Genetic polymorphisms of tumor necrosis factor receptor-associated factor 3 and their association with acute lymphoblastic leukemia.

Impact of NQO1, GSTM1 and GSTT1 genetic variants on susceptibility and relapse in childhood acute lymphoblastic leukemia.

Development and characterization of anti-CXCR4 chimeric antigen receptor T cells.

Blast cell segmentation and leukemia classification using hybrid Deep Kronecker WideResNet using blood smear images.

ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

Gasoline stations and risk of childhood cancer: a population-based cohort study in Quebec, Canada.

Handgrip strength and body composition in children and adolescents with acute lymphoblastic leukemia: A cross-section study.

Children treated for acute lymphoblastic leukemia (ALL) are at risk of neurocognitive deficits in attention-concentration, working memory, executive function, and psychomotor speed. This study evaluated longitudinal trajectories and medical/demographic associations with neurocognitive outcomes during treatment of newly diagnosed ALL. Patients ages 3-21 treated on DFCI 16-001 (NCT03020030) across eight North American sites (2017-2022) were evaluated using Cogstate across four timepoints from diagnosis through maintenance phase. Linear mixed models estimated trajectories and interactions with clinical factors over time, incorporating random effects for patients and sites. Among 298 patients (median age 7.9years, 53% male), performance changed significantly over time in varying directions for executive functioning, attention, visual learning, and working memory-accuracy (all p < 0.001). There was a significant interaction overall between age and time for psychomotor function (interaction p = 0.01) and working memory-accuracy (interaction p < 0.001). Older age was associated with worse performance on working memory-speed (β = -0.04) and attention (β = -0.05). Female sex was associated with worse performance on psychomotor function (β = -0.27) and working memory-accuracy (β = -0.50), but better on visual learning (β = 0.47) and working memory-speed (β = 0.30). A greater-than-expected proportion of participants performed below -1.5 SD on tests of attention, executive functioning, and psychomotor functioning at multiple timepoints. While most patients demonstrated normal neurocognitive functioning, including variable trajectories, a subgroup performed poorly on attention, executive functioning, and psychomotor functioning. Risk factors include older age at diagnosis and female sex, which may provide insight into groups warranting early intervention.

Measurable residual disease detection in acute leukemia: Technological advances and clinical translation.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The pro-drug 6-mercaptopurine (6-MP), essential during maintenance, is converted into active 6-thioguanine (6-TGN) and toxic 6-methylmercaptopurine (6-MMP) metabolites, resulting in marked variability in efficacy and toxicity. 6-MP therapy is further limited by poor adherence, variable absorption, and complex metabolism. Allopurinol is sometimes used to correct skewed metabolism, though its precise clinical role remains unclear. This study aimed to develop population pharmacokinetic (popPK)-based strategies to optimize 6-MP dosing in children and improve therapeutic outcomes. A popPK model was developed using 6-MMP and 6-TGN concentrations from the pediatric oncology cohort. Model-based simulations in 1000 virtual patients were performed to explore optimized dosing strategies, with and without allopurinol, aiming to reach the therapeutic target (6-MMP <5700pmol/8×108RBC and 6-TGN between 230 and 450pmol/8×108RBC). The popPK model revealed a linear correlation between 6-MP dose and metabolite concentrations. Allopurinol co-administration substantially shifted metabolites' distribution from 80% 6-MMP/20% 6-TGN to 21% 6-MMP/79% 6-TGN. Simulations identified optimal 6-MP doses of 40-75mg/m2 without allopurinol, and only 10-15mg/m2 when co-administered. Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have a poor prognosis. In Ph+ALL04, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) was indicated for all patients, and was performed in those who remained in CR at the scheduled time of transplantation, with 4-year event-free survival (EFS) and overall survival (OS) rates of 54% (95% confidence interval [CI]: 38%-68%) and 78% (95% CI: 62%-88%), respectively. The Japan Children's Cancer Group conducted ALL-Ph13, a multicenter single-arm Phase 2 clinical trial, to improve outcomes and reduce HSCTs by using chemotherapy with tyrosine kinase inhibitors (TKIs) guided by minimal residual disease (MRD). The primary endpoint was the 3-year EFS rate. Between 2013 and 2017, 41 of 43 enrolled patients with Ph+ ALL aged 1-19years were eligible. Imatinib was started on Day 15 of induction and switched to dasatinib if MRD-positive after consolidation IB. TKIs were administered until the end of maintenance treatment (Week 104), with temporary discontinuation due to the severity of nonhematological adverse events and resumption at 80% of the original dose. When MRD was positive after the three HR blocks, HSCT was performed. Following four sepsis-related deaths, the protocol was amended in 2016, after which no such deaths occurred. Six patients (15%) underwent HSCT in the first CR, one per protocol indication and five without. The 3-year EFS and OS rates were 65% (95% CI: 48%-78%) and 85% (95% CI: 70%-93%), respectively. As several relapses occurred beyond 3years, the 5-year EFS and OS rates were also calculated: 48% (95% CI: 30%-64%) and 85% (95% CI: 70%-93%), respectively. Compared with Ph+ALL04, HSCT was substantially reduced in ALL-Ph13 while maintaining comparable outcomes. Further optimization of treatment, particularly the duration of TKI administration, is needed to maintain long-term EFS.

Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.

Gamma delta T cell reconstitution in Acute Lymphoblastic Leukemia patients post allogeneic HSCT predicts clinical outcome and overall survival.

A review of treatment strategies for elderly patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia.

An Adaptive Deep Learning Architecture Integrating Local Feature Enrichment, Adaptive Learning Rate, and Channel Recalibration for Acute Lymphoblastic Leukemia Image Classification

Central nervous system (CNS) relapse remains a clinically significant yet underexplored pattern of recurrence in adult patients with acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic cell transplantation (allo-HCT). We retrospectively analyzed 748 adult ALL patients who underwent allo-HCT between 2009 and 2022 following a modified hyper-CVAD regimen with six planned doses of intrathecal (IT) chemoprophylaxis. Most patients received total body irradiation (TBI)-based conditioning. CNS relapse occurred in 38 (5.1%) patients at a median of 10.6 months post-HCT. Notably, 84.2% of CNS relapses occurred in Philadelphia chromosome (Ph)-positive ALL. Thus, Ph-positive ALL compared to Ph-negative ALL (9.7% vs. 1.4%, p < 0.001) and hyperleukocytosis at diagnosis (8.1% vs. 2.5%, p < 0.001) were associated with CNS relapse. Notably, negative pre-transplant measurable residual disease (MRD) in Ph-positive ALL and prophylactic IT and TBI-based conditioning were associated with reduced CNS relapse risk in Ph-negative ALL. Five-year overall survival of CNS relapse and the other relapse was 30.4% and 7.6%, respectively, and isolated CNS relapse showed the most favorable outcomes. Our findings suggest that Ph-positive ALL with poor molecular response and high initial tumor burden may represent a biologically distinct high-risk subgroup for CNS relapse, warranting novel CNS-directed preventive strategies to improve post-HCT outcomes.

High‑dose methotrexate (HD‑MTX) is a cornerstone of pediatric acute lymphoblastic leukaemia (ALL) therapy. However, deviations from protocol-mandated infusion durations need regular monitoring as part of standard quality care. Hence, an observational quality assessment study was planned with a secondary objective to evaluate the acute toxicity in patients who did not receive the infusion within the recommended time period. This study enrolled 42 children (75 cycles) who received HD-MTX (3-5g/m2 over 24h) according to the ICiCLe ALL-14 protocol. The actual infusion duration was recorded, and 48-h MTX levels were measured using an enzyme-multiplied immunoassay technique. Toxicity was graded via CTCAE v5.0. Only 35% of cycles were completed within the targeted 24-h window [Median (IQR): 23.75h (21.25, 25.33)]. Prolonged infusions (> 25h) resulted in significantly higher 48-h MTX levels compared to shortened infusions (median 0.475 vs 0.270µmol/L; p = 0.015). Multivariable analysis identified male sex (OR, 12.24), T-ALL immunophenotype (OR, 8.36), and the infusion duration (OR, 1.50 per hour) as independent predictors of delayed clearance. A 48-h level > 0.315µmol/L predicted development of toxicity (AUC 0.686), though no life-threatening event or mortality was recorded in any cycle. Additionally, MTX levels did not differ significantly across the four HD-MTX cycles that each patient received, and elevated levels in one cycle did not predict delayed clearance in subsequent cycles. Deviations in infusion duration were high and independently drive pharmacokinetic variability and toxicity. Ensuring timely drug delivery is as critical as dose precision.

Hyperglycemia during treatment for pediatric acute lymphoblastic leukemia (ALL) is often induced by corticosteroids and asparaginase. Although insulin remains the standard therapy, oral metformin presents a promising alternative due to its ease of use, lower risk of hypoglycemia, and noninvasive route of administration-factors that can significantly enhance patient comfort and quality of life. To evaluate the efficacy and safety of oral metformin in managing therapy-induced hyperglycemia (TIH) in children with ALL. An ambispective analysis was conducted over 6 years (September 2018-August 2024) in pediatric ALL patients who developed hyperglycemia during induction or re-induction. We assessed the effectiveness of metformin in controlling hyperglycemia and the need for insulin in cases of suboptimal response. Out of 281 ALL patients, 54 (19.2%) developed TIH, with a median age of 12 years (range 5-16). Most cases (57.4%, n=31) occurred in the preadolescent/adolescent group. Pre-B ALL accounted for 85.2% (n=46), and T-ALL for 14.8% (n=8). A WBC count >20×109/L was noted in 44.4% (n=24). BMI was normal in 63% (n=34), whereas 22.2% (n=12) were overweight. Extremes of BMI (underweight/obese) were seen in 7.4% (n=4) each. Most cases occurred during induction (49 patients), with 17 experiencing recurrence during re-induction. Hyperglycemia typically appeared within a week of initiating steroids. The mean baseline glucose was 240mg/dL (range: 201-338mg/dL), which declined to 137mg/dL at Day 7 (range: 110-174mg/dL), with a mean reduction from baseline of 103mg/dL. Metformin (up to 1500mg/day) successfully controlled blood glucose in 36 induction-phase patients (73.4%, 95% CI 59.7-83.8), whereas 13 (26.5%) required insulin. During re-induction, seven patients needed dual therapy. Insulin was added for glucose >300mg/dL, signs of ketoacidosis, or poor response to metformin. In the TIH group, febrile neutropenia and culture-positive sepsis occurred in 42.6% (n=23) and 24.1% (n=13), respectively-higher than in non-hyperglycemic patients. All patients reverted to euglycemia after steroid tapering, with no long-term hypoglycemic therapy needed. Metformin was well-tolerated, with no adverse effects warranting discontinuation. Glycemic management did not interfere with leukemia remission or treatment completion. Oral metformin proved to be a safe and effective first-line option for managing TIH in pediatric ALL. Insulin therapy could be avoided in majority of the patients (73.4% in induction, 68.1% in re-induction), making this drug an attractive first-line option for children with treatment-induced non-severe hyperglycemia.

IDH2 Clonal Hematopoiesis and IKAROS Loss Cooperate in a B-ALL Subtype after Lenalidomide Therapy for Multiple Myeloma.

Role of cystatin C in predicting the risk of hypermethotrexemia and kidney injury after high-dose methotrexate chemotherapy in childhood acute lymphoblastic leukemia.