Publications by authors named "Alix E Seif"

76 Publications

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

J Exp Med 2021 Jul 5;218(7). Epub 2021 May 5.

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
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http://dx.doi.org/10.1084/jem.20201750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105723PMC
July 2021

Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients.

Transplant Cell Ther 2021 Feb 10;27(2):169.e1-169.e9. Epub 2020 Dec 10.

Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34 cell dose was 10.2 × 10/kg (range, 4.54 to 20 × 10/kg), and the median TCRαβ cell dose was 2.53 × 10/kg (range, 0 to 44.9 × 10/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology. Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3, CD4, and CD8 T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4 T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.
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http://dx.doi.org/10.1016/j.jtct.2020.10.006DOI Listing
February 2021

Presentation acuity, induction mortality, and resource utilization in infants with acute leukemia.

Pediatr Blood Cancer 2021 Jul 11;68(7):e28940. Epub 2021 Mar 11.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: Treatment of infants with acute leukemia remains challenging, especially for acute lymphocytic leukemia (ALL). Infants have shown markedly higher rates of induction mortality compared with noninfants. There are limited data on presentation acuity and supportive care utilization in this age group.

Methods: In retrospective analyses of patients treated for new onset ALL or acute myeloid leukemia (AML) at pediatric hospitals contributing to the Pediatric Health Information System, we compared presentation acuity, induction mortality, and resource utilization in infants relative to noninfants less than 10 years at diagnosis.

Results: Analyses included 10 359 children with ALL (405 infants, 9954 noninfants) and 871 AML (189 infants, 682 noninfants). Infants were more likely to present with multisystem organ failure compared to noninfants for both ALL (12% and 1%, PR = 10.8, 95% CI: 7.4, 15.7) and AML (6% vs. 3%; PR = 2.0, 95% CI: 1.0, 3.7). Infants with ALL had higher induction mortality compared to noninfants, even after accounting for differences in anthracycline exposure and presentation acuity (2.7% vs. 0.5%, HR = 2.1, 95% CI: 1.0, 4.8). Conversely, infants and noninfants with AML had similar rates of induction mortality (3.2% vs. 2.1%, HR = 1.2, 95% CI: 0.3, 3.9), which were comparable to rates among infants with ALL. Infants with ALL and AML had greater requirements for blood products, diuretics, supplemental oxygen, and ventilation during induction relative to noninfants.

Conclusions: Infants with leukemia present with higher acuity compared with noninfants. Induction mortality and supportive care requirements for infants with ALL were similar to all children with AML, and significantly higher than those for noninfants with ALL.
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http://dx.doi.org/10.1002/pbc.28940DOI Listing
July 2021

Identifying relapses and stem cell transplants in pediatric acute lymphoblastic leukemia using administrative data: Capturing national outcomes irrespective of trial enrollment.

Pediatr Blood Cancer 2020 May 11:e28315. Epub 2020 May 11.

Center for Childhood Cancer Research, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Introduction: Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using administrative data representing hospitalizations at US pediatric institutions.

Methods: We developed daily billing and ICD-9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort.

Results: We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were > 90% at both hospitals. Five-year relapse incidence in the 10 150-patient PHIS cohort was 10.3% (95% CI 9.8%-10.9%) with 7.1% (6.6%-7.6%) of children underwent HSCTs. Patients in higher-risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status.

Conclusions: Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on- or off-therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials.
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http://dx.doi.org/10.1002/pbc.28315DOI Listing
May 2020

Acute Kidney Injury in Children after Hematopoietic Cell Transplantation Is Associated with Elevated Urine CXCL10 and CXCL9.

Biol Blood Marrow Transplant 2020 07 9;26(7):1266-1272. Epub 2020 Mar 9.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic HCT provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant. Children (>2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at 2 large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value, which was recorded ±1 day from when the research urine sample was obtained, as compared with the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI). A total of 176 patients were included from 2 pediatric centers. Thirty-six patients from 1 center were analyzed as a discovery cohort and the remaining 140 patients from the second center were analyzed as a validation cohort. AKI rates were 18% to 35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (P < .01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-γ and interferon-α. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding. CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.
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http://dx.doi.org/10.1016/j.bbmt.2020.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306432PMC
July 2020

Significance of minimal residual disease in pediatric mixed phenotype acute leukemia: a multicenter cohort study.

Leukemia 2020 07 14;34(7):1741-1750. Epub 2020 Feb 14.

Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, USA.

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003). Patients who cleared MRD by EOC had worse survival compared with those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.
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http://dx.doi.org/10.1038/s41375-020-0741-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332384PMC
July 2020

Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists.

Cancers (Basel) 2020 Jan 10;12(1). Epub 2020 Jan 10.

Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.
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http://dx.doi.org/10.3390/cancers12010169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016792PMC
January 2020

Transient atypical monocytosis after α/β T-cell-depleted haploidentical hematopoietic stem cell transplantation.

Pediatr Blood Cancer 2020 04 22;67(4):e28139. Epub 2019 Dec 22.

Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1002/pbc.28139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721203PMC
April 2020

The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation.

Clin Infect Dis 2020 12;71(12):3044-3054

Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Background: BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function.

Methods: In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use.

Results: We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure.

Conclusions: Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.
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http://dx.doi.org/10.1093/cid/ciz1194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819507PMC
December 2020

Partially CD3-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy.

Biol Blood Marrow Transplant 2020 03 22;26(3):493-501. Epub 2019 Nov 22.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3/CD19 depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age ≥15 years was associated with decreased OS (P= .05) and EFS (P= .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.022DOI Listing
March 2020

Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric solid organ transplant recipients.

Pediatr Transplant 2019 09 18;23(6):e13510. Epub 2019 Jun 18.

Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.

Information about HAdV infection in SOT recipients is limited. We aimed to describe HAdV infection epidemiology and outcomes in a single-center retrospective cohort during the era of PCR availability. SOT recipients transplanted at the CHOP 2004-2013 were followed up for 180 days post-transplant. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. HAdV disease was defined by organ-specific radiologic and/or laboratory abnormalities. No HAdV surveillance protocols were employed during the study period; testing was solely per clinician discretion. Progression of HAdV infection was defined as HAdV disease or ≥1-log viral load increase since a corresponding site's first positive specimen. Of the assembled 425 SOT recipients, 227 (52.6%) had ≥1 HAdV PCR. Twenty-four (10.6%) had ≥1 HAdV-positive PCR. HAdV-positive subjects were younger than uninfected subjects (2.0 years vs 6.5, P = 0.001). Infection incidence rates were highest in liver recipients (15.3%), followed by heart (8.6%), kidney (8.3%), and lung (4.2%). Four subjects (16.7%) met HAdV disease criteria at virus detection. Five subjects (20.8%) had progression of HAdV infection. All-cause mortality rates in positive and negative subjects were 0% and 3.9%, respectively. HAdV infection was infrequently detected in SOT recipients. Over one-third of HAdV-positive patients met disease criteria at detection or had infection progression, but none died. This low all-cause mortality raises questions about benefits of HAdV surveillance. Larger multicenter studies are needed to assess incidence variance by center and comparative effectiveness of therapeutic interventions.
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http://dx.doi.org/10.1111/petr.13510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706289PMC
September 2019

Unintended consequences of evolution of the Common Terminology Criteria for Adverse Events.

Pediatr Blood Cancer 2019 07 9;66(7):e27747. Epub 2019 Apr 9.

Center for Pediatric Clinical Effectiveness, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined.

Procedure: This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs.

Results: The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment-comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10-14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach.

Conclusions: CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting.
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http://dx.doi.org/10.1002/pbc.27747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681806PMC
July 2019

Disparities in pediatric acute myeloid leukemia (AML) clinical trial enrollment.

Leuk Lymphoma 2019 09 7;60(9):2190-2198. Epub 2019 Feb 7.

Division of Oncology, The Children's Hospital of Philadelphia , Philadelphia , PA , USA.

Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%,  = .004; 34% vs. 58%,  = .003; 46% vs. 58%,  = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%,  = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%,  = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.
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http://dx.doi.org/10.1080/10428194.2019.1574002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685754PMC
September 2019

Comparable on-therapy mortality and supportive care requirements in Black and White patients following initial induction for pediatric acute myeloid leukemia.

Pediatr Blood Cancer 2019 04 26;66(4):e27583. Epub 2018 Dec 26.

Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Background: Black patients with acute myeloid leukemia (AML) are more likely to present with high acuity and consequently experience higher rates of induction mortality than white patients. Given the consistently identified racial disparities in overall survival (OS) among patients with AML, we aimed to evaluate whether there were sustained on-therapy racial differences in inpatient mortality, intensive care unit (ICU) requirements, or supportive care beyond initial induction.

Procedure: Within a retrospective cohort of 1239 children diagnosed with AML between 2004 and 2014 in the Pediatric Health Information System (PHIS) database who survived their initial course of induction chemotherapy, we compared on-therapy inpatient mortality, ICU-level care requirements, treatment course duration, cumulative length of hospital stay (LOS), and resource utilization after induction I by race.

Results: Over the period from the start of induction II through completion of frontline chemotherapy, there were no significant differences in mortality (adjusted odds ratios [OR], 1.01; 95% confidence intervals [CI], 0.41-2.48), ICU-level care requirements (adjusted OR, 0.93; 95% CI, 0.69-1.26), LOS (adjusted mean difference, 3.2 days; 95% CI, -2.3-9.6), or supportive care resource utilization for black patients relative to white patients. Course-specific analyses also demonstrated no differences by race.

Conclusion: Although black patients have higher acuity at presentation and higher induction mortality, such disparities do not persist over subsequent frontline chemotherapy treatment. This finding allows interventions aimed at reducing disparities to be directed at presentation and induction.
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http://dx.doi.org/10.1002/pbc.27583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386601PMC
April 2019

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.

Oncogene 2019 03 26;38(13):2241-2262. Epub 2018 Nov 26.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.
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http://dx.doi.org/10.1038/s41388-018-0567-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440839PMC
March 2019

Allogeneic hematopoietic stem cell transplantation in adolescent patients with chronic granulomatous disease.

J Allergy Clin Immunol Pract 2019 Mar 2;7(3):1052-1054.e2. Epub 2018 Nov 2.

Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa.

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http://dx.doi.org/10.1016/j.jaip.2018.10.034DOI Listing
March 2019

Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma.

Bone Marrow Transplant 2020 03 4;55(3):531-537. Epub 2018 Sep 4.

Department of Pediatrics, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA.

Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012)) and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041) were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.
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http://dx.doi.org/10.1038/s41409-018-0298-yDOI Listing
March 2020

Resource utilization and toxicities after single versus tandem autologous stem cell rescue in high-risk neuroblastoma using a national administrative database.

Pediatr Blood Cancer 2018 12 1;65(12):e27372. Epub 2018 Aug 1.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: High-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) has improved event-free survival for children with high-risk neuroblastoma. Common regimens include carboplatin/etoposide/melphalan (CEM), busulfan/melphalan (BuMel), and tandem HDC-ASCR [thiotepa/cyclophosphamide (TC) followed by CEM]. To complement clinical trial data and to evaluate the clinical burden associated with these regimens, resource ultilization (RU) was evaluated. An administrative database was used to evaluate RU in a previously developed high-risk neuroblastoma cohort. Single CEM and BuMel patients were followed for 60 days from the first day of the HDC-ASCR preparative regimen or until death, whichever came first. Tandem patients were followed from the first day of the first HDC-ASCR preparative regimen through day 60 from the first day of the second HDC-ASCR. Resources compared included inpatient days, ICU-level care, and medications administered.

Results: A cohort of 578 patients was evaluated; 422 patients underwent single HDC-ASCR with CEM, 67 received BuMel, 72 underwent TC/CEM, and 17 received only the first portion of tandem HDC-ASCR. The median number of inpatient days and days of exposure to antibiotics, opioids, and total parenteral nutrition were higher in the tandem group than in the CEM and BuMel groups. However, the rate of use of several ICU-level resources per 1000 hospital days was lower for the tandem group.

Conclusions: These data suggest that while patients undergoing tandem HDC-ASCR were hospitalized longer, the severity of illness during hospitalization was not greater in tandem patients.
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http://dx.doi.org/10.1002/pbc.27372DOI Listing
December 2018

Outcomes of Human Adenovirus Infection and Disease in a Retrospective Cohort of Pediatric Hematopoietic Cell Transplant Recipients.

J Pediatric Infect Dis Soc 2019 Sep;8(4):317-324

Infectious Disease Diagnostics Laboratory, Children's Hospital of Philadelphia, Pennsylvania.

Background: Human adenoviruses (HAdVs) are associated with significant morbidity and death after hematopoietic cell transplantation (HCT). In this study, we sought to determine the incidence of HAdV infection among pediatric HCT recipients in the polymerase chain reaction (PCR) testing era, identify risk factors for viremia among patients undergoing HAdV surveillance, and assess the effectiveness of preemptive cidofovir.

Methods: A single-center retrospective cohort of patients who underwent a transplant within a 10-year period was assembled. The incidence of and outcomes of patients with HAdV infection and disease were determined by PCR results and chart review. A Cox regression model was used for surveilled allogeneic HCT recipients to identify factors associated with viremia. We also used a discrete-time failure model with inverse probability treatment weights to assess the effectiveness of preemptive cidofovir for infection.

Results: Among 572 HCT recipients, 76 (13.3%) had ≥1 sample that was HAdV PCR positive (3.5% of autologous HCT recipients and 19.7% of allogeneic HCT recipients). Among 191 allogeneic HCT recipients under surveillance, 58 (30.4%) had HAdV detected from any source, and 50 (26.2%) specifically had viremia. The mortality rate was higher in allogeneic HCT recipients with HAdV infection versus those without infection (25.9% vs 11.3%; P = .01). Factors associated with infection included an age of 6 to 12 years, an absolute lymphocyte count of <200 cells/μL, recent prednisone exposure, and recent bacteremia. Preemptive cidofovir was not associated with a reduced risk of infection progression (odds ratio, 0.96 [95% confidence interval, 0.30-3.05]).

Conclusions: HAdV infection is common and associated with an increased rate of death after allogeneic HCT. Using prediction models that incorporate factors associated with HAdV might help target surveillance. Preemptive cidofovir therapy was not protective in a subset of HAdV-positive patients. Larger observational or randomized investigations are necessary, because the utility of surveillance requires effective preemptive therapies.
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http://dx.doi.org/10.1093/jpids/piy049DOI Listing
September 2019

Hospital Variation in Intensive Care Resource Utilization and Mortality in Newly Diagnosed Pediatric Leukemia.

Pediatr Crit Care Med 2018 06;19(6):e312-e320

Division of Pediatric Critical Care Medicine, Department of Pediatrics and Public Health Sciences, Penn State Hershey Milton S. Hershey Medical Center, Hershey, PA.

Objectives: To evaluate hospital-level variability in resource utilization and mortality in children with new leukemia who require ICU support, and identify factors associated with variation.

Design: Retrospective cohort study.

Setting: Children's hospitals contributing to the Pediatric Health Information Systems administrative database from 1999 to 2011.

Patients: Inpatients less than 25 years old with newly diagnosed acute lymphocytic leukemia or acute myeloid leukemia requiring ICU support (n = 1,754).

Interventions, Measurements, And Main Results: Evaluated exposures included leukemia type, year of diagnosis, and hospital-wide proportion of patients with public insurance. The main outcome was hospital mortality. Wide variability existed in the ICU resources used across hospitals. Combined acute lymphocytic leukemia and acute myeloid leukemia mortality varied by hospital from 0% (95% CI, 0-14.8%) to 42.9% (95% CI, 17.7-71.1%). A mixed-effects model with a hospital-level random effect suggests significant variation across hospitals in mortality (p = 0.007). When including patient and hospital factors as fixed effects into the model, younger age, acute myeloid leukemia versus acute lymphocytic leukemia diagnosis, leukemia diagnosis prior to 2005, hospital-wide proportion of public insurance patients, and hospital-level proportion of leukemia patients receiving ICU care are significantly associated with mortality. The variation across hospitals remains significant with all patient factors included (p = 0.021) but is no longer significant after adjusting for the hospital-level factors proportion of public insurance and proportion receiving ICU care (p = 0.48).

Conclusions: Wide hospital-level variability in ICU resource utilization and mortality exists in the care of children with leukemia requiring ICU support. Hospital payer mix is associated with some mortality variability. Additional study into how ICU support could be standardized through clinical practice guidelines, impact of payer mix on hospital resources allocation to the ICU, and subsequent impact on patient outcomes is warranted.
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http://dx.doi.org/10.1097/PCC.0000000000001525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986594PMC
June 2018

Opioid utilization among pediatric patients treated for newly diagnosed acute myeloid leukemia.

PLoS One 2018 8;13(2):e0192529. Epub 2018 Feb 8.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

Purpose: A cohort of pediatric patients with AML treated at hospitals contributing to the Pediatric Health Information System was used to evaluate differences in opioid utilization by sex, age, race, and insurance.

Methods: Billing data were used to compute the prevalence of opioid exposure and to quantify rates of utilization among those exposed to opioids as days of use per 1000 inpatient days. Multivariable regressions were used to compare opioid prevalence, and rates of utilization among those exposed.

Results: On average across courses, 95.2% of patients were exposed to analgesics, 84.7% were exposed to non-opioid analgesics and 77.7% were exposed to opioids. The proportion of opioid-exposed patients increased with age, but did not differ by gender, race, or insurance status. Analyses limited to patients exposed to opioids revealed modest differences in days of opioid use among female patients (adjusted rate ratio (aRR) = 1.19, 95% CI: 1.11, 1.28), patients <1 year (aRR = 1.37, 95% CI: 1.21, 1.55) or ≥10 years of age (aRR = 1.63, 95% CI: 1.46, 1.82), whereas Asian patients received fewer days of opioids compared with white patients (aRR = 0.76, 95% CI: 0.61, 0.95). There was moderate hospital-level variability in both the prevalence of opioid utilization overall and preference for specific opioid medications. There was greater inconsistency in practice concerning choices for supplemental and alternative opioids than in first-line opioid utilization.

Conclusion: Additional work is needed to discern whether observed differences in opioid utilization by age and race reflect a difference in treatment or a difference in the experience of pain. Future studies should also explore the factors which guide decisions on opioid selections in an attempt to explain the variability across institutions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805309PMC
April 2018

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

Cancer Med 2018 01 23;7(1):3-12. Epub 2017 Dec 23.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.
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http://dx.doi.org/10.1002/cam4.1206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773964PMC
January 2018

Nutritional risk factors predict severe acute graft-versus-host disease and early mortality in pediatric allogeneic hematopoietic stem cell transplantation.

Pediatr Blood Cancer 2018 Feb 28;65(2). Epub 2017 Oct 28.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Malnutrition is a pro-inflammatory state, yet data on nutritional risk factors and development of acute graft-versus-host disease (aGVHD) are extremely limited.

Procedure: We conducted a retrospective cohort analysis of pediatric patients up to age 21 years who underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the Children's Hospital of Philadelphia from January 2011 to September 2014 to determine whether malnutrition was associated with development of aGVHD and early mortality. We identified body mass index (BMI) percentile and serum albumin levels as potential markers of malnutrition and defined two composite nutritional risk variables as any of the following: albumin < 2.8 g/dl, weight loss ≥10% from baseline, and low BMI [<25th (NUT25) or <5th percentile (NUT5)]. Nutritional markers and GVHD grade were assessed at baseline, 30, 60, and 90 days post-HSCT, and patients were censored upon development of GVHD.

Results: BMI <25th or <5th percentile, NUT25, and NUT5 at the beginning of any 30-day period predicted a three- to fourfold risk of developing of severe (grade III-IV) aGVHD in the subsequent 30 days in models adjusted for age, sex, donor source, and degree of human leukocyte antigen matching. Mortality at day 100 was low, but NUT25 risk at baseline conferred an increased risk of death (7.9% vs. 1%, P = 0.035).

Conclusions: Malnutrition is a targetable risk factor in pediatric HSCT; prospective trials are needed to investigate this relationship further and identify effective nutritional interventions.
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http://dx.doi.org/10.1002/pbc.26853DOI Listing
February 2018

Creation of a pediatric mature B-cell non-Hodgkin lymphoma cohort within the Pediatric Health Information System Database.

PLoS One 2017 23;12(10):e0186960. Epub 2017 Oct 23.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

Mature B-cell non-Hodgkin lymphoma (B-NHL) constitutes a collection of relatively rare pediatric malignancies. In order to utilize administrative data to perform large-scale epidemiologic studies within this population, a two-step process was used to assemble a 12-year cohort of B-NHL patients treated between 2004 and 2015 within the Pediatric Health Information System database. Patients were identified by ICD-9 codes, and their chemotherapy data were then manually reviewed against standard B-NHL treatment regimens. A total of 1,409 patients were eligible for cohort inclusion. This process was validated at a single center, utilizing both an institutional tumor registry and medical record review as the gold standards. The validation demonstrated appropriate sensitivity (91.5%) and positive predictive value (95.1%) to allow for the future use of this cohort for epidemiologic and comparative effectiveness research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186960PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653357PMC
November 2017

Absolute lymphocyte counts at end of induction correlate with distinct immune cell compartments in pediatric B cell precursor acute lymphoblastic leukemia.

Cancer Immunol Immunother 2018 02 20;67(2):225-236. Epub 2017 Oct 20.

Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, 950 West 28th Avenue, Reid Lab (Room 3062), Vancouver, BC, V5Z 4H4, Canada.

Several retrospective studies in children with B cell precursor (BCP) acute lymphoblastic leukemia (ALL) provided clinical evidence that higher absolute lymphocyte counts (ALC) early into treatment significantly correlated with improved relapse-free and overall survival. It still remains unknown, however, whether the predictive role of higher ALCs reflects general bone marrow recovery or a more specific attribute of immune function. To investigate this question, we implemented a prospective observational cohort study in 20 children with BCP ALL on day 29 (D29) of induction chemotherapy and immunophenotyped their lymphoid (T, B and natural killer cells) and myeloid (neutrophils, monocytes, dendritic cells) compartments. In a first evaluation of a cohort treated with Children's Oncology Group-based induction chemotherapy, the immune cell compartments were differentially depleted at D29. Neither gender, risk status, minimal residual disease, nor bone marrow recovery markers correlated with D29 ALC. In contrast, both CD3 T cell and dendritic cell compartments, which did not correlate with age, significantly correlated with D29 ALC (p < 0.0001). In addition, subset complexity of cellular immune compartments was preserved at D29. This study reveals that D29 ALC significantly correlates with distinct immune cell compartments but not with bone marrow recovery markers, suggesting that higher D29 ALCs may contribute to leukemia control by inducing specific host immune activity.
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http://dx.doi.org/10.1007/s00262-017-2070-3DOI Listing
February 2018

Outcomes of matched sibling donor bone marrow transplantation in children using single-agent calcineurin inhibitors as prophylaxis for graft versus host disease.

Pediatr Blood Cancer 2018 Jan 27;65(1). Epub 2017 Jul 27.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort.

Procedure: We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014.

Results: Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5-8.3) and donor age of 6 years (IQR 3-10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2-4 acute GVHD was 25.5%, grades 3-4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194-318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4-90.6%) and event-free survival was 78.9% (95% CI: 65.1-87.7%). No patient experienced graft failure.

Conclusions: Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population.
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http://dx.doi.org/10.1002/pbc.26726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699955PMC
January 2018

Complications preceding early deaths in Black and White children with acute myeloid leukemia.

Pediatr Blood Cancer 2017 Dec 20;64(12). Epub 2017 Jul 20.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Black patients have a twofold increased risk of induction mortality compared to White patients with acute myeloid leukemia (AML). We reviewed diagnosis and billing data from Pediatric Health Information System for 28 AML Induction I deaths to investigate conditions preceding death in White and Black patients. Half of deaths occurred within 10 days of initial diagnostic admission. Respiratory, cardiac, renal, and infectious complications were common prior to both White and Black deaths. Deaths in White patients were more commonly preceded by intracranial hemorrhage compared to deaths in Black patients. Future studies should assess management approaches of complications by race to identify modifiable processes that reduce mortality.
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http://dx.doi.org/10.1002/pbc.26712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733774PMC
December 2017