Search Results (909)

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy defined by the uncontrolled proliferation of lymphoid precursors. Accurate diagnosis and effective therapeutic strategies hinge on a comprehensive understanding of the genetic and molecular landscape of ALL. This review synthesizes the latest updates in cytogenetic and molecular classifications, emphasizing the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) revisions. Key chromosomal alterations such as BCR::ABL1 and ETV6::RUNX1 and emerging subtypes including Ph-like ALL, DUX4, and MEF2D rearrangements are examined for their prognostic significance. Furthermore, we assess novel diagnostic tools, notably next-generation sequencing (NGS) and optical genome mapping (OGM). While NGS excels at identifying point mutations and small indels, OGM offers high-resolution structural variant detection with 100% sensitivity in multiple validation studies. These advancements enhance our grasp of leukemogenesis and pave the way for precision medicine in both B- and T-cell ALL. Ultimately, integrating these innovations into routine diagnostics is crucial for personalized patient management and improving clinical outcomes. Full article

Background and aim: Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, tissues, or cells that target rare and severe diseases. ATMPs have shown promising clinical outcomes but are associated with high costs, raising questions about cost-effectiveness. Hence, this systematic review aims to analyze the cost-effectiveness and cost-utility profiles of the European Medicines Agency-authorized ATMPs for treating rare diseases. Methods: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching PubMed, Embase, Web of Science, and ProQuest scientific databases. Economic evaluations reporting incremental cost-effectiveness/utility ratios (ICERs/ICURs) for ATMPs were included. Costs were standardized to 2023 Euros, and a cost-effectiveness plane was constructed to evaluate the results against willingness-to-pay (WTP) thresholds of EUR 50,000, EUR 100,000, and EUR 150,000 per QALY, as part of a sensitivity analysis. Results: A total of 61 studies met the inclusion criteria. ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon. Tisagenlecleucel demonstrated a positive cost-effectiveness profile in the treatment of acute lymphoblastic leukemia (58%), while axicabtagene ciloleucel showed a positive profile in the treatment of diffuse large B-cell lymphoma (85%). Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. Conclusions: ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes. Full article

Chromosomal microarray analysis (CMA) was performed for 40 patients with B-ALL undergoing treatment according to the ALL-2016 protocol to investigate the copy number alterations (CNAs) and copy neutral loss of heterozygosity (cnLOH) associated with minimal residual disease (MRD)-positive remission. Aberrations involving over 20,000 genes were identified, and a random forest approach was applied to isolate a subset of genes whose CNAs and cnLOH are significantly associated with poor therapeutic response. We have assembled the triple matched healthy population data and used that data as a reference, but not as a matched control. We identified a recurrent cluster of cnLOH in the 19q13.2–19q13.31 region, significantly enriched in MRD-positive patients (70% vs. 47% in the reference group vs. 16% in MRD-negative patients). This region includes the pregnancy-specific glycoprotein (PSG) gene family and the oncogene ERF, suggesting a potential role in leukemic persistence and treatment resistance. Additionally, we observed significant deletions involving 7p22.3 and 16q13, often as part of large-scale losses affecting almost the entire chromosomes 7 and 16, indicative of global chromosomal instability. These findings highlight specific genomic regions potentially involved in therapy resistance and may contribute to improved risk stratification in B-ALL. Our findings emphasize the value of high-resolution CMA in diagnostics and risk stratification and suggest that PSG genes and other candidate genes could serve as biomarkers for predicting treatment outcomes. Full article

Background/Objective: In patients with acute lymphoblastic leukemia (ALL), it has been demonstrated that the treatment has a negative effect on bone health. The n-3 polyunsaturated fatty acids (LCPUFAs-ω3) may attenuate bone resorption. We evaluated the effects of LCPUFAs-ω3, vitamin D, and calcium supplementation on bone turnover markers and changes in vitamin D concentrations during 6 weeks of supplementation and during 6 weeks of post-intervention follow-up in pediatric patients with ALL. Methods: Thirty-six pediatric patients with ALL were randomly assigned to the ω-3VDCa group (100 mg/kg/d LCPUFAs-ω3 + 4000 IU vitamin D + 1000 mg calcium) or the VDCa group (4000 IU vitamin D + 1000 mg calcium) for 6 weeks. Blood samples were collected to determine 25(OH)D, PTH, ICTP, and TRAP-5b (biomarkers of bone resorption) and osteocalcin (OC, a biomarker of bone production) levels at baseline, 6 weeks, and 12 weeks after supplementation. The 25(OH)D analysis was performed using ultra-high-performance liquid chromatography coupled to a mass spectrometer, and PTH and bone turnover markers were measured by ELISA. Results: The 25(OH)D concentration increased in both groups (ω3VDCa group: 19.4 ng/mL vs. 44.0 ng/mL, p < 0.0001; VDCa group: 15.3 ng/mL vs. 42.8 ng/mL, p = 0.018) and remained significantly higher at 12 weeks. At 12 weeks, ICTP showed lower concentrations in the ω-3VDCa group than in the VDCa group (0.74 ng/mL vs. 1.05 ng/mL, p = 0.024). Conclusions: Combined omega-3 and 4000 IU vitamin D supplementation for 6 weeks had a positive effect on bone health, as indicated by serum ICTP, with no effect on serum 25(OH)D levels over vitamin D supplementation alone. Full article

Current treatments against leukemia present several limitations, prompting the search for new therapeutic agents, particularly those derived from natural products. In this context, structural modifications were performed on the triterpene 3α,24-dihydroxylup-20(29)-en-28-oic acid (T1), isolated from Phoradendron wattii. Among the five derivatives obtained, 3α,24-dihydroxy-30-oxolup-20(29)-en-28-oic acid (T1c) exhibited the highest activity, with an IC₅₀ value of 12.90 ± 0.1 µM against THP-1 cells. T1c significantly reduced cell viability in both acute lymphoblastic leukemia (CCRF-CEM, REH, JURKAT, and MOLT-4) and acute myeloid leukemia (THP-1) cell lines, inducing apoptosis after 48 h of treatment, while showing minimal cytotoxicity toward normal mononuclear cells (MNCs). In silico molecular docking studies were conducted against three key protein targets: BCL-2 (B-cell lymphoma 2), EGFR (epidermal growth factor receptor, tyrosine kinase domain), and FLT3 (FMS-like tyrosine kinase 3). The lowest binding energies (kcal/mol) observed were as follows: T1–BCL-2: −10.12, EGFR: −12.75, FLT3: −14.05; T1c–BCL-2: −10.23, EGFR: −14.50, FLT3: −14.07; T2–BCL-2: −11.59, EGFR: −15.00, FLT3: −14.03. These findings highlight T1c as a promising candidate in the search for anti-leukemic drugs which deserves further study. Full article

Background: In childhood acute lymphoblastic leukemia (ALL), in addition to classical chromosomal abnormalities, loss of heterozygosity (LOH), including copy-neutral LOH, is also observed. While LOH has been described in the literature, its clinical relevance in pediatric ALL remains unclear. The aim of this study is to identify and analyze patterns of LOH, assess their frequency, and evaluate their association with clinical characteristics and early treatment response during the induction phase of the ALL protocol. Methods: The study included 853 pediatric ALL patients, of whom 120 had B-ALL LOH+ and 58 had T-ALL LOH+. LOH was analyzed using CytoScan HD SNP microarrays. Patients were stratified using multiple correspondence analysis (MCA) and hierarchical clustering on principal components (HCPC), which identified three genetically and clinically distinct clusters. Results: In B-ALL, two clusters with extensive LOH—particularly involving chromosome 9—were associated with poor prognosis and suboptimal response to therapy. In contrast, Cluster 2, characterized by CDKN2A duplication and rare LOH, showed a favorable clinical course. In T-ALL, Cluster 1 had LOH in CDKN2A but favorable outcomes; Cluster 2 exhibited biallelic CDKN2A deletion and aggressive disease; Cluster 3 lacked CDKN2A alterations and showed a genetically stable profile. LOH was common on chromosomes not typically affected by trisomy and rare on those gained. Conclusions: Our study indicates that LOH profiling can positively influence patient stratification by identifying high-risk subgroups, inform prognosis by highlighting unfavorable genetic alterations, and help predict poor treatment response in specific clinical profiles. Full article

In acute lymphoblastic leukemia (ALL), neutropenia and fever of unknown origin may occur, indicating the use of antimicrobials to control a probable infection. However, in 60–70% of cases there is no obvious infectious focus so treatment is empirical, increasing the risk of developing systemic inflammatory response syndrome (SIRS). The construction of a prognostic model of fever and development of SIRS based on the identification of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs) and inflammatory cytokines, can help identify children with ALL and fever or SIRS and who do not have an infection. A cohort of 30 children with recently diagnosed ALL and absence of infectious microorganisms before starting the remission induction phase was studied. Two groups were identified: (1) a group with SIRS (fever, tachycardia, tachypnea, and leukopenia, without focus of infection) and (2) a group without SIRS. The DAMPs, namely HMGB1 and S100A8 proteins, were quantified by ELISA and inflammatory mediators were determined by multiple protein analysis. The medians of DAMPs and inflammatory mediators in children with SIRS were higher than in children who did not have SIRS, and the delta values of the biomarkers studied in patients with and without SIRS showed important differences, with statistically higher medians in patients with SIRS compared to those without SIRS. HMGB1 together with IL-1β, IL-8, IL-10, and MCP-1 can serve as biomarkers to identify children with ALL and fever or SIRS who should not receive antimicrobial treatment because the origin of their fever is not due to an infectious agent. Full article

Over the past two decades, the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation. Once considered the subtype with the worst prognosis, Ph+ ALL is now associated with the possibility of long-term survival in a significant proportion of patients. This dramatic improvement has been driven by the advent of tyrosine kinase inhibitors (TKIs) and, more recently, by the incorporation of blinatumomab, a bispecific T-cell engager antibody, into frontline therapeutic strategies. In this evolving context, two major areas have become the focus of clinical investigation: on the one hand, the identification of high-risk patients who truly benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT); on the other, the characterization of patients who can achieve durable responses without transplantation and who may be candidates for treatment discontinuation of TKIs. This review aims to summarize the current evidence supporting the concept of treatment-free remission (TFR) in Ph+ ALL. Full article

The Wnt signaling pathway plays a critical role in regulating normal hematopoiesis and immune cell development. However, its dysregulation has emerged as a key driver of leukemogenesis. Leukemic stem cells exploit aberrant Wnt signaling to sustain self-renewal, evade apoptosis, and promote unchecked proliferation. In this review, we highlight the dual roles of canonical and non-canonical Wnt pathways in acute leukemia, emphasizing their distinct and overlapping contributions to disease progression. We also evaluate current preclinical and clinical strategies targeting Wnt signaling, identifying both promising advances and persistent obstacles to therapeutic translation. By elucidating the molecular mechanisms underlying Wnt pathway dysregulation in leukemic cells, this review underscores the potential of Wnt-directed therapies as a novel class of interventions to improve outcomes for patients with acute leukemia. Full article

Mitochondria are critical for cellular energy, and while large deletions in their genome (mtDNA) are linked to primary mitochondrial diseases, their significance in cancer is less understood. Given cancer’s metabolic nature, investigating mtDNA deletions in tumors at various stages could provide insights into disease origins and treatment responses. In this study, we analyzed 148 bone marrow samples from 129 pediatric patients with B-cell (B-ALL) and T-cell (T-ALL) acute lymphoblastic leukemia at diagnosis, remission, and relapse using long-range PCR, next-generation sequencing, and the Splice-Break2 pipeline. Both T-ALL and B-ALL exhibited significantly more mtDNA deletions than did the controls, with T-ALL showing a ~100-fold increase and B-ALL a ~15-fold increase. The T-ALL samples also exhibited larger deletions (median size > 2000 bp) and greater heterogeneity, suggesting increased mitochondrial instability. Clustering analysis revealed distinct deletion profiles between ALL subtypes and across disease stages. Notably, large clonal deletions were detected in some B-ALL remission samples, including one affecting up to 88% of mtDNA molecules, which points toward treatment-driven selection or toxicity. A multivariate analysis confirmed that disease type, timepoint, and WHO subtype significantly influenced mtDNA deletion metrics, while age and gender did not. These findings suggest that mtDNA deletion profiling could serve as a biomarker for pediatric ALL and may indicate mitochondrial toxicity contributing to late effects in survivors. Full article

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine. Full article

Menin inhibitors are a class of targeted agents that exemplify how a deeper understanding of leukemia pathogenesis can unify seemingly distinct genetic acute leukemia subgroups under a common therapeutic strategy. In particular, acute leukemia with NPM1 mutations (NPM1m) and KMT2A rearrangements (KMT2Ar) represent the primary targets of this emerging drug class. Acute myeloid leukemia (AML) with NPM1m—which accounts for approximately 30% of AML cases and AML or acute lymphoblastic leukemia (ALL) with KMT2Ar—and is present in 5–10% of cases, shares a common pathogenetic mechanism: the aberrant activation of the MEIS1–HOXA axis. These leukemic subsets are associated with poor prognosis, particularly in the relapsed/refractory (R/R) setting. For KMT2Ar AML, the prognosis is especially dismal, with a median overall survival (OS) of 2.4 months and a complete remission (CR) rate of only 5%. In NPM1m AML, intensive chemotherapy achieves remission in approximately 80% of cases, but relapse remains a major challenge, occurring in nearly 50% of patients. Relapsed NPM1m AML is linked to a poor prognosis, with a median OS of 6.1 months (12-month OS: 30%) and a median relapse-free survival (RFS) of 5.5 months (12-month RFS: 34%). Menin inhibitors directly target the leukemogenic transcriptional program driven by HOX and MEIS1, disrupting oncogenic signaling and offering a promising therapeutic approach for these high-risk patients. This class of agents has rapidly progressed through clinical development, showing promising antileukemic activity in both treatment-naïve and R/R AML. Currently, six menin inhibitors are in clinical evaluation as monotherapy or in combination regimens: revumenib, ziftomenib, bleximenib (previously JNJ-75276617), enzomenib (previously DSP-5336), DS-1594, and BMF-219. In this review, we critically analyze the clinical development and therapeutic potential of the four most extensively studied menin inhibitors—revumenib, ziftomenib, bleximenib, and enzomenib. We discuss their efficacy, safety profiles, and potential roles within the current treatment algorithm. The continued clinical evaluation of menin inhibitors may redefine treatment paradigms for NPM1m and KMT2Ar AML and other acute leukemia with the aberrant MEIS1-HOXA axis, offering new hope for patients with limited therapeutic options. Full article

Despite the successes achieved in recent years in the treatment of childhood acute lymphoblastic leukemia (ALL), high-risk ALL in particular still represents a considerable challenge, with poorer outcomes. The PI3K/AKT/mTOR signaling pathway is frequently constitutively activated in ALL and consequently leads to unrestricted cell proliferation, without showing frequent mutations in the most important representatives of the signaling pathway. Recent studies have shown that fine balanced protein expression is a common way to adjust oncogenic B cell directed receptor signaling and to mediate malignant cell proliferation and survival in leukemic cells. Too low expression of inhibitory phosphatases can lead to constitutive signaling of kinases, which are important for cell proliferation and survival. In contrast, marked high expression levels of key phosphatases enable cells with distinct pronounced oncogenic B cell directed receptor signaling to escape negative selection by attenuating signal strength and thus raising the threshold for deletion checkpoint activation. One of the most important B cell receptor-dependent signaling cascades is the PI3K/AKT signaling pathway, with its important antagonist SHIP1. However, recent data show that the inositol-5-phosphatase SHIP1 is differentially expressed across the heterogeneity of the ALL subtypes, making the overall therapeutic strategy targeting SHIP1 more complex. The aim of this article is therefore to provide an overview of the current knowledge about SHIP1, its expression in the various subtypes of ALL, its regulation, and the molecules that influence its gene and protein expression, to better understand its role in the pathogenesis of leukemia and other human cancers. Full article

Acute lymphoblastic leukemia (ALL) is the most common cancer affecting children, making up about 80% of all acute leukemia cases in the pediatric population. While treatment with L-asparaginase (ASNase) has greatly improved survival rates, its bacterial origin often causes immune reactions in some patients, which can reduce how well the therapy works. To overcome this challenge, previous in silico studies designed a humanized chimeric ASNase by swapping out the predicted immunogenic parts of the bacterial enzyme with similar, less immunogenic segments from the human version—while keeping the enzyme’s active site intact. In this study, the chimeric L-asparaginase designed was successfully cloned, expressed, and purified using the Escherichia coli Rosetta strain. The production conditions (37 °C, 0.01 mM IPTG, 2–4 h) were optimized, and we purified the enzyme in a single step with nickel-affinity chromatography. The enzyme’s activity was confirmed in vitro, showing that it is possible to produce a functional humanized variant in a bacterial system. These results lay important groundwork for future research to assess the immune response and therapeutic potential of this novel chimeric enzyme. Full article

Background: Asparaginase (ASPase) plays an important role in the therapy of acute lymphoblastic leukemia (ALL). Serum ASPase activity (SAA) can be modified and even abolished by host immune responses; therefore, current treatment guidelines recommend to monitor SAA during treatment administration. The SAA monitoring schedule needs to be carefully planned to reduce the number of samples without hampering the possibility of measuring pharmacokinetics (PK) parameters in individual patients. Complex modelling approaches, not easily applicable in common practice, have been applied in previous studies to estimate ASPase PK parameters. This study aimed to estimate PK parameters by using a simplified approach suitable for real-world settings with limited sampling. Methods: Our study was based on 434 patients treated in Italy within the AIEOP-BFM ALL 2009 trial. During the induction phase, patients received two doses of pegylated ASPase and were monitored with blood sampling at five time points, including time 0. PK parameters were estimated by using the individually available SAA measurements with simple modifications of the classical non-compartmental PK analysis. We also took the opportunity to develop and validate a series of limited sampling models to predict ASPase exposure. Results: During the induction phase, average ASPase activity at day 7 was 1380 IU/L after the first dose and 1948 IU/L after the second dose; therapeutic SAA levels (>100 IU/L) were maintained until day 33 in 90.1% of patients. The average AUC and clearance were 46,937 IU/L × day and 0.114 L/day/m², respectively. The database was analyzed for possible associations of PK parameters with biological characteristics of the patients, finding only a limited dependence on sex, age and risk score; however, these differences were not sufficient to allow any dose or schedule adjustments. Thereafter the possibility of further sampling reduction by using simple linear models to estimate the AUC was also explored. The most simple model required only two samplings 7 days after each ASPase dose, with the AUC being proportional to the sum of the two measured activities A(7) and A(21), calculated by the formula AUC = 14.1 × [A(7) + A(21)]. This model predicts the AUC with 6% average error and 35% maximum error compared to the AUC estimated with all available measures. Conclusions: Our study demonstrates the feasibility of a direct estimation of PK parameters in a real-life situation with limited and variable blood sampling schedules and also offers a simplified method and formulae easily applicable in clinical practice while maintaining a reliable pharmacokinetic monitoring. Full article