Incidence of bacteremias and invasive mycoses during different phases of chemotherapy and immunotherapy treatment in high-risk neuroblastoma patients treated with SIOPEN/HR-NBL1 protocol

Background Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. It accounts for about 10% of all pediatric cancers and usually affects children within the first 10 years of life (90%). NB has a broad spectrum of clinical presentations at onset, from localized stage (L1-L2 stage) to metastatic stage (M stage), which mainly involves sites such as the bone marrow and skeleton. The majority of patients with high-risk NB (which constitute about 50% of total cases) are >18 months old at diagnosis with stage M disease and unfavorable biological characteristics, while the remaining 15-20% of high-risk patients are defined as such regardless of age and stage of disease, due to the presence of amplification of the MYCN oncogene. For these patients, the therapeutic approach consists of the following phases: 1) induction chemotherapy according to the RAPID COJEC regimen 2) surgery 3) high-dose myeloablative chemotherapy and autologous hematopoietic stem cell transplantation 4) differentiation therapy with cis-retinoic acid 5) maintenance therapy with anti-GD2 monoclonal antibody associated or not with cytokines such as IL-2. Infectious diseases, particularly of bacterial and fungal origin, represent an important cause of morbidity and mortality for patients undergoing antineoplastic therapy and their frequency is related with the intensity of chemotherapy. The genesis of the infectious risk is multifactorial (neutropenia, use of indwelling central venous catheters, high-dose myeloablative chemotherapy, oncological surgery), with an incidence that varies in relation to the treatment protocols. Data about infectious complications during treatment of HR-NB is limited and is often extrapolated from clinical trials conducted to evaluate the safety and efficacy of new treatment protocols. In previous studies, it was observed that children receiving aggressive treatment for NB had a high incidence of severe infectious complications. Furthermore, recent studies suggest that these patients could represent a new population at risk of invasive fungal infections. Aims of the study We performed a retrospective single-center study on bloodstream infections and invasive fungal diseases (identified as “severe infections”) in children treated for HR-NB at the IRCCS Giannina Gaslini (GCH) with the primary aim to evaluate their incidence in patients treated according to the SIOPEN/HR-NBL1 protocol, comparing the different phases of chemotherapy and immunotherapy. We also evaluated the safety profile of this protocol in terms of severe infections risk compared to acute lymphoblastic leukemia and non-lymphoblastic leukemia treatment protocols. Secondary aim was to evaluate the proportions of infectious episodes related to the presence of moderate to severe neutropenia (absolute neutrophil count < 1000 cells/microL) and of indwelling central venous catheters. Materials and methods The study sample consists of patients affected by HR-NB at the onset of the disease, treated according to the SIOPEN/HR-NBL1 protocol at the GCH between February 2002 and September 2021. The clinical, laboratory, biochemical and follow-up data regarding the patients were extrapolated from the Italian Neuroblastoma Registry (INBR), the data relating to each severe infectious episode were extrapolated from the database on bacteremias and invasive mycoses in haemato-oncology patients followed at our Institute, active since 1989. Infection rates (IRs) were used to quantify the burden of severe infections. IRs were calculated as the number of bacteremias and invasive mycoses per person – days at risk (PDR) and expressed as episodes per 100 PDR with 95% Confidence Intervals (95% CI). The percentage of neutropenia-related and CVC-related infections, diagnosed according to pre-established definitions, was assessed. Infection-attributable mortality was also evaluated. Results We confirm that bacteremias and invasive mycoses represent only a small percentage of febrile episodes in HR-NB, but we demonstrate that the frequency of infectious complications is not negligible with a total cumulative incidence of 59.8%, especially in induction (57.7% of severe infections) and consolidation phases (38.5% of severe infections). During the maintenance phase, however, the rate of infectious complications was low (3.8%) and mainly related to the presence of the CVC. In our study, a significant proportion (16.3%) of infectious episodes were not associated with major risk factors. As expected, neutropenia was confirmed to be an important risk factor for the development of infections (29.8%), while the proportion of CVC-related infections was higher than expected (53.9%), confirming the causal role of this device. The incidence rate of bacteremias (93.3%) was significantly higher than that of invasive mycoses (6.7%) probably due to the shorter duration of the neutropenic phases and the low frequency of severe mucositis, differently from what reported in the literature for patients with acute lymphoblastic leukemia and non-lymphoblastic leukemia.