Effect of Antibacterial Prophylaxis on Febrile Neutropenic Episodes and Bacterial Bloodstream Infections in Dutch Pediatric Patients with Acute Myeloid Leukemia:A Two-Center Retrospective Study

Bloodstream infections (BSIs), especially those caused by Gram-negative rods (GNR) and viridans group streptococci (VGS), are common and potentially life-threatening complications of pediatric acute myeloid leukemia (AML) treatment. Limited literature is available on prophylactic regimens. We retrospectively evaluated the effect of different antibacterial prophylaxis regimens on the incidence of febrile neutropenic (FN) episodes and bacterial BSIs. Medical records of children (0–18 years) diagnosed with de novo AML and treated at two Dutch centers from May 1998 to March 2021 were studied. Data were analyzed per chemotherapy course and consecutive neutropenic period. A total of 82 patients had 316 evaluable courses: 92 were given with single-agent ciprofloxacin, 138 with penicillin plus ciprofloxacin, and 51 with teicoplanin plus ciprofloxacin. The remaining 35 courses with various other prophylaxis regimens were not statistically compared. During courses with teicoplanin plus ciprofloxacin, significantly fewer FN episodes (43% vs. 90% and 75%; p < 0.0001) and bacterial BSIs (4% vs. 63% and 33%; p < 0.0001) occurred than with single-agent ciprofloxacin and penicillin plus ciprofloxacin, respectively. GNR and VGS BSIs did not occur with teicoplanin plus ciprofloxacin and no bacterial BSI-related pediatric intensive care unit (PICU) admissions were required, whereas, with single-agent ciprofloxacin and penicillin plus ciprofloxacin, GNR BSIs occurred in 8% and 1% (p = 0.004), VGS BSIs in 24% and 14% (p = 0.0005), and BSI-related PICU admissions were required in 8% and 2% of the courses (p = 0.029), respectively. Teicoplanin plus ciprofloxacin as antibacterial prophylaxis is associated with a lower incidence of FN episodes and bacterial BSIs. This may be a good prophylactic regimen for pediatric AML patients during treatment

Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P &lt; .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P &lt; .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.</p

Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia

NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98-NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).</p

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Increased survival disparities among children and adolescents & young adults with acute myeloid leukemia: A Dutch population-based study

For many cancers, adolescents and young adults (AYAs) have a poorer prognosis than pediatric patients. Our study evaluates survival outcomes of children (0-17 years) and AYAs (18-39 years) diagnosed with acute myeloid leukemia (AML) in the Netherlands between 1990 and 2015 (N = 2058) utilizing the population-based Netherlands Cancer Registry, which includes information on therapy and site of primary treatment. Five- and 10-year relative (disease-specific) survival were estimated for all patients, children and AYAs. Multivariable analyses were performed using generalized linear models (excess mortality) and logistic regression (early mortality). AYAs with AML had a substantially lower 5- and 10-year relative survival than children (5-year: 43% vs 58%; 10-year: 37% vs 51%). The gap in 5-year relative survival was largest (nearly 20 percent-points) in 2010 to 2015, despite survival improvements over time across all ages. The multivariable-adjusted excess risk of dying was 60% higher in AYAs (95% CI: 37%-86%). Early mortality (death within 30 days of diagnosis) declined over time, and did not differ between children and AYAs. In conclusion, AYAs diagnosed with AML in the Netherlands had a worse prognosis than pediatric patients. The survival gap seemed most pronounced in recent years, suggesting that improvements in care resulting in better outcome for children have not led to equal benefits for AYAs

Characteristics and treatment of acute myeloid neoplasms with cutaneous involvement in infants up to 6 months of age: A retrospective study.

BACKGROUND Myeloid neoplasms account for 50% of cases of pediatric leukemias in infants. Approximately 25%-50% of patients with newborn leukemia have cutaneous extramedullary disease (EMD). In less than 10% of patients, aleukemic leukemia cutis or isolated extramedullary disease with cutaneous involvement (cEMD) occurs when skin lesions appear prior to bone marrow involvement and systemic symptoms. Interestingly, in acute myeloid leukemia with cutaneous EMD (AML-cEMD) and cEMD, spontaneous remissions have been reported. METHOD This is a multicentric retrospective cohort study aiming to describe characteristics, treatment, and outcome of infants with either cEMD or presence of cutaneous disease with involvement of the bone marrow (AML-cEMD). This study included patients born between 1990 and 2018 from Italy, the Netherlands, Switzerland, and the United States, diagnosed between 0 and 6 months of life with cEMD or AML-cEMD. Descriptive statistics, Fisher's exact test, Kaplan-Meier method, and log rank test were applied. RESULTS The cohort consisted of n = 50 patients, including 42 AML-cEMD and eight cEMD patients. The most common genetic mutation found was a KMT2A rearrangement (n = 26, 52%). Overall 5-year event-free survival (EFS) and overall survival (OS) were 66% [confidence interval (CI): 51-78] and 75% [CI: 60-85], respectively. In two patients, complete spontaneous remission occurred without any therapy. Central nervous system (CNS) involvement was found in 25% of cEMD patients. No difference in outcomes was observed between the AML-cEMD and cEMD groups, but none of the latter patients included in the study died. KMT2A rearrangements were not associated with poorer prognosis. CONCLUSION In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population