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Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

•The National Marrow Donor Program (NMDP) received preliminary search requests for over 3300 domestic and 3700 international allogeneic hematopoietic cell transplant candidates during the initial phase of the coronavirus disease 2019 (COVID-19) pandemic.•Despite a decrease in preliminary search requests, the number of unrelated donor grafts infused at domestic transplant centers following the initial phase of COVID-19 was only 4% less than the same period of time 1 year earlier.•Of over 2800 transportation legs and over 1600 transports completed through the NMDP, only 1 product was delivered outside of the requested time window in the initial period after COVID-19.

•Carbapenems are associated with acute graft-versus-host disease (aGVHD) in pediatric patients.•No association exists between broad-spectrum cephalosporins and aGVHD; antipseudomonal penicillins demonstrated an inconsistent association.•Pretransplantation carbapenems may especially impact aGVHD risk.•More research is needed to define the mechanism underlying this association.

In this paper we propose a methodology to integrate human expertise with effective control laws to drive artificial agents in a complex joint task. We use Supervised Machine Learning to derive human-inspired strategies that succeed in task performance independently from the operating conditions of the samples provided in the training phase. Numerical simulations validate the efficiency of the proposed human-inspired strategies against simpler yet computationally expensive rule-based strategies.

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Understanding the role that children play in the clinical burden and propagation of severe acute respiratory syndrome coronavirus 2, responsible for coronavirus disease 2019 (COVID-19) infections, is emerging. While the severe manifestations and acute clinical burden of COVID-19 have largely spared children compared with adults, understanding the epidemiology, clinical presentation, diagnostics, management, and prevention opportunities and the social and behavioral impacts on child health is vital. Foremost is clarifying the contribution of asymptomatic and mild infections to transmission within the household and community and the clinical and epidemiologic significance of uncommon severe post-infectious complications. Here, we summarize the current knowledge, identify resources, and outline research opportunities. Pediatric infectious diseases clinicians have a unique opportunity to advocate for the inclusion of children in epidemiological, clinical, treatment, and prevention studies to optimize their care as well as to represent children in the development of guidance and policy during pandemic response.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Objective.Evidence is clear that the nation is experiencing an increasing number of incompetent to stand trial (IST) admissions to state hospitals. As a result, defendants in need of treatment can wait in jail for weeks for admission for restoration. This study was conducted to better understand this growing population and to inform hospital administration about the characteristics of IST admissions.Methods.The study was conducted at the Department of State Hospitals (DSH) facility in Napa (DSH-Napa), a 1200-bed primarily forensic inpatient psychiatric facility located in northern California. The records of patients found IST and admitted to DSH-Napa for restoration of competence between the dates of 1/1/2009 and 12/31/2016 were eligible for inclusion in the study.Results.There were a total of 3158 unduplicated IST admissions available during the specified time period. Our data indicate that the number of admissions with more than 15 prior arrests increased significantly, from 17.7% in 2009 to 46.4% in 2016. In contrast, the percent of patients reporting prior inpatient psychiatric hospitalization evidenced a consistent decrease over time from over 76% in 2009 to less than 50% in 2016.Conclusion.Our data add to the body of literature on the potential causes of the nationwide increase in competency referrals. The literature is clear that jails and prisons are now the primary provider of the nation’s mental health care. Our data suggest that another system has assumed this role: state hospitals and other providers charged with restoring individuals to competence.

Acute myeloid leukemia (AML) predominantly affects older adults, and often requires allogeneic hematopoietic cell transplantation (alloHCT) for cure. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), beginning in 2001, the largest growth in alloHCT for malignant diseases occurred in patients ≥65y. However, whether this is due to expanded utilization of alloHCT for AML is unclear. Using a linked dataset, we examined patients with AML in California to assess population-based alloHCT utilization over time and factors associated with receipt of alloHCT across age groups.

It is well established that focused effort is required for timely and broad adoption of evidence-based practices (EBP). The NMDP has created a continuous dissemination and implementation (D&I) process for transplant and cellular therapy (TCT) research utilizing implementation science methods to help address the evidence-to-practice gap, contributing to expansion of access. Here, we report on the development and application of this process.

Disparities exist in clinical trials participation. ACCESS (NCT04904588) is a multi-center, phase II trial primarily to determine overall survival at one year following transplantation of peripheral blood stem cells from mismatched unrelated donors (MMUD) using post-transplantation Cyclophosphamide for patients with hematologic malignancies. Using MMUD expands access for ethnically diverse (ED) patients to HCT. We sought to understand whether there were disparities in ACCESS participants compared to mismatched unrelated donors from a real-world sample and in the intersectionality of race/ethnicity and social determinants of health (SDOH).

Efficacy of mobilization of peripheral blood stem cells (PBSC) is critical in providing patients with optimal products. We wanted to determine if pre-mobilization donor characteristics and lab values routinely obtained prior to mobilization could predict CD34+ yield. Our aim was to develop predictive models to understand donor traits associated with mobilization response, thereby facilitating optimal donor selection and apheresis procedure planning.

Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000–7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (<1 cm fluid), or severe (fluid in all three regions with >1 cm fluid in at least two regions).

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

•Survival continues to improve in patients receiving cellular therapies.•Patient-reported outcomes bring the patient's perspective to clinical registry data.•The cellular therapy registry has patient-reported data on approximately 1000 patients.•Patient-reported outcomes data are shared back to participating centers

•Implementing research into clinical practice is critical to improve outcomes.•Implementation science (IS) systematically drives adoption of evidence-based practices.•Applying IS to the field of HCT/CT will drive practice changes that benefit patients.

Introduction:Next-generation sequencing (NGS) represents a promising modality for measurable residual disease (MRD) testing in patients with acute myeloid leukemia (AML), but systematic efforts are required to define the appropriate targets, test characteristics, and clinical implications. We recently reported that detection of persistent NPM1or FLT3internal tandem duplication (ITD) mutations in adults with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death compared with those testing negative (JAMA 2023, PMID: 36881031). FLT3tyrosine kinase domain (TKD) variants are present in 7-10% of adult patients with AML but the utility of this target for AML MRD testing in CR1 prior to alloHCT was previously unknown.

Background:In the past year, multiple studies have demonstrated the drastically increased risk of relapse and death in patients with Acute Myeloid Leukemia (AML) who have persistent FLT3internal tandem duplication (ITD) mutations detectable in clinical remission by next generation sequencing (NGS). Translating this evidence into a change in clinical practice requires both widely available testing and a clear understanding of the clinical implications of FLT3-ITD detection at defined threshold levels. In the largest of the recent studies (Pre-MEASURE, PMID: 36881031), we performed FLT3-ITD MRD detection in blood DNA collected from 608 patients at the time of first remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT). To evaluate cross-assay comparability and the impact of residual disease burden levels, we performed analysis on this cohort using a commercially available FLT3-ITD MRD NGS assay.

Introduction: Detection of measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplant (alloHCT) in patients with acute myeloid leukemia (AML) in remission is associated with increased relapse and inferior survival after transplant. We recently reported that next-generation sequencing (NGS) detection of mutated NPM1or FLT3-ITD in first complete remission (CR1) blood prior to alloHCT is strongly associated with increased relapse and death (PMID: 36881031). However, the prognostic implications of detecting persistence of other common AML-associated mutations at this treatment landmark remain incompletely defined. Around 20% of patients diagnosed with AML have variants in isocitrate dehydrogenase ( IDH) genes (~7% for IDH1) and clinical outcomes are known to differ due to co-occurrence of other mutations, IDHsubtypes, treatment strategies, and patient factors. Studies have examined the relationship between residual IDH1variants ( IDH1m) in CR and subsequent clinical outcomes, but definitive standardized evidence to inform decision-making for the clinical utility of IDH1mas a target for AML MRD testing was not previously available.

Introduction

Background: Post-transplant cyclophosphamide (PTCy) has become a standard of care for graft-versus-host disease (GvHD) prophylaxis in recipients of human leukocyte antigen (HLA)-matched and mismatched unrelated donor (MMUD) allografts, generating new opportunities for successful hematopoietic cell transplantation (HCT) regardless of patient ancestry. The National Marrow Donor Program (NMDP)-sponsored 15-MMUD study, which used PTCy-based GvHD prophylaxis (PMID 3390526), demonstrated encouraging overall survival (OS) in adult patients receiving MMUD bone marrow grafts matched at ≤7/8 HLA alleles. Currently, the follow-up ACCESS study (NCT04904588) will determine if similar outcomes can be achieved using MMUD peripheral blood stem cell allografts. As part of its 5-year strategic plan, the NMDP aims to determine the extent of differences in GvHD-free, relapse-free survival (GRFS) between 8/8 and 7/8 URD allografts using PTCy and seeks to develop approaches over time to close the presumed gap in URD outcomes.

Introduction:Current therapies for patients with acute myeloid leukemia (AML) push the limits of chemotherapy intensity but cure only 30% of adults and 70% of children. Recently developed antibody-based therapies and molecularly-targeted agents only modestly improve outcomes for select patient subsets. Thus, new approaches are needed. Given the success of chimeric antigen receptor (CAR) T-cell therapies for acute lymphoblastic leukemia (ALL), we developed and optimized a novel CD33 CAR T-cell (CD33CART) construct for clinical testing in a multicenter Phase I/II clinical trial in children, adolescents, and young adults (AYA) with relapsed/refractory (r/r) AML. ( Qin H, et al. JITC 2021) We report interim results following completion of the dose-escalation phase.

The impact of the cellular composition of PBSC grafts on the immune reconstitution as well as graft-versus-host and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT) is only poorly understood. DKMS and NMDP joined forces to comprehensively characterize the cellular composition of 2,000 PBSC products using a 34-color flow cytometry panel to define immune effector cell subsets of interest and hematopoietic stem cells. In parallel, we have created a biobank of unstimulated donor PBMC and PBSC graft samples for future analyses. As part of this larger effort, we investigated the effect of cryopreservation on the cellular composition of PBSC products. Cryopreservation of PBSC grafts was used frequently during the COVID19-pandemic and facilitated more flexible timelines for transplantation. Still, one third of the US patients and 15% of the German patients continue to receive cryopreserved PBSC grafts. Ongoing studies are investigating the impact of cryopreservation on immune-effector cell function and the outcome of hematopoietic stem cell transplantation. Several observational studies have reported delayed neutrophil and platelet engraftment with cryopreserved products. More recently, less chronic GVHD was reported for patients who had received cryopreserved PBSC products. Cryopreservation affects the cellular composition and hence has the potential to change immune effector cell functions of the graft, but available data on the alterations of cell population frequencies are scarce. We analyzed the cellular composition of 20 fresh grafts and compared them to their frozen and thawed counterparts. Cryopreservation of product samples followed routine clinical procedures using a 10% DMSO containing cryo-medium and a controlled rate freezing. After thawing at 37°C, cells were washed, stained with a 34-parameter phenotyping panel, fixed and analyzed immediately on a full spectrum flow cytometer. Following spectral unmixing and manual spillover correction, proportions of immune cells were assessed using manual gating. First, we investigated the relative frequencies of 10 non-overlapping individual cell populations relative to viable CD45+ cells, including several lymphocyte populations, monocytes, granulocytes, hematopoietic stem cells (HSC) and dendritic cells. Granulocytes showed the largest decrease after cryopreservation and thawing (18.2 % vs 3.5 %; p<0.001). The loss of granulocytes results in an increase of relative frequencies of many other immune cell populations including monocytes (35.4 % vs 44.7 %; p=0.018), B cells (5.8 % vs 9.6 %; p=0.006), and HSC (1.0 % vs 1.5 %; p<0.001). We therefore also calculated changes relative to the viable non-granulocyte cells. By doing so, a significant relative increase of cells was observed for HSC (1.2 % vs 1.6 %; p<0.001), whereas monocyte and B cell frequencies changed only marginally. This suggests that HSC are more resilient to freezing than other cell types. When comparing the proportions of 40 other immune cell (sub-) populations relative to their parent population in the gating hierarchy, we found a profound and significant decrease of the relative frequencies for CD16+ myeloid dendritic cells (mDCs, 68 % vs 30 % of all mDCs; p<0.001) and granulocytic myeloid derived suppressor cells (gMDSCs, 2 % vs 1 % of all MDSCs; p<0.001). In an independent set of analyses performed at Roswell Park Comprehensive Cancer Center, Buffalo, comparable results were obtained with a significant increase of HSC, a significant decrease of CD16+ mDCs, and a trend of a decrease of gMDSCs. As CD16+ mDCs may have a role in the development of chronic GVHD after alloHCT, this decrease may be meaningful. In summary, we found that cryopreservation of PBSC allografts resulted in a decreased relative frequency of granulocytes, and CD16+ mDCs, as well as an increased relative frequency of HSCs. The results provide some insight into the impact of cryopreservation on PBSC graft composition and warrant further efforts to explore the potential mechanisms for the differential outcomes observed using fresh vs cryopreserved PBSCs.

Background: Acute myeloid leukemia (AML) predominantly affects older adults (median age at diagnosis is 67yrs), and often requires allogeneic hematopoietic cell transplantation (alloHCT) for cure. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), beginning in 2001, the largest growth in alloHCT for malignant diseases occurred in patients ≥65yrs. However, whether this is due to expanded utilization of alloHCT for newly diagnosed AML is unclear. Using a novel linked dataset, we examined patients with newly diagnosed AML in California to assess population-based alloHCT utilization over time and factors associated with receipt of alloHCT across age groups.