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Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1 , EBF1 , PAX5 , CDKN2A/B , RB1 , BTG1 , ETV6 , and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1 -deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1 -deleted primary BCR-ABL1 -like and non- BCR-ABL1 -like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1 plus and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or L-asparaginase and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1 -like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses.

Venous thromboembolism (VTE) is relatively common in children with acute lymphoblastic leukemia (ALL). Thrombotic risk factors in ALL are asparaginase and steroids. However, within the ALL populations treated on the same regimen, it is less clear which other risk factors play a role. Furthermore, few data are available on the effect of VTE on ALL outcomes. In 778 children (1‐18 years) with newly diagnosed precursor‐B‐lineage or T‐lineage ALL, treated in the Dutch Childhood Oncology Group (DCOG) ALL‐10 protocol in the Netherlands (October 2004 to April 2013), we conducted a nested case control study with 59 VTE cases and 118 controls to identify risk factors for VTE. Fifty‐nine of 778 ALL patients developed VTE (7.6%), with cerebral venous sinus thrombosis (CVST) in 26 of 59 patients (44.1%). VTE occurred during induction treatment in 59.3% (n = 35) and in 40.7% (n = 24) during medium risk intensification. Conditional multivariable logistic regression analysis showed that age and ALL subtype were significantly associated with VTE (age ≥7 years: OR 2.72, 95% CI 1.33‐5.57; ALL subtype T‐ALL: OR 2.95, 95% CI 1.02‐8.57). A multivariable Cox model showed no association between the occurrence of VTE and event free survival. In CVST patients, permanent disability was present in 34.6%. Within this large pediatric ALL cohort, we demonstrated a high morbidity in CVST patients. Age ≥7 years at diagnosis and T‐ALL subtype were the main risk factors for VTE, and should be considered in preventive strategies.

We assessed the epidemiologic progress against childhood and adolescent acute lymphoblastic leukaemia (ALL) in the Netherlands over a 26 year period. ALL patients <18 years were selected from the Netherlands Cancer Registry and the Dutch Childhood Oncology Group. Trend analyses were performed over time and by age group and ALL subtype. Between 1990 and 2015, 2997 ALL patients were diagnosed, i.e. 115 patients (range 87–147) per year. Overall incidence remained stable at 37 per million children, despite increases for B-cell precursor ALL (BCP-ALL) at age 10–14 years (AAPC + 1.4%, p  = 0.04) and T-cell ALL at 15–17 years (AAPC + 3.7%, p  = 0.01). Five-year survival increased from 80% in 1990–94 to 91% in 2010–15 ( p  < 0.01). Mortality decreased by 4% annually ( p  < 0.01). Patients 15–17 years were increasingly treated in a paediatric oncology centre, from 35% in 1990–94 to 87% in 2010–15 and experienced a 70% reduction of risk of death compared to those treated outside such a centre ( p  < 0.01). Significant progress against childhood ALL has been made in the Netherlands, visible by improved survival rates coinciding with declining mortality rates. These outcomes were accompanied by stable incidence rates, despite increases for BCP-ALL at age 10–14 years and T-cell ALL at age 15–17 years.

Measurable residual disease (MRD) is regularly tested at later timepoints after the end of first consolidation (EOC) in children with acute lymphoblastic leukemia (ALL). The question remains whether this is useful for detecting (molecular) relapse. We investigated the clinical relevance of MRD after EOC in intermediate risk patients treated on DCOG-ALL-10 ( n  = 271) and DCOG-ALL-9 ( n  = 122), with MRD <0.05% at EOC. EOC MRD-negative patients ( n  = 178) had excellent outcomes, irrespective of MRD results at later timepoints; 6-year cumulative incidence of relapse (6-y CIR) of 7.4% (95% CI, 3.9%–12.3%) for those with MRD negativity at all later timepoints compared to 3.8% (95% CI, 0.3%–16.8%) for those with one or more later timepoints being positive ( p  = 0.51). Patients with positive EOC MRD ( n  = 91) of whom the subsequent timepoints were MRD negative ( n  = 43), had comparable good outcomes, 6-y CIR of 7.0% (95% CI, 1.8%–17.2%). In contrast, patients being MRD positive at EOC and MRD positive at one or more subsequent timepoints ( n  = 48) had a higher risk of relapse, 6-y CIR 29.4% (95% CI, 17.2%–42.8%), p  < 0.001. These findings were confirmed in the validation cohort of ALL-9 as well as using the updated EuroMRD guidelines. In EOC MRD-negative patients, subsequent MRD measurements can be abandoned. For EOC MRD-positive patients the subsequent MRD measurement might be informative for further risk stratification.

Recent trials show 5-year survival rates >95% for ETV6 :: RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5–75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7–52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6 :: RUNX1 ALL.

Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8 + T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.

Approximately 25% of the pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases are genetically unclassified. More thorough elucidation of the pathobiology of these genetically unclassified (‘B-other’) cases may identify novel treatment options. We analyzed gene expression profiles of 572 pediatric BCP-ALL cases, representing all major ALL subtypes. High expression of STAP1 , an adaptor protein downstream of the B-cell receptor (BCR), was identified in BCR-ABL1 -like and non- BCR-ABL1 -like B-other cases. Limma analysis revealed an association between high expression of STAP1 and BCR signaling genes. However, STAP1 expression and pre-BCR signaling were not causally related: cytoplasmic Igμ levels were not abnormal in cases with high levels of STAP1 and stimulation of pre-BCR signaling did not induce STAP1 expression. To elucidate the role of STAP1 in BCP-ALL survival, expression was silenced in two human BCP-ALL cell lines. Knockdown of STAP1 did not reduce the proliferation rate or viability of these cells, suggesting that STAP1 is not a likely candidate for precision medicines. Moreover, high expression of STAP1 was not predictive for an unfavorable prognosis of BCR-ABL1 -like and non- BCR-ABL1 -like B-other cases. Remarkably, DUX4 -rearrangements and intragenic ERG deletions, were enriched in cases harboring high expression of STAP1 .

A better understanding of lymphocyte dynamics during current treatment regimens in pediatric AML is urgently needed to understand whether the application of bispecific T-cell-engagers (BiTEs) during periods of low tumor burden could be a viable treatment strategy. In this study, we found that induction 1, comprising mitoxantrone-etoposide-cytarabine in nearly all patients (as part of the NOPHO-DBH AML-2012 protocol), led to preserved or increased relative lymphocyte abundances alongside marked blast reduction in most cases. This was accompanied by a shift towards higher T-cell fractions, potentially creating a favorable window for BiTE therapy. The absence of a correlation between blast reduction and lymphocyte changes suggests that chemotherapy exerts differential effects on the lymphocyte compartment. Despite the heterogeneity of agents used in induction 2, more than half of patients showed a decline in lymphocyte levels. Nonetheless, the increase in T- and B-cells observed in most patients from the NOPHO-AML 2004 cohort after induction 2 suggests that lymphocyte recovery at this treatment stage is not uniformly impaired. Our transcriptomic and ex vivo functional data align with preclinical findings in adult AML and provide a basis for further investigations in in vivo models and early clinical trials. Such efforts should prioritize novel BiTE constructs targeting multiple tumor-associated (e.g., NCT05673057) or tumor-specific antigens.