Philadelphia chromosome-positive acute lymphoblastic leukaemia in children and adolescents: A changing treatment landscape and a methodological challenge.

Children with acute lymphoblastic leukaemia (ALL) are at risk of metabolic and cardiovascular complications. We evaluated the development of overweight and obesity for 5 years after diagnosis in children and adolescents treated for ALL. The medical records of children diagnosed with ALL at one centre during 2000-2018 were assessed. Weight and height measurements were retrieved from medical records and were used to calculate age- and sex-adjusted International Obesity Task Force-Body Mass Index (ISO-BMI). ISO-BMI was determined at selected time points during treatment and up to 5 years after diagnosis, and the change in mean ISO-BMI was assessed. We studied 115 patients diagnosed with ALL, 54 (47%) of whom were male. Mean age at diagnosis was 6.6 ± 4.6 (range 0-17.99) years. ISO-BMI increased significantly during treatment (p < 0.0001) and remained elevated at 5 years after diagnosis (p < 0.0001). The number of overweight and obese patients increased from 17% and 4% at diagnosis to 26% and 16% at the five-year follow-up. Patients treated for ALL are at significant risk of weight gain and obesity, with the prevalence of overweight and obesity doubling from diagnosis to 5 years post-treatment. ISO-BMI remained persistently elevated across all treatment risk groups.

From the bench of molecular understanding to the bedside of optimal therapy for BCR::ABL1 and ABL-class acute lymphoblastic leukemia in children and adolescents

Acute lymphoblastic leukemia (ALL) preferentially localizes in the bone marrow (BM) and displays recurrent patterns of medullary and extra-medullary involvement. Leukemic cells exploit their niche for propagation and survive selective pressure by chemotherapy in the BM microenvironment, suggesting the existence of protective mechanisms. Here, we established a three-dimensional (3D) BM mimic with human mesenchymal stromal cells and endothelial cells that resemble vasculature-like structures to explore the interdependence of leukemic cells with their microenvironment. This model recapitulates recurrent topologic differences between B-cell and T-cell precursor ALL, whereby B-ALL interacts more closely with the mesenchymal compartment. Migration versatility was found to be associated with subtype, consistent with increased motility observed in T-ALL in vivo. Single-cell RNA signatures revealed similarities to profiles from in vivo patient derived xenografts, suggesting relevant states ex vivo. Furthermore, enhanced migration, adherence and cell cycle heterogeneity was visualized in our co-culture model. Finally, drug response experiments in this 3D model confirm clinically relevant sensitivity and resistance patterns that reflect specific disease phenotypes and may provide a broader dynamic range for drug response testing.

Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-28779-9.

The European ALLTogether protocol for childhood acute lymphoblastic leukemia, initiated in Sweden 2019, introduced earlier asparaginase during induction, dexamethasone instead of prednisone for all patients, and omitted anthracyclines from low-risk induction to reduce treatment-related toxicity. Consolidation-1 was based on the Induction 1B-phase developed by the BFM-group, replacing mercaptopurine, methotrexate, and asparaginase used in the previous NOPHO ALL2008 protocol, ALL2008. Following implementation, early treatment toxicity was considered unacceptably high, prompting a protocol amendment. We compared the prevalence of 14 predefined toxicities, the number of inpatient days, and weight changes during induction and consolidation-1 between the two protocols. We conducted a population-based cohort study in Sweden, reviewing patient records from 117 children treated under ALLTogether protocol and 234 matched controls under ALL2008 protocol. The mean number of toxicities per patient was similar between the protocols (2.5 [290/117] vs. 2.3 [547/234]). ALLTogether cohort had significantly greater weight gain, with over 50% experiencing a>10% increase (p<0.01). Hyperglycemia (OR 5.17, 95% CI 1.93-13.82) and osteonecrosis (3.4%vs. 0%, p=0.012) were more common, while liver dysfunction (0.59, 0.38-0.93) was less frequent in the ALLTogether protocol. The number of inpatient days was similar across protocols, except for the initial hospitalization, which was longer in ALLTogether (median 11vs. 7 days, p<0.01). The early introduction of asparaginase likely contributed to increased weight gain, hyperglycemia, and osteonecrosis. While overall toxicity burden remained similar between protocols, the shift in toxicity profile may explain the perception of increased early toxicity during treatment with the ALLTogether protocol. ClinicalTrials.gov identifier: NCT03911128; EudraCT numbers: 2018-001795-38 and 2008-003235-20.

Background and Objectives: Childhood acute lymphoblastic leukemia (ALL) carries substantial morbidity, mortality, and economic burden, particularly in middle-income countries. The Pediatric Early Warning System (PEWS) is designed to trigger timely escalation of care, yet its independent impact on survival among critically ill leukemic children has not been well defined in Kazakhstan and Central Asia. Materials and Methods: We conducted a retrospective review all ICU admissions for patients aged 0–18 years with ALL at the National Center of Pediatrics, Almaty, across two periods: pre-implementation (January 2020–December 2022) and post-implementation of 24 h PEWS monitoring (September 2023–December 2024). The primary outcome was ICU mortality. Seven domains of covariates—demographic, clinical history, transfusion, vital signs, symptoms, laboratory, and instrumental data—were extracted. Univariable and multivariable logistic regression models were used to assess associations with mortality. Results: Among 255 admissions (105 during PEWS implementation; 150 prior to PEWS implementation), overall ICU mortality was 21.7%. After adjustment, PEWS implementation was not associated with reduced ICU mortality (AOR 0.89), despite a lower unadjusted mortality (15.9% vs. 26.6%). The most clinically relevant secondary findings included strong associations between mortality and bilateral pneumonia (AOR 7.45), ≥4 episodes of hyperthermia within 24 h of ICU admission (AOR 5.42), and systemic inflammatory response syndrome (AOR 4.61). Conclusions: These findings suggest that, within this high-acuity cohort, inflammatory and cardiorespiratory derangements outweigh any potential survival benefit from ward-based PEWS surveillance. Optimizing outcomes will require integrating early warning systems with timely deterioration management, focused cardiopulmonary support, and resource allocation tailored to the clinical context—rather than relying solely on surveillance scores.

Over the past decades, survival outcomes for childhood acute lymphoblastic leukaemia (ALL) have significantly improved. However, adverse drug reactions (ADRs), particularly those related to 6-mercaptopurine (6-MP), remain a major concern. Myelosuppression associated with 6-MP administration can lead to infections or treatment interruptions. Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. This study investigates genetic variants influencing 6-MP response in children with ALL. Seventeen tagSNPs in key enzymes involved in 6-MP metabolism, GMPS, IMPDH1, XO, and ITPA, were analysed. Genetic data were correlated with clinical and pharmacological parameters in 280 ALL patients treated under DFCI ALL 05-001, 11-001, and 16-001 protocols at CHU Sainte-Justine. Outcomes included 6-MP dose intensity, 6-TGN and 6-MMP metabolite levels, and hematologic and hepatic toxicities during consolidation II and maintenance phases. Results revealed that the rs6710015 variant allele in the XO gene is linked to lower 6-TGN and higher 6-MMP levels, while rs1884725 variant allele in the same gene is correlated with reduced neutropenia and higher cumulative 6-MP doses. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.

Elevated visceral fat is associated with poor cardiovascular health but is not well characterized in survivors of childhood cancer. We examined central adiposity and associated risk factors in a pediatric acute lymphoblastic leukemia (ALL) survivorship cohort. Visceral adipose tissue (VAT) mass and estimated waist circumference (WC) were extracted from dual energy x-ray absorptiometry (DXA) scans on 70 survivors of pediatric ALL >10 years from diagnosis. Waist-to-height ratios (WHtRs), a body shape index (ABSI), ABSI z scores, and descriptive statistics were calculated to examine central adiposity. We tested sensitivity/specificity of WHtR at established thresholds for identifying VAT ≥85th percentile (%le). VAT z scores were shifted positively relative to population norms with 25.7%≥85th %le. Mean WHtR was 0.55±0.06 with 82.9% above the "take action" threshold of 0.5. A WHtR ≥0.59 had a sensitivity of 90.2% (95% CI 82.0-98.4) and specificity of 68.4% (95% CI 47.5-89.3) for identifying individuals with VAT ≥85th %le. The mean ABSI z score was 1.88±0.85; higher in women, in high risk ALL, and post-cranial radiation (p=0.01-0.02). The ABSI z scores for 94.3% of survivors fell in the highest quintile of population values. Nearly the entire cohort of long-term survivors of pediatric ALL have an elevated WC relative to height, weight, and population norms, regardless of their body mass index (BMI) or visceral fat. This suggests that a broader screening approach, which considers waist indices, may be better able to detect those at increased cardiometabolic risk. Evaluation and confirmation in a larger prospective cohort is indicated.

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and while chemotherapy has significantly improved survival rates, it can also lead to long-term side effects, including immune system dysfunction. This study aimed to investigate in detail, using flow cytometry, the T-cell subpopulations in the peripheral blood of children who have completed ALL treatment and compare them to a group of healthy children. The study group consisted of 20 patients, aged 5 to 18 years, with blood samples collected at least one year after treatment completion. Of the 52 T-cell subpopulations analyzed, 16 showed statistically significant differences. Children after ALL treatment had lower absolute values of TCRγδ+ and higher values of double-positive CD4+CD8+ and CD8+ T cells. They also had higher absolute numbers of memory T cells, including total CD45RO+ T cells, and the CD45RO+CD8+ and CD45RO+CD27+ subpopulations. Furthermore, post treatment patients showed higher absolute values of activated T cells (HLA-DR+, HLA-DR+CD8+, HLA-DR+CD57+, and CD25+CD8+), as well as CD57+ and CCR7+ T cells. The absolute leukocyte and granulocyte counts were lower in the study group, while the total lymphocyte count was significantly higher compared to the control group. The findings indicate persistent changes in T-cell subpopulations after ALL treatment, suggesting ongoing immune system rebuilding and chronic antigenic stimulation, possibly due to viral reactivation or chemotherapy-related tissue damage. The increased number of TCRγδ+ cells, which are responsible for eliminating cancer cells, may be a positive aspect of this rebuilding.

Glucocorticoid metabolizing enzymes predict initial glucocorticoid sensitivity in childhood ALL

Mapping skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) in childhood acute lymphoblastic leukemia survivors using a novel technique oxcest MRI

Blinatumomab versus high-dose chemotherapy in the first-line therapy of high-risk childhood B-cell acute lymphoblastic leukemia: The results of a Phase 3 trial of the cALL-pol consortium in Poland

Backtracking the cellular origins of ETV6::RUNX1 childhood acute lymphoblastic leukemia in cord blood (ReCord study)

Parental perspectives on financial distress during treatment for childhood acute lymphoblastic leukemia: A qualitative report from Children's oncology group (COG) study ACCL20N1CD

Associations between serum asparaginase activity and asparaginase-associated toxicities in pediatric ALL patients receiving calaspargase: A report from the DFCI ALL consortium

BackgroundDoxorubicin induced cardiotoxicity in childhood cancer survivors is mediated by mitochondrial dysfunction. The aims of this research are to determine (i) the frequency of mitochondrial DNA (mtDNA) mutations in long-term survivors of childhood acute lymphoblastic leukemia (ALL), and (ii) to determine if co-administration of dexrazoxane reduces the occurrence of mutations.MethodsPatients previously treated on Dana-Farber Cancer Institute Childhood ALL protocols and at least 4 years from the date of ALL diagnosis were enrolled in this study. MtDNA was isolated from samples of peripheral blood lymphocytes. A vertical denaturing gradient gel electrophoresis method was used for detecting sequence variants in the 22 transfer RNA (tRNA) genes and flanking regions of the human mitochondrial genome. The patients were divided into two cohorts, those with mutations and those without, and compared. The patients and variants were also compared to healthy controls. Mutational status was compared with echocardiographic measurements.ResultsOf the patients who received chemotherapy, there were 51/167 (31%) children who were found to have 61 different sequence variants in mtDNA with 9 patients having more than one variant. There was no association between mutation status and cumulative doxorubicin dose, though patients receiving < 300 mg/m2 had fewer mutations of any kind. At a median time of 8.5 years after diagnosis, the number of ALL patients with mtDNA sequence variants was 2.4-fold higher than the number of control children with sequence variants (8 sequence variants in 7/55 or 12.7%). Among patients receiving doxorubicin-based therapies, with (n = 34) or without dexrazoxane (n = 132), there were no statistically significant differences in the patient characteristics or in the frequencies, locations, types, and distribution of mtDNA sequence variants. The mutational status was not associated with echocardiographic changes.ConclusionsThe results of this study indicate that doxorubicin chemotherapy is associated with increases in mtDNA sequence variants in lymphocytes. The role of mtDNA mutations in late-onset cardiomyopathy of doxorubicin, and the potential antimutagenic activity of dexrazoxane, were not established but warrant further investigation.

Association between COMT activity and development of infections during therapy for pediatric acute lymphoblastic leukemia

Prognostic factors influencing relapse and survival of childhood acute lymphoblastic leukemia with the ALL-BFM IC 2009 protocol

Biphasic effects of cyclophosphamide on l-asparaginase hypersensitivity and resistance in mice