Pediatric Acute Lymphoblastic Leukemia Research Articles

Delineation of features, responses, outcomes, and prognostic factors in pediatric PDGFRB-positive acute lymphoblastic leukemia patients: A retrospective multicenter study.

PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB-positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. Pediatric PDGFRB-positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B-ALL and 4 T-ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31-33 abnormalities, and one suffered from a complex karyotype. The 3-year event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow-up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine-kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p<.05). Pediatric PDGFRB-positive ALL has a poor outcome associated with high-risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high-risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine-kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB-positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB-positive ALL patients.

Review of current knowledge about infections accompanied by paediatric acute lymphoblastic leukemia with emphasis on challenges regarding the treatment of refugees

Review of current knowledge about infections accompanied by paediatric acute lymphoblastic leukemia with emphasis on challenges regarding the treatment of refugees

A Novel NRAS Variant Near the Splice Junction in Moroccan Childhood Acute Lymphoblastic Leukemia: A Molecular Dynamics Study.

The RAS genes are importantly implicated in oncogenesis and are frequently mutated in childhood acute lymphoblastic leukemia. This study is the first to our knowledge, to determine the mutational status of NRAS and KRAS genes in Moroccan pediatric acute lymphoblastic leukemia (ALL). Polymerase chain reaction and Sanger sequencing were performed for 45 ALL samples to explore the coding exons. The functional effect of the mutation was evaluated using in silico prediction tools and molecular modeling. We identified a novel variant c.290 G > C p.Arg97Thr within NRAS gene in a patient with T-ALL, which is a rare missense point mutation affecting the last base of exon 3. Analyses revealed that p.Arg97Thr impairs the adjacent splice site efficiency. Moreover, it leads to structural modifications at local and global levels of the protein through the loss of hydrogen bonds. Additionally, the molecular dynamics (MD) simulation showed that it slightly increases the stability of NRAS protein by locally decreasing the flexibility of the mutated region. No variant was detected within KRAS gene. R97 at NRAS gene is an overlapping splice site residue. Our findings suggest that the NRAS p.Arg97Thr variant may disrupt the splicing machinery and functions of the protein, thus playing a vital role in leukemogenesis. In addition, the highly druggable pocket may possibly be studied for its therapeutic implications.

Quantitative pharmacology of dual-targeted bicistronic CAR-T-cell therapy using multiscale mechanistic modeling.

Despite the initial success of single-targeted chimeric-antigen receptor (CAR) T-cell therapy in hematological malignancies, its long-term effectiveness is often hindered by antigen heterogeneity and escape. As a result, there is a growing interest in cell therapies targeting multiple antigens (≥2). However, the dose-exposure-response relationship and specific factors influencing the pharmacology of dual-targeted CAR-T-cell therapy remain unclear. In this study, we have developed a multiscale cellular kinetic-pharmacodynamic (CK-PD) model using case studies from CD19/CD22 and GPRC5D/BCMA autologous CAR-Ts. Initially, an invitro tumor-killing model characterized the impact of individual binder affinities and their contribution to overall potency across varying (1) effector: target (ET) ratios and (2) tumor-associated antigen (TAA) expressing cell lines. Subsequently, an integrated CK-PD model was developed in pediatric acute lymphoblastic leukemia (ALL) patients, which accounted for CAR-T-cell product composition and relative antigen abundance in patients' tumor burden to characterize patient-level multiphasic cellular kinetics using multiple bioanalytical assays (e.g., flow and qPCR-based readouts). Global sensitivity analysis highlighted relative antigen expression, maximum killing rate constant, and CAR-T expansion rate constant as major determinants for observed exposure of dual-targeted CAR-T-cell therapy. This modeling framework could facilitate dose-optimization and construct refinement for dual-targeted bicistronic CAR-T-cell therapies, serving as a valuable tool for both forward and reverse translation in drug development.

Paediatric Acute Lymphoblastic Leukaemia: A Narrative Review of Current Knowledge and Advancements.

This review aims to provide an update on current knowledge regarding paediatric acute lymphoblastic leukaemia (ALL), focusing on recent advancements in diagnosis and treatment, as well as future directions in the field. ALL is the most frequently diagnosed paediatric malignancy, with advances leading to a 90% survival rate. The heterogeneity of childhood ALL requires a precise diagnostic algorithm incorporating morphological, immunophenotypic, and cytogenetic analyses. Research is exploring next-generation sequencing and artificial intelligence-aided techniques for future diagnostic approaches. Despite these advancements, global disparities in healthcare access hinder prompt diagnosis and management. The pathophysiology of ALL involves chromosomal and genetic alterations which disrupt cell-cycle regulation and result in uncontrolled lymphoblast proliferation. Environmental factors also contribute to leukaemogenesis. Risk-stratification based on genetic subtypes has significant implications for risk-based therapy. Chemotherapy is administered in three phases: induction, consolidation, and maintenance, with prophylactic intrathecal chemotherapy considered essential. For high-risk, refractory, or relapsed ALL, haematopoietic stem cell transplantation and novel therapies such as tyrosine kinase inhibitors, chimeric antigen receptor T-cell therapy, and blinatumomab immunotherapy, have improved outcomes. Ongoing clinical trials aim to further improve treatment efficacy, reduce toxicity, and increase survival. Although prevention strategies for ALL exist at three levels, the supporting evidence remains limited, highlighting a need for further research. Continued research and clinical trials are essential to addressing the gaps treatment efficacy and prevention strategies. Efforts to improve global healthcare access and integrate novel diagnostic and therapeutic approaches are crucial for advancing outcomes for paediatric patients with ALL.

Hemophagocytic lymphohistiocytosis caused by multiple infections during primary chemotherapy for pediatric acute lymphoblastic leukemia: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder that occurs as a consequence of immune dysregulation. HLH can be primary (familial or non-familial) or secondary to infection, autoimmune disease or malignancy. Malignancy-associated HLH is often accompanied by hematologic and lymphoid neoplasms. This report describes the case of a 3-year-old girl with an initial diagnosis of acute lymphoblastic leukemia who subsequently developed HLH during primary chemotherapy. She was admitted with a pulmonary infection, and initial blood tests showed thrombocytopenia and anemia. Whole-exome sequencing of gene and whole transcriptome RNA sequencing data indicated mutations of UNC13D. The hospital course was complicated by multiple infections, altered mental status and acute respiratory distress syndrome. HLH secondary to multiple infections that achieved remission following targeted therapy with ruxolitinib, in conjunction with corticosteroids and other complementary treatments. This report provides a synopsis of the diagnostic and treatment procedures implemented in this case.

Acute pancreatitis following asparaginase treatment in pediatric acute lymphoblastic leukemia with a heterozygous SPINK1 c.194 + 2T&gt;C intronic variant: a case report

BackgroundAsparaginase is a critical component of chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but its use is often complicated by asparaginase-associated pancreatitis (AAP). Genetic predispositions, such as variants in the SPINK1 gene, have been linked to an increased risk of pancreatitis. However, the role of genetic factors in relation to asparaginase treatment remains incompletely understood, partly because mutations in pancreatitis-causing genes are rarely found in pediatric ALL.Case descriptionA four-year and three-month-old Chinese girl was admitted to our hospital due to fever for half a day, with no history of significant prior medical history. Initial blood tests revealed hematological abnormalities, including leukopenia, anemia, and thrombocytosis. Bone marrow aspiration identified 81.5% blast cells with B-lymphocyte morphology and immunophenotype, leading to a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL). The patient began treatment under the CCCG-ALL-2015 protocol, which included PEG-asparaginase (PEG-asp). On day 10 of induction, she developed AAP, which was primarily characterized by severe epigastric pain and elevated serum amylase. Despite effective symptom management with analgesics and anti-inflammatory therapy, AAP recurred following administration of L-asparaginase (L-asp). Genetic analysis revealed a heterozygous SPINK1 c.194 + 2T&amp;gt;C variant (rs148954387), a well-known pathogenic variant associated with increased susceptibility to pancreatitis. Sanger sequencing confirmed that the SPINK1 variant was inherited from her asymptomatic mother. The patient's AAP was managed conservatively, and an asparaginase-free regimen ultimately achieved complete remission without recurrence of pancreatitis.ConclusionsThe identification of the SPINK1 c.194 + 2T&amp;gt;C variant, which is recognized as pathogenic, provides valuable information for understanding the heightened risk of AAP in our pediatric ALL patient. Our case underscores the potential role of genetic predisposition in the development of AAP and highlights the importance of considering genetic screening prior to asparaginase therapy in pediatric ALL patients to identify those at increased risk.

Enhancing outcomes of childhood acute lymphoblastic leukemia in workplace diversity in Thailand: multicenter study on behalf of the Thai Pediatric Oncology Group.

The Thai Pediatric Oncology Group (ThaiPOG) has adapted treatment regimens from the Children's Oncology Group (COG) to enhance outcomes for childhood acute lymphoblastic leukemia (ALL). This study examined the risk factors and treatment results of pediatric ALL in Thailand. This multicenter study included newly diagnosed children (< 18years) with ALL in 19 centers between January 1, 2015, and December 31, 2019. Most of the 1,157 patients (97.6%) were treated according to ThaiPOG protocols. The genetic testing was performed in 71% of patients. The patients were classified as standard (n = 539), high (n = 402), and very high (n = 130) risks. The 5-year event-free survival (EFS) and overall survival (OS) rates were 75% (95% confidence intervals (CI), 72%-77.8%) and 81.7% (95% CI, 78.9%-84.1%), respectively. The 5-year EFS rates of the standard-, high-, and very high-risk groups were 78.5% (95% CI, 74.1%-82.3%), 73.6% (95% CI, 68.5%-78%) (p = 0.761), and 65% (95% CI, 55.1%-73.3%) (p = 0.001), respectively, and the 5-year OS rates were 86.9% (95% CI, 83.1%-89.9%), 77.3% (95% CI, 72.5%-81.4%) (p = 0.001), and 73.1% (95% CI, 63.7%-80.4%) (p = 0.001), respectively. The independent risk factors for relapse and death were age ≥ 10years, white blood cells (WBCs) ≥ 50,000/mm3, M2 or M3 marrow status at the end of induction, and high-risk group. The overall outcome of Thai pediatric ALL has improved after the implementation of new modified COG treatment protocols. High-risk characteristics of ALL increased adverse outcome risk.

Clinical features and long-term prognostic analysis of relapsed pediatric acute lymphoblastic leukemia

Objective: To investigate the clinical characteristics and long-term prognostic factors of relapsed pediatric acute lymphoblastic leukemia (ALL). Methods: Clinical data including the age, time from initial diagnosis to relapse, relapse site, and molecular biological features of 217 relapsed ALL children primarily treated by the Chinese Children's Leukemia Group (CCLG)-ALL 2008 protocol in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences between April 2008 and April 2015 were collected and analyzed in this retrospective cohort study. Kaplan-Meier analysis was used to evaluate the overall survival (OS) rate and event free survival (EFS) rate for univariate analysis, and Cox proportional-hazards regression model was used to evaluate the influencing factors of OS rate and EFS rate for multivariate analysis. Results: The age at initial diagnosis of 217 relapsed patients was 5 (3, 7) years. There were 135 males and 82 females. The time from initial diagnosis to relapse of 217 children was 22 (10, 39) months. After relapse, 136 out of 217 children (62.7%) received treatment and the follow-up time was 65 (47, 90) months. The 5-year OS rate and EFS rate of the 136 relapsed children were (37±4) % and (26±4) %, respectively. The predicted 10-year OS rate and EFS rate were (35±5) % and (20±4) %, respectively. Univariate analysis showed that the 5-year OS rate in the group of patients with late relapse (43 cases) was significantly higher than those with very early (54 cases) and early relapse (39 cases) ((72±7)% vs. (16±5)%, (28±8)%, χ2=35.91, P<0.05), 5-year OS rate of the isolated extramedullary relapse group (20 cases) was significantly higher than isolated bone marrow relapse group (102 cases) and combined relapse group (14 cases) ((69±11)% vs. (31±5)%, (29±12)%, χ2=9.14, P<0.05), 5-year OS rate of high-risk group (80 cases) was significantly lower than standard-risk group (10 cases) and intermediate-risk group (46 cases) ((20±5)% vs. (90±10)%, (54±8)%, χ2=32.88, P<0.05). ETV6::RUNX1 was the most common fusion gene (13.2%, 18/136). The predicted 10-year OS rate of relapsed children with positive ETV6::RUNX1 was significantly higher than those without ETV6::RUNX1 (118 cases) ((83±9)% vs. (26±5)%, χ2=14.04, P<0.05). The 5-year OS for those accepted hematopoietic stem cell transplantation (HSCT) after relapse (42 cases) was higher than those without HSCT (94 cases) ((56±8)% vs. (27±5)%, χ2=15.18, P<0.05). Multivariate analysis identified very early/early relapse (HR=3.91, 95%CI 1.96-7.79; HR=4.15, 95%CI 1.99-8.67), bone marrow relapse including isolated bone marrow relapse and combined relapse (HR=6.50, 95%CI 2.58-16.34; HR=5.19, 95%CI 1.78-15.16), with ETV6::RUNX1 (HR=0.23, 95%CI 0.07-0.74) and HSCT after relapse (HR=0.24, 95%CI 0.14-0.43) as independent prognostic factors for OS (all P<0.05). Conclusions: Relapsed pediatric ALL mainly occurs very early and often affects bone marrow, which confer poor outcome. ETV6::RUNX1 is the most common genetic aberration with a favorable outcome. HSCT could rescue the outcome of relapsed children, though the survival rate is still poor.

Lymphocyte subsets in pediatric acute lymphoblastic leukemia and their prognostic value.

To study the changes of lymphocyte subsets in children with acute lymphoblastic leukemia (ALL) at initial diagnosis and compare them with those of healthy children and patients who have achieved complete remission (CR). Furthermore, we aim to analyze the prognostic significance of lymphocyte subsets in these patients. From May 2011 to December 2015, 405 children with ALL were enrolled in this study. Peripheral blood was collected at the time of diagnosis, and lymphocyte subsets were detected by flow cytometry. Then, the percentages of lymphocyte subsets in each group were compared. In addition, survival and prognostic factor analyses were performed to determine the prognostic value of lymphocyte subsets. Lymphocyte subsets in children with ALL were dramatically different from those in healthy children and patients achieving CR. Additionally, lymphocyte subsets were correlated with different minimal residual disease and risk parameters. Furthermore, percentages of CD3+ T cells and CD4+ T cells and the ratio of CD4/CD8 were associated with different clinical outcomes. Multivariate analysis demonstrated the percentage of CD4+ T cell as an independent predictor for clinical prognosis. Lymphocyte subsets in pediatric ALL undergo dramatic changes and were related to prognosis, especially CD4+ T cells.

Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: a population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite

Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: a population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite

Philadelphia chromosome-positive or Philadelphia chromosome-like B-cell precursor acute lymphoblastic leukemia with multilineage involvement in pediatric patients: a report of two cases and literature review.

Based on driver mutations and gene expression profiles, the International Consensus Classification currently divided the entity 'Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukemia (ALL)' into two subtypes: lymphoid-only and multilineage involvement (Ph+ ALL-L and -M, respectively). The similar biological characteristics of Ph-like ALL and Ph+ ALL drove us to assume that Ph-like ALL-M subtypes exist. This report presents two pediatric ALL cases (one Ph+ and one Ph-like) with minimal residual disease negativity established by multicolor flow cytometry but persistent transcript detection by quantitative PCR (qPCR) even after second-line treatment with tyrosine kinase inhibitors combined with blinatumomab immunotherapy. Using droplet digital PCR, BCR::ABL1 or TPM3::PDGFRB transcripts were identified in CD19+ cells as well as in non-CD19+ cells, suggesting the presence of a Ph+ or Ph-like ALL-M subtype originating from hematopoietic stem cells. This report provides information for better characterization, diagnosis, and treatment of these ALL subtypes.

Distinct Immunophenotypes in the DNA Index-Based Stratification of Pediatric B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) presents a challenge in hematological malignancies due to its heterogeneity, which impacts treatment outcomes. Stratification based on the DNA index (DNAi) categorizes patients into favorable prognosis (hyperploid), standard prognosis (normoploid), and uncertain or poor prognosis (hypoploid) groups. In this study, we explored whether specific immunophenotypic markers are associated with each DNAi-based group and their potential connection to prognostic categories, aiming to provide new insights that may contribute to a better understanding of prognosis in B-ALL. In this study, we utilized flow cytometry to analyze immunophenotypic markers and combined this with DNA index (DNAi) measurements to stratify pediatric B-ALL patients into distinct risk categories. Our methodology focused on accurately classifying patients into hyperploid, normoploid, and hypoploid groups based on their DNA content, facilitating a comparative analysis of immunophenotypic characteristics across these groups. Our analysis revealed that hypoploid B-ALL patients displayed a significantly lower percentage of cells in the S phase of the cell cycle compared to normoploid and hyperploid groups. Additionally, distinct immunophenotypic profiles were observed in hypoploid patients, characterized by higher expression levels of HLA-DR and a notable co-expression of CD34 and CD22. This study found that hypoploid B-ALL patients have distinct characteristics, such as lower S-phase cell percentages and specific immunophenotypic profiles, including higher HLA-DR expression and CD34/CD22 co-expression. These differences across DNA index-based prognostic categories warrant further research to explore their potential prognostic significance.

Assessing changes in brain structure in new-onset children with acute lymphoblastic leukemia.

Brain structure injury was presented in acute lymphoblastic leukemia (ALL) after treatment; however, its alterations in new-onset stage are still unclear. We aim to explore white matter (WM) and grey matter (GM) alterations using surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) in new-onset pediatric ALL. Thirty-five ALL and 33 typically developing (TD) children were prospectively recruited and underwent three-dimensional T1-weighted and diffusion tensor (DTI) imaging. DTI metrics, cortical GM features, anddeep GM nuclei volume were compared between groups differences. In ALL, the only increased FA in the body of corpus callosum (PFWE-corrected = 0.023) and left superior corona radiata (PFWE-corrected = 0.045) were presented. Relative to TDs, pediatric ALL presented a significant decrease in cortical surface area (CSA), thickness (CT), and volume in orbital gyri, supramarginal gyrus, middle temporal gyrus, and superior temporal gyrus (all CWP = 0.01). Additionally, increased CT and CSA were found in lingual gyrus and left sulcus intermedius primus, respectively (all CWP = 0.01). Smaller volumes in pediatric ALL were observed in bilateral thalamus, caudate, hippocampus, and right putamen (PFDR-corrected < 0.05). Widespread brain structural abnormalities were found in new-onset pediatric ALL, which suggest disease itself can cause brain structural injury. This study revealed the altered white matter integrity and gray matter morphology characteristics in childhood acute lymphoblastic leukemia on new-onset stage. It is suggested that there may be structural impairment before chemotherapy. MRI is a sensitive way for early detection on brain structural damage in childhood acute lymphoblastic leukemia.

Cost-utility of nelarabine for the first-line treatment of newly diagnosed pediatric T-cell acute lymphoblastic leukemia in Canada.

The Children's Oncology Group (COG)-AALL0434 trial investigated the addition of nelarabine to the augmented Berlin-Frankfurt-Münster (aBFM) protocol in patients (1.0-30.99years) with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL). Despite demonstrating superior outcomes, nelarabine is not currently funded by many health systems, in part due to a lack of cost-effectiveness data. We estimated the cost-utility of nelarabine for this indication from a Canadian public healthcare payer perspective. We developed a microsimulation model that followed hypothetical patients with newly diagnosed T-ALL from post-induction therapy to death. Three health states were modeled: relapse-free, post-relapse, and death. Efficacy was estimated using AALL0434 and retrospective data from Ontario, Canada. Costs were obtained from Canadian sources. Utility estimates and long-term mortality risks were sourced from literature. Total healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were reported. Probabilistic and scenario analyses were conducted. Incorporating nelarabine in the aBFM protocol increased costs by $51,670 Canadian dollars per patient, but resulted in 1.97 more QALYs and an ICER of $26,184/QALY. Most of the identified cost and benefit were accrued within the AALL0434 trial period (first 11years post diagnosis) and while patients were in the relapse-free health state. Across multiple scenarios, the ICER was stable under an assumed $50,000/QALY threshold. Incorporating nelarabine into aBFM was cost-effective across different scenarios and assumptions. These results support its funding by public and private payers.

Budget impact analysis of TPMT and NUDT15 pharmacogenomic testing for 6-mercaptopurine in pediatric acute lymphoblastic leukemia patients.

Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective. A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results. Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model. Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

Delayed excretion of high-dose methotrexate in pediatric acute leukemia correlates with laxative and constipation management.

Delayed excretion of high-dose methotrexate (HD-MTX) in pediatric acute lymphoblastic leukemia (ALL) can result in significant morbidity. While methotrexate is primarily renally excreted, HD-MTX may overwhelm renal excretion and increase reliance on fecal elimination. This study evaluated the association between laxative use for constipation and delayed excretion of HD-MTX. This multisite chart review included pediatric patients with ALL (2010-2020) who received HD-MTX (5g/m2). Delayed excretion was defined as a serum MTX concentration greater than 0.4µM at Hour 48. We identified use of laxative medications after each HD-MTX infusion, with receipt of two or more doses considered a proxy for constipation. Multilevel logistic regression models evaluated associations between clinical factors and delayed HD-MTX excretion to account for multiple MTX cycles per individual. A total of 533 eligible patients received 1875 HD-MTX infusions. Patients were mostly male (59.8%), Hispanic (56.7%), with a median age of 9.5years. Delayed excretion was observed following 42.7% of HD-MTX infusions, and patients received two or more laxative doses during 19.9% of infusions. Independent of other factors, individuals who received two or more laxative doses were nearly 60% (odds ratio 1.58; 95% confidence interval: 1.19-2.09; p=.002) more likely to experience delayed excretion compared to those receiving fewer than two laxative doses. Receipt of at least two laxative doses was independently associated with delayed methotrexate excretion in pediatric patients with ALL. Future prospective studies are needed to confirm the secondary effects of constipation and confirm the association with constipation and identify clinical benefits that optimize drug excretion.

Enhancer looping protein LDB1 modulates MYB expression in T-ALL cell lines in vitro by cooperating with master transcription factors

BackgroundDespite significant progress in the prognosis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) in recent decades, a notable portion of children still confronts challenges such as treatment resistance and recurrence, leading to limited options and a poor prognosis. LIM domain-binding protein 1 (LDB1) has been confirmed to exert a crucial role in various physiological and pathological processes. In our research, we aim to elucidate the underlying function and mechanisms of LDB1 within the background of T-ALL.MethodsEmploying short hairpin RNA (shRNA) techniques, we delineated the functional impact of LDB1 in T-ALL cell lines. Through the application of RNA-Seq, CUT&Tag, and immunoprecipitation assays, we scrutinized master transcription factors cooperating with LDB1 and identified downstream targets under LDB1 regulation.ResultsLDB1 emerges as a critical transcription factor co-activator in cell lines derived from T-ALL. It primarily collaborates with master transcription factors (ERG, ETV6, IRF1) to cooperatively regulate the transcription of downstream target genes. Both in vitro and in vivo experiments affirm the essential fuction of LDB1 in the proliferation and survival of cell lines derived from T-ALL, with MYB identified as a significant downstream target of LDB1.ConclusionsTo sum up, our research establishes the pivotal fuction of LDB1 in the tumorigenesis and progression of T-ALL cell lines. Mechanistic insights reveal that LDB1 cooperates with ERG, ETV6, and IRF1 to modulate the expression of downstream effector genes. Furthermore, LDB1 controls MYB through remote enhancer modulation, providing valuable mechanistic insights into its involvement in the progression of T-ALL.

Comparative Evaluation of the Immunophenotypic Profile of Acute Lymphoblastic Leukaemia in Adult and Paediatric Age Groups in Iraq

Background: Immunophenotyping is a primary tool for investigating acute lymphoblastic leukemia (ALL). Acute lymphoblastic leukemia accounts for 75 - 80% of pediatric leukemia cases and 14% of adult leukemia cases. However, the prognostic factors, treatment strategies, and pathogenic pathways differ between these groups. Objectives: This study aims to compare the pattern of antigen expression between adult and pediatric ALL patients in the Iraqi population and to evaluate the frequency of aberrant myeloid antigen expression in both groups. Methods: A total of 131 patients with de-novo ALL were studied from May 2014 to May 2015. The diagnosis of ALL was confirmed by morphology and immunophenotyping of peripheral blood and bone marrow aspirate specimens using a panel of fluorochrome-labeled antibodies in 6 - colored flow cytometry. Results: The B-ALL phenotype was prevalent in 44 (68.7%) of adult patients compared to 51 (76.1%) in the pediatric group. CD10 expression was present in 49 (76.6%) of adults, mostly with B-ALL. The pediatric group had lower CD10 expression in T-ALL (P = 0.039). CD20 expression was significantly lower in adults compared to children. In T-ALL, significant differences between adult and pediatric groups were observed in CD1a and CD2 expression. Aberrant myeloid antigen expression was present in 29 (45.3%) adults and 30 (44.8%) pediatric patients, with CD33 and CD13 being the most prevalent in both groups. Conclusions: There was an increased T-cell lineage and aberrant antigen expression in both adult and pediatric ALL cases in this Iraqi sample. Adults with ALL tend to display higher levels of CD20 and lower levels of CD1a and CD2 compared to children, markers associated with poorer prognoses.

Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.