Efficacy and toxicity of high-risk therapy of the Dutch Childhood Oncology Group in childhood acute lymphoblastic leukemia.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) and high-risk (HR) features have a poor outcome and are treated with HR blocks, often followed by allogenic stem cell transplantation (SCT). PROCEDURE: This article analyses the outcomes of children treated with HR blocks between 2004 and 2017 according to DCOG ALL10/11 protocols. 1297 patients with newly diagnosed ALL were consecutively enrolled, of which 107 met the HR criteria (no complete remission; minimal residual disease (MRD) > 10-3 after consolidation; "MLL-AF4" translocation and in ALL-10 also poor prednisone response). Patients were treated with one induction and consolidation course followed by three HR chemotherapy blocks, after which they received either SCT or further chemotherapy. MRD levels were measured at end of induction, consolidation, and after each HR block. RESULTS: At five years, the event-free survival was 72.8% (95% CI, 64.6-82.0), and the cumulative incidence of relapse was 13.0% (95% CI, 6.3-19.8). Patients with only negative or low-positive MRD levels during HR blocks had a significantly lower five-year cumulative incidence of relapse (CIR) of 2.2% (95% CI, 0-6.6) compared with patients with one or more high-positive MRD levels (CIR 15.4%; 95% CI, 3.9-26.9). During the entire treatment protocol, 11.2% of patients died due to toxicity. CONCLUSIONS: The high survival with HR blocks seems favorable compared with other studies. However, the limit of treatment intensification might have been reached as the number of patients dying from leukemia relapse is about equal as the number of patients dying from toxicity. Patients with negative or low MRD levels during HR blocks have lower relapse rates.

Central Venous Catheter-related Bloodstream Infections Caused by Enterobacterales in Pediatric Oncology Patients: Catheter Salvage or Removal.

BACKGROUND: The aim was to determine whether salvage treatment with systemic antibiotics is a safe and effective strategy for Enterobacterales bloodstream infections (BSI) in pediatric oncology patients with a central venous catheter (CVC). METHODS: A retrospective study was performed on oncology and stem cell recipient patients with a CVC and blood culture with Enterobacterales , at the Princess Máxima Centre for Pediatric Oncology, Utrecht, the Netherlands. Analyses were performed for all BSI and for episodes meeting central line-associated bloodstream infection (CLABSI) criteria. The cumulative incidence of an event (ie, removal, intensive care admission or death) was estimated after blood culture collection for episodes primarily treated with antibiotics. The effect of prognostic factors on the hazard of the event of interest was assessed by estimating a Cox proportional hazard regression model. RESULTS: In total, 95 CVC-related Enterobacterales BSIs in 82 patients were included; 12 (13%) BSIs required immediate CVC removal and for 83 (87%) BSIs CVC salvage was attempted. The cumulative incidence of events at 60 days was 53.0% [95% confidence interval (CI): 41.7-63.1] for BSIs (n = 83), and 64.4% (95% CI: 48.3-76.7) for CLABSIs (n = 45). The events occurred after a median of 6 (Q1-Q3: 2-15) and 6 (Q1-Q3: 2-20) days for BSIs and CLABSIs, respectively. Intensive care admission after salvage treatment was required in 16% of the BSIs and CLABSIs, resulting in death in 5% and 2% of cases, respectively. No significant association between risk factors and events was found. CONCLUSIONS: The cumulative incidence of an event at 60 days after salvage treatment for Enterobacterales CLABSIs and BSIs in pediatric oncology patients is high. Immediate CVC removal appears recommendable for this patient group.

Prognostic factors for multi-organ dysfunction in pediatric oncology patients admitted to the pediatric intensive care unit.

Background: Pediatric oncology patients who require admission to the pediatric intensive care unit (PICU) have worse outcomes compared to their non-cancer peers. Although multi-organ dysfunction (MOD) plays a pivotal role in PICU mortality and morbidity, risk factors for MOD have not yet been identified. We aimed to identify risk factors at PICU admission for new or progressive MOD (NPMOD) during the first week of PICU stay. Methods: This retrospective cohort study included all pediatric oncology patients aged 0 to 18 years admitted to the PICU between June 2018 and June 2021. We used the recently published PODIUM criteria for defining multi-organ dysfunction and estimated the association between covariates at PICU baseline and the outcome NPMOD using a multivariable logistic regression model, with PICU admission as unit of study. To study the predictive performance, the model was internally validated by using bootstrap. Results: A total of 761 PICU admissions of 571 patients were included. NPMOD was present in 154 PICU admissions (20%). Patients with NPMOD had a high mortality compared to patients without NPMOD, 14% and 1.0% respectively. Hemato-oncological diagnosis, number of failing organs and unplanned admission were independent risk factors for NPMOD. The prognostic model had an overall good discrimination and calibration. Conclusion: The risk factors at PICU admission for NPMOD may help to identify patients who may benefit from closer monitoring and early interventions. When applying the PODIUM criteria, we found some opportunities for fine-tuning these criteria for pediatric oncology patients, that need to be validated in future studies.

The results of concentration of care: Surgical outcomes of neuroblastoma in the Netherlands.

INTRODUCTION: In the Netherlands pediatric oncological care for solid tumours is concentrated in one centre since November 2014. One of the most frequently diagnosed solid non-brain tumours in children is the neuroblastoma. Results of surgical treatment of neuroblastoma since the start of this centralization are presented and compared to a historic cohort. METHODS: The new national cohort of neuroblastoma (n = 111) consists of all consecutive patients treated between January 1st, 2015 and April 1st, 2021. The historic neuroblastoma cohort consists of all operated neuroblastoma patients in the Netherlands between 1998 and 2014 (n = 244). Intra-operative complications and surgical outcome were registered. Post-operative complications were divided in short (<30 days after surgery) and long term (>30 days). The severity of complications was graded using the Clavien Dindo Classification (CDC) system. RESULTS: Intraoperative outcomes showed significant differences in favour of the new cohort with less blood loss (p < 0.001), fewer vascular complications (p < 0.001) and shorter duration of surgery (p < 0.001). Short term complications were comparable in numbers, but significantly more patients had CDC grade 3/4/5 complications in the historic cohort (p = 0.005). Long term complications did not differ. Estimated overall survival showed a better survival in the new cohort (log rank 0.022). CONCLUSION: Centralization of care for neuroblastoma patients has led to a significant improvement of both intraoperative outcomes and short term complications.

Risk factors associated with tinnitus in 2948 Dutch survivors of childhood cancer: a Dutch LATER questionnaire study.

BACKGROUND: Tinnitus is a serious late effect of childhood cancer treatment. The aim of this study was to determine the occurrence and risk factors for tinnitus in a national cohort of childhood cancer survivors (CCS). METHODS: Data were collected within the national Dutch Childhood Oncology Group - Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort by a self-reported health questionnaire among 5327 Dutch CCS treated between 1963 and 2002. Siblings (N = 1663) were invited to complete the same questionnaire. Relevant patient characteristics and treatment factors were obtained from the Dutch LATER database. The occurrence of tinnitus in survivors was compared to siblings. To study the effect of risk factors, multivariate logistic regression models were estimated. RESULTS: In total, 2948 CCS and 1055 siblings completed the tinnitus item. Tinnitus was reported in 9.5% of survivors and in 3.7% of siblings (odds ratio [OR] 3.0, 95% confidence interval [CI] 2.9-3.1). Risk factors associated with tinnitus in CCS were total cumulative dose cisplatin ≥400 mg/m2 (OR 2.4, 95% CI 1.4-4.0), age at diagnosis (≥10 years: OR 2.1, 95% CI 1.6-2.8), cranial irradiation/total body irradiation (TBI; OR 1.9, 95% CI 1.5-2.5), and neuro/ear, nose, throat (ENT) surgery (OR 1.8, 95% CI 1.1-2.9). Fifty-one percent of CCS with tinnitus had received treatment with either cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery. CONCLUSIONS: Tinnitus in CCS was present nearly 3 times more often than in siblings. Awareness in CCS previously treated with cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery is warranted. As only half of affected CCS had a history of these treatments, it seems that other factors might be associated with tinnitus occurrence in this population.