[Experience with an international study on standard-risk relapsed childhood acute lymphoblastic leukemia (IntReALL SR 2010 study) in Japan].

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients.

BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.

Disseminated Enterovirus Infection Complicated by Rhabdomyolysis in a Child with Acute Lymphoblastic Leukemia.

Enterovirus is not a common cause of myositis and rhabdomyolysis in children. We report a case of a two-year-old boy with acute lymphoblastic leukemia with disseminated enterovirus infection complicated by hepatitis, myositis, and rhabdomyolysis. The case was managed successfully with supportive care and high-dose intravenous immunoglobulins.

The Outcome of Modified St. Jude Total XV Protocol in Turkish Children with Newly Diagnosed Acute Lymphoblastic Leukemia: A Single-Center Retrospective Analysis.

Objective: This study examines the prognostic factors and outcomes of Turkish children with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated with Modified St. Jude Total XV Protocol, which was modified by adding high-dose methylprednisolone (HDMP) before induction in the original protocol. Materials and Methods: A cohort of 183 newly diagnosed ALL patients aged 1-18 years received Modified St. Jude Total XV Therapy between January 1, 2008 and January 30, 2016. HDMP was administered for 7 days, with randomized doses at 10 or 20 mg/kg/d, tapered during the subsequent 7 days to 5 and 10 mg/kg/d, followed by 2 mg/kg/d for 2 weeks. Absolute blast count in peripheral blood and minimal residual disease (MRD) in bone marrow were assesses at the end of the initial HDMP treatment (Day 7). MRD in the bone marrow was measured on day 15 and at the end of the induction period. These patients were followed until July 15, 2019. Results: The five-year event-free (EFS) and overall survival (OAS) rates for all patients were 85.6±2.6% and 89.2±2.3%, respectively. The steroid good responder rate (<1 000/mm3 absolute blast count in peripheral blood on Day 7) was 88%, with 97% of children achieving complete remission post-induction. No significant differences were observed between the two groups in survival rate and infection frequency. EFS and OAS correlated with initial leukocyte count, age 10-18 years at diagnosis, CD20 positivity at diagnosis, and gram-negative bacterial infection during remission induction. Conclusion: The notable response rates on day 7 and 15, along with encouraging EFS and OAS outcomes with Modified St. Jude Total XV in childhood ALL patients underscore the early and high response effect of HDMP. Short-term HDMP can be initiated at the onset of induction, administered at 10 mg/kg/day for the initial 7 days, aiming to minimize potential side effects.

Acute Leukemia and Latent Tuberculosis Infection in Italy: Quantiferon-Tb Test Screening in a Low Tuberculosis Incidence Country.

Background: Identification of latent tuberculosis infection (LTBI) is a critical step of tuberculosis surveillance, especially in low-incidence countries. However, it is limited to situations with a higher probability of developing active disease, e.g., patients with hematological malignancies. According to guidelines, in TB non-endemic countries, no clear screening program is established at diagnosis for patients with acute leukemia (AL). The primary endpoint of this study was to establish the prevalence of LTBI in patients with a diagnosis of AL using QuantiFERON (QFT)-TB. Secondarily, radiological and clinical features driving the increased risk of LTBI were evaluated. Methods: QFT-TB screening was performed before induction or consolidation in all patients with AL (myeloid and lymphoid) treated at our Institution between October 2019 and August 2023. Results: We accrued 62 patients, of whom 7 (11,3%) tested positive, without any symptoms or signs of active TB, and 2 (3,2%) resulted as indeterminate. All positive patients started prophylaxis with isoniazid 300 mg daily, while patients whose test was indeterminate did not receive any prophylaxis. Active TB was excluded by imaging, as well as microscopic, cultural, and molecular examination on bronchoalveolar lavage if signs of any infection were detected. During the 46 months of observation, no patients developed TB reactivation. Conclusions: Despite the low sample size, 1/10 of our patients had prior TB exposure, hinting that LTBI could be more common than expected in Italy. This finding suggests implementing TB screening in the pre-treatment setting, particularly at a time when more active treatments are becoming available also for patients ineligible for intensive chemotherapy.

Health-related quality of life among pediatric patients with acute lymphoblastic leukemia: An exploratory cross-sectional study.

BACKGROUND: Improved survival rates broadened the pediatric oncology focus to include health-related quality of life (HRQoL). This cross-sectional study aimed to examine HRQoL by treatment phase and disease risk level in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), including those in early survivorship. PROCEDURE: A subset of data from a larger prospective cohort study was analyzed. Data were collected from 73 patients (73 parent reports and 28 self-reports). Parent proxy and self-report PROMIS measures assessed HRQoL across treatment phases (early intensive, maintenance, and off treatment) and disease risk groups (standard vs high). Analyses assessed the relationship between parent proxy and patient self-reports and the differences in HRQoL among treatment phases and risk groups. RESULTS: Parent proxy reports generally indicated worse fatigue, pain interference, and mobility compared with patient self-reports. Self-reports in the early intensive treatment group suggested worse depressive symptoms, fatigue, mobility, and upper extremity function compared with those in later phases. Parent proxy reports showed worse fatigue and depressive symptoms in early intensive treatment group relative to those in later phases. Patient self-reports in the maintenance group demonstrated the best peer relationships scores. Parent proxy reports in the high-risk group reported significantly higher depressive symptoms and fatigue compared with the standard-risk group. CONCLUSIONS: Differences in HRQoL suggest targets for further assessment and intervention. The early treatment and immediate post-survivorship periods may represent particularly critical time points. Longitudinal studies with larger and diverse samples should further explore HRQoL trajectories in this population.

A Chronological Overview of Using Deep Learning for Leukemia Detection: A Scoping Review.

Leukemia is a rare but fatal cancer of the blood. This cancer arises from abnormal bone marrow cells and requires prompt diagnosis for effective treatment and positive patient prognosis. Traditional diagnostic methods (e.g., microscopy, flow cytometry, and biopsy) pose challenges in both accuracy and time, demanding an inquisition on the development and use of deep learning (DL) models, such as convolutional neural networks (CNN), which could allow for a faster and more exact diagnosis. Using specific, objective criteria, DL might hold promise as a tool for physicians to diagnose leukemia. The purpose of this review was to report the relevant available published literature on using DL to diagnose leukemia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles published between 2010 and 2023 were searched using Embase, Ovid MEDLINE, and Web of Science, searching the terms "leukemia" AND "deep learning" or "artificial neural network" OR "neural network" AND "diagnosis" OR "detection." After screening retrieved articles using pre-determined eligibility criteria, 20 articles were included in the final review and reported chronologically due to the nascent nature of the phenomenon. The initial studies laid the groundwork for subsequent innovations, illustrating the transition from specialized methods to more generalized approaches capitalizing on DL technologies for leukemia detection. This summary of recent DL models revealed a paradigm shift toward integrated architectures, resulting in notable enhancements in accuracy and efficiency. The continuous refinement of models and techniques, coupled with an emphasis on simplicity and efficiency, positions DL as a promising tool for leukemia detection. With the help of these neural networks, leukemia detection could be hastened, allowing for an improved long-term outlook and prognosis. Further research is warranted using real-life scenarios to confirm the suggested transformative effects DL models could have on leukemia diagnosis.

Recurrent Cerebral Venous Sinus Thrombosis Occurred in an Acute Lymphoblastic Leukemia Child with Mutated Lipoprotein Lipase Gene during Asparaginase Therapy.

Cerebral venous sinus thrombosis (CVST) and hyperlipidemia are severe complications of L-Asparaginase (L-Asp) during the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Herein, we reported a 9-year-old B-ALL boy who underwent abnormal hypertriglyceridemia and CVST presenting as seizures and disturbance of consciousness twice during the induction therapy. Fortunately, he survived treatment with anticoagulant and lipid-lowering therapy. No thrombophilia-related gene mutation was detected, but a heterozygous mutation in lipoprotein lipase (LPL) gene was identified. His neurological symptoms were managed with short-term anticoagulant therapy and long-term lipid-lowering therapy. This case illustrated the manifestation and potential pathogenesis of CVST and highlighted the essentiality of screening baseline lipid profile and dyslipidemia- and thrombophilia-related gene mutation.

Flow Cytometry-Based Detection of Minimal/Measurable Residual Disease Predicts Survival Outcomes in Pediatrics, Adolescents, and Young Adults With T-acute Lymphoblastic Leukemia.

BACKGROUND: Measurable/minimal residual disease (MRD) is considered the single most powerful high-risk factor in acute leukemia, including T-cell acute lymphoblastic leukemia (T-ALL). In this study, we evaluated the impact of flow cytometry (FC)-based detection of MRD on survival outcomes in pediatrics, adolescents, and young adults (AYA) with T-ALL. METHODS: We included 139 patients, 88 pediatric patients between the ages of one and 14 years, and 51 AYA patients between 15 and 39 years of age, over a period of three years and were treated with the Indian Collaborative Childhood Leukemia Group (ICiCLe) protocol. MRD assessment was performed on post-induction (PI) bone marrow aspirate samples using a 10-color 11-antibody MRD panel on a Gallios instrument (Beckman Coulter, Miami, FL, USA). MRD value > 0.01% was considered positive. PI-MRD status was available in 131 patients. RESULTS: The five-year event-free survival (5-year EFS) in PI-MRD positive patients was inferior to those of negative patients (13.56% vs 79.06%), which was statistically significant (P < 0.001). However, the five-year overall survival (5-year OS) did not show any statistically significant difference between PI-MRD positive and negative T-ALL patients (92.93% vs 94.28%). The hazard ratio (HR) for 5-year EFS and MRD positivity was 8.03 (p-value < 0.0001). HR for 5-year EFS and early T-cell precursor ALL (ETP-ALL) was 2.63 (p = -0.02). CONCLUSIONS: PI-MRD detected using FC is a strong predictive factor of inferior survival outcomes in pediatrics, AYA patients with T-ALL. PI-MRD positivity can be used to modify the treatment of T-ALL patients, especially in resource-constrained developing countries where molecular tests are not widely available.

CoTCoNet: An optimized coupled transformer-convolutional network with an adaptive graph reconstruction for leukemia detection.

BACKGROUND: Swift and accurate blood smear analyses are crucial for diagnosing leukemia and other hematological malignancies. However, manual leukocyte count and morphological evaluation remain time-consuming and prone to errors. Additionally, conventional image processing methods struggle to differentiate cells due to visual similarities between malignant and benign cell morphology. METHOD: In response to above challenges, we propose Coupled Transformer Convolutional Network (CoTCoNet) framework for leukemia classification. CoTCoNet integrates dual-feature extraction to capture long-range global features and fine-grained spatial patterns, facilitating the identification of complex hematological characteristics. Additionally, the framework employs a graph-based module to uncover hidden, biologically relevant features of leukocyte cells, along with a Population-based Meta-Heuristic Algorithm for feature selection and optimization. Furthermore, we introduce a novel combination of leukocyte segmentation and synthesis, which isolates relevant regions while augmenting the training dataset with realistic leukocyte samples. This strategy isolates relevant regions while augmenting the training data with realistic leukocyte samples, enhancing feature extraction, and addressing data scarcity without compromising data integrity. RESULTS: We evaluated CoTCoNet on a dataset of 16,982 annotated cells, achieving an accuracy of 0.9894 and an F1-Score of 0.9893. We tested CoTCoNet on four diverse, publicly available datasets (including those above) to assess generalizability. Results demonstrate a significant performance improvement over existing state-of-the-art approaches. CONCLUSIONS: CoTCoNet represents a significant advancement in leukemia classification, offering enhanced accuracy and efficiency compared to traditional methods. By incorporating explainable visualizations that closely align with cell annotations, the framework provides deeper insights into its decision-making process, further solidifying its potential in clinical settings.

Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

The Role of the JAK-STAT Pathway in Childhood B-Cell Acute Lymphoblastic Leukemia.

B-cell lymphoblastic leukemia is a hematologic neoplasm that poses a serious health concern in childhood. Genetic aberrations, such as mutations in the genes IL-7, IL7R, JAK1, JAK2, TLSP, CRLF2, and KTM2A or gene fusions involving BCR::ABL1, ETV6::RUNX1, and PAX5::JAK2, often correlate with the onset of this disease. These aberrations can lead to malfunction of the JAK-STAT signaling pathway, which is implicated in various important biological processes, including those related to immunology. Understanding the mechanisms underlying the malfunction of the JAK-STAT pathway holds potential for research on drugs targeting its components. Available drugs that interfere with the JAK-STAT pathway include fludarabine, ruxolitinib, and fedratinib.

TLR Agonists Modify NK Cell Activation and Increase Its Cytotoxicity in Acute Lymphoblastic Leukemia.

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.

Blinatumomab Maintenance Therapy Following Bone Marrow Transplantation for Early Relapsed Pediatric B-cell Precursor Acute Lymphoblastic Leukemia and Analysis of Lymphocyte Subset Changes.

Blinatumomab, a CD19/CD3 bispecific T-cell engager, is recognized as an effective immunotherapy for relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the efficacy and safety of blinatumomab in post-hematopoietic stem cell transplantation (HSCT) maintenance therapy has not been established. A 5-year-old male patient with BCP-ALL suffered a relapse in his bone marrow during maintenance therapy. After re-induction therapy with UK-R3 regimen, 2.3% of the blasts remained. Then the blinatumomab was administered, and he achieved minimal residual disease (MRD)-negative complete remission (CR). After two cycles of blinatumomab, he underwent allogeneic bone marrow transplantation (BMT) from his human leukocyte antigen (HLA)-matched sibling, following conditioning with total body irradiation, etoposide, and cyclophosphamide. Two cycles of blinatumomab maintenance therapy were initiated to prevent relapse. There was no exacerbation of graft-versus-host disease (GVHD) or other severe adverse events. CR was maintained for >22 months after BMT. A t-distributed symmetric neighbor embedding (tSNE) analysis revealed that blinatumomab altered the CD8+ population, as with pre-HSCT use, and markedly reduced the CD8+19dim+/CD8+CD19- ratio (i.e., naïve lymphocyte predominance). Blinatumomab maintenance therapy after HSCT may be considered a safe treatment.

Ikaros sets the threshold for negative B-cell selection by regulation of the signaling strength of the AKT pathway.

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection.

Upregulation of the long noncoding RNA GJA9-MYCBP and PVT1 is a potential diagnostic biomarker for acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common type of blood cancer in children. Aberrant expression of long noncoding RNAs (lncRNAs) may set stages for ALL development. LncRNAs are emerging as a novel diagnostic and prognostic biomarker for ALL. Herein, we aimed to evaluate the expression of lncRNA GJA9-MYCBP and PVT1 in blood samples of ALL and healthy individuals. METHODS: As a case-control study, 40 pairs of ALL and healthy individual samples were used. The expression of MYC and each candidate lncRNA was measured using quantitative real-time PCR. Any possible association between the expression of putative noncoding RNAs and clinicopathological characteristics was also evaluated. RESULTS: LncRNA GJA9-MYCBP and PVT1 were significantly upregulated in ALL samples compared with healthy ones. Similarly, mRNA levels of MYC were increased in ALL samples than control ones. Receiver operating characteristic curve analysis indicated a satisfactory diagnostic efficacy (p-value <.0001), suggesting that lncRNA GJA9-MYCBP and PVT1 may serve as a diagnostic biomarker for ALL. Linear regression analysis unveiled positive correlations between the expression level of MYC and lncRNA GJA9-MYCBP and PVT1 in ALL patients (p-values <.01). CONCLUSIONS: In this study, we provided approval for the clinical diagnostic significance of lncRNA GJA9-MYCBP and PVT1that their upregulations may be a diagnostic biomarker for ALL.

Systematic review: genetic polymorphisms in the pharmacokinetics of high-dose methotrexate in pediatric acute lymphoblastic leukemia patients.

Variations in pharmacokinetic responses to high-dose methotrexate are essential for the prognosis and management of toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL) patients. This systematic review aimed to identify and evaluate genetic polymorphisms that are significantly associated with the pharmacokinetic parameters of methotrexate during the consolidation phase of pediatric ALL treatment. Using the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we systematically reviewed the literature from 2013 to 2023. The databases used were PubMed and Scopus. The outcomes of interest are the study design, patient characteristics, sample size, chemotherapy protocol utilized, pharmacokinetic parameters identified, and genetic polymorphisms implicated. We included 31 articles in the qualitative synthesis and found that the SLCO1B1, ABCB1, ABCC2, and MTHFR genes appear to play significant roles in MTX metabolism and clearance. Among these, variations in SLCO1B1 have the most significant and consistent impact on methotrexate clearance. These implicated variants may contribute to the precision and tailoring of HD-MTX treatment in pediatric ALL patients.

Acute Pancreatitis Caused by Pegylated (PEG)-Asparaginase Associated With Severe Hypertriglyceridemia.

Pegylated (PEG)-asparaginase is used during the induction and intensification phases of treatment for B-cell acute lymphoblastic leukemia (B-ALL). It works by depleting the external sources of asparagine, causing the death of lymphoblasts. It has several adverse effects, including pancreatitis and hypertriglyceridemia; however, the simultaneous occurrence of both is uncommon. We present the case of an 18-year-old man with B-ALL who developed acute epigastric pain radiating to the back and non-bloody, non-bilious emesis following treatment with PEG-asparaginase. He was diagnosed with acute interstitial pancreatitis and severe hypertriglyceridemia. Conservative management was used for the pancreatitis, while hypertriglyceridemia was treated with an insulin infusion. Pancreatic toxicity and hypertriglyceridemia can necessitate the discontinuation of PEG-asparaginase, limiting treatment options and potentially increasing the risk of relapse. Therefore, further studies are needed to identify the factors contributing to hypertriglyceridemia and pancreatitis, aiding clinicians in monitoring and prevention.