Pediatric Acute Lymphoblastic Leukemia Research Articles

Very early remission and increased apoptosis with the use of Pentoxifylline in children with acute lymphoblastic leukemia.

Despite the improvement in survival in acute lymphoblastic leukemia (ALL), there are still cases with evasion of chemotherapy-induced apoptosis. The IKK/NF-κB signaling pathway contributes to antiapoptotic gene expression. Pentoxifylline (PTX) inhibits IkB phosphorylation, blocking NF-κB and antiapoptotic activity. We conducted a randomized, double-blind clinical trial on pediatric ALL patients undergoing induction therapy, assigning them to PTX or placebo group. Bone marrow aspirates were obtained on days 1, 8, 15, and 22. Apoptosis was assessed using Annexin-V/propidium iodide. Results indicated that the PTX group exhibited higher apoptosis on day-8 (41.3% vs. 19.4%, p =0.029) and day-15 (35.0% vs. 14.2%, p <0.01). On day-8, the PTX group displayed an MRD of 0.25% vs. 18.2% (p <0.01) in placebo group; on day-15, the PTX group demonstrated an MRD of 0.09% vs. 1.4% (p =0.02). Patients achieving an MRD <0.01% on day-8 demonstrated a 3-year Overall Survival (OS) of 81.6% vs. 58.3% (p =0.03); on day-15, patients with MRD <0.01% had a 3-year OS of 77.9% vs. 54.5% (p =0.03). The PTX group achieved an MRD of <0.01% earlier on days-8 and 15, along with a higher apoptosis rate, indicating a more favorable therapeutic response. In the entire cohort, patients achieving MRD <0.01% on day-8 or 15 displayed superior OS. Our study demonstrates that PTX enhances apoptosis and reduces MRD in pediatric acute lymphoblastic leukemia patients. https://clinicaltrials.gov/, identifier NCT02451774.

Microfluidic Affinity Selection of B-Lineage Cells from Peripheral Blood for Minimal Residual Disease Monitoring in Pediatric B-Type Acute Lymphoblastic Leukemia Patients.

Assessment of minimal residual disease (MRD) is the most powerful predictor of outcome in B-type acute lymphoblastic leukemia (B-ALL). MRD, defined as the presence of leukemic cells in the blood or bone marrow, is used for the evaluation of therapy efficacy. We report on a microfluidic-based MRD (MF-MRD) assay that allows for frequent evaluation of blood for the presence of circulating leukemia cells (CLCs). The microfluidic chip affinity selects B-lineage cells, including CLCs using anti-CD19 antibodies poised on the wall of the microfluidic chip. Affinity-selected cells are released from the capture surface and can be subjected to immunophenotyping to enumerate the CLCs, perform fluorescence in situ hybridization (FISH), and/or molecular analysis of the CLCs' mRNA/gDNA. During longitudinal testing of 20 patients throughout induction and consolidation therapy, the MF-MRD performed 116 tests, while only 41 were completed with multiparameter flow cytometry (MFC-MRD) using a bone marrow aspirate, as standard-of-care. Overall, 57% MF-MRD tests were MRD(+) as defined by CLC numbers exceeding a threshold of 5 × 10-4%, which was determined to be the limit of quantitation. Above a threshold of 0.01%, MFC-MRD was positive in 34% of patients. The MF offered the advantage of the opportunity for efficiently processing small volumes of blood (2 mL), which is important in the care of pediatric patients, especially infants. The minimally invasive means of blood collection are of high value when treating patients whose MRD is typically tested using an invasive bone marrow biopsy. MF-MRD detection can be useful for stratification of patients into risk groups and monitoring of patient well-being after completion of treatment for early recognition of potential impending disease recurrence.

New insights into hematopoietic cell transplantation in ALL: Who should be transplanted, when, and how

Advancements in multi-agent chemotherapy through clinical trials conducted by multi-institutional collaborative groups worldwide, along with risk stratification using molecular genetic features and treatment responses, including minimal residual disease, have significantly improved outcomes for children and adolescents with acute lymphoblastic leukemia (ALL) over the past half-century. However, for a certain number of high-risk patients, including those with relapsed or refractory disease, for whom existing chemotherapy alone is insufficient for cure, allogeneic hematopoietic cell transplantation (HCT) has provided a potential opportunity for leukemia cure. For these patients, the appropriate selection of donor and stem cell source, conditioning regimen, timing of transplantation, and comprehensive supportive care, including effective graft-versus-host disease prophylaxis, are prerequisites for successful HCT. While HCT from a human leukocyte antigen (HLA)-matched sibling has traditionally been the preferred option, less than 25 % of patients currently have such a donor in developed countries. Consequently, alternative donor HCT options, such as those from matched unrelated donors identified through high-resolution HLA typing, unrelated cord blood donors, and more recently, haploidentical donors using post-transplant cyclophosphamide or TCRαβ+/CD19+ cell-depleted grafts, are providing broader access to HCT for patients lacking matched sibling donors. Nonetheless, HCT carries the risk of various acute and late toxicities. In particular, the use of myeloablative conditioning with total body irradiation, a standard in pediatric ALL, is associated with significant long-term sequelae. As our understanding of the pathophysiology of the disease improves and novel molecular targeted therapies and immunotherapies are developed, the indication for HCT in pediatric ALL is becoming more selective, leading to a gradual decrease in the number of transplants performed. However, further optimization and evolution of allogeneic HCT are needed to both maximize its anti-leukemia effects and minimize transplant-related complications, as there remain cases that undoubtedly require HCT for the cure of leukemia.

Baseline characteristics of parents enrolled in ACCL20N1CD: Financial distress during treatment for pediatric acute lymphoblastic leukemia (ALL) in the US.

220 Background: Personal costs of childhood cancer can contribute to disparities in health outcomes. The purpose of ACCL20N1CD is to examine trajectories of parental costs and the associated financial distress, cost coping behaviors, and household material hardships (HMH) during treatment for pediatric ALL. Objective is to report baseline characteristics of the parents and their households. Methods: The study used a prospective cohort design with repeated measures. Setting was Children’s Oncology Group (COG) practices at National Cancer Institute Community Oncology Research Program (NCORP) institutions. Parents who use English or Spanish, and have children newly diagnosed with ALL treated at COG NCORP practices were eligible. Parents were asked to complete surveys at 3 time points, including baseline (T1; during induction and &lt;7 days after planned induction remission evaluation). Surveys included items about (a) parent socio‐economic status, financial distress measured by 8-item Personal Wellness Scale (PFWS), and cost coping behaviors, and (b) HMH. Factors related to high PFWS scores were evaluated by logistic regression. Results: Of 104 evaluable parents, most were female (83.7%), white (65.4%), non-Hispanic (48.1%), partnered (79.8%), &gt; high school diploma (93.3%), used English (84.6%), worked full (48.1%) or part (5.8%) time, and paid for their child’s care with public insurance (57.7%). Median household income=$50,000 (Inter-Quartile Range/IQR 20,000-100,000) for 4 (IQR 4-5) people. Not including wages lost due to caregiving, out of pocket payments for medical care + other ALL-related costs in the prior month &gt;15% of monthly income for 51.9% of households, which is considered financially catastrophic. 24.0% of households lacked food stability; 21% had housing insecurity. Conclusions: At baseline, sizeable proportions of parents exhibit high out of pocket costs, high financial distress level, and multiple cost coping behaviors with implications for future health and individual and household quality of life.

Molecular characterization and biomarker identification in paediatric B-cell acute lymphoblastic leukaemia.

B-cell acute lymphoblastic leukaemia (B-ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Managing B-ALL remains challenging due to its heterogeneity and relapse risk. This study aimed to delineate the molecular features of paediatric B-ALL and explore the clinical utility of circulating tumour DNA (ctDNA). We analysed 146 patients with paediatric B-ALL who received systemic chemotherapy. The mutational landscape was profiled in bone marrow (BM) and plasma samples using next-generation sequencing. Minimal residual disease (MRD) testing on day 19 of induction therapy evaluated treatment efficacy. RNA sequencing identified gene fusions in 61% of patients, including 37 novel fusions. Specifically, the KMT2A-TRIM29 novel fusion was validated in a boy who responded well to initial therapy but relapsed after 1 year. Elevated mutation counts and maximum variant allele frequency in baseline BM were associated with significantly poorer chemotherapy response (p = 0.0012 and 0.028, respectively). MRD-negative patients exhibited upregulation of immune-related pathways (p < 0.01) and increased CD8+ T cell infiltration (p = 0.047). Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B-ALL management.

Repetitive intra-articular therapy in fungal arthritis: Adjunct to systemic therapy in a patient with pediatric acute lymphoblastic leukemia

Repetitive intra-articular therapy in fungal arthritis: Adjunct to systemic therapy in a patient with pediatric acute lymphoblastic leukemia

Effect of Smart Pill Box on Improving Adherence to 6-Mercaptopurine Maintenance Therapy in Pediatric ALL

Abstract Introduction 6-Mercaptopurine (6-MP) forms the backbone of maintenance chemotherapy for acute lymphoblastic leukemia (ALL). A Children's Oncology Group study found 3.9-fold increased risk of relapse in children with 6-MP adherence less than 90%. Objective This article estimates the impact of smart pill box in improving adherence to 6-MP during maintenance phase chemotherapy in children with ALL. Material and Methods It is a prospective interventional study done at pediatric oncology clinic of a tertiary care hospital. Participants being 40 newly diagnosed children with ALL. Baseline adherence was assessed and impact of smart pill box was estimated after using it for 60 days. Subjective and objective assessment of baseline adherence and adherence after intervention was done by subjecting the parents of the children to Morisky Medication Adherence Score 8 (MMAS-8) and measurement of patient's red blood cells (RBC) 6-MP metabolites (6-thioguanine [TGN] and 6-methylmercaptopurine [MMP]) levels, respectively, pre- and postintervention. Results The mean age was 7.39 ± 4.29 years. NUDT15*3 polymorphism was present in 10.26%, and none had TPMT polymorphism. Baseline assessment of adherence to 6-MP by MMAS-8 revealed low, medium, and high adherence in 7.5, 35, and 57.5%, respectively. Baseline 6-TGN and 6-MMP levels by cluster analysis revealed poor adherence in 10%. Following intervention, mean MMAS-8 improved from 7.34 ± 0.78 to 7.66 ± 0.55 (p-value &lt; 0.015) and the median 6-TGN level improved from 150 to 253 pmol/8 × 108 RBCs (p-value &lt; 0.001). Conclusion Nonadherence to 6-MP is widely prevalent in Indian children. Simple measures like smart pill box can improve adherence.

Survival of Children with Acute Lymphoblastic Leukemia with Risk Group-Based Protocol Changes: A Single Center Experience with 460 Patients over a 20-Year Period.

Recent treatments for pediatric acute lymphoblastic leukemia (ALL) are founded on risk stratification. We examined the survival rates and prognostic factors of patients over a 20-year period at a single institution. This study analyzed patients diagnosed with ALL and treated at the Pediatric Department of Samsung Medical Center (SMC). Patients were categorized into standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. The SMC protocol for the HR group underwent two changes during the study period: A modified Children's Cancer Group (CCG)-1882 protocol was used from 2000 to 2005, the Korean multicenter HR ALL-0601 protocol from 2006 to 2014, and the Korean multicenter HR ALL-1501 protocol from 2015 to 2019. Of the 460 patients, complete remission was achieved in 436 patients (94.8%). The 10-year overall survival rate (OS) was 83.8±1.9% for all patients. OS according to the SMC risk group was as follows: 95.9±1.4% in the SR group, 83.8±3.6% in the HR group, and 66.2±6.9% in the VHR group. The 5-year OS within the HR group varied according to the treatment protocol: 73.9±7.5%, in the modified CCG-1882 protocol, 83.0±3.9%, in the 0601 protocol, and 96.2±2.6%, in the 1501 protocol. For those aged 15 years and older, the OS was only 56.5±13.1%. Relapse occurred in 71 patients (15.4%), and the OS after relapse was 37.7±6.0%. The treatment outcomes of patients with ALL improved markedly. However, there is a need to further characterize adolescents and young adult patients, as well as those who have experienced relapses.

Cerebral Sinus Venous Thrombosis in Pediatric Acute Lymphoblastic Leukemia: Incidence, Clinical Characteristics, and Long-term Neurologic Outcomes.

To describe the incidence, clinical characteristics, and long-term outcomes of cerebral sinus venous thrombosis in children with acute lymphoblastic leukemia. This was a retrospective cohort study comprising pediatric patients with newly diagnosed or first-relapse acute lymphoblastic leukemia who developed cerebral sinus venous thrombosis at Texas Children's Hospital from 2002 to 2019. Nineteen cases (1.7%) with cerebral sinus venous thrombosis were identified in all pediatric patients with acute lymphoblastic leukemia (n = 1129). Increased risk of cerebral sinus venous thrombosis was observed with age >10 years (P = .006). Twelve cases (63%) occurred during the induction, 4 (21%) during maintenance, and 3 (16%) during the consolidation phases of leukemia therapy. Seizures (10/19) and headaches (9/19) were the most common presenting symptoms. After treatment with anticoagulation therapy, we observed full resolution of thrombosis in 10 (53%) and partial resolution in 8 patients (42%). Long-term neurologic outcomes at follow-up in the 14 patients who survived included normal neurologic examinations (n = 10), epilepsy (n = 3), and focal neurologic deficits (n = 2). The death occurred in 5 individuals. Cerebral sinus venous thrombosis is a notable complication of pediatric acute lymphoblastic leukemia therapy. Older age (>10 years) was a risk factor for developing cerebral sinus venous thrombosis. Despite variable patient presentations and treatment durations, favorable clinical outcomes were observed in most patients after the treatment with anticoagulation for a minimum of 3 months.

Selected stem cell populations in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia is characterized by a disturbed maturation of hematopoietic stem cells (HSCs) resulting in development of a malignant clone. Despite relatively positive outcome, there are still instances of disease relapse occurring due to ineffective disease eradication or primary leukemic clone alterations. Unclear significance of stem cells in the course of ALL led us to investigate and establish crucial changes in two stem cell populations - very small embryonic-like stem cells (VSELs) and HSCs during the induction phase of treatment. In a retrospective study selected stem cells in peripheral blood and bone marrow of 60 pediatric ALL subjects and 48 healthy controls were subjected to flow cytometric analysis at 4 different time points. Both VSELs and HSCs were elevated at the moment of ALL diagnosis compared to healthy controls, but profoundly decline until day 15. Further observations revealed an increase in HSCs with a concomitant depletion of VSELs until week 12. ALL patients with high HSCs showed positive correlation with bone marrow blasts at diagnosis. Patients with lower VSELs or HSCs at diagnosis had slightly improved response to applied therapy. We observed higher initial bone marrow lymphoblast values in patients with lower VSELs or higher HSCs in the high-risk group. The significance of VSELs in predicting treatment outcome can be illustrated by lower day 15 MRD level of patients with lower VSELs at diagnosis. We found HSCs and VSELs to be valid participants in pediatric ALL with possible contribution in the neoplastic process and prediction of initial treatment outcome.

Association of CD34 Expression with Future Relapse in Pediatric T-cell Acute Lymphoblastic Leukemia

Background: Developing novel prognostic markers is crucial for childhood T-cell acute lymphoblastic leukemia (T-ALL). Objectives: This study aimed to investigate whether the prognostic impact of CD34, a progenitor marker, is associated with outcomes. Methods: This retrospective cohort study included 82 risk-adapted pediatric patients with T-ALL who were treated under the National Protocol of Childhood ALL in China (NPCLC)-ALL2008 from March 2008 to December 2016. Results: CD34 expression was observed in 37.8% of all T-ALL patients, with a median expression level of 62.7%. Patients with CD34 expression had a favorable event-free survival (EFS, 74.2% [66.3% - 82.1%]) with a hazard ratio of 0.69 (P = 0.33) and a reduced cumulative incidence of relapse (CIR, 22.6% [15.0% - 30.2%]; P = 0.86) at five years. Even after adjusting for potential factors and competing events in multivariable regression models, there was no connection between the CD34 immunophenotype and the risk of recurrence. Conclusions: CD34 expression did not serve as a predictive factor for relapse in this limited series. Larger multicenter studies are recommended to determine whether this biomarker at initial diagnosis can predict outcomes.

The Effects of Pediatric Acute Lymphoblastic Leukemia Treatment on Cardiac Repolarization.

Background: In recent years, cardiac dysfunction in childhood cancer survivors has become an important issue. Studies are focusing on identifying means for the early identification of patients at risk. Considering this, our study aims to investigate 24-hour Holter electrocardiogram (ECG) repolarization changes throughout doxorubicin (DOX) and cyclophosphamide (CPM) administration in pediatric patients treated for acute lymphoblastic leukemia (ALL). Methods: This was an investigator-driven, single-center, prospective, observational study. Enrolled children had a baseline bedside ECG examination performed before starting chemotherapy (T0). Serial Holter ECG examinations were conducted at three moments during their treatment protocol: day 8 (T1), day 29 (T2), and day 36 (T3). This study evaluated several ECG repolarization parameters, such as the QT interval, corrected QT interval (QTc), and QTc dispersion, as well as ST segment variations. Results: We evaluated 37 children diagnosed with ALL. The T0 examination revealed that over a third of patients had a resting heart rate (HR) outside the normal range for their age and sex. During chemotherapy, statistically significant increases in both HR as well as QT and QTc dispersion values were noticed, especially during the first DOX administration. What is more, a significant increase in the percentage of patients with ST segment depression from T1 to T2 and T3 was noticed. Rhythm disturbances were rare in the study population, with only a few patients presenting ventricular or supraventricular extrasystoles. Conclusions: This study reveals silent repolarization changes occurring early during anticancer treatment in children treated for ALL. These findings could aid in a better understanding of the cardiac toxicity mechanism, and they could potentially improve cardiac risk stratification for oncologic patients. Because of the small number of patients, our results need to be validated by larger studies.

Machine learning-based evaluation of prognostic factors for mortality and relapse in patients with acute lymphoblastic leukemia: a comparative simulation study

BackgroundPredicting mortality and relapse in children with acute lymphoblastic leukemia (ALL) is crucial for effective treatment and follow-up management. ALL is a common and deadly childhood cancer that often relapses after remission. In this study, we aimed to apply and evaluate machine learning-based models for predicting mortality and relapse in pediatric ALL patients.MethodsThis retrospective cohort study was conducted on 161 children aged less than 16 years with ALL. Survival status (dead/alive) and patient experience of relapse (yes/no) were considered as the outcome variables. Ten machine learning (ML) algorithms were used to predict mortality and relapse. The performance of the algorithms was evaluated by cross-validation and reported as mean sensitivity, specificity, accuracy and area under the curve (AUC). Finally, prognostic factors were identified based on the best algorithms.ResultsThe mean accuracy of the ML algorithms for prediction of patient mortality ranged from 64 to 74% and for prediction of relapse, it varied from 64 to 84% on test data sets. The mean AUC of the ML algorithms for mortality and relapse was above 64%. The most important prognostic factors for predicting both mortality and relapse were identified as age at diagnosis, hemoglobin and platelets. In addition, significant prognostic factors for predicting mortality included clinical side effects such as splenomegaly, hepatomegaly and lymphadenopathy.ConclusionsOur results showed that artificial neural networks and bagging algorithms outperformed other algorithms in predicting mortality, while boosting and random forest algorithms excelled in predicting relapse in ALL patients across all criteria. These results offer significant clinical insights into the prognostic factors for children with ALL, which can inform treatment decisions and improve patient outcomes.

Developmental and epileptic encephalopathies after successful treatment of pediatric ALL: A case series and review of literature.

Successful treatment of acute lymphoblastic leukemia (ALL) requires multiagent chemotherapy regimens and central nervous system prophylaxis, including intrathecal methotrexate. Although acute symptomatic seizures can occur during ALL treatment, epilepsy is less common. Furthermore, drug resistant epilepsy (DRE) is rare, presenting with two phenotypes: focal epilepsy, such as temporal lobe, or epileptic encephalopathies (EE), such as Lennox-Gastaut syndrome (LGS). For ALL survivors, the development of DRE has significant impact on morbidity, mortality, and quality of life. We describe four patients with ALL remission, who developed EEs, of which 3 had LGS. Mean age at ALL diagnosis was 1.9 years; range 1.1-2.5 years. All, but one, had normal development prior to ALL. No patient had CNS leukemic involvement. All patients received CNS prophylaxis with intrathecal methotrexate, without cranial radiotherapy. Three had symptomatic methotrexate neurotoxicity during treatment. The mean age at first seizure was 5.6 years; range 3.9-7.5 years, with a mean latency of 3.7 years from ALL diagnosis. All patients developed drug resistant EEs, moderate intellectual disability, and neuropsychiatric co-morbidities. Two patients had a minimal response to corpus callosotomy (CC), and one did not respond the ketogenic diet. Successful treatment of childhood ALL is rarely associated with the development of DRE and EEs. Young age at ALL diagnosis (<3 years) may be a predisposing factor. Palliative treatments, including ketogenic diet and CC have limited benefit in these patients. Individual genetic susceptibility to MTX toxicity is likely related to epileptogenesis, and further research is required for epilepsy biomarkers.

The significance of CD49f expression in pediatric B-cell acute lymphoblastic leukemia.

CD49f is an adhesion molecule present on malignant lymphoblasts in B-cell acute lymphoblastic leukemia; it is associated with a poor prognosis. CD49f expression has been proposed as a marker for measurable residual disease (MRD) marker, but this marker has yet to be implemented in clinical practice. In this study, we used flow cytometry to detect CD49f expression by leukemic blasts in paired bone marrow and cerebrospinal fluid samples at diagnosis and bone marrow at day 15 of treatment. At diagnosis, 93% of bone marrow and 100% of cerebrospinal fluid lymphoblasts expressed CD49f. The intensity of CD49f expression statisticallysignificantly increased during treatment (P < .001). In MRD-negative end-of-treatment samples, only a small population of hematogones expressed CD49f. Interestingly, the intensity of CD49f expression varied among the different groups of recurrent genetic abnormalities. The ETV6::RUNX1 fusion and ETV6::RUNX1 combined with the high hyperdiploid group were associated with increased expression, whereas the Philadelphia-like group showed low CD49f expression. The lower CD49f expression at diagnosis predicted a lower MRD rate at day 15 of treatment. We concluded that CD49f can be used as an MRD marker and possible prognostic factor in B-cell acute lymphoblastic leukemia.

Minimal Residual Disease in Pediatric Acute Lymphoblastic Leukemia

Background and ObjectiveThe detection of minimal residual disease at the end of initial therapy in Acute Lymphoblastic Leukemia to assess risk stratification is gaining clinical significance. While minimal residual disease assesses the extent of remission, remission is still defined by bone marrow morphology. The aim of this study is to determine the significance of minimal residual disease. Methods: In this cross-sectional study conducted at Zheen Oncology Center and Azadi hospital in Duhok, Iraq, data was collected from 46 patients’ records. Residual disease was detected by flow cytometry. On day 29 of induction therapy, a bone marrow sample was obtained for morphology and flow cytometry. The presence or absence of MRD was determined by using 8-color flow cytometry. Results: The median age of the study was 7 years and the male to female ratio was 1.7:1. B-cell lymphoblastic leukemia accounted for 80.43% and T-cell was 19.57%. Bloodounts at diagnosis revealed a mean white blood cell count of 74.32 x /L, mean hemoglobin level of 8.75, g/dL, and a mean platelet count of 97.84 x L. Minimal residual diease positive results were seen in 29 cases; 21 cases were of B-cell leukemia (56.75) and 8 (88.88) cases were T-cell leukemia. Minimal residual disease negative results were achieved in 17 cases; 43.24% were of B-cell origin (p value &lt;0.001), 11.11% were of T-cell origin (p value 0.008). Remission was achieved in 81.08 cases of B-cell (p value 0.103), and 66.66 of T-cell (p value 0.403). 16.21% of B-cell leukemia passed away (p value &lt;0.001) and 33.33% of T-cell leukemia (p value 0.065). Conclusion: Flow cytometry should be done in addition to bone marrow morphology.

Uncovering possible silent acquired long QT syndrome using exercise stress testing in long-term pediatric acute lymphoblastic leukemia survivors.

An example of chemotherapy-induced cardiotoxicity in cancer survivors is acquired long QT syndrome (aLQTS), which may cause serious yet preventable life-threatening consequences. Our objective was to identify and characterize childhood acute lymphoblastic leukemia (ALL) survivors with possible aLQTS using maximal exercise testing. In this cross-sectional study with exploratory analysis, a total of 250 childhood ALL survivors were evaluated for abnormal QT interval prolongation using the McMaster cycle exercise test. A total of 198 survivors (102 males; 96 females), having reached their peak (mean 32.1 ± 8.4 mL/kg/min; range 15.5-57.8 mL/kg/min), were included in our analyses. Two survivors were excluded for possible congenital LQTS. QT intervals were corrected for heart rate using the Bazett, Fridericia, and Rautaharju formulas at rest (supine, sitting, and standing positions), at the end of each stage of the CPET, and at 1, 3, and 5 minutes into the recovery period. The corrected QT (QTc) of borderline (n = 37) and long QT survivors (n = 20) was significantly longer than normal survivors (n = 141) at rest, exercise, and recovery. Out of 57 survivors presenting an abnormal QTc prolongation, 40 survivors (70%) showed no QT interval anomalies at rest but developed various anomalies during exercise. No significant differences were found between the groups for any of the measured clinical characteristics or cardiac parameters. The standardization of exercise testing in the regular follow-up of oncology patients is necessary for appropriate cardiac prevention and surveillance to enhance the health and quality of life of the ever-increasing number of cancer survivors.

Upregulation of Insulin-like Growth Factor-I in Response to Chemotherapy in Children with Acute Lymphoblastic Leukemia.

The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), p = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), p < 0.001). This increase correlated with the levels of CRP (rho = 0.37, p < 0.001) and IL-6 (rho = 0.39, p = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, p = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.

Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.