First name
Caitlin
Middle name
W
Last name
Elgarten

Title

Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update.

Year of Publication

2023

Number of Pages

JCO2202224

Date Published

01/2023

ISSN Number

1527-7755

Abstract

PURPOSE: To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients.

METHODS: The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered.

RESULTS: We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients.

CONCLUSION: The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.

DOI

10.1200/JCO.22.02224

Alternate Title

J Clin Oncol

PMID

36689694

Title

Absolute lymphocyte count recovery following initial acute myelogenous leukemia therapy: Implications for adoptive cell therapy.

Year of Publication

2022

Number of Pages

e30062

Date Published

11/2022

ISSN Number

1545-5017

Abstract

BACKGROUND: An adequate absolute lymphocyte count (ALC) is an essential first step in autologous chimeric antigen receptor (CAR) T-cell manufacturing. For patients with acute myelogenous leukemia (AML), the intensity of chemotherapy received may affect adequate ALC recovery required for CAR T-cell production. We sought to analyze ALC following each course of upfront therapy as one metric for CAR T-cell manufacturing feasibility in children and young adults with AML.

PROCEDURE: ALC data were collected from an observational study of patients with newly diagnosed AML between the ages of 1 month and 21 years who received treatment between the years of 2006 and 2018 at one of three hospitals in the Leukemia Electronic Abstraction of Records Network (LEARN) consortium.

RESULTS: Among 193 patients with sufficient ALC data for analysis, the median ALC following induction 1 was 1715 cells/μl (interquartile range: 1166-2388), with successive decreases in ALC with each subsequent course. Similarly, the proportion of patients achieving an ALC >400 cells/μl decreased following each course, ranging from 98.4% (190/193) after course 1 to 66.7% (22/33) for patients who received a fifth course of therapy.

CONCLUSIONS: There is a successive decline of ALC recovery with subsequent courses of chemotherapy. Despite this decline, ALC values are likely sufficient to consider apheresis prior to the initiation of each course of upfront therapy for the majority of newly diagnosed pediatric AML patients, thereby providing a window of opportunity for T-cell collection for those patients identified at high risk of relapse or with refractory disease.

DOI

10.1002/pbc.30062

Alternate Title

Pediatr Blood Cancer

PMID

36370087

Title

Unrelated donor α/β T cell- and B cell-depleted HSCT for the treatment of pediatric acute leukemia.

Year of Publication

2022

Number of Pages

1175-1185

Date Published

2022 Feb 22

ISSN Number

2473-9537

Abstract

Unrelated donor (URD) hematopoietic stem cell transplant (HSCT) is associated with an increased risk of severe graft-versus-host disease (GVHD). TCRαβ/CD19 depletion may reduce this risk, whereas maintaining graft-versus-leukemia. Outcome data with TCRαβ/CD19 depletion generally describe haploidentical donors, with relatively few URDs. We hypothesized that TCRαβ/CD19-depletion would attenuate the risks of GVHD and relapse for URD HSCT. Sixty pediatric and young adult (YA) patients with hematologic malignancies who lacked a matched-related donor were enrolled at 2 large pediatric transplantation centers between October 2014 and September 2019. All patients with acute leukemia had minimal residual disease testing, and DP typing was available for 77%. All patients received myeloablative total body irradiation- or busulfan-based conditioning with no posttransplant immune suppression. Engraftment occurred in 98%. Four-year overall survival was 69% (95% confidence interval [CI], 52%-81%), and leukemia-free survival was 64% (95% CI, 48%-76%), with no difference between lymphoid and myeloid malignancies (P = .6297 and P = .5441, respectively). One patient (1.7%) experienced primary graft failure. Relapse occurred in 11 patients (3-year cumulative incidence, 21%; 95% CI, 11-34), and 8 patients (cumulative incidence, 15%; 95% CI, 6.7-26) experienced nonrelapse mortality. Grade III to IV acute GVHD was seen in 8 patients (13%), and 14 patients (26%) developed chronic GVHD, of which 6 (11%) had extensive disease. Nonpermissive DP mismatch was associated with higher likelihood of acute GVHD (odds ratio, 16.50; 95% CI, 1.67-163.42; P = .0166) but not with the development of chronic GVHD. URD TCRαβ/CD19-depleted peripheral HSCT is a safe and effective approach to transplantation for children/YAs with leukemia. This trial was registered at www.clinicaltrials.gov as #NCT02323867.

DOI

10.1182/bloodadvances.2021005492

Alternate Title

Blood Adv

PMID

34872106

Title

Risk of bacterial bloodstream infection does not vary by central-line type during neutropenic periods in pediatric acute myeloid leukemia.

Year of Publication

2022

Number of Pages

1-8

Date Published

2022 Apr 25

ISSN Number

1559-6834

Abstract

<p><strong>BACKGROUND: </strong>Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy.</p>

<p><strong>OBJECTIVE: </strong>To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML.</p>

<p><strong>METHODS: </strong>We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics.</p>

<p><strong>RESULTS: </strong>The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75-1.32) and TIC IRR = 0.83 (95% CI, 0.49-1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar.</p>

<p><strong>CONCLUSIONS: </strong>In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.</p>

DOI

10.1017/ice.2022.82

Alternate Title

Infect Control Hosp Epidemiol

PMID

35465865

Title

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

Year of Publication

2021

Number of Pages

e29384

Date Published

2021 Oct 28

ISSN Number

1545-5017

Abstract

<p><strong>BACKGROUND: </strong>The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed.</p>

<p><strong>METHODS: </strong>We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.</p>

<p><strong>RESULTS: </strong>We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4&nbsp;days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.</p>

<p><strong>DISCUSSION: </strong>Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.</p>

DOI

10.1002/pbc.29384

Alternate Title

Pediatr Blood Cancer

PMID

34709713

Title

Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Year of Publication

2021

Number of Pages

e29281

Date Published

2021 Oct 01

ISSN Number

1545-5017

Abstract

<p><strong>BACKGROUND: </strong>High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.</p>

<p><strong>METHODS: </strong>Patients on AAML0531 received cytarabine (1600&nbsp;mg/m )/daunorubicin (150&nbsp;mg/m )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48&nbsp;mg/m )/cytarabine (8000&nbsp;mg/m ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.</p>

<p><strong>RESULTS: </strong>MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p&nbsp;=&nbsp;.87; measurable residual disease [MRD]+: 57% vs. 46%, p&nbsp;=&nbsp;.34); or intensification I response (CR: 79% vs. 94%, p&nbsp;=&nbsp;.27; MRD+: 27% vs. 20%, p&nbsp;=&nbsp;1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p&nbsp;=&nbsp;.63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p&nbsp;=&nbsp;.66). MA was associated with slower neutrophil recovery (median 34 vs. 27&nbsp;days, p&nbsp;=&nbsp;.007) and platelet recovery (median 29 vs. 24.5&nbsp;days, p&nbsp;=&nbsp;.04) and longer hospital stay (32 vs. 28&nbsp;days, p&nbsp;=&nbsp;.01) during induction II.</p>

<p><strong>CONCLUSION: </strong>Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).</p>

DOI

10.1002/pbc.29281

Alternate Title

Pediatr Blood Cancer

PMID

34596937

Title

Incidence of CMV Infection and Disease and Adverse Events Associated with Antiviral Therapy in a Retrospective Cohort of Allogeneic Hematopoietic Cell Transplant Recipients at an Academic Children's Hospital.

Year of Publication

2021

Date Published

2021 Jul 02

ISSN Number

2048-7207

Abstract

<p><strong>BACKGROUND: </strong>Cytomegalovirus (CMV) is a significant source of morbidity and mortality among transplant recipients; the epidemiology is less understood in pediatric hematopoietic cell transplantation (HCT) cohorts. Furthermore, there is a paucity of data related to CMV prophylactic and preemptive strategies.</p>

<p><strong>METHODS: </strong>A single-center retrospective observational cohort of allogeneic HCT recipients at the Children's Hospital of Philadelphia January 1, 2004-December 31, 2017 was constructed. Subjects were followed for 180 days after transplant to determine whether they had CMV infection or disease. Data on antiviral therapy were collected as were outcomes of CMV disease and adverse events (AEs) related to the antiviral therapy.</p>

<p><strong>RESULTS: </strong>Between January 2004 and March 2017, 345 allogeneic HCTs in 333 patients undergoing CMV surveillance testing were identified. CMV DNAemia was detected during the 180-day follow-up in 89 (25.8%) HCTs. CMV recipient-positive transplants were most likely to have CMV infection (47%). Infection rates were high for those receiving a CMV-specific prophylaxis regimen (50%). CMV DNAemia progressed to CMV disease 11.2% of the time. Of 224 subjects receiving CMV-specific prophylaxis, 19.2% experienced ≥1 AE. Of 53 receiving preemptive therapy during any CMV DNAemia episode, 32.1% experienced ≥1 AE.</p>

<p><strong>CONCLUSIONS: </strong>CMV infection is common in pediatric allogeneic HCT recipients. The CMV-specific prophylaxis regimen employed in this cohort did not effectively prevent DNAemia, progression to CMV disease was uncommon, and AEs from prophylaxis and preemptive therapy were frequent. Novel approaches that reduce the impact of CMV on pediatric allogeneic HCT recipients are needed.</p>

DOI

10.1093/jpids/piab041

Alternate Title

J Pediatric Infect Dis Soc

PMID

34213545

Title

Broad spectrum antibiotics and risk of graft-versus-host disease in pediatric patients transplanted for acute leukemia: association of carbapenem use with risk of acute GVHD.

Year of Publication

2021

Number of Pages

177.e1-177.e8

Date Published

2021 Feb

ISSN Number

2666-6367

Abstract

<p>Variation in the gastrointestinal microbiota after hematopoietic cell transplantation has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD-risk in pediatric patients transplanted for acute leukemia. We performed a retrospective analysis in a dataset merged from two sources: (1) Center for International Blood and Marrow Transplant Research, an observational transplant registry, and (2) Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to three classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) anti-pseudomonal penicillins and (3) carbapenems. The primary outcome was grade 2-4 aGVHD; secondary outcomes were grade 3-4 aGVHD and lower gastrointestinal (GI) GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (sub-cohort) included transplant characteristics, GVHD-risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2,550 patients at 36 centers; the sub-cohort included 1,174 patients. In adjusted models, carbapenems were associated with an increased risk of grade 2-4 aGVHD in the full cohort (aOR 1.24, 95%CI 1.02-1.51) and sub-cohort (subHR 1.31, 95%CI 0.99-1.72), as well as with an increased risk of grade 3-4 aGVHD (subHR 1.77, 95%CI 1.25-2.52). Early carbapenem exposure (prior to day 0) especially impacted aGVHD-risk. For antipseudomonal penicillins the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad spectrum antibiotics, should be used judiciously in pediatric transplant patients to minimize aGVHD-risk. Further research is needed to clarify the mechanism underlying this association.</p>

DOI

10.1016/j.jtct.2020.10.012

Alternate Title

Transplant Cell Ther

PMID

33718896

Title

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

Year of Publication

2021

Number of Pages

e28940

Date Published

2021 Mar 11

ISSN Number

1545-5017

Abstract

<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>METHODS: </strong>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&nbsp;years at diagnosis.</p>

<p><strong>RESULTS: </strong>Analyses included 10&nbsp;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&nbsp;=&nbsp;10.8, 95% CI: 7.4, 15.7) and AML (6% vs. 3%; PR&nbsp;=&nbsp;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&nbsp;=&nbsp;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&nbsp;=&nbsp;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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

DOI

10.1002/pbc.28940

Alternate Title

Pediatr Blood Cancer

PMID

33704911

Title

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

Year of Publication

2020

Number of Pages

e28315

Date Published

2020 May 11

ISSN Number

1545-5017

Abstract

<p><strong>INTRODUCTION: </strong>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.</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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&nbsp;&gt;&nbsp;90% at both hospitals. Five-year relapse incidence in the 10&nbsp;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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

DOI

10.1002/pbc.28315

Alternate Title

Pediatr Blood Cancer

PMID

32391940

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