Broadening mould-active strategies in paediatric haemato-oncology patients

Abstract

Invasive mould disease (IMD) is a life-threatening infection in immunocompromised and hospitalized pediatric patients, particularly in those with haematological malignancies. This research aimed to develop and/or optimize mould-active dosing strategies for preventing and treating IMD in paediatric cancer patients. In Chapter 2 the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with acute lymphoblastic leukaemia (ALL) are described from 2012-2018. Among 643 patients, the incidence rate of probable and proven IMD was 7.3% during early ALL treatment, with Aspergillosis diagnosed in 89.4% of cases. Our data suggests that patients with IMD were generally older than those not developing IMD. Serum galactomannan was the trigger for diagnostic workup in only 11% of the episodes, questioning its screening value. Persistent fever and respiratory symptoms were common at presentation, with the lungs involved in 94% of the patients and a remarkably high CNS involvement(34%). Half of the patients with CNS involvement were asymptomatic at the time of diagnosis. The combination of liposomal amphotericin B and voriconazole seems to be justified given the azole resistance frequency for Aspergillus isolates of 21%. The 6- and 12-week mortality rates after IMD diagnosis were 10.6% and 14.9%, respectively. These findings highlight the importance of effective prophylaxis and early brain imaging in children even in the absence of neurological symptoms. A review of the pharmacokinetic data of triazoles in paediatric patient populations is provided in Chapter 3. This review shows that fluconazole is extensively studied in the neonatal population and voriconazole in children and adolescents, while isavuconazole, itraconazole and posaconazole are studied to a limited extend. Fluconazole data in children and adolescents are understated, and there is an urgent need for pharmacokinetic studies of other triazoles in neonates and infants. Future studies should address the pharmacokinetics of newer triazoles the bioavailability of available formulations, foor interaction, administration over a nasogastric tube, the effect of CYP genotypes, other metabolic routes, unbound drug concentrations, the development and pharmacokinetics of new children-friendly formulations, the pharmacokinetics of triazoles in critically ill patients, and the impact of dialysis, ECMO, renal or hepatic impairment. Better understanding of the pharmacokinetics is necessary for optimal clinical care. The pharmacokinetics of isavuconazole in Dutch paediatric cancer patients is examined in Chapter 4, revealing a reduced isavuconazole bioavailability of 41% when administered via a nasogastric tube with opened capsules. The administration of the reconstituted injection formulation over a nasogastric tube, demonstrating bioequivalence compared to oral administration, in combination with TDM should be considered. This study reported a five-fold range in unbound isavuconazolefraction, advocating for using unbound concentrations for TDM and for defining target concentrations. In Chapter 5 the pharmacokinetics of a twice-a-week micafungin regimen in Dutch paediatric patients with ALL are explored. The pharmacokinetic data obtained from this large paediatric (n=61) cohort were combined with an adult (n=20) cohort and supported the pharmacokinetically equivalence to a daily regimen. The predicted exposures (AUC0-168) for varying dosing regimens exceeded the adult reference exposure, likely caused by a slower clearance in our cohort. The efficacy of thistwice-a-week micafungin regimen for Aspergillus prophylaxis in Dutch paediatric patients with ALL was studied in Chapter 6. A twice-a-week micafungin regimen during early ALL treatment significantly reduced proven and probable Aspergillus infections in the micafungin cohort (1.2%; n=169) compared to the historical cohort (5.8%; n=643). This regimen was generally well tolerated, suggesting it as a viable option for a patient-friendly Aspergillus prophylaxis regimen during early ALL treatment in high-incidence areas. This thesis provides an overview of invasive mould disease in paediatric patients with ALL, covering the epidemiology, the pharmacokinetics of new mould-active agents, and the efficacy of new prophylactic and treatment strategies.