Invasive Fungal Infections in Pediatric Acute Lymphoblastic Leukemia: Incidence, Characterization, Outcome and Risk Analysis of Study ALL-BFM 2000

With achievable survival rates of above 90%, non-leukemic events gather a high proportion of treatment failure causes with infections forming the majority. We analysed the incidence and outcome of reported invasive fungal infections as serious adverse events (SAE according to NIH criteria) in study ALL-BFM 2000 with the aim to characterize risk factors to optimize antifungal prophylaxis and treatment. A total of 4867 patients with ALL were enrolled from August 1999 to May 2010. Analysis of (mandatory) SAE reporting revealed 144 cases (3%). Fungal infections related to hematopoietic stem cell transplantation were excluded. According to the EORTC/MSG classification 65 (1.3%) were proven, 53 (1.1%) probable/possible and 26 (0.5%) not classifiable. There were 19 (0.4%) deaths and 41 (0.8%) events were classified as life threatening according to FDA definition. Positive mycological results were available in 98 cases: Aspergillus ssp. in 72, Candida ssp. in 21, Mucor in 3, Rhizopus and Fusarium in 1 case each. Fatality occurred in 16 cases with Aspergillus (22%) and in 1 each of the other species. Out of 41 life-threatening infections 30 were due to Aspergillus, 5 to Candida and 4 to the other species. Regarding all fungal infections, there was a significantly rising risk with increasing age (7.2% >15 y, 4.8% 10-<15 and 2.1% >1-< 10y; p<0.001), significance of age-dependent differences remained conserved for the life-threatening and fatal infections. Additionally, female gender appeared to impose a significant higher risk (all fungal infections, 2.4 vs. 3.7%, p=0.005). With respect to the treatment phase, the risk of fungal events was highest during induction, especially in the case of delayed treatment response, and during intensive block chemotherapy in the high-risk arm. This study on a very large population of children with ALL demonstrates that invasive fungal infections represent an important cause of morbidity and mortality in this cohort, giving support to reflect prophylactic measures for patients at high risk in the future.