First name
Michael
Last name
Nieder

Title

Prospective Evaluation of Galactomannan and (1→3) β-d-Glucan Assays as Diagnostic Tools for Invasive Fungal Disease in Children, Adolescents, and Young Adults With Acute Myeloid Leukemia Receiving Fungal Prophylaxis.

Year of Publication

2021

Date Published

2021 Jun 26

ISSN Number

2048-7207

Abstract

BACKGROUND: Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell β-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis.

METHODS: Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC).

RESULTS: Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1-43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%.

CONCLUSIONS: The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

DOI

10.1093/jpids/piab036

Alternate Title

J Pediatric Infect Dis Soc

PMID

34173659

Title

Effect of Caspofungin vs Fluconazole Prophylaxis on Invasive Fungal Disease Among Children and Young Adults With Acute Myeloid Leukemia: A Randomized Clinical Trial.

Year of Publication

2019

Number of Pages

1673-1681

Date Published

2019 11 05

ISSN Number

1538-3598

Abstract

<p><strong>Importance: </strong>Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds.</p>

<p><strong>Objective: </strong>To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy.</p>

<p><strong>Design, Setting, and Participants: </strong>This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018).</p>

<p><strong>Interventions: </strong>Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle.</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival.</p>

<p><strong>Results: </strong>The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole).</p>

<p><strong>Conclusions and Relevance: </strong>Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility.</p>

<p><strong>Trial Registration: </strong>ClinicalTrials.gov Identifier: NCT01307579.</p>

DOI

10.1001/jama.2019.15702

Alternate Title

JAMA

PMID

31688884

Title

Antifungal prophylaxis in pediatric hematology/oncology: new choices & new data.

Year of Publication

2012

Number of Pages

21-6

Date Published

2012 Jul 15

ISSN Number

1545-5017

Abstract

<p>A severe complication of the treatment of pediatric cancers is the development of an invasive fungal infection (IFI). The data to support antifungal prophylaxis in pediatric oncology patients derive primarily from adult patients, and thus the optimal agent to utilize is not clear. Fluconazole has been a standard option, but agents with antimold activity are now available, each with limitations. Pediatric dosing for voriconazole and posaconazole is uncertain and multiple drug interactions exist. The echinocandins are well-tolerated, but only available in intravenous form. Ultimately, studies demonstrating biologic risk factors for the development of IFI may lead to personalized prophylactic strategies.</p>

DOI

10.1002/pbc.23415

Alternate Title

Pediatr Blood Cancer

PMID

22102607

Title

Prevention of bacterial infection in pediatric oncology: what do we know, what can we learn?

Year of Publication

2012

Number of Pages

16-20

Date Published

2012 Jul 15

ISSN Number

1545-5017

Abstract

<p>Bacterial sepsis continues to be a leading cause of morbidity and toxic death in children receiving intensive therapy for cancer. Empiric therapy for suspected infections and treatment of documented infections are well-established standards of care. The routine use of prophylactic strategies is much less common in pediatric oncology. This paper will review the current literature on the use and risks of antimicrobial prophylaxis as well as non-pharmacological methods for infection prevention and will address areas in need of further research.</p>

DOI

10.1002/pbc.23416

Alternate Title

Pediatr Blood Cancer

PMID

22102612

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