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.

2021

177.e1-177.e8

2021 Feb

2666-6367

<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>

10.1016/j.jtct.2020.10.012

Transplant Cell Ther

33718896

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

2021

e28940

2021 Mar 11

1545-5017

<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>

10.1002/pbc.28940

Pediatr Blood Cancer

33704911

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

2020

e28315

2020 May 11

1545-5017

<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>

10.1002/pbc.28315

Pediatr Blood Cancer

32391940

Pediatric acute myeloid leukemia: updates on biology, risk stratification, and therapy.

2019

2019 Dec 05

1531-698X

<p><strong>PURPOSE OF REVIEW: </strong>Despite advances in therapy over the past decades, overall survival for children with acute myeloid leukemia (AML) has not exceeded 70%. In this review, we highlight recent insights into risk stratification for patients with pediatric AML and discuss data driving current and developing therapeutic approaches.</p>

<p><strong>RECENT FINDINGS: </strong>Advances in cytogenetics and molecular profiling, as well as improvements in detection of minimal residual disease after induction therapy, have informed risk stratification, which now relies heavily on these elements. The treatment of childhood AML continues to be based primarily on intensive, conventional chemotherapy. However, recent trials focus on limiting treatment-related toxicity through the identification of low-risk subsets who can safely receive fewer cycles of chemotherapy, allocation of hematopoietic stem-cell transplant to only high-risk patients and optimization of infectious and cardioprotective supportive care.</p>

<p><strong>SUMMARY: </strong>Further incorporation of genomic and molecular data in pediatric AML will allow for additional refinements in risk stratification to enable the tailoring of treatment intensity. These data will also dictate the incorporation of molecularly targeted therapeutics into frontline treatment in the hope of improving survival while decreasing treatment-related toxicity.</p>

10.1097/MOP.0000000000000855

Curr. Opin. Pediatr.

31815781

Tisagenlecleucel for the treatment of B cell acute lymphoblastic leukemia.

2018

2018 Aug 15

1744-8328

<p><strong>INTRODUCTION: </strong>Cure rates for pediatric and young adult patients with refractory or recurrently relapsed acute lymphoblastic leukemia are dismal. Survival from time of relapse is typically measured in weeks to months, and standard chemotherapy and currently approved targeted therapy achieve remission in less than a third of affected patients. To date, the only definitive curative therapy has been allogeneic hematopoietic stem cell transplant (HSCT). Advances in immunotherapy, with the introduction of chimeric antigen receptor T cell therapies and the development of tisagenlecleucel, have changed the landscape. Areas covered: This review will describe the pharmacology of tisagenlecleucel and summarize the clinical evidence for its use in the treatment of multiple-relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Also discussed are other immunotherapies for B-ALL as well as the most commonly-encountered toxicities and corresponding management strategies. Expert commentary: Early phase trials indicate that tisagenlecleucel significantly improves survival for patients with B-ALL that is refractory or in second or later relapse. In responding patients, remissions have been reported on the order of years, and thus, tisagenlecleucel may herald a dramatic shift in the treatment paradigm of this largely fatal disease.</p>

10.1080/14737140.2018.1512411

Expert Rev Anticancer Ther

30111196

Successful treatment of pulmonary mucormycosis in two pediatric hematopoietic stem cell transplant patients.

2018

e13270

2018 Nov

1399-3046

<p>Pulmonary mucormycosis diagnosed immediately after hematopoietic stem cell transplantation frequently portends a poor prognosis. However, here we describe two cases in children that were treated successfully to highlight the efficacy of a multidisciplinary approach. Despite diagnosis in the immediate post-transplant period and requirement for ongoing immunosuppression to prevent or treat GVHD, both are long-term survivors due to early surgical debridement with transfusion support and prompt initiation of targeted antifungal therapy. In the absence of evidence-based treatment guidelines, survival of pulmonary mucormycosis is achievable even in high-risk patients with a multidisciplinary team to guide management.</p>

10.1111/petr.13270

Pediatr Transplant

30014584

Hospital-Level Variability in Broad-Spectrum Antibiotic Use for Children With Acute Leukemia Undergoing Hematopoietic Cell Transplantation.

2018

1-9

2018 May 08

1559-6834

<p>OBJECTIVETo explore the prevalence and drivers of hospital-level variability in antibiotic utilization among hematopoietic cell transplant (HCT) recipients to inform antimicrobial stewardship initiatives.DESIGNRetrospective cohort study using data merged from the Pediatric Health Information System and the Center for International Blood and Marrow Transplant Research.SETTINGThe study included 27 transplant centers in freestanding children's hospitals.METHODSThe primary outcome was days of broad-spectrum antibiotic use in the interval from day of HCT through neutrophil engraftment. Hospital antibiotic utilization rates were reported as days of therapy (DOTs) per 1,000 neutropenic days. Negative binomial regression was used to estimate hospital utilization rates, adjusting for patient covariates including demographics, transplant characteristics, and severity of illness. To better quantify the magnitude of hospital variation and to explore hospital-level drivers in addition to patient-level drivers of variation, mixed-effects negative binomial models were also constructed.RESULTSAdjusted hospital rates of antipseudomonal antibiotic use varied from 436 to 1121 DOTs per 1,000 neutropenic days, and rates of broad-spectrum, gram-positive antibiotic use varied from 153 to 728 DOTs per 1,000 neutropenic days. We detected variability by hospital in choice of antipseudomonal agent (ie, cephalosporins, penicillins, and carbapenems), but gram-positive coverage was primarily driven by vancomycin use. Considerable center-level variability remained even after controlling for additional hospital-level factors. Antibiotic use was not strongly associated with days of significant illness or mortality.CONCLUSIONAmong a homogenous population of children undergoing HCT for acute leukemia, both the quantity and spectrum of antibiotic exposure in the immediate posttransplant period varied widely. Antimicrobial stewardship initiatives can apply these data to optimize the use of antibiotics in transplant patients.Infect Control Hosp Epidemiol 2018;1-9.</p>

10.1017/ice.2018.96

Infect Control Hosp Epidemiol

29734957