Clofarabine for Lymphodepletion Before CAR-T-Cell Infusion: A Brief Case Report.

Given the shortage of fludarabine, alternative preparative lymphodepleting regimens for CAR-T-cell therapy need to be identified. We present a case of relapsed/refractory B-cell acute lymphoblastic leukemia requiring multiple lines of salvage therapy with persistent extensive disease, who underwent lymphodepletion with clofarabine and cyclophosphamide before tisagenlecleucel CD19+ CAR-T-cell infusion with eventual remission. We offer evidence of clofarabine's activity against B-cell acute lymphoblastic leukemia in combination with tisagenlecleucel therapy. In this patient, clofarabine did not decrease CAR-T-cell effectiveness, supported by presence of cytokine release syndrome and ultimate minimal residual disease negativity both on flow cytometry and next-generation sequencing.

Low CD4 count may be a risk factor for non-tuberculous mycobacteria infection in pediatric hematopoietic cell transplant recipients.

BACKGROUND: HCT leaves patients in a relative state of immune deficiency both during their initial transplant admission and for several years following discharge. NTM are generally harmless colonizers of the outside environment, but for immunocompromised patients, they can cause significant disease due to a paucity of T-cell defense. While routine prophylaxis against NTM is recommended for patients with low CD4 counts in certain clinical settings (eg, AIDS), this is not yet established for HCT patients despite their higher risk. METHODS: Here we build upon our prior work to determine risk factors for NTM in pediatric HCT patients by comparing NTM patient characteristics to matched HCT controls. RESULTS: We followed 272 patients across a 13-year time period, with 11 cases of NTM. Patients with NTM had a significantly lower CD4 count at Day 365 than matched HCT controls (105.5 ± 97.0 cells/µl vs. 856.2 ± 446.1 cells/µl, respectively; p = .001). No other potential risk factors (eg, CMV, GvHD, disease type) were found to be statistically significant, including use of T-cell depleting agents. This is consistent with an average diagnosis of NTM at Day +323 (ie, outside immediate post-transplant period). All-cause mortality was similar between NTM and control HCT groups, with an NTM attributable mortality of <10%. CONCLUSION: Since reduced CD4 counts are associated with NTM, and cost and morbidity are high, azithromycin prophylaxis for CD4 count <200 cells/µl in high-risk patients should be considered.

Diabetes, metformin and cancer risk in myotonic dystrophy type I.

Myotonic dystrophy type I (DM1) is an autosomal dominant multisystem disorder characterized by myotonia and muscle weakness. Type 2 diabetes (T2D) and cancer have been shown to be part of the DM1 phenotype. Metformin, a well-established agent for the management of T2D, is thought to have cancer-preventive effects in the general population. In our study, we aimed to assess the association between T2D, metformin use and the risk of cancer in DM1 patients. We identified a cohort of 913 DM1 patients and an age-, sex- and clinic-matched cohort of 12,318 DM1-free controls from the UK Clinical Practice Research Datalink, a large primary care records database. We used Cox regression models to assess cancer risk in T2D patients who were metformin users or nonusers compared to patients without T2D. Separate analyses were conducted for DM1 patients and controls. T2D was more prevalent in DM1 than in controls (8% vs. 3%, p < 0.0001). DM1 patients with T2D, compared to those without T2D, were more likely to develop cancer (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 1.18-10.97; p = 0.02), but not if they were treated with metformin (HR = 0.43, 95% CI = 0.06-3.35; p = 0.42). Among controls, we observed no significant associations between T2D and cancer risk in either users or nonusers of Metformin (HR = 1.28, 95% CI = 0.91-1.79; p = 0.16 and HR = 1.13, 95% CI = 0.72-1.79; p = 0.59, respectively). These results show an association between T2D and cancer risk in DM1 patients and may provide new insights into the possible benefits of Metformin use in DM1.

Risk Factors, Clinical Outcomes, and Cost-of-Care Related to Graft Failure in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients.

Allogeneic hematopoietic cell transplantation (HCT) has the capacity to cure numerous malignant and nonmalignant disorders. A dreaded complication is graft failure (GF), as it puts patients at high risk of infection and disease relapse. There are few contemporary data on the risks, outcomes, and economic burden of GF in pediatric patients. In this study, we address this gap by focusing on 14 years of transplant at our single center, for which data are compared in 2 time periods: 2005 to 2010 (n = 146) and 2011 to 2018 (n = 144). In the 290 patients studied, the median age was 9.33 years, and 50.3% had malignant versus nonmalignant disease. Cell source included bone marrow (51%), cord blood (19.7%), unmanipulated peripheral blood stem cells (PBSCs; 12.1%), and CD34-selected PBSCs (17.2%). Twenty-one percent of patients had reduced-intensity conditioning (RIC), and 54.8% of transplants were fully HLA matched. Most patients received serotherapy with rabbit anti-thymocyte globulin (39.3%) or alemtuzumab (42.8%). The incidence of neutropenic and non-neutropenic GF (NGF and NNGF) was 6.6% and 3.8%, respectively. Multivariate analysis demonstrated alemtuzumab (odds ratio [OR], 6.256, P < .001) was the main variable associated with a higher rate of GF in both time periods, whereas RIC (OR, 11.8, P < .001) and cell source (CD34-selected PBSCs; OR, 4.22, P = .04) showed period-specific effects. Specifically, from time periods 1 to 2, cord blood transplants were discontinued at our center, with a concomitant increase in CD34-selected grafts and a shift from more episodes of NGF to NNGF. Overall survival was 69% in the entire HCT cohort and 50% among patients with GF. Survival among GF patients improved from time periods 1 to 2 (20% versus 80%, P = .001), potentially due to a higher incidence of NNGF and increased ability to perform stem cell boosts from the same donor once cord blood transplants were phased out. Inpatient length of stay was consistently higher for patients with GF. Similar trends were seen for inpatient costs, although improvements were seen in our entire HCT population over time. In summary, GF remains a significant challenge in pediatric HCT and poses an economic burden on the health care system.

Clinical and Economic Impact of Cytomegalovirus Infection among Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

The literature on the impact of cytomegalovirus (CMV)-related hospitalization in pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients is limited. The aim of this study was to determine utilization and outcomes of CMV-related hospitalization in alloHCT recipients using a single-center clinical database. This was a retrospective study of 240 children aged 3 months to 21 years (median age, 9.5 years) who underwent alloHCT between 2005 and 2016. The impacts of CMV-related length of stay (LOS) and total healthcare costs were quantified. Factors associated with prolonged CMV viremia (>25 days' duration) were also examined. In at-risk patients with CMV infection, the incidence of CMV viremia was 38% (59 of 155), the median time to onset was 33 days (range, 0 to 292 days), and the median time to resolution was 25 days (range, 3 to 48 days; n = 53). CMV infection was associated with a 23.3-day increase in LOS (P = .004) and added hospital costs of $45,443 (P = .162) compared with patients without CMV infection. In multivariable analysis, receipt of alemtuzumab (P = .027) was associated with CMV viremia of >25 days' duration. Our data show that CMV viremia is associated with prolonged LOS and higher hospital costs and indicate the need for improved and cost-effective CMV prevention strategies. Further studies of patient outcomes and costs in pediatric alloHCT recipients is needed.

Body mass index modifies bladder cancer risk associated with low estrogen exposure among Egyptian women after menopause.

PURPOSE: Investigators have reported inconsistent findings regarding associations between body mass index (BMI) and bladder cancer risk, and they have postulated that sex steroids mediate such associations. We assessed the impact of BMI on the relationship between bladder cancer risk and combinations of age at first childbirth, parity, and age at menopause, among Egyptian women. METHODS: We used data from our multicenter case-control study of 419 cases and 786 controls in logistic regression models to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of such associations. RESULTS: Age > 18 years at first childbirth and parity ≤ 6 were significantly associated with bladder cancer risk, which was higher when both factors (AOR = 2.31, 95% CI = 1.55-3.43) and age at menopause < 45 years (AOR = 3.51, 95% CI = 1.88-6.55) were present. Early menopause was associated with higher bladder cancer risk in obese (AOR = 2.90, 95% CI = 1.40-5.98) but not normal weight women (AOR = 0.98, 95% CI = 0.58-1.65; Pinteraction = 0.11), and the risk was greatest when both first childbirth at age > 18 years and parity ≤ 6 were present (AOR = 7.60, 95% CI = 1.84-31.35); however, overweight and obesity were associated with significantly lower bladder cancer risk (AOR = 0.59, 95% CI = 0.43-0.81, and AOR = 0.26, 95% CI = 0.18-0.38, respectively). CONCLUSION: Body mass index appears to modify bladder cancer risk in Egyptian women after menopause by slightly enhancing the risk associated with low estrogen exposure among the obese only. Longitudinal studies of the BMI role in bladder malignancy in this distinctive population are required.

Bone Marrow Harvest in Pediatric Sibling Donors: Role of Granulocyte Colony-Stimulating Factor Priming and CD34+ Cell Dose.

To ensure optimal clinical outcomes for patients while retaining adequate protection for donors, the National Marrow Donor Program developed guidelines specifying that up to 20 mL/kg of bone marrow can be harvested from donors. These guidelines, originally developed for unrelated adult donors, are followed in children as well. We studied the impact of granulocyte colony-stimulating factor (G-CSF) priming on the cellular composition of harvested bone marrow, sought to develop an algorithm to optimize bone marrow harvest volume from pediatric matched sibling donors, and studied the impact of CD34+ cell dose on clinical outcomes. We analyzed data from 92 bone marrow harvests and clinical outcomes for 69 sibling recipient-donor duos, The mean age of recipients was 9.85 ± 5.90 years, and that of donors was 11.85 ± 6.36 years. G-CSF priming was not associated with higher yield of CD34+ cells/µL. The median CD34+ cell count obtained from donors was 700 cells/µL (range, 400-1700 cells/µL) in donors age <6 years, 360 cells/µL (range, 100-1100 cells/µL) in donors age 6 to 12 years, and 300 cells/µL (range, 80-800 cells/µL) in donors age >12 years (P < .001). The number of CD34+ cells infused had no impact on traditional clinical outcomes; however, it was significantly related to graft-versus-host disease/relapse/rejection-free survival. Our investigation revealed that ultimately, a CD34+ cell count of approximately 3 to 5 × 106/kg was a threshold beyond which increasing CD34+ cell dose did not impact outcome. In this study, we addressed the broad question of whether harvesting up to 20 mL/kg of bone marrow from a child donor is truly necessary for optimal outcomes in every pediatric case.

Timing and Utility of Relapse Surveillance after Allogeneic Hematopoietic Cell Transplantation in Children with Leukemia.

The utility and optimal timing of routine bone marrow (BM) and cerebrospinal fluid (CSF) surveillance after allogeneic hematopoietic cell transplantation (alloHCT) in children with leukemia have not been previously studied. To examine the current practice concerning relapse surveillance in this population, we conducted a national survey of pediatric bone marrow transplant physicians. Sixty-two of 152 potential participants (41%) completed the survey. For acute lymphoblastic leukemia (ALL) patients, 41 physicians (66%) reported performing routine BM analysis in all such patients, 15 (24%) in some patients and 6 (10%) in no patients. Data were similar for acute myeloid leukemia (AML). Among those who do such screening in the ALL population, 11 physicians (24%) reported performing 1 BM analysis in the first year, 11 (24%) performed 2, 6 (13%) performed 3, 12 (27%) performed 4, and 5 (12%) performed 5 to 10. Data were similar for AML. The most common time point for screening in both diseases was day 100, followed closely by day 365. With respect to central nervous system (CNS) screening in ALL, 11 physicians (18%) screened all patients, 28 (45%) screened no patients, and 23 (37%) screened only patients with prior CNS disease. Use of intrathecal chemotherapy in these patients also varied, with 7 (12%) doing so in all patients, 17 (29%) only in previously CNS-positive patients, and 35 (59%) in no patients. To assess the utility of surveillance procedures, we performed a retrospective review of 108 childhood leukemia patients after alloHCT at our center. Forty-one relapses (38%) occurred with a median time to relapse of 171 days. Five (12%) occurred after day 365. Of the 36 relapses within the first year, 20 (56%) were identified by clinical suspicion, whereas 16 (44%) were identified by routine screening procedures. The percentages of patients in whom routine screening detected relapse at days 100, 180, 270, and 365, respectively, was 6.7%, 11.1%, 11.9%, and 0%. That is, by day 365, no patient (of 38) who had routine BM surveillance had evidence of relapse on analysis of the BM. Our survey confirms a lack of standardization regarding routine BM and CSF relapse surveillance after alloHCT in children with leukemia. We have demonstrated that while day 365 post-alloHCT is a very commonly utilized time point for routine screening, the yield of such screening at this time is very low, such that the performance of these procedures may not be justified at that time. Prospective collaboration among pediatric alloHCT centers may help to provide more robust evidence-based guidelines designed to maximize utility and minimize risk.

Safety of hematopoietic cell infusion in children with malignant and non-malignant diseases.

HPC infusions have been associated with a variety of adverse events related to either patient or HPC product-related factors. Studies documenting infusion-related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion-related adverse events were classified as follows: grade 0-absent, grade I-mild, grade II-moderate, grade III-severe, grade IV-life-threatening, and grade V-death. The percentage of patients with grade 0, I, and II-IV AEs was as follows: 0 = 67%, I = 23.4%, and II-V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II-IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion-associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion-associated AEs (P < .001). Patients >10 years who received autologous HPC infusions had higher risk of AEs when compared to patients <10 years (P = .01). Our study demonstrated that despite a high incidence of infusion-associated hypertension, HPC infusion is relatively safe in children. Investigating strategies to optimize management of hypertension in the setting of HPC infusion is warranted.

Training Teachers to Teach Epidemiology in Middle and High Schools.

Objective The purpose of this study was to evaluate the outcomes of a workshop which was designed to prepare teachers to teach epidemiology to middle and high school students. Methods The workshop introduced the fundamental enduring understandings of epidemiology as well as a pedagogical framework for teaching it. Using an online questionnaire and telephone interviews, we assessed post-workshop outcomes. Results The majority (80%) of workshop alumni had taught epidemiology with the most common approach (52%) being the inclusion of epidemiologic concepts into other courses. Teachers felt that learning epidemiology was a valuable experience for their students and reported that students found it engaging and relevant to their lives. Conclusions These preliminary findings suggest that there may be benefit to teaching epidemiology in middle and high schools. Further research should directly evaluate public health-related outcomes among students, such as improvements in health literacy and health behavior.

Risk Factors for Subtherapeutic Tacrolimus Levels after Conversion from Continuous Intravenous Infusion to Oral in Children after Allogeneic Hematopoietic Cell Transplantation.

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], -4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, -3.8; 95% CI, 1.276 to 11.43; P = .017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.

Risk Factors and Utility of a Risk-Based Algorithm for Monitoring Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections in Pediatric Recipients after Allogeneic Hematopoietic Cell Transplantation.

Infectious complications, particularly viral infections, remain a significant cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT). Only a handful of studies in children have analyzed the risks for and impact of viremia on alloHCT-related outcomes. We conducted a retrospective study of 140 pediatric patients undergoing alloHCT to investigate the incidence of and risk factors for cytomegalovirus (CMV), adenovirus (ADV), and Epstein-Barr virus (EBV) viremia and viral disease after alloHCT. Furthermore, we assessed the impact of viremia on days of hospitalization and develop an algorithm for routine monitoring of viremia. Patients were monitored before alloHCT and then weekly for 180 days after alloHCT. Patients were considered to have viremia if CMV were > 600 copies/mL, EBV were > 1000 copies/mL, or ADV were > 1000 copies/mL on 2 consecutive PCRs. The overall incidences of viremia and viral disease in all patients from day 0 to +180 after alloHCT were 41.4% (n = 58) and 17% (n = 24), respectively. The overall survival for patients with viremia and viral disease was significantly lower compared with those without viremia (58% versus 74.2%, P = .03) and viral disease (48.2% versus 71.2%, P = .024). We identified that pretransplantation CMV risk status, pre-alloHCT viremia, and use of alemtuzumab were associated with the risk of post-alloHCT viremia. The average hospitalization days in patients with CMV risk (P = .011), viremia (P = .024), and viral disease (P = .002) were significantly higher. The algorithm developed from our data can potentially reduce viral PCR testing by 50% and is being studied prospectively at our center. Improved preventative treatment strategies for children at risk of viremia after alloHCT are needed.

Survival Impact of Early Post-Transplant Toxicities in Pediatric and Adolescent Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Malignant and Nonmalignant Diseases: Recognizing Risks and Optimizing Outcomes.

In pediatric and adolescent patients undergoing allogeneic hematopoietic cell transplantation, treatment-related toxicities remain a clinical challenge. A paucity of data investigates the risks for and survival impact of treatment-related toxicities in this population. Here the authors assess the relative toxicity of myeloablative, reduced-toxicity, and reduced-intensity conditioning regimens; identify patient-related predictors of post-transplant toxicities; and investigate the impact of early post-transplant toxicities on transplant-related mortality (TRM). In this retrospective study, 164 patients (aged 1 to 22 years) underwent allogeneic stem cell transplantation after busulfan-based conditioning for malignant and nonmalignant diseases between 2000 and 2014. The number of grades III to IV toxicities between days 0 and +30 was calculated for each patient. TRM was calculated to 2 years. Median patient age was 9 years, and median number of toxicities was 3 (range, 0 to 17). The 100-person day incidence of post-transplant toxicities in myeloablative conditioning was not different from the incidence in reduced-toxicity conditioning (13.88 versus 13.59, P = .812). Reduced intensity was less toxic than both myeloablative and reduced toxicity (13.75 versus 8.41, P < .001). Age ≥ 12 years (.276 with SE = .138, P = .045) and unrelated donor transplant (.318 with SE = 0.113, P = .005) were risk factors for ≥3 toxicities. Having ≥3 toxicities or a performance score < 90 conferred higher risk of TRM (P = .021). In pediatric and adolescent patients undergoing hematopoietic cell transplantation, reduced-toxicity conditioning was not significantly less toxic than myeloablative conditioning. Additionally, the number of post-transplant toxicities correlated with the risk of mortality. Further investigations to confirm our findings are warranted.

Acute gastrointestinal graft-vs-host disease is associated with increased enteric bacterial bloodstream infection density in pediatric allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Bacterial septicemia remains the leading cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (AlloHCT). While murine studies have found acute gastrointestinal graft-vs-host disease (aG-GVHD) to be associated with increased incidence of enteric bacterial bloodstream infections (EB-BSI), this association has not been studied in humans. We hypothesized that in patients who developed aG-GVHD, the EB-BSI density after onset of aG-GVHD would be higher than before onset and higher than in patients without acute GVHD (aGVHD). METHODS: We retrospectively reviewed data collected on 264 pediatric AlloHCT recipients with malignant and nonmalignant disease. We calculated and compared EB-BSI densities in the following 3 subgroups: patients without aGVHD and patients with aG-GVHD, both before and after onset of aG-GVHD. We also examined the effect of aG-GVHD onset on the first episode of EB-BSI using Cox proportional hazards models. RESULTS: The overall incidence of aG-GVHD was 28.8% (n = 76). Analyses done both at 120 and 180 days post-AlloHCT showed that the EB-BSI density increased after aG-GVHD onset (0.95 infections/person-year before aG-GVHD vs 2.7 infections/person-year after aG-GVHD at day 120 [P = .006]; 0.95 infections/person-year before aG-GVHD vs 2.26 infections/person-year after aG-GVHD at day 180 [P = .033]). On multivariate analysis, the onset of aG-GVHD had a positive hazard ratio of 1.47 (P = .077) on time to first EB-BSI. CONCLUSIONS: Our results support the theory that aG-GVHD predisposes pediatric AlloHCT recipients to EB-BSI. Prophylactic agents such as probiotics should be studied prospectively in patients with aG-GVHD.

Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation.

Only a few studies in children have evaluated the efficacy of prophylactic regimens using tacrolimus on acute graft-versus-host disease (aGVHD). As a result, optimal tacrolimus levels in children after matched sibling donor allogeneic hematopoietic cell transplantation (alloHCT) are not well defined. We measured the association between subtherapeutic levels (<10 ng/mL) during weeks 1 to 4 after alloHCT and the cumulative incidence of grades II to IV aGVHD in children. Additionally, we identified optimal lower cutoff levels for tacrolimus. Sixty patients (median age, 8 years) received tacrolimus/mycophenolate mofetil between March 2003 and September 2012. Twenty-three had a malignant disease and 37 nonmalignant disorders. The stem cell source included peripheral blood stem cells (n = 12) and bone marrow or cord blood (n = 48). Conditioning regimen varied. Specifically, 38.3% received a myeloablative regimen, 36.7% receiving a reduced-toxicity regimen, and 25% receiving a reduced-intensity regimen. Tacrolimus was initiated at .03 mg/kg/day via continuous i.v. infusion or .12 mg/kg/day orally. The dose was adjusted to maintain daily steady state concentrations within a range of 10 to 20 ng/mL. The overall incidence of grades II to IV aGVHD was 33.3%. On multivariate analysis, a mean tacrolimus level < 10 ng/mL during week 3 (P = .042; 95% confidence interval, 1.051 to 14.28) was significantly associated with increased incidence of grades II to IV aGVHD. Using weekly receiver operator curves, the optimal lower cutoff for tacrolimus levels was 10 to 11.2 ng/mL. Further prospective studies are warranted to study the incidence of aGVHD comparing the conventional tacrolimus levels of 5 to 15 versus 10 to 15 ng/mL.

Health-related quality of life after allogeneic hematopoietic stem cell transplantation for sickle cell disease.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy that affects over 100,000 people in the United States. Patients with SCD are known to experience suboptimal health-related quality of life (HRQoL). In addition to the physical manifestations of SCD, psychological and social stress, along with academic difficulties, secondary to the chronicity of the disease and its complications often affect patients with SCD. Although medical therapy of SCD has improved, allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapy. The objective of this study was to measure HRQoL before and after allo-HCT by assessing physical, psychological, and social functioning in patients with SCD who have undergone reduced-toxicity conditioning (busulfan/fludarabine/alemtuzumab) followed by allo-HCT. Patients < 21 years of age undergoing allo-HCT (matched siblings and unrelated donors) for SCD and their primary caregiver were enrolled using either the English or Spanish version of the PedsQoL 4.0. Data were collected at 3 time points: before allo-HCT and on days 180 and 365 after allo-HCT. The change in HRQoL from baseline was assessed with unadjusted and adjusted mixed-effects models in which subjects were treated as random effects, and variance component structure was used. Seventeen patients and 23 primary caregivers were enrolled and reported a mean overall HRQoL of 66.05 (SD, 15.62) and 72.20 (SD, 15.50) at baseline, respectively. In the patient-reported analysis with adjusted mixed-effects models, the estimated improvements in overall HRQoL were 4.45 (SE, 4.98; P = .380) and 16.58 (SE, 5.06; P = .003) at 180 and 365 days, respectively, after allo-HCT. For parent-reported overall HRQoL, the estimated improvements were 1.57 (SE, 4.82; P = .747) and 9.28 (SE, 4.62; P = .053) at 180 and 365 days, respectively, after allo-HCT. Similar results were found across the physical, social, and emotional HRQoL domains with mixed-effects models after adjustment of demographic and medical variables. In addition to the alleviation of clinical manifestations of SCD, these patients demonstrated significant improvement in most aspects of HRQoL by 1 year after allo-HCT. These data represent the trajectory of HRQoL during the initial year of follow-up within this population and should be integrated into the decision-making process when considering allo-HCT in patients with SCD.

Human herpesvirus-6 viremia is not associated with poor clinical outcomes in children following allogeneic hematopoietic cell transplantation.

HHV-6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV-6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV-6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV-6, CMV, EBV, and ADV. HHV-6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3-26.7%) of patients had HHV-6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15-day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV-6 viremia (58%) than in those without HHV-6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV-6 viremia in multivariate analysis. Similarly, HHV-6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV-6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV-6 PCR should only be performed on clinical suspicion.

Evaluation of the Balanced Menus Challenge: a healthy food and sustainability programme in hospitals in Maryland.

OBJECTIVE: The Balanced Menus Challenge (BMC) is a national effort to bring the healthiest, most sustainably produced meat available into health-care settings to preserve antibiotic effectiveness and promote good nutrition. The present study evaluated the outcomes of the BMC in the Maryland/Washington, DC region. DESIGN: The BMC is a cost-effective programme whereby participating hospitals reduce meat purchases by 20 % of their budget, then invest the savings into purchasing sustainably produced meat. A mixed-methods retrospective assessment was conducted to assess (i) utilization of the BMC 'implementation toolkit' and (ii) achievement of the 20 % reduction in meat purchases. Previous survey data were reviewed and semi-structured interviews were conducted. SETTING: Hospitals located in the Maryland/Washington, DC region, USA, that adopted the BMC. SUBJECTS: Twelve hospitals signed the BMC in the Maryland/Washington, DC region and six were available for interview. RESULTS: Three hospitals in the Maryland/Washington, DC region that signed the BMC tracked their progress and two achieved a reduction in meat procurement by ≥20 %. One hospital demonstrated that the final outcome goal of switching to a local and sustainable source for meat is possible to achieve, at least for a portion of the meal budget. The three hospitals that reduced meat purchases also received and used the highest number of BMC implementation tools. There was a positive correlation between receipt and usage of implementation tools (r=0·93, P=0·005). CONCLUSIONS: The study demonstrates that hospitals in the Maryland/Washington, DC region that sign the BMC can increase the amount of sustainably produced meat purchased and served.

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

Pilot trial of risk-adapted cyclophosphamide intensity based conditioning and HLA matched sibling and unrelated cord blood stem cell transplantation in newly diagnosed pediatric and adolescent recipients with acquired severe aplastic anemia.

BACKGROUND: Cyclophosphamide-based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non-malignant diseases. PROCEDURE: We piloted a risk-adapted AlloHSCT approach, using fludarabine and anti-thymocyte globulin based conditioning with high (200 mg/kg) and low (60 mg/kg) dose cyclophosphamide as upfront treatment in newly diagnosed pediatric patients with acquired SAA incorporating alternative donor sources, including cord blood. Average risk for non-engraftment patients with <10 transfusions received low dose cyclophosphamide (60 mg/kg); High Risk, those with ≥10 transfusions received conditioning regimen with higher intensity cyclophosphamide (200 mg/kg). RESULTS: Seventeen patients were enrolled and underwent AlloHSCT including 12 males and 5 females with mean age of 8 years (range 3-16), and median follow-up time of 39 months (range 1-135). Donor sources included MRD BM (6/6 [n = 9], 5/6 [n = 2]) and unrelated CB (5/6 [n = 4], 4/6 [n = 2]). Five year OS was 67.6% (37.9-85.4). Three secondary graft failures (17.6%) occurred in the low dose cyclophosphamide arm. CONCLUSIONS: Upfront treatment with risk-adapted cyclophosphamide conditioning AlloSCT is well tolerated for the management of newly diagnosed pediatric and adolescent patients with acquired SAA. However, the increased risk of graft rejection in the lower dose arm warrants additional research regarding the optimal intensity of cyclophosphamide-based conditioning regimen to reduce toxicity without increasing graft failure.