The incidence of invasive fungal infections in children, adolescents and young adults with acute lymphoblastic leukaemia/lymphoma treated with the UKALL2011 protocol: a multicentre retrospective study

Invasive fungal infections (IFIs) pose a significant risk to patients with haematological malignancies (Pagano et al, 2006). However epidemiological data in paediatric acute lymphoblastic leukaemia (ALL) is scarce (Groll et al, 2014). Differences in the biology of ALL, pre-existing and treatment-associated co-morbidities, sensitivity and specificity of diagnostics and dosing and pharmacokinetics of anti-fungal (AF) agents preclude direct comparison with adult cohorts. The reported incidence of IFI in paediatric ALL is hugely variable, ranging from 0 01% to 22% (Afzal et al, 2009; Hale et al, 2010; Das et al, 2018), interpretation limited by differing chemotherapy protocols, patient populations and diagnostic strategies. In particular, there is uncertainty on the value of prophylactic AF agents in this cohort and many institutions opt to devise their own clinical guidelines. With this in mind, we conducted a retrospective study in two London centres to explore the incidence and outcome of IFI in children and young people undergoing contemporary ALL therapy and to identify risk factors associated with IFI. Patients with ALL treated on the UKALL2011 protocol, a phase 3 randomised controlled trial, at Great Ormond Street Hospital (GOSH) and University College London Hospital (UCLH) between 1 January 2013 and 1 January 2017 were included. In induction, patients were randomised to receive either a short course of dexamethasone (10 mg/m/day) for 14 days or a standard course of 6 mg/m/day for 28 days. In the second randomisation, patients received either high dose methotrexate or standard interim maintenance (IM). Medical records and online databases were used to collate data during induction, consolidation, IM and delayed intensification. IFIs were classified as proven, probable and possible according to revised European Organization for Research and Treatment of Cancer (EORTC) criteria (De Pauw et al, 2008). Risk factors for IFI were analysed using logistic regression (Stata version 15.1; StataCorp, College Station, TX). Over the 4-year period, 290 patients [male = 159 (55%), female = 131 (45%)] with a median age of 5 years (range 1–24 years), were treated for ALL [B-lineage n = 247 (85%), T-lineage n = 43 (15%)] at GOSH (n = 227) and UCLH (n = 63). Young adults aged 20–24 years (n = 15, 5%) who received AF prophylaxis were excluded from our analysis. Routine AF prophylaxis was not otherwise implemented (n = 275). Median follow-up was 17 months (range 3–41). In total, 22 (8 0%) patients experienced IFI, giving an incidence of proven, probable and possible infection of 7 (2 5%), 4 (1 5%) and 11 (4%) respectively. Of the seven with proven IFI, one had a positive blood culture only, a candida subspecies. The remaining 6 patients had disseminated disease, all candida subspecies with the exception of one case of Scedoporium apiospermum. Four patients had probable IFI; in three of these, the mycological criterion was a positive serum beta D glucan. In the 4th case, aspergillus niger was identified in the sputum. Eleven patients had possible IFI, all with involvement of the lower respiratory tract (one case of suspected dissemination). Positive mycological findings and the breakdown of IFI by site and treatment phase (induction 50%, consolidation 45%, IM 5%) is demonstrated in Table I.