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Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID.Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed.We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes.According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (0.05 × 10The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Background Portal venous gas (PVG) is a rarely observed clinical finding generally associated with intestinal ischemia. The proper clinical response to the finding of PVG depends somewhat on the setting in which it is observed. Here we describe a case in which extensive arterial gas emboli (AGE) were encountered during point-of-care ultrasound (POCUS) and subsequent computed tomography (CT) identified PVG secondary to gastric wall ischemia as the likely source. Case Report A 69-year-old woman with history of metastatic colon cancer presented to the emergency department (ED) with altered mental status. On arrival, she was hypotensive, hypothermic, cachectic, and with abdominal distension. POCUS was performed to evaluate the source of the patient's hypotension, revealing the presence of PVG, as well as gas bubbles in all four chambers of the heart and the aorta. CT scan revealed gastric wall ischemia and confirmed the presence of significant air emboli throughout the portal venous system. Given the overall poor prognosis, the decision was made to forego further chemotherapy or surgery and the patient died later that week while under hospice care. Why Should an Emergency Physician Be Aware of This? AGE can occur in the setting of PVG. This may cause multi-organ failure by disrupting blood flow to organs, especially in patients with circulatory dysfunction, such as shock. Depending on the setting in which it is diagnosed, early detection of PVG may expedite earlier assessments of a patient's negative prognosis or initiation of attempted life-saving treatment. In this case report, we show that POCUS can be used to obtain an expedited diagnosis in a critically ill patient.

Background: The experience of hematopoietic stem cell transplant (HSCT) on both the patients and their caregivers is complex and challenging during hospitalization and post discharge. Complex patient populations require heightened attention on discharge practices to ensure that they are prepared for home regimens. “Rooming in” is a standardized intervention implemented prior to discharge that allows patients and caregivers to assume post discharge care with the support of staff. Other complex patient populations have reported positive outcomes related to “rooming in.” Aims: The purpose of this study was to assess the feasibility of a standardized “rooming in” intervention for discharge of pediatric HSCT patients. An additional aim was to describe the quality of discharge teaching, readiness for hospital discharge, and postdischarge coping difficulty in a cohort of HSCT patients using validated questionnaires. Method: Data were collected via medical chart review. A prospective cohort completed validated study questionnaires at discharge and 30 days postdischarge. Results: All caregivers of post-HSCT patients were able to complete the “rooming in” intervention. There was no statistically significant difference for length of stay between the retrospective and prospective cohorts. Caregivers enrolled on the study rated the Quality of Discharge Teaching Scale–Parent Form high ( Mdn = 165). Conclusion: We conclude that “rooming in” is a feasible discharge intervention for caregivers of pediatric HSCT patients.

Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evalua...

Total body irradiation is an important part of the conditioning regimens frequently used to prepare patients for allogeneic hematopoietic stem cell transplantation (SCT). Volumetric-modulated arc therapy enabled total body irradiation (VMAT-TBI), an alternative to conventional TBI (cTBI), is a novel radiotherapy treatment technique that has been implemented and investigated in our institution. The purpose of this study is to (1) report our six-year clinical experience in terms of treatment planning strategy and delivery time and (2) evaluate the clinical outcomes and toxicities in our cohort of patients treated with VMAT-TBI. This is a retrospective single center study. Forty-four patients at our institution received VMAT-TBI and chemotherapy conditioning followed by allogeneic SCT between 2014 and 2020. Thirty-two patients (73%) received standard-dose TBI (12-13.2 Gy in 6-8 fractions twice daily), whereas 12 (27%) received low-dose TBI (2-4 Gy in one fraction). Treatment planning, delivery, and treatment outcome data including overall survival (OS), relapse-free survival (RFS), and toxicities were analyzed. The developed VMAT-TBI planning strategy consistently generated plans satisfying our dose constraints, with planning target volume coverage90%, mean lung dose ∼50% to 75% of prescription dose, and minimal hotspots in critical organs. Most of the treatment deliveries were100 minutes (range 33-147, mean 72). The median follow-up was 26 months. At the last follow-up, 34 of 44 (77%) of patients were alive, with 1- and 2-year OS of 90% and 79% and RFS of 88% and 71%, respectively. The most common grade 3+ toxicities observed were mucositis (31 patients [71%]) and nephrotoxicity (6 patients [13%]), both of which were deemed multifactorial in cause. Four patients (9%) in standard-dose cohort developed grade 3+ pneumonitis, with 3 cases in the setting of documented respiratory infection and only 1 (2%) deemed likely related to radiation alone. VMAT-TBI provides a safe alternative to cTBI. The dose modulation capability of VMAT-TBI may lead to new treatment strategies, such as simultaneous boost and further critical organ sparing, for better malignant cell eradication, immune suppression, and lower toxicities.

BackgroundAllogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.ObjectiveThe effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.MethodsWe studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.ResultsFour regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P< .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P< .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P= .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P= .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P< .001).ConclusionsGiven the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4(+) and CD4(+)CD45RA(+) cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4(+) cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.

Background Outcomes of COVID-19 infection among children with underlying malignancy remain unclear, with limited data available to date. Here we report clinical characteristics and outcomes following COVID-19 infection among children with underlying malignancy or a history of hematopoietic stem cell transplant (HSCT) during the first year of the global COVID-19 pandemic, in Dallas, TX. Methods: We retrospectively reviewed children with a history of malignancy or prior HSCT and positive SARS-CoV-2 polymerase chain reaction (PCR) result between March 1, 2020 - March 31, 2021. Demographic, clinical, and outcome data were reviewed, and analyzed according to underlying condition and disease severity. Results: Forty-six patients with underlying malignancy or HSCT met inclusion criteria. Median age was 9 years, with twenty (43%) female, and twenty-seven (59%) of Hispanic ethnicity. Underlying conditions included Acute Lymphoblastic Leukemia (67%), Acute Myelogenous Leukemia (9%), HSCT (11%), sarcoma (9%), solid tumors (9%), and Hodgkin's lymphoma (2%). Fifteen subjects (33%) were asymptomatic, with twenty-four children (52%) classified as having mild, five (11%) with severe, and two (4%) with critical COVID-19 disease. The most common symptoms at presentation were fever (46%), cough (39%), and gastroenteritis (19%). Thirty-four children (74%) were hospitalized, with seven (15%) requiring intensive care unit (ICU) care. 17% of patients were admitted for treatment of COVID-19 alone, with other indications including neutropenic fever, relapse, and chemotherapy. Six (13%) patients required non-invasive ventilation, and two patients (4%) required invasive mechanical ventilation. Median length of stay was 9 days (IQR 4.5-24.5), with median ICU stay of 3.5 days (IQR 2-26.7). Seven children (15%) received COVID-19 targeted therapy including steroids, remdesivir or convalescent plasma. Among severe and critically ill children, six (86%) had underlying hematologic malignancies (5 HR ALL, 1 AML), and two (28%) a prior history of HSCT. Two children (4%) died. Thirty-six patients (78%) achieved documented clearance of SARS-CoV-2 by PCR, at median of 43.5 days (IQR 28.7-65.2). Conclusion: Among children with underlying malignancy or a history of HSCT, COVID-19 results in a spectrum of illness ranging from asymptomatic disease to death. Rates of hospitalization are high compared to the general pediatric population, and illness may be complicated by additional factors including co-infection, neutropenic fever, relapse of malignancy and need for chemotherapy. Children with hematologic malignancy or a history of HSCT may be at increased risk for severe disease. Additional studies are urgently needed to elucidate risk factors for severe/critical COVID-19 disease among children with underlying malignancy. Disclosures No relevant conflicts of interest to declare.

Introduction: Inborn errors of immunity such as hemophagocytic lymphohistiocytosis (HLH) and chronic granulomatous disease (CGD) are characterized by hyperinflammation. Hematopoietic cell transplantation (HCT) in the setting of hyperinflammation leads to high morbidity and mortality. Consequently, there is increasing use of less intense conditioning regimens, which can increase risk of mixed chimerism or graft failure. We sought to study the effect of common regimens on outcomes after HCT using data reported to the Center for International Blood and Marrow Transplant Research. Methods : 365 patients aged Results : Patient demographics were similar across the three treatment groups. Patients with HLH were more likely to receive the Flu/Mel regimen. Although unrelated donor HCTs were predominant across the treatment groups, cord blood graft was more common in the Bu/Cy group. Conditioning regimens changed over the study period with most Flu/Mel/TT and Flu/Bu regimens used after 2010. Consequently, outcomes were censored 2-years post-HCT to account for differences in follow-up. The day-100 incidence of VOD was higher with Bu/Cy (18%) compared to Flu/Mel (4%) and Flu/Mel/TT or Flu/Bu (7%) regimens (p Conclusion : The data does not support the use of a reduced intensity Flu/Mel regimen for hyperinflammatory inborn errors of immunity. Although we did not observe differences in event-free survival between Bu/Cy and Flu/Mel/TT or Flu/Bu regimens, lower incidences of VOD and bacterial infections favor Flu/Mel/TT or Flu/Bu regimens. Disclosures Pulsipher: Bellicum: Honoraria; Jasper: Honoraria; Novartis: Honoraria; Miltenyi: Honoraria, Research Funding; Mesoblast: Honoraria; Adaptive: Research Funding. Stenger:ISCT: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Research Funding.

Background With >36 years of data collected, PIDTC prospective (6901) and retrospective (6902) natural history studies provide an unprecedented opportunity to study hematopoietic cell transplantation (HCT) outcomes for SCID over time. Methods Patients in this 6901/6902 analysis met PIDTC diagnostic criteria for SCID and underwent HCT. Categorial variables were analyzed between decades (a) 1982-89 (b) 1990-99 (c) 2000-09 (d) 2010-18 using the chi-square test. Continuous outcomes were compared using the Kruskal-Wallis test. Kaplan-Meier method was used for estimates of overall survival (OS). Results 896 children with typical (n=742) and atypical (n=154) SCID requiring HCT between 1982-2018 were enrolled. Diagnosis of SCID for reasons other than family history or newborn screening was common (60%) in early cohorts (a-c) dropping to 30% in cohort (d). Distribution of SCID genotypes changed over time (Fig 1), and novel/unknown genotypes also decreased from (a) 53% to (d) 13%, p Conclusion This longitudinal data set, spanning the implementation of NBS and advancements in diagnostics and supportive care, highlights improved OS after HCT for SCID, including alternative donors. Exploration of decreased toxicity approaches that maintain high OS and engraftment are warranted.

Background Adoptive immunotherapy using banked virus-specific T-lymphocytes (VSTs) derived from partially HLA-matched donors has been successful in restoring antiviral immunity after hematopoietic stem cell transplantation (HSCT), although broad availability of this therapy is currently limited, and best methods for donor-recipient matching remain unclear. Objective To determine the feasibility and efficacy of third-party VSTs for the treatment of immunocompromised pediatric patients with refractory viral infections in a multicenter phase I/II consortium study. Design/Methods There are two arms to this study. Arm A are pediatric subjects who had infections with CMV, EBV, and/or adenovirus after hematopoietic stem cell transplant (HSCT) and had failed antiviral therapy, or who had toxicities related to anti-viral drug-related. Arm B enrolls patients with primary immunodeficiency disorders with refractory viral infection prior to HSCT. A VST bank containing products generated from 40 donors at Children's National was utilized, and antiviral HLA mapping was applied to identify the most suitable product for each patient referred. Patients received a dose of 2 × 10^7 VSTs/m2, with optional additional doses given 28 days after the initial VST infusion. Viral PCRs were monitored for efficacy, and VST persistence and expansion in vivo was measured via IFN-g ELISpot and flow cytometry. Results Twenty-three patients were enrolled from 11 study sites to date. Twenty-two were treated in Arm A (after HSCT), at a median time of 95 days post-HSCT (range 16-476). Fourteen patients were treated for adenovirus and 9 for CMV. Patients received a median of 1 infusion (range 1-3). Infused VSTs were matched at a median of 3/10 HLA alleles (range 2-5), and 22 had confirmation of antiviral activity through at least one shared HLA allele. Of 18 evaluable patients, 14 had antiviral responses at 1-month post-infusion (4/5 with CMV, and 10/13 with adenovirus, Figure 1), including 7 who had complete resolution of viremia. No GVHD was observed after infusion, and 17 of 23 (74%) are virus free up to 15 months post-infusion. Virus-specific T-cell activity was higher by day 45 (mean 177 IFN-g SPW) post-infusion than at baseline (mean 13 IFN-g SPW, p=0.045). VSTs remained detectable for up to 3 months via flow cytometry staining of discordant HLA alleles (Figure 2). Conclusions Third-party VSTs utilized from a single bank can be distributed and administered in a multicenter consortium setting, and are safe and feasible for the treatment of refractory viral infections in pediatric patients. Preliminary efficacy data shows high rates of response and long-term survival. Studies of targeting strategies and characterization of T-cell epitopes are ongoing.

Internal jugular vein (IJV) thrombosis is an unusual condition, especially when it develops bilaterally. This is a case of bilateral IJV thrombosis in a 77-year old female who presented to the emergency department with neck and arm swelling after discontinuing apixaban and undergoing an oropharyngeal procedure. The diagnosis of bilateral IJV thrombosis was made with the use of point-of-care ultrasound to evaluate bilateral jugular vein distention and bilateral upper extremity pitting edema found on her physical examination.

X-linked severe combined immunodeficiency (X-SCID) is a disorder of adaptive immunity caused by mutations in the IL-2 receptor common gamma chain gene resulting in deficiencies of T and natural killer cells, coupled with severe dysfunction in B cells. X-SCID is lethal without allogeneic stem cell transplant or gene therapy due to opportunistic infections. An infant with X-SCID became infected with SARS-CoV-2 while awaiting transplant. The patient developed severe hepatitis without the respiratory symptoms typical of COVID-19. He was treated with convalescent plasma, and thereafter was confirmed to have SARS-CoV-2 specific antibodies, as detected with a microfluidic antigen array. After resolution of the hepatitis, he received a haploidentical CD34 selected stem cell transplant, without conditioning, from his father who had recovered from COVID-19. SARS CoV-2 was detected via RT-PCR on nasopharyngeal swabs until 61 days post transplantation. He successfully engrafted donor T and NK cells, and continues to do well clinically.

Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 μg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-μg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.

Background Bacteremia is a major cause of morbidity and mortality among children with acute myelogenous leukemia (AML) and chemotherapy-induced neutropenia. Data evaluating the utility of bacterial prophylaxis in this pediatric population are limited. In April 2014, Children’s Health (CH) implemented the use of cefepime bacterial prophylaxis for AML patients undergoing induction and intensification chemotherapy. The objective of this study was to evaluate the impact of this practice on the frequency of documented bacterial bloodstream infections (BSIs). Methods This was an observational, retrospective cohort study of patients < 21 years of age with AML admitted at CH from January 2010 through December 2018. The primary outcome was frequency of documented BSIs before (PRE; Jan 2010 to Mar 2014) and after (POST; Apr 2014 to Dec 2018) implementation of routine bacterial prophylaxis. Secondary outcomes included differences in total antibiotic days per neutropenia days and the occurrence of neutropenia-associated C. difficile infection between groups. Results Of 90 patients with AML who met the cohort inclusion criteria, 38 and 52 were treated during the PRE and POST prophylaxis periods, respectively. The incidence rate of documented BSIs per 1000 neutropenia days decreased from 15.5 to 2.8 after the implementation of routine cefepime prophylaxis (incidence rate ratio 0.18, Poisson regression 95% CI 0.09 to 0.33, P< 0.001). Patients were more likely to have febrile neutropenia in the PRE group (OR 11.9, 95% CI 6.6 to 20.8). The POST group had more antibiotic days per total neutropenia days (0.76 PRE vs 0.97 POST, P< 0.0001), but the frequency of first-episode C. difficile infection was not significantly different between groups (OR 0.36, 95% CI 0.1 to 1.4). Conclusion Universal cefepime prophylaxis for children with AML and chemotherapy-induced neutropenia was associated with a significant reduction in the incidence of febrile neutropenia and neutropenia-associated BSIs without increasing the incidence of C. difficile infection. Disclosures All Authors: No reported disclosures

Background Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients. Methods This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture. Results Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture. Conclusions BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.

In a 250 patient cohort from the US and Canada in the current era (2010–2018), we show that over 90% of patients with severe combined immunodeficiency (SCID) can be genetically-characterized.

Background Allogeneic HSCT is a well-established treatment for children with AL. For pts lacking a compatible matched related or unrelated donor, HLA-haplo-HSCT represents an alternative. Promising results were reported with selective depletion of αβ T and B cells (Locatelli, Blood 2017). PX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. BPX-501 provides broad virus and tumor-specific immunity; the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid. Aims Evaluate the safety and efficacy of BPX-501 in pediatric pts with AL by determining whether BPX-501 infusion can increase efficacy outcomes through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods A subset of pts had high-risk ALs. BPX-501 was planned to be infused on day14±4 after the allograft with no post-transplant GvHD prophylaxis allowed. Pts who developed steroid-resistant GvHD could receive ≥1 dose of rimiducid. Results As of June 30, 2018, 100 pts with AL (described in Table 1) were efficacy evaluable. Median time for neutrophil and platelet engraftment was 16 and 12 days, respectively. Four pts (4.1%) experienced primary graft failure. Of 96 evaluable pts, 5 (3.1%) developed Grade III-IV aGvHD. Of 82 evaluable pts, 12 developed cGvHD (18.1%), with 3 moderate-severe. Rimiducid was administered to 10 pts. Best overall clinical response (CR/PR) post-rimiducid was 80% (8 pts). Among responding patients, 7 (87.5%) had a CR. Six (6.6%) pts died after transplantation. Efficacy outcomes in AL subsets are in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. Conclusion BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a highly effective transplantation strategy for pediatric pts with AL. Rimiducid was an effective treatment for pts with steroid-resistant GvHD.

Background Invasive fungal sinusitis (IFS) is a cause of significant morbidity and mortality among children with hematologic malignancy and hematopoietic stem cell transplant (HSCT) recipients, with an estimated mortality of 18–80%. Since 2007, our center has employed a clinical algorithm for the early detection and treatment of IFS among children with prolonged febrile neutropenia. Methods We reviewed all EORTC defined cases of proven IFS among children with underlying hematologic malignancy or prior HSCT admitted to our institution between July 1, 2004 and December 31, 2018, and compared clinical characteristics and outcomes (including underlying malignancy, chemotherapy regimen at the time of viremia, absolute neutrophil count, absolute lymphocyte count, treatment regimens, and 6 month mortality) between the pre (July 1, 2004–December 31, 2006) and post-protocol (January 1, /2007–December 31, 2018) periods. Results We identified 33 cases of proven IFS during the study period, with 6 in the pre-protocol and 27 in the post-protocol period. The most common underlying primary diagnosis was acute lymphoblastic leukemia (ALL) at > 50% with 8% of individuals with prior HSCT. Twenty-five cases (92%) during the protocol period were diagnosed via nasal endoscopy per protocol, with 17 (63%) reporting no clinical complaints of sinusitis. Median absolute neutrophil count (ANC) at the time of IFS diagnosis was 155/mm3 (IQR 0 – 375/ mm3; n = 12) with median duration of neutropenia 16.5 days (IQR 10.5–18.25, n = 12) at the time of diagnosis. Most individuals required one definitive debridement. Isolated fungal specimens included Bipolaris spp. (24%), Aspergillus spp. (20%), Curvularia spp. (20%), with Fusarium and Exserohilum spp. each at 12%, and Rhizopus spp. At least one patient had a co-infection with more than one fungal species. Pre-protocol cause-specific mortality at 6 months was 33.3% compared with 14.8% (P = 0.29) in the post- protocol period. Conclusion IFS is a cause of significant morbidity and mortality among children with hematologic malignancy or prior HSCT. An aggressive protocol with early nasal endoscopy and targeted debridement may help decrease morbidity and mortality associated with this entity. Additional well-designed studies are needed to assess the potential benefits of this approach in the diagnosis and management of IFS among high-risk children. Disclosures All authors: No reported disclosures.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency due to mutations in the WAS gene expressed in hematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice when an appropriate human leukocyte antigen-matched donor is available. The use of the extracorporeal membrane oxygenation (ECMO) circuit to infuse donor cells for HSCT has not been previously published in the literature. We describe a case of a child who had successful engraftment after HSCT with infusion of the donor stem cells through the ECMO circuit.

WOS: 000398771800023, PubMed ID: 27697500, Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 +/- 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates., Jeffrey Modell Foundation; National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease [U54 AI 082973, R13AI094943], Supported by a grant from Jeffrey Modell Foundation (to M.d.l.M.). The Primary Immune Deficiency Treatment Consortium (PIDTC) is supported by the National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease grants U54 AI 082973 and R13AI094943.

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment for children with Acute Leukemia (AL). For patients lacking a compatible matched related or unrelated donor, HLA-haploidentical HSCT (haplo-HSCT) from a relative represents a viable alternative. Promising results were reported with a novel method of selective depletion of αβ T and B cells (Locatelli, Blood 2017). This approach is associated with limitations such as suboptimal adaptive immune reconstitution, increased risk of infection and disease relapse. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Aims To evaluate the safety and efficacy of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with AL in morphological complete remission (CR). The objective was to determine whether BPX-501 infusion can increase relapse-free survival (RFS) and overall survival (OS) through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods This multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 safety switch (BPX-501) in patients with malignant or non-malignant disorders. A subset of patients had acute high-risk leukemias (AML and ALL). BPX-501 was planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of rimiducid to activate iC9. The efficacy-evaluable population (EEP) was defined as any patient with AL who received HSCT, BPX-501 infusion, and at least one follow-up assessment. Results At clinical cut-off (June 30, 2018), 100 patients (EU: 75, US: 25) with AL met the EEP definition. Median follow-up was 14.7 mos (1 - 40.6 mos). Key baseline characteristics are shown in Table 1. The median time for neutrophil and platelet engraftment was 16 (15 - 17) and 12 (11 - 12) days, respectively. Four patients (4.1% [95% CI: 0 - 8%]) experienced primary graft failure. Of 96 evaluable patients, 21 patients developed Grade I-IV aGvHD (21.7% [95% CI: 13.5 - 29.8%]). Five patients developed Grade III-IV aGvHD (3.1% [95% CI: 0 - 6.5%]). Of 82 evaluable patients, 12 patients developed cGvHD (18.1% [95% CI: 8.2 - 22%]), with only three cases being moderate-severe. Rimiducid was administered to 10 patients with steroid-resistant acute GvHD. Best overall clinical response of CR or PR post-rimiducid administration was seen in 8 patients (80%). Among responding patients, 7 patients (87.5%) had a CR. Six patients died after transplantation (6.6% [95% CI: 1.4 - 11.7%]). Relapse Free Survival (RFS) was 82.2% (95% CI: 74.5 - 89.7%). Overall Survival (OS) was 90.1% (95% CI: 83.9 - 96.3%). Efficacy outcomes (TRM, RFS and OS) in AL subsets (AML and ALL) are shown in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 9.96% ± 11.6% (0 - 54.9%) and 85.58 ± 165.57 cells/ul (0 - 1001 cells/ml), respectively. Conclusion The adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with AL. Compared to data from children receiving only αβ T and B-cell depleted haplo-HSCT or matched unrelated donor HSCT (https://bloodcell.transplant.hrsa.gov/research/transplant_data/us_tx_data/survival_data/survival.aspx), this novel approach resulted in a comparable risk of transplant-related mortality and a lower risk of recurrence. Rimiducid was also an effective treatment for patients who developed steroid-resistant GvHD. Disclosures Locatelli: bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Qasim:Orchard: Equity Ownership; Autolus: Equity Ownership; Servier: Research Funding; Bellicum: Research Funding. Nemecek:Novartis Pharmaceuticals Corporation: Other: advisory boards.

Background Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to rescue trilineage cytopenias and to prevent occurrence of myeloid malignancies in patients with Fanconi Anemia (FA). HLA-identical family donor HSCT is a recommended treatment strategy with an ≥80% cure rate, and outcomes of HSCT from unrelated donors have progressively improved over time. However, HLA-partially matched (haplo) HSCTs have been historically associated with inferior results. Innovative approaches of graft manipulation, such as selective depletion of αβ-T and B cells, have recently been reported to improve the outcomes of haplo-HSCT in children with non-malignant disorders, however obstacles remain, such as delayed recovery of adaptive immunity with a risk of life-threatening infections. Novel strategies aimed at accelerating immune reconstitution are warranted to optimize the outcomes of patients transplanted from a HLA-haploidentical family donor. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Aims To evaluate the safety and efficacy (acceleration of immune recovery and prevention of transplant-related mortality while maintaining low rates of acute and chronic GvHD) of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with FA. Methods This is a multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizing αβ-T- and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified to express iC9 (BPX-501 T cells). BPX-501 cells were planned to be infused on day14±4 after the allograft per protocol. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy were eligible to receive ≥1 dose of dimerizing rimiducid activating iC9. The efficacy-evaluable population (EEP) was defined as any patient with FA who received HSCT, BPX-501 infusion and had at least one follow-up assessment. Results At the time of clinical cut-off (June 30th, 2018), 14 patients met the EEP definition. Nine and 5 patients were transplanted in the EU and US, respectively. The median follow-up was 23.5 mos (0.75 - 42 mos). Key baseline and transplant characteristics are detailed in Table 1. The median time for neutrophil and platelet engraftment was 14 (11-15) and 10 (8 - 11) days, respectively. One patient experienced primary graft failure (7.7% [95% CI: 0-22.2%]). Only one patient developed Grade I aGvHD (7.7% [95% CI: 0-22.2%]). Two patients developed cGvHD (19.2% [95% CI: 4-43.2%]), both cases being moderate. Rimiducid was not administered to any patient. One patient died after transplantation due to brain hemorrhage 25 days post HSCT. The event was unrelated to BPX-501 (TRM 7.1% [95% CI: 0-20.6%]). No patients died of infectious complications. The probability of both overall survival (OS) and disease-free survival (DFS) was 92.9% (95% CI: 79.4-100%). The median time from last red blood cell (RBC) transfusion was 23.6 mos (0.2 - 41.9 mos). CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 360 days, respectively. IgA and IgM levels achieved normal values by 30 and 180 days, respectively. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 3.35% ± 2.94% (0 - 8.4%) and 29.09 ± 39.56 cells/ml (0 - 135 cells/ml), respectively. Conclusion These data indicate that the adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with FA. Further, despite the addition of BPX-501, low rates and severity of both acute and chronic GvHD was observed, a finding that could translate into significant long-term benefit, in terms of reduction of squamous cell carcinoma a well-known complication occurring in FA patients after HSCT. Disclosures Aldinger: Bellicum Pharmaceuticals, Inc.: Employment. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Combotox is a 1:1 mixture of RFB4-dgA and HD37-dgA which are immunotoxins that target the CD22 and CD19 antigens, respectively. Combotox has different toxicities and targets than chemotherapy and is, thus, a new candidate for the treatment of patients with relapsed ALL. Preclinical data have demonstrated which Combotox is effective in killing pre-B-ALL cell lines and cells from patients with pre-B ALL.We designed and conducted a Phase 1 dose-escalation study using Combotox in children with refractory or relapsed B-lineage-ALL. Seventeen patients aged 1 to 16 years were enrolled in this multi-institution study. They were treated at 4-dose levels: 2 mg/m2, 4 mg/m2, 5 mg/m2, and 6 mg/m2.The maximum tolerated dose was 5 mg/m2 and graft versus host disease defined the maximum tolerated dose. Three patients experienced complete remission. Six additional patients experienced a decrease of95% in their peripheral blood blast counts, and 1 patient experienced a decrease of 75%.Combotox can be safely administered to children with refractory leukemia. It has clinically important anticancer activity as a single agent. The recommended dose for future studies is 5 mg/m2/dose.

Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m(2)/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0+/-0.3 vs 3.9+/-0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1+/-1.5 vs 19.3+/-2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3+/-1.7 vs 27.3+/-3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.

Purpose To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors. Patients and Methods Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized. Results Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent. Conclusion The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.

The role of the thymus in immune reconstitution in adults receiving chemotherapy is controversial. Detection of T-cell-receptor gene rearrangement excisional circles (TREC) in peripheral blood T cells has been shown to estimate thymic output. Therefore, we measured TREC levels to assess the contribution of the thymus to immune recovery following treatment with fludarabine. Patients who had received fludarabine alone or a fludarabine containing regimen were identified. Cryopreserved peripheral-blood mononuclear cells were obtained and analyzed by four-color flow cytometry utilizing fluorochrome-conjugated antibodies against CD4, CD8, CD45RO and CD27. Proportions of naïve T cells in each CD4+ and CD8+ subset were measured by gating on CD45RO-negative, CD27+ cells. Quantification of TREC in sorted naïve CD4+ and CD8+ T cells was performed by real-time PCR. Thirteen patients received a mean of 3.8 +/- 0.4 courses of fludarabine and samples were obtained at a average of 18.8 (range 3.6-40.3) months after completing chemotherapy. Ten (77%) had detectable TREC levels. There was a positive correlation (Spearman's rank correlation) between the degree of TREC expression and the percentage of naïve T cells (r = 0.6, p = 0.03), naïve CD4+ (r = 0.6, p = 0.03) and naïve CD8+ (r = 0.66, p = 0.01) cells. We conclude that increased thymic output as demonstrated by an increase in TREC levels correlated with, and was predictive ofincreased numbers of naive T cell following fludarabine administration. The thymus appears to play a role in immune recovery in adults after receiving chemotherapy.

Background. To determine the maximumtolerated duration and dose-limiting toxicity of a daily schedule of orally administered cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. Methods. Patients received oral cyclophosphamide (50 mg/m 2 /dose) in the morning followedbytopotecan(0.8mg/m 2 /dose)8–12hr later for an escalating number of consecutive days (10, 14, and 17 days). Results. Seventeen pediatric patients were treated with oral cyclophosphamide and topotecan for durations of 10–17 days for a total of 58 treatment courses. Reversible hematologic toxicity (neutropenia and thrombocytopenia) was the dose-limiting toxicity. Nonhematologic toxicities of greater than grade 3 were not observed. A partial response (neuroblastoma following myeloablative chemotherapy and stem cell rescue) and prolonged stable disease (medulloblastoma) were each observedin one patient.Conclusions. The recommended duration of therapy with a daily schedule of both oral cyclophosphamide (50 mg/m 2 /day) and topotecan (0.8 mg/m 2 /day) for previously treated pediatric patients with recurrent or refractory solid tumors is 14 consecutive days. The observed dose limiting toxicity (DLT) was reversible neutropenia. This regimen was well tolerated in heavily pretreated patients and demonstrated activity against recurrent pediatric solid tumors. Pediatr Blood Cancer 2004;42:93–98. 2003 Wiley-Liss, Inc.

Purpose This study was undertaken to determine if central venous catheter (CVC)-related infection in children with cancer could be prevented by monthly flushing of the catheter with urokinase. Patients and Methods Between August 1994 and July 1998, 103 patients with cancer were randomized at the time of subcutaneous CVC placement to receive monthly flushing of their catheters with either 5000 IU of urokinase–heparin or heparin alone. Patients subsequently had blood cultures taken from their CVCs during an episode of fever. Results Seventy-four of the 103 patients (72%) enrolled in the study received at least 6 catheter flushes: 40 with urokinase–heparin and 34 with heparin. The median number of flushes was 9.5 in the urokinase–heparin group and 10.2 in the heparin-only group (P = 0.62). There were 5 positive blood cultures in the urokinase–heparin group and seven in patients receiving heparin alone (P = 0.27). Staphylococcus epidermidis was isolated from the blood of 3 patients receiving urokinase–heparin and 6 in those receiving heparin alone (P = 0.17). Conclusion Prophylactic monthly catheter flushes with 5000 IU urokinase did not significantly decrease the number of documented bacteremic events in children with cancer who have CVCs.

~ cute myelogenous leukemia (AML) is characterized by the overproduction of immature myeloid cells in the bone marrow, which leads to bone marrow failure and infiltration of organs such as the liver and spleen. During the past several decades progress has been made in our knowledge of the biologic study and treatment of AML. The use of more intensive chemotherapy, hematopoietic stem cell transplantation, and improved supportive care have improved the cure rate of AML from 10% to 40% during the past 2 decades. Unfortunately, the cure rate for AML continues to lag behind that for most children with ALL. The development of new therapeutic interventions will be required to continue to improve the prognosis for children with AML, with the ultimate goal of cure for all children with AML.

Background: The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. Methods: We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). Results: Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell - depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin- induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. Conclusions: Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.) Copyright © 2014 Massachusetts Medical Society.

BACKGROUND Traditionally, children with malignant disease who present with fever and neutropenia are hospitalized for parenteral antibiotics. More recently, outpatient strategies have been proposed for lower risk cohorts of such patients. The authors sought to identify clinical and laboratory parameters that are associated with a low risk of bacteremia in children with malignant disease who presented with febrile neutropenia. METHODS A multicenter, retrospective cohort of children with malignant disease and fever with neutropenia was established in three pediatric oncology centers over a 5-year period. A total of 1171 episodes of febrile neutropenia (absolute neutrophil count [ANC] 1 year. The endpoints examined were 1) bacteremia and 2) intensive care unit admission or death related to bacteremia. The odds ratio was used to determine which of the following admission parameters and cut-off values were associated with the lowest risk for bacteremia: ANC, absolute phagocyte count (APC), absolute monocyte count (AMC), platelet count, and admission temperature. RESULTS A total of 189 episodes of bacteremia were identified among the 1171 episodes of febrile neutropenia (14% bacteremia). Only 11 of 1171 episodes (0.9%) resulted in intensive care unit admission, and 3 of these patients died. All 11 patients had an AMC < 30 cells per mm3. The lowest frequency of bacteremia (6.1%) occurred in the children with an admission AMC of ≥ 155 cells per mm3. None of the patients identified as low risk by AMC required an intensive care unit admission or died. No level of ANC, APC, temperature, or platelet count was associated with a statistically significant decrease in the risk for bacteremia in the patient population. CONCLUSIONS Adverse outcomes due to bacteremia are infrequent in pediatric oncology patients who present with fever and neutropenia are treated with parental antibiotics. Patients with fever and neutropenia and an AMC value of ≥ 155 cells per mm3 have the lowest risk for bacteremia and may be potential candidates for outpatient management. Cancer 2001;92:909–13. © 2001 American Cancer Society.

Background A routine chest radiograph is often performed to evaluate initial fever in patients undergoing hematopoietic stem cell transplantation (HSCT) given the signs and symptoms of infectious pulmonary pathology may be subtle or absent. Studies in patients receiving conventional chemotherapy have shown that chest radiographs do not appear to be helpful in the evaluation of asymptomatic patients with febrile neutropenia. We performed a retrospective review of pediatric stem cell transplant recipients to determine if chest radiographs are useful in the evaluation of initial fever. Procedure We retrospectively identified 81 consecutive pediatric hematopoietic stem transplant recipients who had a chest radiograph performed as a routine part of the evaluation of initial fever during stem cell transplantation. Results Seventy-six (94%) of the chest radiographs performed had no evidence of pulmonary infiltrate. Of the five children with positive radiographs, three had symptomatic respiratory infection and two (40%) were asymptomatic. One asymptomatic patient had a history of pulmonary infection with persistent stable infiltrates prior to transplantation. This patient did not have any evidence of pneumonia during the transplant. The second asymptomatic patient had subsequent resolution of the infiltrate with antibiotic administration. None of the patients had a change made in the empiric antibiotic regimen based upon the results of the chest film. Conclusions Routine radiographs are not useful in the evaluation of asymptomatic children at the time of an initial febrile event while undergoing HSCT. Pediatr Blood Cancer 2011; 57: 666–668. © 2010 Wiley-Liss, Inc.

Purpose: To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. Patients and Methods: Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. Results: In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. Conclusions: ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.

BACKGROUND Children with cancer who develop an episode of chemotherapy-induced febrile neutropenia usually are admitted to the hospital for intravenous empiric antibiotic therapy. In the current study, the authors examined the use of ciprofloxacin as outpatient management in selected patients with fever during an episode of neutropenia. METHODS Febrile neutropenic patients with a diagnosis of cancer were eligible for outpatient management with oral ciprofloxacin if they appeared well and demonstrated the following characteristics: age 1–21 years, malignancy in remission, absolute phagocyte count > 100/mm3, > 7 days since the initiation of the last course of chemotherapy, and reliable parents. Eligible children received a single dose of ceftazidime and were observed for 2–23 hours. Patients were discharged receiving oral ciprofloxacin (20/mg/kg/day divided in 2 doses) until the patient was afebrile for 24 hours, had sterile blood cultures, and had evidence of bone marrow recovery. Patients were admitted if they appeared toxic, had positive blood cultures, or were febrile for ≥ 5 days. RESULTS Forty-five evaluable episodes occurred in 32 children. Forty of the 45 patients (89%) were treated successfully in the outpatient setting. The 95% lower confidence bound on the proportion of successful outcomes was 70%. Five children required hospitalization: 2 due to noncompliance, 1 to receive intravenous acyclovir for herpes zoster, and 2 (4%) whose blood cultures were positive for Streptococcus viridans and S. pneumoniae. All had uncomplicated hospitalizations. CONCLUSIONS The current study demonstrates that very carefully selected, low risk patients with febrile neutropenia may be treated successfully without hospitalization using oral ciprofloxacin. Additional research is required to refine further the optimal criteria for the selection of appropriate patients for outpatient management. Cancer 2000;88:1710–4. © 2000 American Cancer Society.

Management of low grade optic glioma in children and adolescents remains controversial. Treatment with chemotherapy may delay or eliminate the need for radiation therapy. Children with newly diagnosed optic chiasm glioma were eligible for enrollment in this phase II trial and received intravenous carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely for toxicity and tumor status. Twelve children were enrolled. Six patients had stable disease, four a partial response and two progressed on therapy. Overall progression free survival was 83 +/- 11%. The median duration of follow-up was 38.6 months (range 18-63 months). No deaths were noted in our series. Thrombocytopenia was the major toxicity, and two patients required platelet transfusions. One child developed an urticarial reaction requiring discontinuation of therapy. Another child developed unilateral high frequency hearing loss. No renal toxicity was encountered. We have demonstrated that carboplatin can eliminate or delay radiation therapy in children and adolescents with low grade optic glioma. CBDCA deserves further investigation in larger clinical trials as a treatment for children with optic chiasm glioma.

Problem The safety of early hospital discharge (i.e., before the absolute neutrophil count [ANC] exceeds 500 cell/mm3) of febrile neutropenic children and adolescents with cancer who had experienced prolonged neutropenia (i.e., for more than 7 days) following admission has not been studied. Method of Study. Three hundred and thirty-nine consecutive admissions of children and adolescents with cancer for management of febrile neutropenia were reviewed. Early discharge criteria included absence of fever for 24 hours prior to discharge, sterile blood cultures for 24 hours, evidence of bone marrow recovery defined as a sustained increase in platelet count and ANC or absolute phagocyte count (APC), and control of local infection if present. Children hospitalized with febrile neutropenia who remained neutropenic for more than 7 days were analyzed to assess their outcomes following discharge if they had met criteria for early hospital discharge. Results Thirty-three patients inwhom neutropenia had persisted for more than 7 days were discharged before attaining an ANC greater than 500/mm3 when they met the early discharge criteria. Only two children (6%) required readmission for recurrent fever, a rate which was not different from that of patients discharged after a more transient episode of neutropenia (2 of 33 vs. 3 of 121, P = 0.3). Both patients who were readmitted had a source of local infection which worsened despite oral antibiotics. Both patients appeared clinically well at the time of readmission and had sterile cultures during their second hospitalization with resolution of local infection. Conclusion This study confirms that low-risk criteria used to select children with cancer for discharge before complete resolution of neutropenia can be safely applied to those patients whose neutropenia lasted more than 7 days following admission. Med. Pediatr. Oncol. 28: 191–195 © 1997 Wiley-Liss, Inc.

Pneumocystis carinii pneumonia (PCP) is a potentially life-threatening but preventable infection that may occur after hematopoietic stem cell transplantation (HSCT). Intravenous pentamidine has been used in the prevention of PCP in the post-transplant period, although there are few trials published in the literature evaluating its safety and efficacy.We retrospectively reviewed the medical records of children who underwent HSCT from January 1, 2005, to October 1, 2011, who received intravenous pentamidine as first-line PCP prophylaxis initiated at admission. Demographic, clinical, microbiologic, management and outcome data were collected.One hundred sixty-seven consecutive HSCTs in 137 pediatric patients were given intravenous pentamidine before myeloablation and then every 28 days until the subject was at least a minimum 30 days post-HSCT, had stable neutrophil engraftment (absolute neutrophil count1000/mm for 3 days without growth factor support) and for allogeneic patients, no evidence of active graft versus host disease and weaning on their immunosuppressive therapy. No cases of PCP were seen in this cohort. Ten (7%) had a grade I side effect of nausea/vomiting requiring slower infusion time and 2 (2%) had a grade IV reaction with anaphylaxis (rash) and hypotension with 1 child requiring transfer to the intensive care unit.Intravenous pentamidine was safe and effective for the prevention of PCP in pediatric HSCT patients. Given the potential neutropenic effects of trimethoprim-sulfamethoxazole, compliance with drug administration and inferior efficacy of other PCP prophylactic medications, intravenous pentamidine should be considered as first-line therapy for the prevention of PCP in children undergoing HSCT.

We examined the use of gastrostomy tubes in malnourished children with cancer as part of our ongoing efforts to improve their supportive care. Patients were examined on the basis of percentage of weight loss and percentage of desirable body weight. Twenty-five patients underwent gastrostomy tube placement followed by aggressive enteral nutritional support. Gastrostomy tubes were placed at a mean of 3.5 months (range, 0.3 to 8 months) after diagnosis; mean weight loss had been 10.1% (range, to 21%) of desirable body weight. There were no immediate postoperative complications. Gastrostomy tube feedings were well tolerated by all patients. All children gained or maintained weight, and 60% of the severely malnourished children returned to a desirable body weight after an average of 4.9 months (range, 1 to 13 months). Weight gain averaged 12.9% (range, to 45.4%) of desirable body weight. The most common complications were 38 episodes of inflammation at the gastrostomy tube site during periods of severe neutropenia, which were treated successfully with topically or orally administered antibiotics, and 13 episodes of cellulitis, which required intravenously administered antibiotics. The infection rate was 1.58 episodes per 1000 days of use compared with a rate of 5.0 per 1000 days previously reported with total parenteral nutrition. The monthly costs of gastrostomy tube nutrition support were 9% of those associated with use of total parenteral nutrition. Gastrostomy tube use in children with cancer is a safe, effective, and cost-effective method of reversing malnutrition. Further investigation with larger numbers of patients is warranted. (J PEDIATR 1995;127:58-62)

A variety of clinical and laboratory parameters have been used to predict bacteremia. We hypothesize that the generation of a cytokine profile could be used to identify patients at higher risk of bacteremia at the time of presentation with febrile neutropenia. We prospectively evaluated children with cancer who presented with an episode of febrile neutropenia. A multiplexed flow cytometric assay was performed which measured 15 cytokines and chemokines obtained before the initiation of antibiotics. Fifty-eight episodes of chemotherapy-induced febrile neutropenia were included in this study during which 4 patients (7%) had bacteremia. An interleukin-5 level of >8 pg/dL had a sensitivity of 67% and a specificity of 96% to predict bacteremia. An monocyte chemotactic protein-1 level >1650 pg/dL had a sensitivity of 80% and a specificity of 82% to predict bacteremia. Erythrocyte sedimentation rate, C-reactive protein, protein C, and other cytokines/chemokines were not predictive of bacteremia. Elevations of interleukin-5 and monocyte chemotactic protein-1 are predictive of bacteremia in children with cancer who have febrile neutropenia. Prospective studies should be undertaken to determine whether these parameters retain predictive value in a larger series of patients and can select children for outpatient management or early discharge.

The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.