Search

Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.

UK barrister John Horan, who was disabled as the result of a stroke, uses the example of his own case to argue that discrimination on the grounds of disability in courts, tribunals and regulatory panels will only be stopped if judges and their peers take a realistic approach based on morality and humanity. He supports his argument with references to the United Nations Convention on the Rights of Persons with Disabilities, the Equal Treatment Bench Book developed by the Judiciary of the UK and other sources. This is his personal view.

Allogeneic hematopoietic cell transplantation (HCT) may be curative for patients with marrow and immune disorders, but acute graft-vs-host-disease (aGVHD) and infections cause significant morbidity and non-relapse mortality. We conducted a multicenter, double blind, placebo-controlled phase II trial of costimulation blockade with abatacept (Aba) combined with standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate (CNI + MTX) following HLA matched unrelated donor transplant (n=140). In order to assess whether Aba produces clinically relevant compromise of immune reconstitution, and whether this reconstitution is influenced during CMV reactivation, we longitudinally evaluated post-transplant whole blood samples with multiparameter flow cytometry using markers for CD3, CD4, CD8, CD197 and CD45RA to measure reconstitution of CD4 and CD8 T cell populations and their respective memory subsets over time. We show here that post-transplant CMV reactivation induces a marked expansion of CD8 effector memory (EM) cells, which is similar in Aba vs placebo pts. We found that development of moderate (gr 2–4) or severe (gr 3–4) GVHD does not cause more CMV reactivation in patients, but patients with moderate GVHD show a blunted expansion of CD8 EM cells compared to those without GVHD. Remarkably, CD8 EM expansion was essentially absent among CMV reactivating patients with severe aGVHD. Our results suggest that adding abatacept to CNI/MTX does not materially affect reconstitution of T cell immunity in the presence or absence of CMV reactivation, but aGVHD remains a major driver of compromised immune recovery after HCT.

Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life and premature mortality. Hematopoietic cell transplantation (HCT) is curative in SCD. Excellent outcomes have been achieved in young children with HLA matched related donors (MRD), with low rates of acute and chronic graft versus host disease (GVHD). Adolescent patients with SCD receiving MRD HCT and patients with SCD receiving matched unrelated donor (MUD) HCT, remain at highest risk for GVHD and resulting morbidity and mortality. Building on the encouraging experience with abatacept (CTLA-4Ig) for GVHD prophylaxis in URD HCT for hematologic malignancies, we launched an early phase, multicenter trial (n=25) through the Sickle Cell Transplant Advocacy and Research Alliance (STAR) of abatacept in pediatric SCD patients at high risk for GVHD. Patients with severe sickle cell disease were eligible if they were receiving a MRD HCT and either they or their donor were at least 10 years or if they were receiving a MUD HCT. Twenty-five patients have been enrolled to date with 23 patients completing conditioning and HCT. All patients received reduced intensity conditioning (RIC) with distal alemtuzumab, fludarabine, thiotepa and melphalan and marrow grafts. Four doses of abatacept (10 mg/kg/dose IV on days -1,+5,+14, +28) were added to standard GVHD prophylaxis using tacrolimus and methotrexate. Abatacept dosing was extended to eight doses for the last 11 patients (+60, +90, +120, +150). Tacrolimus was tapered at day 180 if no GHVD was present. The median age at HCT was 11 (3-21 years); 13 received a MRD HCT and 10 a MUD HCT. All patients engrafted with neutrophils at a median of 21 days (range 13-26) and platelets at a median of 23 days (13-55). As of 10/1/2019, median follow up is 804 days (range 46 – 1139). The mean myeloid and T-cell chimerisms at one (n=17) and two years (n=10) were 97.9 +/- 4.9 and 94.2 +/- 10.0 and 96.6 +/- 8.9 and 97.5 +/-4.3, respectively. Three evaluable patients at 2 years did not have chimerism studies sent. There have been 4 cases of EBV viremia (1 PTLD) and 6 cases of CMV viremia (1 disease). Grades 3-4 acute GVHD was seen in one patient and chronic/overlap in 5 patients with two patients currently receiving sytemic immune suppression. There has been no cerebral hemorrhages but one patient developed non-infectious encephalopathy of unclear etiology. The overall and sickle cell free survival at 2 years post HCT in evaluable patients (N=13) is 100% and 100%, respectively. The preliminary results in first 23 patients enrolled to date suggest that incorporating abatacept into GVHD prophylaxis is a safe and efficacious approach to improving outcomes in HCT for pediatric SCD.

OBJECTIVES/SPECIFIC AIMS: Aim 1: To compare microbiome diversity among patients who develop BSI post hematopoietic stem cell transplantation (HSCT) and patients without BSI. Aim 2: To compare microbiome diversity among patients who develop moderate to severe acute GVHD post HSCT and patients without GVHD. Aim 3: To describe alterations in specific bacterial orders (Enterobacteriaceae, Clostridia, and Lactobacillales) in pediatric patients undergoing HSCT. METHODS/STUDY POPULATION: Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from stool specimens collected at baseline (start of preparative regimen to transplant day), early (day 7–14 post HSCT), and late (day 21–28 post HSCT) from 46 children was performed. Microbiome diversity was assessed by the Shannon index as well as UniFrac analysis, and compared among patients with and without GVHD/BSI. Baseline bacterial diversity was compared among patients by primary diagnosis, race, timing of antibiotic introduction and method of supplemental nutrition. RESULTS/ANTICIPATED RESULTS: Median age was 9 years (range 0.5–19.2 years). There were 36 patients with hematologic malignancies. Patients with nonmalignant disease had a characteristic pattern of microbiome diversity (and microbiota order distribution) at baseline that persisted throughout the first month of transplant (p=0.004). Over all patients, there was an early and persistent drop in microbiome diversity throughout the transplant course. Early introduction of broad spectrum antibiotics (prior to transplant day) negatively impacted microbiome diversity (p=0.02). There was no difference in microbiome diversity among patients who developed BSI, when compared with patients without BSI. Similarly, we did not find an association between microbiome diversity and the development of moderate to severe acute GVHD. Ongoing analysis is examining the individual variations in microbiome at the species level, and their relation to transplant characteristics and clinical outcomes. DISCUSSION/SIGNIFICANCE OF IMPACT: In our analysis, microbiome diversity decreased during HSCT, but in contrast to published data, mainly in adult HSCT populations, we found no association between gut microbiome diversity and GVHD or BSI. There are ongoing clinical trials in children and adults using probiotics in HSCT with the aim of decreasing GVHD. Further analysis of our data at the species level may further inform the relationship between gut microbiome alterations and HSCT complications in children and guide clinical interventions.

Tailoring pre-emptive CMV therapy to hematopoietic cell transplant recipients' risk for reactivation could make this approach more cost-effective. To determine the feasibility of creating a risk classification system for this purpose, we analyzed 169 pediatric HCTs involving seropositive recipients or donors. Using risk factors derived from multivariable analysis, we stratified patients as having no risk factors, any one, any two, or all three risk factors (age, donor type, and presence of GVHD). The cumulative incidence of reactivation was 4.7%, 10.1%, 21.1%, and 40.9%, respectively (P ≤ 0.001). These results demonstrate the feasibility of creating a risk classification schema. Pediatr Blood Cancer 2015;62:364-366. © 2014 Wiley Periodicals, Inc.

Background: Recent studies have shown that an elevated ferritin level prior to hematopoietic stem cell transplant (HSCT), serving as a surrogate marker of body iron load, is independently associated with transplant related mortality (TRM) and inferior overall survival (OS) in adult oncology patients. Study Design and Methods: We performed a retrospective cohort study of 112 children with leukemia treated at our institution over a 10 year period, and compared TRM and OS after HSCT in those children with and without high red-blood cell (RBC) transfusions. Both groups were similar in regards to age, diagnoses, donor type (matched related, matched unrelated, mismatched related, mismatched unrelated), stem cell source (peripheral blood, umbilical cord, bone marrow), baseline liver, cardiac and renal function, and median follow-up time. However, more children in the low RBC transfusion event cohort had high Karnofsky/Lansky performance scores (83.5% vs 54.5%, p=0.001) and fewer had recurrent leukemia or other forms of advanced disease compared with the children more heavily transfused (41.8% vs 87.9%, p

s / Biol Blood Marrow Transplant 21 (2015) S54eS78 S69 after RIC (34 vs 29%; p1⁄40.04). There was no statistical difference between MAC vs RIC for OS, LFS, RI and NRM (Figure 1). The analyses were performed separately for pts

Monte-Carlo techniques for prediction of IC yield in the presence of inter-die parameter variations are well established in the literature [Luigi P. Monte-Carlo simulation of semiconductor device and process modelling; critical review. IEEE Trans CAD 1990; CAD-9: 1164--76], but their use in commercial design is limited by their high computational cost. This paper presents a novel technique which shows a great reduction in the simulation cost and sustains the accuracy. It does this by first using Principal Component Analysis (PCA) [Cureton EE et al. Factor analysis: an applied approach. Hillsdale, New Jersey: Laurence Erlbaum Associates, 1983] to identify the significant orthogonal directions of variation in the process space. The next steps involve the development of an accurate approximation of the two dimensional yield boundary. Finally, an analytic integration in the process space provides the yield. The steps involved in the yield calculation also conveniently produce performance distributions and this is described.

Objective To identify the etiologic agent and risk factors associated with a hospital ward outbreak of gastroenteritis. Setting A regional referral hospital in upstate South Carolina. Methods We reviewed patient charts, surveyed staff, and tested stool from acutely ill persons. A case was defined as diarrhea and vomiting in a staff member or patient from January 5 to 13, 1996. Results The initial case occurred on January 5 in a staff nurse who subsequently was hospitalized on the ward and visited by many staff colleagues. The staff were at a significantly greater risk for gastroenteritis than were patients (28/89 [31%] vs 10/91 [11%]; relative risk [RR], 2.9; 95% confidence interval [CI95], 1.5-5.5). All 10 case-patients had been exposed to case-nurses (assigned nurses who were primary caretakers), and eight had documented exposure to case-nurses 1 to 2 days before their illness. Patients exposed to case-nurses had a significantly increased risk of illness (8/57 [14%] vs 0/32; RR, >4.5; CI95, undefined). Neither staff nor patients had significantly increased risk from food, water, ice, or exposure to case-patients. Electron microscopy identified small round-structured viruses (SRSVs) in nine of nine stool samples. Conclusion This nosocomial outbreak of gastroenteritis was likely caused by SRSVs introduced by a staff member and spread via person-to-person transmission from and among staff. The potential for spread of SRSV-associated gastroenteritis from and among staff should be considered in developing strategies to prevent similar outbreaks in hospital settings.

We compared outcomes after hematopoietic cell transplantation in patients of African American (n = 84) and Caucasian (n = 215) descent with severe aplastic anemia. African Americans and Caucasians were matched for age, donor-recipient human leukocyte antigen match, graft type, and transplantation year. The median follow-up of surviving patients was 5 years. In multivariate analysis, overall mortality risks were higher for African Americans compared to Caucasians (relative risk 1.73, P = 0.01). The 5-year probabilities of overall survival adjusted for interval from diagnosis to transplantation, and performance score was 58% for African Americans and 73% for Caucasians. The day-100 cumulative incidence of grade III-IV, but not grade II-IV acute graft-versus-host disease (GVHD), was higher in African Americans compared to Caucasians (29% vs. 13%, P = 0.006). Although the 5-year cumulative incidence of chronic GVHD was not significantly different between the racial groups, African Americans were more likely to have extensive chronic GVHD compared to Caucasians (72% vs. 49%, P = 0.06). Survival differences between Caucasians and African Americans can be attributed to multiple factors. Our data suggest that some of the observed survival differences between Caucasians and African Americans may be explained by higher rates of acute GVHD and severity of chronic GVHD.

International audience; A domino portrait is an approximation of an image using a given number of sets of dominoes. This problem was first formulated in 1981 by Ken Knowlton in a patent application, which was finally granted in 1983. Domino portraits have been generated most often using integer linear programming techniques that provide optimal solutions, but these can be slow and do not scale well to larger portraits. In this paper we propose a new approach that overcomes these limitations and provides high quality portraits. Our approach combines techniques from operations research, artificial intelligence, and computer vision. Starting from a randomly generated template of blank domino shapes, a subsequent optimal placement of dominoes can be achieved in constant time when the problem is viewed as a minimum cost flow. The domino portraits one obtains are good, but not as visually attractive as optimal ones. Combining techniques from computer vision and large neighborhood search we can quickly improve the portraits. Empirically, we show that we obtain many orders of magnitude reduction in search time.

Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies that arise within bone marrow precursors of the myeloid, monocyte, erythroid, and megakaryocytic lineages (Pizzo and Poplack 2005). It comprises between 15% and 20% of all leukemias occurring during childhood. The incidence of new cases varies during childhood by year of age; the highest incidence is in early childhood, with about 12 cases per million in children up to age 2, declining steadily thereafter to its lowest incidence of about 4 per million at age 9, then climbing again during adolescence (Fig. 10.1). AML affects male and female children and black and white children in the US about equally (Ries and Smith 1999). Survival after AML (5-year relative survival) has increased steadily in the US over the period 1975–2005, from a rate of 18.8% in 1975–1977 to 60.2% in the period 1999–2005 for children diagnosed from 0 to 14 years of age (Fig. 10.2). It is likely that the growth and refinement of allogeneic hematopoietic stem cell transplant (HSCT) from related and unrelated donors since the 1970s has contributed to this improvement. However, survival after AML still lags considerably behind acute lymphoblastic leukemia (ALL), for which survival had reached 89.0% in the interval 1999–2005 (Ries and Smith 1999). Again in contrast to ALL, survival after AML was slightly better for females than for males with AML, but there were no detectable differences between blacks and whites (Ries and Smith 1999). Within Europe from 1988 to 1997, regional differences in survival after AML in children were pronounced from North to East, where survival was significantly poorer.

A domino portrait is an approximation of an image using a given number of sets of dominoes. This problem was first stated in 1981. Domino portraits have been generated most often using integer linear programming techniques that provide optimal solutions, but these can be slow and do not scale well to larger portraits. In this paper we propose a new approach that overcomes these limitations and provides high quality portraits. Our approach combines techniques from operations research, artificial intelligence, and computer vision. Starting from a randomly generated template of blank domino shapes, a subsequent optimal placement of dominoes can be achieved in constant time when the problem is viewed as a minimum cost flow. The domino portraits one obtains are good, but not as visually attractive as optimal ones. Combining techniques from computer vision and large neighborhood search we can quickly improve our portraits to be visually indistinguishable from those found optimally. Empirically, we show that we obtain many orders of magnitude reduction in search time.

Background: AYA patients with cancer comprise a unique and understudied population with higher treatment-related toxicity than younger children. Objective: To describe the outcome of AYA patients with AML treated with intensive chemotherapy and GO. Methods: AYA patients (ages 16-21) on Children’s Oncology Group (COG) trials AAML03P1 and AAML0531 were analyzed and compared to younger patients. Both trials included patients with newly diagnosed AML. Differences in disease characteristics, treatment response, treatment-related mortality (TRM) and relapse risk (RR) were compared. Patients received either 5 chemotherapy courses or 3 followed by stem cell transplant (SCT) dependent on donor availability alone in 03P1, and risk stratification and donor availability in 0531. On AAML0531, patients with t(8;21) or inv(16) were considered low risk and did not receive SCT. High risk patients had adverse cytogenetics (-7, -5/5q-), high FLT3 -ITD HAR (>0.4) or slow response with >15% marrow disease after induction 1. High risk patients received SCT if any donor was available. All other patients were intermediate risk and received SCT if a matched family donor was available. GO (3 mg/m2/dose) was administered to all patients on AAML03P1 while patients on AAML0531 were randomized to treatment with or without GO. Patients scheduled to receive GO received one dose on induction 1, day 6, and for patients that did not proceed to SCT, a second dose was given on intensification 2, day 7. Results: A total of 1350 patients 21 years old and younger were studied. Significantly different characteristics of AYA compared to younger patients are presented in Table 1, whereas gender, race, ethnicity, t(8;21) and inv(16) were similar between age groups. | | Age < 16 Years (n=1144) | Age 16-21 Years (n=206) | p value | | ------------------------------ | ----------------------- | ----------------------- | ------- | | Normal Cytogenetics | 225 (20.5%) | 70 (36.5%)

Introduction: Splenic dysfunction is a critical complication of SCD that begins in early childhood and can cause fatal sepsis. Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD, however, its long-term effect on the spleen in patients who had SCD is not well characterized. This information could be helpful to further inform medical professionals and families considering HSCT for SCD. Better understanding of the splenic function of patients after transplant for SCD could also provide important information regarding these patients' future risk of infection and other possible problems related to asplenia. Methods: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. Patients were excluded for analysis if they had pre-HSCT splenectomy, died less than one year post-transplant, failed to engraft, or had no post-HSCT spleen function testing. Tc99m liver-spleen (LS) scans and red blood cell (RBC) pit counts, validated tests to evaluate the spleen in SCD, were used to assess splenic function. Splenic uptake on scans was classified as either present or absent. RBC pit count was classified as either normal or abnormal. If a patient had multiple LS scans or RBC pit counts post-HSCT, then the most recent test was used for this analysis. Results: Fifty-five evaluable patients were identified (53 patients with a post-HSCT LS scan, 29 patients with a post-HSCT RBC pit count, and 27 patients with both tests). Almost all (52/55, 95%) patients had hemoglobin SS or Sβ0 disease. Median age at transplant was 8.8 years (range 1.8-22.0 years). Conditioning regimen and stem cell source varied, however, 48/55 (87%) received myeloablative conditioning and an HLA-identical sibling donor HSCT. At a median 2.0 years post-HSCT (range 0.9-8.9 years), 48/53 (91%) had spleen uptake present on LS scan. At a median 3.2 years post-HSCT (range 1.0-11.4 years), 24/29 (83%) had a normal RBC pit count. Analysis of patients who had both pre- and post-HSCT tests showed that patients had significantly improved outcomes post-HSCT: Table Pre-HSCT Post-HSCT p-value Spleen Uptake Present on LS scan 17/36 (47%) 32/36 (89%) 0.0002 Normal RBC pit count 6/20 (30%) 17/20 (85%) 0.0004 All patients (17/17, 100%) with LS scan spleen uptake pre-HSCT had uptake present post-HSCT compared to 15/19 (79%) patients with absent spleen uptake pre-HSCT had uptake present post-HSCT (p=0.11). Four patients had absent spleen uptake at 1 year post-HSCT but had uptake present at 2 years post-HSCT. Conclusion: Our study represents the largest comprehensive evaluation of long-term splenic function in patients after HSCT for SCD. Our results suggest that successful HSCT mitigates damage to the spleen induced by SCD. In patients with splenic function pre-transplant, HSCT appears to preserve this function. In patients lacking splenic function, HSCT appears to engender the return of function in most, but not all patients. Disclosures No relevant conflicts of interest to declare.

From January to April, 1990, 695 measles cases were reported to the Puerto Rico Health Department; there were 12 measles-associated deaths (case fatality ratio, 17/1000), more than in any year since 1967. We conducted a case-control study of risk factors for severe measles. We identified 16 children (ages 5 to 34 months) with severe measles and selected children with nonsevere measles as controls (39 hospitalized and 38 nonhospitalized). Controls were frequency matched to severe measles cases by region of residence. One case and two controls had been vaccinated. An underlying illness was present in 50% of cases and 16% of nonhospitalized controls (Mantel-Haenszel weighted odds ratio 5.3; 95% confidence interval 1.4, 20.2). In a multivariate analysis cases were significantly more likely than hospitalized controls to be from families with an annual income of$5000 (odds ratio (OR), 26.9), to have a mother without a high school degree (OR 11.1), to be anemic (hemoglobin10 g/dl) (OR 15.9) and have an underlying illness (OR 18.3). During measles outbreaks preventing severe illness requires aggressive control measures and strategies to increase vaccine coverage of children with underlying illnesses and of low socioeconomic status.

Graft failure rates after HLA matched sibling bone marrow (BM) transplants for severe aplastic anemia (SAA) are about 10%. We analyzed factors that may affect rates of hematopoietic recovery, graft-versus-host (GVHD) and overall survival after a second HLA-matched sibling donor transplant in 166 patients with SAA with graft failure after a first HLA-matched sibling donor transplant. Transplantations occurred between 1986 and 2004; median follow up of surviving patients is 8 years. One hundred and forty patients (84%) received their second transplant for secondary graft failure and 26 (16%), for primary graft failure. The median age at second transplantation was 17 years; 90% of patients were younger than 30 years. Sixty-seven percent had performance scores 95%) received GVHD prophylaxis regimen that included a calcineurin-inhibitor. Probabilities of neutrophil recovery at day 28 and platelet recovery at day 60 after second transplantation were 63% and, 62%. Rates of acute grades 2–4 GVHD at day 100 and chronic GVHD at 5 years were 9% and 16%, respectively. Early mortality rates were high, 30% at day-100. Risks of early mortality were lower when pre-transplant performance scores were 90–100% (relative risk [RR] 0.17, 95% CI 0.06–0.47, p=0.001) and when second transplant occurred >3 months from first transplant (RR 0.32, 95% CI 0.15–0.68, p=0.003). Similarly, risks of overall mortality were lower in patients with performance scores 90 – 100% (RR 0.53, 95% CI 0.30–0.95, p=0.033) and when second transplant occurred >3 months from first transplant (RR 0.47, 95% CI 0.29–0.76, p=0.002). Of the 47 patients who received their second transplant ≤ 3 months after their first transplant, 22 had primary graft failure after their first transplant and 25, early secondary graft failure. Fifteen of these 47 patients failed to achieve neutrophil recovery after their second transplant; 12 of 15 had primary graft failure after first transplant. Other factors such as use of a different donor, conditioning regimen, graft type and growth factor administration did not affect outcome after second transplantation. The 5-year probabilities of overall survival in patients with performance scores 90–100% whose second transplants occurred ≤ 3 months and >3 months after their first transplant were 56% and 76%, respectively. Corresponding rates for patients with performance scores

n/a