Invasive Fungal Infections in Pediatric Patients with High-Risk Acute Lymphoblastic Leukemia during Initial Phases of Therapy: A Retrospective Evaluation
Authors: Shliakhtsitsava Ksenya , Grapsy Jillian , Hsu Christina , Almatrafi Mohammad , Sebert Michael , Pacheco Martha , Huang Rong , Sue Paul 
Published: November 2020

BACKGROUND
Patients with newly diagnosed acute lymphoblastic leukemia (ALL) are at increased risk of infection. While previously published guidelines recommend primary antifungal prophylaxis in patients with T-cell ALL, we sought to determine the pattern of invasive fungal disease (IFI) at our center so as to assess risk factors for IFI, beyond the diagnosis of T-ALL, with the administration of dexamethasone and an anthracycline during induction. The current practice at Children's Health Children's Medical Center Dallas is to provide primary antifungal prophylaxis with micafungin during induction therapy for hospitalized patients with T-cell ALL and those with Down Syndrome. Additionally, we recently decided to provide primary antifungal prophylaxis to patients with HR B-ALL with hyperglycemia who remain hospitalized during induction. The primary objective of this study was to capture the institution-specific five-year incidence of IFI prior to the start of delayed intensification (DI) phase chemotherapy among pediatric patients with ALL. Secondary objectives were to identify potential IFI risk factors specifically amongst pediatric patients with HR ALL.
METHODS
This retrospective chart review included patients younger than 21 years with newly diagnosed ALL between July 1, 2014 and June 30, 2019. Patients with secondary leukemia, infantile leukemia, or those receiving treatment for a fungal infection at presentation were excluded. The primary outcome was the development of probable or proven IFI, as defined by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria, prior to the start of the DI phase of therapy. Statistical methods included Chi-square test, t-test, and Wilcoxon Rank Sum test, as appropriate to the variable's level of measurement and distribution. Time series analyses were used to assess overall and seasonal trends of IFI incidence over the study period.
RESULTS
Of 220 included patients, there were 13 cases of IFI diagnosed during the induction and consolidation phases of therapy during the five-year period. IFI occurred in 15.3% of the HR group (11/72), 5.9% of the T-cell ALL group (1/17), and 0.8% of the standard risk (SR) group (1/131). Among individuals with HR ALL, the majority of cases occurred in the absence of primary antifungal prophylaxis (90.9%). The most common sites of IFI included the lungs (n=6) and sinuses (n=4). Implicated fungal pathogens included Aspergillus, Candida, Curvularia, Exserohilum, and Bipolaris. Univariate analysis of the potential IFI risk factors in HR ALL patients did not identify any significant differences between those patients that did or did not develop IFI, with respect to pre-existing comorbidities, body mass index, laboratory results at diagnosis, or hospital exposures during induction including length of stay, intensive care admissions, and receipt of systemic antibiotics (Table). Race and ethnicity was significantly different likely due to the skewed distribution of IFI among patients who identified as Asian (p = 0.03; 8/8 identified as Asian and did not develop IFI). With respect to seasonality of ALL diagnosis, the percent of patients in each group (winter, spring, summer, and fall) that developed IFI were 7.4%, 18.2%, 20%, and 31.2%, respectively. However, time series analysis did not show an association between seasonality of diagnosis and development of IFI (p=0.89). During the induction phase of therapy, hyperglycemia, defined as blood glucose 140-200 mg/dL for ≥ 2 days or &gt;200 mg/dL for 1 day, was present in 100% of the HR patients that developed IFI and 74% of the HR patients that did not develop IFI (p=0.12).
CONCLUSION
In this pediatric population, patients with HR B-ALL developed more fungal infections during the early phases of therapy then those with SR disease (15.6% versus 0.8%). In analysis of potential risk factors, there were no significant differences between HR ALL groups that did or did not develop IFI. Larger-scale studies are needed in order to identify potential risk factors that will guide decisions on the routine use of primary antifungal prophylaxis in patients with HR ALL during induction therapy.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Micafungin use for primary antifungal prophylaxis during induction phase of therapy.