Introduction: While it is well-recognised that invasive fungal infections (IFIs) are a major cause of morbidity and mortality in haematological malignancies, epidemiological data in paediatric acute lymphoblastic leukaemia/lymphoma (ALL) is scarce (Groll et al. Lancet Oncology 2014). The incidence of IFI in paediatric ALL is difficult to estimate as differing chemotherapy protocols, patient populations, diagnostic strategies and IFI definitions preclude direct comparisons. Assessment is also limited by major practice variations in the use of prophylactic and empiric systemic antifungals. Despite the lack of published data, there is a concern that IFIs impact on disease outcome and survival, either directly due to infection-related mortality or secondary to chemotherapy omissions, dose reductions and changes to subsequent therapy. To determine the incidence and outcome of IFIs in paediatric, adolescent and young adult patients treated with the UKALL2011 protocol, we conducted a retrospective study in two large London tertiary referral centres over a 4 year period.
Methods: All patients diagnosed and treated with ALL at Great Ormond Street Hospital (GOSH) and University College London Hospital (UCLH) between January 1st 2013 and January 1st 2017 were included in the study. Data on IFIs were collected during the following phases of the UKALL2011 protocol: Induction, consolidation, interim maintenance and delayed intensification. Medical records and online databases were used to collate the data. IFIs were classified as proven, probable and possible according to revised EORTC criteria (De Pauw et al. Clinical Infectious Diseases 2008).
Results: Between January 1st 2013 and January 1st 2017 296 patients (M=160, F=136) with a median age of 5 years (range 10 months -24 years) were treated for ALL (B-lineage n=249, T lineage n=43, NA n=4) at GOSH (n=233) and UCLH (n=63). Cytogenetic risk profile for B-ALL was classified as good (n=133), intermediate (n=86), poor (n=20) or NA (n=10) (Moorman AV et al. Lancet Oncology 2010).
A small cohort of young adult patients aged 20 to 24 years (n=16) received anti-fungal prophylaxis during induction and consolidation in the form of oral itraconazole when the neutrophil count was less than 1.5×109/L. This was substituted with liposomal amphotericin B when vinca alkaloids were scheduled. Routine anti-fungal prophylaxis was not implemented in the remaining cases (n=280)
Over a 4 year period the incidence of proven, probable and possible IFI was 2% (n=6), 1.6% (n=5) and 4% (n=12) respectively. Positive mycological results were available in 7 cases: Candida spp in 5, Aspergillus spp in 1 and Scedosporium spp in 1. Disseminated disease (including CNS disease n=2) occurred in 4 cases, all during induction (Table 1).
IFIs resulted in a treatment delay of a median of 3 weeks (range 1-15) in 16 cases. Omission of chemotherapy and significant dose reductions occurred in 2 and 4 cases respectively.
Follow-up data is available in 22 of the 23 patients diagnosed with a proven, probable or possible IFI during the UKALL2011 protocol (lost to follow-up n=1).With a median follow up of 16 months (range 4-39), 20 patients are alive and in ongoing remission. Three patients proceeded to haematopoietic stem cell transplant (HSCT). Two of these patients died of complications of HSCT. IFI recurrence (candida utilis bacteraemia) was a contributing factor in one case.
Conclusions: The incidence of IFIs is low in ALL patients treated with UKALL2011 protocol, with a low risk of mortality but the potential to compromise timely delivery of chemotherapy. The risk appears to be highest in induction. This data does not support the routine administration of prophylactic anti-fungal therapy in children and young people undergoing chemotherapy for ALL.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.
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