Background</h3> Delirium is common among adults undergoing hematopoietic stem cell transplant (HCT), although the clinical predictors and neuroimaging correlates of postoperative delirium have not been adequately delineated. We therefore examined the frequency of delirium and neuroimaging correlates of post-HCT delirium in a retrospective cohort of 115 adults undergoing BMT. <h3>Methods</h3> Delirium was established using previously validated methods for retrospective identification of chart-assessed postoperative delirium. Chart reviews were independently conducted by a team including a HCT physician, a transplant psychiatrist, a transplant psychologist, and a psychiatry resident on consecutive allogeneic HCT patients who underwent neuroimaging assessments, transplanted between January, 2009 December, 2016Y. Neuroimaging markers of cortical volume loss and white matter hyperintensities were also recorded. <h3>Results</h3> One hundred fifteen patients were included, ranging in age from 20 to 74 (mean age = 49 [SD = 13]). Fifty-three patients (46%) developed post-HCT delirium. In an adjusted model, delirium incidence was associated with older age (OR = 1.92 [1.28, 2.87] per decade, P = .002), greater severity of white matter hyperintensities (OR = 1.95 [1.06, 3.57], P = .031), and treatment regimen intensity (OR = 6.37 [2.20, 18.45], P <.001) but was unrelated to cortical atrophy (P = .777). <h3>Conclusions</h3> Greater incidence of delirium following BMT was associated with greater age, microvascular burden, and more severe treatment regimen. Pre-HCT consideration of microvascular burden and other neuroimaging biomarkers of risk may be warranted.

Effects of ABO incompatibility on the outcome of allogeneic hematopoietic stem cell transplantation

BackgroundABO compatibility between donor and recipient is no necessary in allogeneic hematopoietic stem cell transplantation (AHSCT). Incompatible transplantations can be divided into three groups based on the donor and recipient blood groups. The influence of each kind of incompatibilities on the outcome of patients does not seem to be consistent. This study aimed to investigate the outcome of AHSCT patients focusing on compatibility statues. MethodThis retrospective study was conducted on 186 patients who underwent first AHSCT, includes 108 identical, 38 minor, 32 major and eight bidirectionalABO incompatible recipients. Comparative analysis was performed for common clinical transplantation outcomes. ResultsThere was no statistically significant association betweenABO incompatibility and graft-versus-host disease, WBC or platelet engraftment, and transfusion requirement. WBC engraftment rate was significantly lower in minor-incompatible patients. Furthermore, total and direct bilirubin which (the hemolysis biomarkers) were considerably higher in the bidirectional incompatible group, compared to the other patients. ConclusionOur results indicate that theABO incompatibility might be an effective factor in engraftment time and laboratory hemolysis. Elucidating the impact of ABO incompatibility on the clinical outcome of patients warrants an extended and deep investigation in a large-scale study with comprehensive variables such as survival, relapse, and other complication of transplantation.

Epidemiology, utilisation of healthcare resources and outcome of invasive fungal diseases following paediatric allogeneic haematopoietic stem cell transplantation.

Epidemiology and management practices of invasive fungal diseases (IFD) after allogeneic haematopoietic stem cell transplantation (HSCT) are a subject of constant change. We investigated the contemporary incidence, diagnostics, antifungal management and outcome at a major paediatric transplant centre in Germany. The single-centre retrospective observational study included all paediatric allogeneic HSCT patients (pts) transplanted between 2005 and 2015. Patient-related data were assessed up to 365days post-transplant. The primary endpoint was the incidence of possible, probable and proven IFDs. Secondary endpoints included diagnostics and antifungal treatment; analysis of risk factors; and overall survival with the last follow-up in January 2017. A total of 221 first (196), second (21) or third (4) procedures were performed in 200 pts (median age: 9years, range, 0.5-22) for leukaemia/lymphoma (149) and non-malignant disorders (72). Prophylaxis was administered in 208 HSCT procedures (94%; fluconazole, 116, mould-active agents, 92). At least one computed tomography scan of the chest was performed in 146, and at least one galactomannan antigen assay in 60 procedures. There were 15 cases of proven (candidemia, 4; aspergillosis, 4) or probable (aspergillosis, 7) IFDs, accounting for an incidence rate of 6.8%. Overall mortality at last follow-up was 30%; the occurrence of proven/probable IFDs was associated with a reduced survival probability (P<.001). Morbidity and mortality from IFDs at our institution were consistent with data reported from other centres. Utilisation of healthcare resources for prevention, diagnosis and management of IFDs was considerable.

Third-Party BK Virus Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation

Background. BK virus associated hemorrhagic cystitis (BKV-HC) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT), [Bedi, A., et al. JCO 1995] particularly in recipients of alternative donor transplants, which are being performed with increasing frequency [O'Donnell, P.H., et al, BBMT 2009]. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, with few effective therapeutic options [Seber, A., et al., BMT 1999]. Methods. We assessed the feasibility, safety, and efficacy of administering most closely human leukocyte antigen (HLA)-matched third party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 47 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. We compared their toxicity and survival to a control group of 85 AHSCT patients with BKV-HC treated with standard of care, using inverse probability of treatment weighted (IPTW) estimation to correct for bias due to non-randomization. The control group was matched for age, gender, graft versus host disease prophylaxis, conditioning regimen, AHSCT graft source, and both initial and maximum grade of BKV-HC. Results. On average, BKV disease status improved from 7 to 90 days post CTL infusion, with the primary response endpoint scored on day 28. Among 31 evaluable patients on day 28 who received a single BKV CTL infusion, 18 had a complete response (CR) and 9 a partial response (PR), for an overall response rate of 87%, which increased to 100% among evaluable patients at day 90 (Figure 1). Four of 7 patients who received multiple (1-5) CTL infusions for persistent disease following the first infusion are alive without BKV-HC. Median survival from the date of transplant in the BKV CTL group was 772 days, compared to a median of 171 days for the controls (IPTW adjusted log rank test p-value = 0.02) as shown in Figure 2. One BKV CTL patient with a history of skin graft versus host disease (GVHD) developed grade 3 gastrointestinal GVHD 64 days post CTL infusion, which resolved completely with systemic steroids. There were no cases of graft failure or infusion-related toxicities. BKV CTLs were identified in patient blood samples up to one month post-infusion. Conclusion. This is the largest series of AHSCT patients treated to date with BKV CTLs. The high response rate we observed in this study appeared to confer a survival benefit compared to a historically controlled cohort with BKV-HC treated with standard of care alone. This study demonstrated that administering third party, off-the-shelf banked BKV CTLs is feasible and safe. The safety profile, high response rate, and logistical ease with which potent off-the-shelf BKV CTL therapy were generated and administered warrants further investigation for patients with BKV-HC who have limited alternative therapeutic options. Disclosures Chemaly: ADMA Biologics: Other: Personal fees; Gilead: Research Funding; Janssen: Other: Personal fees; Ansun: Other: Personal fees; Oxford Immunotec: Research Funding; Chimerix: Research Funding; Ablynx: Other: Personal fees; Merck: Research Funding; Clinigen: Other: Personal fees; Gilead: Other: Personal fees; Ansun Pharmaceuticals: Research Funding; Chimerix: Other: Personal fees; Oxford Immunotec: Other: Personal fees; Merck: Other: Personal fees; ReViral: Other: Personal fees. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Jazz: Consultancy; Pfizer: Honoraria; Amgen: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplant Versus Gene Therapy in Sickle Cell Disease: A Systematic Review

BACKGROUND: Despite advancements in medical therapy and supportive care for sickle cell disease (SCD) over the last several decades, disease morbidity and mortality remain unacceptably high. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative therapy for SCD, but is associated with significant risks: conditioning regimen toxicity, graft failure, graft-versus-host disease (GVHD), and death are all potential sequelae, particularly when hematopoietic stem cells (HSC) originate from sources other than HLA-matched related donors (MRD). Gene therapy (GT), which involves ex vivo gene addition or editing of autologous HSCs, has recently emerged as an alternative curative approach for SCD. While GT still carries the risk of conditioning regimen-associated toxicity, the use of autologous over allogeneic HSCT eliminates the risk of GVHD as well as the need for an available HLA-matched donor. Both allogeneic HSCT and GT have demonstrated efficacy against SCD in clinical trials, yet these curative strategies have never been compared. Here, we present preliminary data from a systematic review comparing allogeneic HSCT and GT outcomes in SCD. METHODS: We searched the MEDLINE and EMBASE databases (including American Society of Hematology and European Hematology Association meeting abstracts) for studies evaluating outcomes following allogeneic HSCT and GT in SCD. The references of included studies were screened for additional relevant studies. We included phase I, II, and III clinical trials, retrospective reviews, case reports, and case series involving SCD patients of all ages undergoing allogeneic HSCT or GT. All HSC donor sources (MRD, matched unrelated donors (MUD), haploidentical, autologous) and conditioning regimens were included. Case reports with &lt;2 SCD patients, non-English studies, and pre-clinical studies were excluded. Studies including both SCD and thalassemia patients were included if SCD outcomes were reported separately. We assessed the primary outcomes of overall survival (OS) and event-free survival (EFS)-defined as stable donor erythropoiesis or transgene expression, absence of new or worsening SCD complications, graft rejection, GVHD, or graft failure-at 2 and 5 years post-transplant. All titles and abstracts were screened for full text retrieval. Data on study characteristics, quality, and effects were extracted and analyzed using descriptive statistics. Risk of bias was assessed using the Newcastle-Ottawa Scale. Heterogeneity of outcomes was assessed using sensitivity and subgroup analyses, and publication bias was assessed using funnel plot, where applicable. RESULTS: We identified 828 titles through database searching and 9 titles from references of included studies (Figure). Following removal of duplicate citations (n=142), exclusion of records not meeting eligibility criteria (n=605), and merging 38 studies with their primary article, 52 unique studies were included for data extraction. Of these 52 studies, 49 reported outcomes for allogeneic HSCT and 3 reported outcomes for GT, representing 1026 and 19 unique patients, respectively. Donor HSC source was MRD (n=24), MUD (n=5), haploidentical (n=5), or a combination thereof (n=10) in 44/49 allogeneic HSCT studies which reported these data. Length of follow-up was 3249.5 patient-years in the allogeneic HSCT group versus 24 patient-years in the GT group. Transplant-related mortality was 60/1026 (5.8%) and 0/19 in the allogeneic HSCT and GT groups, respectively. Graft failure was 83/1026 (8.1%) for allogeneic HSCT patients. In the GT group, 1/19 (5.3%) failed to achieve clinically significant anti-sickling globin levels. OS for allogeneic HSCT patients at 2 years was 91% among 158 patients from 8 studies, and 93% at 5 years among 162 patients from 4 studies. EFS for allogeneic HSCT patients at 2 years was 86% among 126 patients from 6 studies, and 89% at 5 years among 192 patients from 5 studies. OS and EFS were not reported for GT studies. Rates of GVHD could not be calculated due to heterogeneity of reporting. CONCLUSIONS: Although data for both allogeneic HSCT and GT in SCD are encouraging, longer follow-up is needed for GT patients in order to better assess regimen efficacy. Furthermore, outcomes reporting is highly heterogeneous both within and between treatment groups, underscoring the need for standardized reporting. Additional outcomes will be reported during the meeting. Disclosures Kuo: Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

Longitudinal Changes in the Intestinal Microbiome Composition Following Gut Decontamination in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Patients: A Pilot Study

Introduction: Early preclinical studies demonstrating that eradication of intestinal bacteria could prevent the development of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) led many adult and pediatric HSCT programs to practice "gut decontamination" (GD) with non-absorbable oral antibiotics for aGVHD prophylaxis. However, there is insufficient data supporting a clear benefit for GD in HSCT patients. Recent adult HSCT studies show that GVHD-related mortality is associated with decreased bacterial diversity in the gut microbiome, suggesting that certain bacterial species are protective against aGVHD. GD may decrease microbiome diversity and lead to worse post-HSCT outcomes. Methods: We conducted a randomized phase 2 study to examine the impact of GD on intestinal microbiome composition in pediatric allogeneic HSCT patients. 20 patients were enrolled and randomized to receive (GD) or not receive (no GD) oral vancomycin-polymyxin per our institutional standard from day -5 through engraftment. Stool samples were collected pre-transplant, weekly until neutrophil engraftment, monthly through day +100, then at 6 months and 1-year post-HSCT. Our primary endpoint is bacterial diversity, quantified by Shannon diversity index, at 2 weeks post-HSCT. Change in diversity is defined as the delta of diversity before transplantation compared to the minimum diversity seen in a single patient in a one-week window (around 14 days post-transplantation). This change in diversity was then averaged (mean) across each treatment arm. The stool microbiome was characterized using shotgun metagenomic sequencing (Nextera Tagmentation and Illumina HiSeq4000 Sequencing) for 10 patients to date, with median count of 1.4x107 reads per sample (range 1.3x106 to 3.3x107). Following quality control (FastQC, Trim Galore, Super Deduper), reads are assigned taxonomic designations using Kraken2 and GenBank (Oct. 2018) database. Secondary endpoints include the frequency of diarrhea (defined as &gt;3 bowel movements per day in the first 7 days post-HSCT), incidence of aGVHD and bacteremia during the first 100 days post-transplant, immune reconstitution, survival, and malignant disease relapse at 2 years after study entry. Comparisons by treatment group were performed with Fisher's exact test (binary) or Wilcoxon rank-sum test (continuous). Results: Baseline patient characteristics were similar between the two arms (Table 1). At present,5 patients (25%) have completed 2 years of follow up, 4 of 15 patients with malignant disease (27%) have had relapse (3 GD, 1 No GD), and 2 patients (10%) in the No GD arm have died (1 malignant relapse, 1 refractory chronic GVHD). Microbiome analysis in the first 10 patients (4 GD, 6 No GD) demonstrates that the average change in Shannon diversity score at 2 weeks is 1.7 (SD 0.86) in GD and 0.65 (SD 0.61) in No GD (Table 2). Diarrhea occurred in 4/10 patients in GD vs 4/10 patients in no GD (p≥0.99).1/10 patients in GD and 3/10 in No GD developed aGVHD grade II or above(p=0.58). Bacteremia within the first 100 days post-HSCT occurred in 1/10 patient in GD, whereas 5/10 patients in No GD had 8 different bacteremia events (p=0.14) (Table 3). Conclusions: This is the first randomized study of gut decontamination in pediatric patients undergoing HSCT with long-term prospective post-transplant stool sample collection and immune monitoring. Though the small sample size is currently not powered to detect differences in clinical outcomes between the 2 study arms, the descriptive microbiome and immune reconstitution data will inform larger studies. There is no statistical difference in the diarrhea, aGVHD, or bacteremia incidence between the two groups but it is interesting that there was 1 vs 8 bacteremia events in GD vs No GD. Microbiota diversity results from our pilot study with 10 patients indicate a trend toward lower diversity at 2 weeks post-transplant in the GD arm. Microbiome analysis of the remaining samples from the remaining 10 patients is underway as well as longitudinal analysis of samples from all patients. Describing the changes to the microbiota composition over time in two groups will provide insight to practice of GD, potential targets for aGVHD, and will provide preliminary data to understand which microbes and microbial gene-pathways may influence immune reconstitution. Disclosures London: United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Ritz:Draper Labs: Consultancy; Kite Pharma: Research Funding; Avrobio: Consultancy; LifeVault Bio: Consultancy; Merck: Research Funding; TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Celgene: Consultancy; Aleta Biotherapeutics: Consultancy; Equillium: Research Funding. Bhatt:ArcBio: Other: Scientific Advisory Board; January.ai: Other: Scientific Advisory Board; Caribou Bioscience: Other: Scientific Advisory Board; Kaleido Biosciences: Consultancy, Other: Paid Consultant; Janssen Human Microbiome Institute: Consultancy, Other: Paid Consultant; Illumina: Honoraria; 10x Genomics: Other: Research collaboration without funding support; Illumina: Other: Research collaboration without funding support; Agilent: Research Funding; Global Oncology, Inc: Other: Nonprofit Board.

Oral cryotherapy for oral mucositis management in patients receiving allogeneic hematopoietic stem cell transplantation: a prospective randomized study.

To explore the best schedule of oral cryotherapy for the prevention of oral mucositis in recipients of myeloablative hematopoietic stem cell transplantation (HSCT). A prospective randomized study was conducted to recruit allogeneic HSCT recipients, who were then randomly allocated into four arms to accept the following: oral cryotherapy during the whole course (arm A) or second half of the course (arm B) of cytotoxic agents administration, regular oral cryotherapy twice a day (arm C), or conventional oral care without cryotherapy (arm D). Status of oral mucositis was daily assessed from the first day of conditioning to the 15th day post-HSCT. A myeloablative conditioning regimen was used which was composed of busulfan, cyclophosphamide, and cytarabine. Totally 160 cases were consecutively enrolled in this study, and 145 cases were eligible for oral mucositis assessment. Both arm A and arm B were associated with a lower incidence and short duration of severe mucositis (≥ grade 3), although no statistical difference was found between these two groups (p = 0.463, p = 0.678). The highest incidence of severe mucositis was observed in arm C. Recovery of mucositis also had a significant diversity among the 4 arms (F = 4.133, p = 0.008). Risk and outcome of severe oral mucositis could be ameliorated by oral cryotherapy during the administration of cytotoxic agents for allogeneic HSCT patients receiving non-radiation myeloablative conditioning regimen, and a half-course schedule could acquire a comparable efficacy compared with the whole-course schedule.