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Background: Children's exposure to chemotherapeutic agents causes several long-term adverse effects but physical activity has been evidenced to be an effective strategy to improve cardiac function. This cross-sectional study aimed to explore the association between physical activity levels, cardiorespiratory fitness, and cardiac parameters measured by echocardiography. Methods: Participants were 216n childhood acute lymphoblastic leukemia survivors who underwent a maximal cardiopulmonary exercise test and self-reported their daily minutes of moderate to vigorous physical activity. They underwent a complete transthoracic echocardiographic assessment. Systolic and diastolic function analysis and strain images analysis were performed. The associations were studied through the preventive fraction (examined with univariate crude and adjusted logistic regression models) of regular physical activity (≥150 min·wk−1) and adequate cardiorespiratory fitness levels (above the median ≥ 32.0 mL·kg−1·min−1) on cardiac parameters. Results: Crude analysis shows that regular physical activity was associated with a significant preventive fraction in mitral E/A ratio (56%; P =.013), while adjusted analyses highlighted a nonsignificant reduction of 74% to 37% in the prevalence of cardiac parameters associated with physical activity. Similar associations of adequate cardiorespiratory fitness on cardiac parameters were observed. Adjusted analyses revealed a nonsignificant reduction of 7% to 86% in the prevalence of cardiac parameters associated with cardiorespiratory fitness. Conclusion: This study reports that regular physical activity and adequate cardiorespiratory fitness were associated with a higher preventive fraction. Thus, engaging in physical activity prevents childhood acute lymphoblastic leukemia survivors' cardiac dysfunctions. These findings are novel and clinically relevant in pediatric cardiooncology and provide additional evidence to strengthen the benefits of exercise as long-term care in childhood cancer survivors. [ABSTRACT FROM AUTHOR]

COVID-19 infection is still a mystery in terms of its long-term effect on health and its consequences on hematological disorders. Prior studies including ours have shown the abnormal changes in hematopoietic cells in COVID-19 patients. In this article, we are presenting 2 cases of pediatric B-lymphoblastic leukemia (B-ALL) with a previous history of COVID-19 infection. The first case describes a 22-month-old boy presenting with lymphadenopathy, neutropenia, and anemia with concurrent COVID-19 infection without any evidence of a hematolymphoid neoplasm as per bone marrow and lymph node biopsy. However, he presented after 2 months with bone marrow biopsy confirming B-ALL. The second case is that of a 4-year-old girl presenting with B-ALL who has had asymptomatic COVID-19 infection 5 months before this current presentation. Both the cases had complete resolution of COVID-19 infection during the time of presentation with acute leukemia. There were notably 2 rare findings along the course of the patients illnesses. First, the unusual plasmacytosis in the marrow during active COVID-19 infection in the first patient and the second, is predilection of development of B-ALL following COVID-19. In both the cases the fluorescence in situ hybridization (FISH) studies showed pathologic alteration of the RUNX1 gene. Overall, there are no literature to support a causal association between acute B-ALL and COVID-19. The diagnosis of B-ALL in these patients after COVID-19 infection may be totally unrelated. However, if we consider Greaves proposed 2-hit model for childhood acute leukemia, that an infectious agent can precipitate development of B-ALL in a genetically susceptible individual. Alteration of the RUNX1 gene in both the patients, opens a door for further exploration of the second-hit hypothesis regarding an infectious agent precipitating development of B-ALL in a genetically susceptible individual.

In the treatment of diseases such as acute childhood leukaemia (ALL) and inflammatory bowel disease (IBD), the thiopurines azathioprine, 6-mercaptopurine, and 6-thioguanine are used. Thiopurines are antimetabolites and immunomodulators used to maintain remission in patients. They are all prodrugs and must be converted into the competing antimetabolites thioguanosine triphosphate and deoxythioguanosine triphosphate for final incorporation into RNA or DNA. The current therapeutic drug monitoring (TDM) method measures the sum of the formed metabolites in the sample, after acidic hydrolysis at high temperature. In this work, the goal is to measure these drugs closer to their pharmacological endpoints, once incorporated into DNA. After extracting DNA from whole blood, followed by DNA hydrolysis, 2′-deoxythioguanosine (dTG) and the complementary natural nucleobase 2′-deoxycytidine (dC) were measured. Chromatographic separation on a HSS T3 column followed by mass spectrometric detection was performed in multi-reaction monitoring (MRM) mode on a Xevo TQ-XS with ESI in positive mode, within 5 min. The concentration range for dTG was 0.04–5 nmol/L, and for dC, 0.1–12.5 µmol/L. The lower limit of detection was determined to a concentration of 0.003 nmol/L for dTG and 0.019 µmol/L for dC. The intra- and inter-assay imprecision for the quality controls ranged between 3.0 and 5.1% and between 8.4 and 10.9%, respectively. Sample stability for up to 4 years is shown. In summary, a sensitive method to quantify the thiopurines incorporated into DNA as dTG has been developed and will be used in further clinical studies for a better understanding of the mode of action of the thiopurines and the use of this method in TDM. [ABSTRACT FROM AUTHOR]

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) exhibits hematological features that are indistinguishable from those of acute megakaryoblastic leukemia. However, TAM typically resolves spontaneously within several months postnatally. Some patients with TAM, however, develop severe clinical manifestations, which can lead to an unfavorable prognosis. TAM originates in utero through the acquisition of somatic GATA1 mutations, resulting in the loss of the full‐length GATA1 protein and excessive production of the N‐terminal truncated short isoform of the GATA1 protein (GATA1s). Herein, we report the pathological findings from an autopsy of a female stillbirth with TAM and DS, including an examination of her placental tissues. Immunohistochemical analysis revealed the expression of GATA1s, but not full‐length GATA1, in CD42b‐positive atypical immature megakaryocytes and blasts in the placental blood vessels. This confirms the diagnosis of TAM and suggests the utility of placental tissue for histological diagnosis. Additional unique findings from the autopsy specimens are discussed. [ABSTRACT FROM AUTHOR]

A 35-year-old male patient with acute myeloid leukemia (AML), with hyperleukocytosis, presented with acute myocardial infarction. The individual had acute onset chest pain and reached the hospital within the window period. His electrocardiogram (ECG) revealed ST elevated myocardial infarction (STEMI), ST elevated myocardial infarction, and thrombolysis was performed. Postthrombolysis, there was no resolution of ST elevation, and coronary angiography revealed normal coronaries. His blood picture showed hyperleukocytosis with 80% blasts, and bone marrow and flow cytometry confirmed the diagnosis of AML. Considering the central role of white blood cell in the remodeling of myocardial tissue, it was obvious that administration of chemotherapy with its inevitable pancytopenia could impose an increased risk for further cardiac complications. Nevertheless, cytarabine-based induction chemotherapy was initiated; on the third day, he developed bilateral diffuse alveolar hemorrhage. He was managed with mechanical ventilation, component support, empirical antibiotics, and other bundled care. The patient died 2 days later with diffuse alveolar hemorrhage and leukemia. [ABSTRACT FROM AUTHOR]

The diagnosis of acute lymphoblastic leukemia (ALL), which is the most common type of cancer in children, has become more accurate with the use of flow cytometry. Here, this technology was used to immunophenotype leukemic cells in peripheral blood samples from Libyan pediatric ALL patients. We recruited 152 newly diagnosed patients at Tripoli Medical Center (Tripoli, Libya) by morphological examination of blood and bone marrow. Twenty-three surface and cytoplasmic antigen markers were used to characterize B and T cells in circulating blood cells by four-color flow cytometry. Six children (3.9%) turned out to have biphenotypic acute leukemia, 88 (57.9%) had B ALL, and 58 (38.1%) had T ALL. There were 68 cases of pro-B ALL CD10-positive (44.7%), 8 cases of pro-B ALL CD10-negative (5.2%), 6 cases of pre-B ALL (3.9%), and 6 of mature-B ALL (3.9%). CD13 was the most commonly expressed myeloid antigen in ALL. We present immunophenotypic data for the first time describing ALL cases in Libya. The reported results indicate that the most common subtype was pro-B ALL, and the frequency of T-ALL subtype was higher compared to previous studies. Six cases were positive for both myeloid and B lymphoid markers. Our findings may provide the basis for future studies to correlate immunophenotypic profile and genetic characteristics with treatment response among ALL patients. [ABSTRACT FROM AUTHOR]

Rearrangements and overexpression of CRLF2 are hallmarks of poor outcomes in BCR::ABL1-like B-ALL, and CRLF2 overexpression is a high-risk marker in T-ALL. However, CRLF2 alterations in pediatric hematologic malignancies other than B-ALL have not been reported. In this study, we analyzed the CRLF2 overexpression, rearrangements (P2RY8::CRLF2 and IGH::CRLF2), activation (pSTAT5 and pERK), and the expression of dominant-negative IKZF1 isoforms (Ik6 and Ik8), implied in CRLF2 dysregulation, in 16 pediatric patients (AML, n = 9; T-ALL, n = 3; LBL, n = 2; HL, n = 1; cytopenia, n = 1). A high frequency of CRLF2 rearrangements and overexpression was found in the 16 patients: 28.6% (4/14) showed CRLF2 overexpression, 93.8% (15/16) were positive for CRLF2 total protein (cell-surface and/or cytoplasmic), while 62.5% (10/16) were positive for P2RY8::CRLF2 and 12.6% (2/16) for IGH::CRLF2. In addition, 43.8% (7/16) expressed Ik6 and Ik8 isoforms. However, only a few patients were positive for the surrogate markers pSTAT5 (14.3%; 2/14) and pERK (21.4%; 3/14). [ABSTRACT FROM AUTHOR]

This retrospective analysis evaluated the use of anti-thymocyte globulin (ATG) with or without post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis in children with acute leukemia undergoing hematopoietic stem cell transplantation (HSCT). The study included 57 children, with 35 in the ATG-PTCy group and 22 in the ATG group. While overall incidence of acute and chronic GvHD did not differ significantly between groups, the ATG-PTCy group had lower rates of grade II-IV acute GvHD (p = 0.013) and moderate-to-severe chronic GvHD (p = 0.001) compared to the ATG group. Importantly, ATG-PTCy significantly improved GvHD/relapse-free survival (GRFS) compared to ATG (65.71% vs. 36.63%; p = 0.003). There were no differences in engraftment, infection rates, immune reconstitution, overall survival, leukemia-free survival, relapse rate, or non-relapse mortality between the two groups. Combining ATG with PTCy may reduce moderate-to-severe GvHD and improve GRFS in children undergoing HSCT for acute leukemia. [ABSTRACT FROM AUTHOR]

Introduction: Acute lymphoblastic leukaemia (ALL) is the most common type of childhood leukaemia with effective chemotherapeutic treatment. However, obesity has been associated with higher ALL chemoresistance rates and lower event‐free survival rates. The molecular mechanism of how obesity promotes chemotherapy resistance is not well delineated. Objectives: This study evaluated the effect of adipocyte maturation on sequestration and metabolism of chemotherapeutic drug daunorubicin (DNR). Methods: Using targeted LC‐MS/MS multi‐analyte assay, DNR sequestration and metabolism were studied in human preadipocyte and adipocyte cell lines, where expressions of DNR‐metabolizing enzymes aldo‐keto reductases (AKR) and carbonyl reductases (CBR) were also evaluated. In addition, to identify the most DNR‐metabolizing AKR/CBR isoforms, recombinant human AKR and CBR enzymes were subject to DNR metabolism. The results were further validated by AKR‐, CBR‐specific inhibitors. Results: This report shows that adipocyte maturation upregulates expressions of AKR and CBR enzymes (by 4‐ to 60‐ folds, p <.05), which is positively associated with enhanced sequestration and metabolism of DNR in adipocytes compared to preadipocytes (by ~30%, p <.05). In particular, adipocyte maturation upregulates AKR1C3 and CBR1, which are the predominate metabolic enzyme isoforms responsible for DNR biotransformation to its metabolites. Conclusion: Fat is an expandable tissue that can sequester and detoxify DNR when stimulated by obesity, likely through the upregulation of DNR‐metabolizing enzymes AKR1C3 and CBR1. Our data partially explains why obese ALL patients may be more likely to become chemoresistant towards DNR, and provides evidence for potential clinical investigation targeting obesity to reduce DNR chemoresistance. [ABSTRACT FROM AUTHOR]

Purpose: High-dose methotrexate (HDMTX) therapy is an important component in treatment regimens for acute lymphoblastic leukemia (ALL). Courses are associated with a risk of renal injury, delayed elimination, and increased systemic toxicity. Recently hypoalbuminemia has been recognized as yet another risk factor. Methods: To examine the impact of serum albumin we reviewed 325 HDMTX 5 g/m2 courses in a cohort of 51 children treated on the NOPHO ALL 2008 protocol, dividing the courses into four groups with different levels of baseline albumin (A < 25 g/L, B 25–29 g/L, C 30–34 g/L and D ≥ 35 g/L). Results: Hypoalbuminemia was present in 51% of the courses, mostly in the early phases of chemotherapy while asparaginase therapy is ongoing, and especially if given less than 2 weeks after a dose (78%). Hypoalbuminemia had a significant impact on the end-of-infusion serum MTX, depending on the degree of hypoalbuminemia: MTX > 150 µM was seen in 37%, 32%, 20% and 8% in groups A to D. Serum albumin < 30 g/L was significantly associated with low MTX clearance < 10 L/h/1.73m2 (78% vs. 36%) and high AUC ≥ 1000 µM*h (44% vs. 31%). The frequency of rising creatinine or prolonged elimination was not increased, but the risk of stomatitis was significantly higher (42% vs. 19%). Conclusion: Low serum albumin is caused by concurrent asparaginase therapy and has a clinically significant impact on MTX disposition. Guidelines for administering HDMTX may need adjustment if serum albumin < 30 g/L, and, if possible, HDMTX courses should not be scheduled soon after asparaginase doses. [ABSTRACT FROM AUTHOR]

Objective: Chimeric antigen-receptor T-cell therapy (CAR-T) is characterised by early phase data at the time of registration, high upfront cost and a complex manufacturing and administration process compared with standard therapies. Our objective was to compare the performance of different models to assess the cost effectiveness of CAR-T using a state-transition model (STM), partitioned survival model (PSM) and discrete event simulation (DES). Methods: Individual data for tisagenlecleucel for the treatment of young patients with acute lymphoblastic leukaemia (ALL) were used to populate the models. Costs and benefits were measured over a lifetime to generate a cost per quality-adjusted life-year (QALY). Model performance was compared quantitatively on the outcomes generated and a checklist developed summarising the components captured by each model type relevant to assessing cost effectiveness of CAR-T. Results: Models generated similar results with base-case analyses ranging from an incremental cost per QALY of $96,074–$99,625. DES was the only model to specifically capture CAR-T wait time, demonstrating a substantial loss of benefit of CAR-T with increased wait time. Conclusion: Although model type did not meaningfully impact base-case results, the ability to incorporate an outcome-based payment arrangement (OBA) and wait time are important elements to consider when selecting a model for CAR-T. DES provided greater flexibility compared with STM and PSM approaches to deal with the complex manufacturing and administration process that can lead to extended wait times and substantially reduce the benefit of CAR-T. This is an important consideration when selecting a model type for CAR-T, so major drivers of uncertainty are considered in funding decisions. [ABSTRACT FROM AUTHOR]

Forty-one families with multiple cases of de novo acute myeloid leukemia (AML), B-cell acute lymphocytic leukemia (B-ALL), or both are presented. The families were randomly collected from physicians, genetic counselors, and other sources. Medical records were collected and reviewed for all families. In 17 of the families, a parent and child with acute leukemia were identified; and in 15 of the pairs, the parent and child were of the same sex. Nine grandparent–grandchild affected pairs with AML-AML were identified, occurring in six families, and six of those pairs were also of the same sex. Anticipation was a common feature of these multigenerational pairs. Twenty families were identified with multiple siblings (none twins) with acute leukemia. This includes 16 sibling pairs and 4 sibling triples. The members of each sibling pair in the AML-AML group and in the B-ALL-B-ALL group were generally of roughly the same age. Curiously, this is not true of those in the AML-B-ALL group. Four of the 41 families had contributions to more than 1 family relationship category. Although inheritance in familial acute leukemia has usually been consistent with an autosomal dominant pattern, these data suggest that an X chromosome gene may be involved in some cases, perhaps in the pseudoautosomal region of the X chromosome as we have reported in familial Hodgkin lymphoma. [ABSTRACT FROM AUTHOR]

AbstractBlinatumomab, a CD19/CD3 bispecific T-cell engager; inotuzumab ozogamicin (INO), a CD22 antibody drug conjugate; and chimeric-antigen receptor (CAR) T-cell constructs are novel immune-therapeutic options for treatment of acute lymphoblastic leukemia (ALL). The use of blinatumomab has recently expanded to multiple B-ALL treatment settings. Despite the efficacy of blinatumomab, its use can be challenging in the real-world because of limited experience with its administration and management of toxicities. Optimal use and sequencing of blinatumomab is critical to improve outcomes, reduce undesired toxicities, and decrease discontinuation rates related to such toxicities. Herein, we discuss strategies to address the unique adverse effects of blinatumomab and ways to optimize its administration and integration into the treatment backbone of B-ALL. We outline our approach to combining and sequencing blinatumomab with other immunotherapies, such as INO and CD19 CAR T-cells, and provide recommendations for the management of toxicities and dose-optimization of blinatumomab therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Methotrexate (MTX) is the primary drug used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, some patients exhibit delayed clearance of high-dose (HD) MTX, which induces severe nephrotoxicity, mucositis, hepatotoxicity, and neurotoxicity. We sought to identify relevant variants associated with delayed clearance of HD-MTX in pediatric patients with ALL. Methods: Whole-exome sequencing of germline DNA was performed in 51 Korean pediatric patients with ALL. A total of 341 HD-MTX infusion data points from 51 patients were analyzed. MTX levels and laboratory measurements reflecting toxicity outcomes were obtained. Correlations between peak serum MTX levels at 24 h and toxicity outcomes were assessed. Analyses were performed to identify variants affecting delayed MTX clearance. Results: The 24 h MTX level strongly correlated with the subsequent creatinine (Cr) level. Moreover, rs2229866 in contactin 2 (CNTN2), rs200687372 in myotubularin Related Protein 9 (MTMR9), rs777260512 in polymerase iota (POLI), rs16954698 in polycystic kidney disease 1-like 2 (PKD1L2), rs117765468 in NSE1 Homolog, SMC5-SMC6 Complex Component (NSMCE1) , and rs1800956 in endoglin (ENG) were identified as candidate variants associated with delayed MTX clearance. In particular, ENG rs1800956 was significantly associated with delayed MTX clearance in all analyses and PKD1L2 rs16954698 was replicated in an external dataset (phs000637.v1.p1) from the Database of Genotypes and Phenotypes (dbGaP). Conclusion: This is the first whole-exome sequencing-based analysis of delayed MTX clearance in pediatric patients with ALL. ENG rs1800956 and PKD1L2 rs16954698 were found to be potentially influential variants associated with delayed MTX clearance. These findings provide insights into HD-MTX-induced nephrotoxicity and may contribute to reducing adverse reactions through treatment modification. [ABSTRACT FROM AUTHOR]

Background: The introduction of antibody–drug conjugates represents a significant advancement in targeted therapy of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Our study aims to investigate the role of the DNA damage response pathway and the impact of PARP1 inhibition, utilizing talazoparib, on the response of AML and ALL cells to Gemtuzumab ozogamicin (GO) and Inotuzumab ozogamicin (INO), respectively. Methods: AML and ALL cells were treated with GO, INO and γ-calicheamicin in order to induce severe DNA damage and activate the G2/M cell-cycle checkpoint in a dose- and time-dependent manner. The efficacy of PARP1 inhibitors and, in particular, talazoparib in enhancing INO or GO against ALL or AML cells was assessed through measurements of cell viability, cell death, cell cycle progression, DNA damage repair, accumulation of mitotic DNA damage and inhibition of clonogenic capacity. Results: We observed that both ALL and AML cell lines activate the G2/M cell-cycle checkpoint in response to γ-calicheamicin-induced DNA damage, highlighting a shared cellular response mechanism. Talazoparib significantly enhanced the efficacy of INO against ALL cell lines, resulting in reduced cell viability, increased cell death, G2/M cell-cycle checkpoint override, accumulation of mitotic DNA damage and inhibition of clonogenic capacity. Strong synergism was observed in primary ALL cells treated with the combination. In contrast, AML cells exhibited a heterogeneous response to talazoparib in combination with GO. Our findings suggest a potential link between the differential responses of ALL and AML cells to the drug combinations and the ability of talazoparibto override G2/M cell-cycle arrest induced by antibody–drug conjugates. Conclusion: PARP1 emerges as a key player in the response of ALL cells to INO and represents a promising target for therapeutic intervention in this leukemia setting. Our study sheds light on the intricate interplay between the DNA damage response pathway, PARP1 inhibition, and response of γ-calicheamicin-induced DNA damages in AML and ALL. These findings underscore the importance of targeted therapeutic strategies and pave the way for future research aimed at optimizing leukemia treatment approaches. [ABSTRACT FROM AUTHOR]

RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of 'writers', 'readers' and 'erasers' which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these 'readers', 'writers', and 'erasers' is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential. M6A RNA modifications: emerging drivers of leukemia growth and progression. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia (ALL) is a complex disease in pediatric oncology, necessitating accurate diagnostic strategies for effective treatment planning. The ability to differentiate between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is crucial for targeted interventions. However, current diagnostic methods are time-consuming and require rapid, dependable tests. This study explores the potential of label-free Raman imaging coupled with chemometrics for rapid blast phenotyping of B-ALL and T-ALL. Our findings demonstrate the efficacy of Raman spectroscopy in sensitively and specifically screening and classifying ALL, as well as its rapidity and reliability. The obtained molecular information allows for label-free and precise leukaemia diagnosis at the single-cell level, surpassing the capabilities of traditional diagnostic techniques. Raman spectra of cancer cells reveal distinctive molecular signatures, specifically heightened protein and nucleic acid content, revealing molecular signatures unique to leukemic phenotypes. Based on that, they could be distinguished from each other and their normal B and T lymphocyte counterparts. This research underscores the analytical power of Raman spectroscopy, positioning it as a valuable tool for identifying and classifying pediatric ALL subtypes. The potential translational applications in clinical practice offer a promising avenue for an expedited and accurate leukaemia diagnosis, paving the way for more targeted and personalised therapeutic approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) with granular blasts was historically referred to as "granular ALL", but this is not recognized as a distinct entity in the current WHO classification. This rare morphological feature is predominantly associated with a B-cell immunophenotype, while T-ALL with prominent cytoplasmic granules is extremely rare, with limited available genetic, molecular, and prognostic data. Here, we report a unique case of ALL in a 9-year-old girl. Initial blood tests revealed leukocytosis, and both peripheral blood and bone marrow morphology showed a high number of blasts with granular cytoplasm and bilobed nuclei. Immunophenotyping confirmed T-cell origin. The patient tested positive for KMT2A::AFDN, with WT1 overexpression, and NRAS and EZH2 mutations were detected by next-generation sequencing (NGS). Remarkably, the patient achieved complete remission after treatment and has shown no signs of relapse for nearly four years. Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases. [ABSTRACT FROM AUTHOR]

This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell–engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens. However, these intense regimens are not tolerated by all, and high-risk patients still have inferior outcomes. Therefore, designing more effective and less toxic strategies remains key to further improving efficacy and safety outcomes. Overall, the treatment landscape is evolving in the frontline, and integration of blinatumomab into different standard frontline regimens may improve overall outcomes with a favorable safety profile. [ABSTRACT FROM AUTHOR]

The ability of flow cytometry to identify and quantify the presence of cell populations defined by their expression profile of specific markers has made this technique a powerful and routinary tool in clinical diagnostic practice. Specifically in the field of hematological malignancies, flow cytometry allows the identification of the correct type and lineage of each patient's disease and also sensitively quantifies the presence of the disease at precise moments during treatment, that is, levels of measurable residual disease (MRD). The quantification of MRD by flow cytometry has allowed the adaptation of tailored therapies to patients, contributing to the improvement of the results of the different protocols in recent decades. In this context, our objective in the present work was to evaluate the potential impact that spectral flow cytometry can provide compared to conventional cytometry, which is the one usually used in clinics. We present here a comparative study of both technologies, spectral versus conventional flow cytometry, in primary samples corresponding to the diagnosis and follow-up of children and adolescents with acute lymphoblastic leukemia. Our initial experience demonstrates the feasibility of incorporating spectral flow cytometry into the routine workflow of a reference laboratory. [ABSTRACT FROM AUTHOR]

Efficient gene transduction and cell viability are critical factors in genetic manipulation for research and therapeutic purposes. In this study, we explored the challenges associated with transducing the NB-4 cell line, a well-established model for acute promyelocytic leukemia (APL), using lentiviral vectors. While the initial transduction efficiency in NB-4 cells reached approximately 30%, we observed a significant decrease in cell viability, a phenomenon not observed in other acute leukemia cell lines such as THP-1 cells. We identified that this toxicity could be mitigated by purifying viral particles through ultracentrifugation or polyethylene glycol (PEG) precipitation, indicating that toxic substances, potentially secondary metabolites released by HEK293, could be responsible for the cell death. Nevertheless, cell selection by puromycin was still ineffective; crucially, we discovered that the human phosphoglycerate kinase (hPGK) promoter, commonly used in the PLKO1 vector, may become silenced in NB-4 cells, preventing effective selection with puromycin. By replacing the hPGK promoter with the elongation factor-1 alpha (EF1α) promoter, we successfully achieved high transduction efficiency and robust selection, demonstrating the potential for this modified vector system to facilitate genetic studies in APL models. These findings provide important insights into optimizing gene transduction protocols not only for NB-4 cells but also for other challenging cell lines, offering a refined approach for gene delivery and selection in cell models. [ABSTRACT FROM AUTHOR]

Myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis, and primary myelofibrosis are a unique group of clonal hematopoietic stem cell neoplasms that share somatic, gain-in-function driver mutations in JAK2, CALR, and MPL. As a consequence, these disorders exhibit similar phenotypic features, the most common of which are the ceaseless production of normal erythrocytes, myeloid cells, platelets alone or in combination, extramedullary hematopoiesis, myelofibrosis, and a potential for leukemic transformation. In the case of polycythemia vera and essential thrombocytosis, however, prolonged survival is possible. With an incidence value in the range of 0.5–2.0/100,000, myeloproliferative neoplasms are rare disorders, but they are not new disorders, and after a century of scrutiny, their clinical features and natural histories are well-defined, though their individual management continues to be controversial. With respect to polycythemia vera, there has been a long-standing dispute between those who believe that the suppression of red blood cell production by chemotherapy is superior to phlebotomy to prevent thrombosis, and those who do not. With respect to essential thrombocytosis, there is a similar dispute about the role of platelets in veinous thrombosis, and the role of chemotherapy in preventing thrombosis by suppressing platelet production. Linked to these disputes is another: whether therapy with hydroxyurea promotes acute leukemia in disorders with a substantial possibility of longevity. The 21st century revealed new insights into myeloproliferative neoplasms with the discovery of their three somatic, gain-of-function driver mutations. Almost immediately, this triggered changes in the diagnostic criteria for myeloproliferative neoplasms and their therapy. Most of these changes, however, conflicted with prior well-validated, phenotypically driven diagnostic criteria and the management of these disorders. The aim of this review is to examine these conflicts and demonstrate how genomic discoveries in myeloproliferative neoplasms can be used to effectively complement the known phenotypic features of these disorders for their diagnosis and management. [ABSTRACT FROM AUTHOR]

AbstractTo overcome the challenges of a manual leukocyte differential count, we have developed FlowDiff, an 8-colour, single tube flow cytometry panel, and investigated whether it could potentially replace the manual differential in our laboratory. The instrument was set up in accordance with the EuroFlow settings, and the protocol comprised a stain-lyse no wash process, taking approximately 30 min of working time, without the addition of a toxic lysis reagent. We found a very good correlation for all leukocyte populations between FlowDiff and the Sysmex XN analyzer in 80 normal, non-flagged samples. In addition, FlowDiff showed a very good correlation with manual differential in 168 abnormal samples, as well as a high diagnostic accuracy. FlowDiff correctly identified all samples with acute leukemia (N = 13) and differentiated all B-lymphomas (N = 49) in samples with lymphocytosis. Moreover, FlowDiff detected an additional five samples with B-lymphocytosis without any prior hematological malignancy, which turned out to be a B-lymphoma. Our data suggest that FlowDiff, our 8-colour flow cytometry-based differential, is comparable to, and can successfully substitute the manual differential. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3‐kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is pivotal in various cancers, including T‐cell acute lymphoblastic leukaemia (T‐ALL), a particularly aggressive type of leukaemia. This study investigates the effects of Neosetophomone B (NSP‐B), a meroterpenoid fungal metabolite, on T‐ALL cell lines, focusing on its anti‐cancer mechanisms and therapeutic potential. NSP‐B significantly inhibited the proliferation of T‐ALL cells by inducing G0/G1 cell cycle arrest and promoting caspase‐dependent apoptosis. Additionally, NSP‐B led to the dephosphorylation and subsequent inactivation of the PI3K/AKT/mTOR signalling pathway, a critical pathway in cell survival and growth. Molecular docking studies revealed a strong binding affinity of NSP‐B to the active site of AKT, primarily involving key residues crucial for its activity. Interestingly, NSP‐B treatment also induced apoptosis and significantly reduced proliferation in phytohemagglutinin‐activated primary human CD3+ T cells, accompanied by a G0/G1 cell cycle arrest. Importantly, NSP‐B did not affect normal primary T cells, indicating a degree of selectivity in its action, targeting only T‐ALL cells and activated T cells. In conclusion, our findings highlight the potential of NSP‐B as a novel therapeutic agent for T‐ALL, specifically targeting the aberrantly activated PI3K/AKT/mTOR pathway and being selective in action. These results provide a strong basis for further investigation into NSP‐B's anti‐cancer properties and potential application in T‐ALL clinical therapies. [ABSTRACT FROM AUTHOR]

The development of cerebral cavernous malformations (CCMs) is a well-recognized sequela of irradiation to the brain in pediatric tumors, particularly in medulloblastoma, glioma, and acute lymphoblastic leukaemia. So far, only one case of cerebral cavernoma after chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has been described. We describe a case of a patient with medulloblastoma aged 18 months at the time of oncological diagnosis who was treated with high-dose chemotherapy followed by HSCT and who developed CCM two years later. The patient was not treated for vascular malformation since he remained asymptomatic until now and is regularly followed with neuro-radiological check-ups. This represents the second case of acquired cavernoma developed in a patient who has not received radiation therapy. [ABSTRACT FROM AUTHOR]

Acute leukemia has rapid onset and severe complications. Anticancer peptides from natural sources have demonstrated efficacy in eliminating various cancers through apoptosis signaling pathways. Additionally, extracellular vesicles containing microRNAs play pivotal roles in promoting tumorigenesis. Therefore, this study aimed to investigate the impact of PG2, a pomegranate peptide that regulates extracellular vesicles, on the induction of acute leukemia cell apoptosis. NB4 and MOLT-4 leukemia cell lines were treated with PG2 alone or in combination with daunorubicin to assess cell viability using the MTT assay. Extracellular vesicles were extracted from PG2-treated NB4 and MOLT-4 cells. Bioinformatic tools were utilized to predict target proteins and microRNAs, following which mRNA and protein expression were determined by using RT‒qPCR and western blotting, respectively. PG2 significantly reduced the viability of NB4 and MOLT-4 cells. Furthermore, the combination of PG2 with daunorubicin had a synergistic effect on NB4 and MOLT-4 cells. Subsequent treatment with PG2 or PG2-treated extracellular vesicles decreased CDK2 expression while increasing microRNA-339-5p and caspase-3 expression in NB4 and MOLT-4 cells. Our findings revealed that the anticancer activity of PG2 through the CDK2/miR-339-5p/caspase-3 pathway is mediated by extracellular vesicles, ultimately inducing apoptosis. PG2 holds promise as a potential antileukemic drug. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusion Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults and the 5‐year survival remains low.We analyzed the gene expression profiles of the complement and coagulation cascades pathway (CCCP) in 998 bone marrow (BM) and 122 peripheral blood (PB) samples of ALL patients and healthy individuals obtained from the TCGA database and evaluated their clinical significance in terms of being diagnostic and prognostic biomarkers.We identified 18 CCCP genes (SERPINA1, C5AR1, F5, CD55, PLAUR, C3AR1, THBD, CD59, PLAU, VWF, CFD, F13A1, C1QA, C1QB, C1QC, A2M, SERPINE1 and CR2) differentially expressed in the BM samples of ALL patients compared to healthy individuals. The expression levels of CD55, F13A1 and CR2 in BM were linked with the overall survival of ALL patients. While in PB only 11 CCCP genes (e.g., SERPINA1, C5AR1, F5, PLAUR, C3AR1, THBD, CFD, F13A1, C1QA, SERPINE1, and CR2) were differentially expressed and F13A1 was significantly associated with ALL patient survival. Machine learning enabled us to predict ALL using the CCCP genes and the accuracy can reach 0.9701 and 0.9167 using the BM and PB, respectively. Furthermore, using single‐cell RNA sequencing, we found that the differential expression of CCCP genes was found with diversity in the BM‐derived immune cells of ALL patients.Our findings suggest that the CCCP genes may play a key role in the progression of ALL and can be used as potential therapeutic targets and diagnostic markers. [ABSTRACT FROM AUTHOR]

AbstractZNF384 gene rearrangements are a distinct subtype of adult B cell acute lymphoblastic leukemia (B-ALL). We screened 46 B-other ALL patients for ZNF384 fusions using fluorescent in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Clinical data, treatment response, and minimal residual disease (MRD) status were analyzed. Ten (21.7%) patients were ZNF384-r positive (nine by FISH, nine by RT-PCR, eight by both). FISH showed atypical signals, including 3’ signal gain and 5’ signal deletion. EP300 was the main fusion partner (n = 5). TAF15::ZNF384, SYNRG::ZNF384, CREBBP::ZNF384, and TCF3::ZNF384 fusions were found in one patient each; one case’s partner gene is unknown. One patient was MRD-negative at the end of the first induction, lower than in patients without ZNF384-r. ZNF384-r incidence matched B-other ALL incidence in Chinese patients. Combined FISH and RT-PCR improved detection. ALL with ZNF384-r has unique features, and lower MRD-negative response may indicate a negative impact on traditional treatments. [ABSTRACT FROM AUTHOR]

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 in vitro 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. [ABSTRACT FROM AUTHOR]

Summary Pegaspargase is a key drug for the treatment of younger adults with acute lymphoblastic leukaemia (ALL). Pegaspargase‐associated hepatotoxicity is most common during induction, and its incidence increases with age and body mass index (BMI). We hypothesized that the delayed administration of pegaspargase during induction is associated with lower risk of hepatotoxicity while retaining efficacy. We retrospectively reviewed 141 adult patients with newly diagnosed ALL who received pegaspargase during induction from November 2013 to February 2024. There were 78 (55.3%) patients who received early pegaspargase (EP) on day 4 and 63 (44.7%) patients who received delayed pegaspargase (DP) on day 15. High‐grade hepatotoxicity (grade ≥ 3 transaminitis and/or hyperbilirubinaemia) occurred more frequently in the EP group (p = 0.06). Rates of complete remission and negative minimal residual disease post induction were not different between cohorts. Univariate logistic regression analysis showed that BMI and age significantly predicted an increased risk of high‐grade hepatotoxicity while DP was associated with a lower risk (odds ratio = 0.44; p = 0.04). Overall survival and event‐free survival were not significantly different between cohorts. Delaying pegaspargase administration from day 4 to day 15 during induction cycle in adults with ALL might reduce the risk of high‐grade hepatotoxicity without adversely impacting clinical efficacy outcomes. [ABSTRACT FROM AUTHOR]

Introduction: L-Asparaginase (L-Asp) is a key drug in the treatment of acute lymphoblastic leukemia (ALL); however, it is commonly associated with the occurrence of adverse events (AE). Risk factors such as age, sex, nutritional status, and some single nucleotide variants (SNVs) in specific genes could be related to hypersensitivity reactions to L-Asp. The objective of this study was to identify the influence of individual characteristics and three SNVs in the GRIA1 and NFATC2 genes on the occurrence of the most significant adverse events caused by the use of L-Asp in Mexican children with ALL. Methods: Eighty-five children from ages 0–17 years old diagnosed with ALL were included. The patients were treated at two hospital centers in Mexico. The SNV genotypes of the GRI1A and NFATC2 genes studied were examined using real-time qPCR. The evaluation of AE was carried out according to the Common Terminology Criteria for adverse events, and the determination of anti-L-Asp antibodies was conducted using Western blot immunoassay. Results: Homozygosity (AA) of the GRIA1 rs4958351 SNV was significantly associated with the occurrence of AE with the use of L-Asp (OR = 4.05; 95% CI = 1.06 to 15.40, p = 0.04) and was strongly associated with the development of anti-L-Asp antibodies (OR = 3.4375, 95% CI = 1.04 to 11.25, p = 0.04). With this, we found a significant risk association for the SNV rs4958351 of the GRIA1 gene. On the other hand, we did not find significant risk associations for the GRIA1 rs6889909 and NFATC2 rs6021191 SNVs, although other populations have shown a significant risk. Discussion: Our study has some limitations, such as the small sample size, the heterogeneity in adverse events due to the patients' different regions of origin, and the limited ability to conduct a more detailed follow-up on pancreatitis. Additionally, since no significant associations were found between the NFATC2 rs6021191 and GRIA1 rs6889909 SNVs and the development of adverse events or the presence of antibodies due to the use of L-Asp, it is necessary to investigate new specific SNVs that may improve the efficacy and safety of treatment in Mexican children with ALL. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions De novo chronic myeloid leukemia in blastic phase (CML‐BP) showing lymphoid immunophenotype mimics Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph‐positive ALL). Although upfront allogeneic hematopoietic cell transplantation (HCT) is considered in both diseases, it is not yet clear whether the transplant outcomes are also similar.Using a registry database, the transplant outcomes between de novo CML‐BP and Ph‐positive ALL in negative‐minimal residual disease (MRD), positive MRD, and nonremission cohorts were compared, respectively. All of the included patients had received tyrosine kinase inhibitor therapy before HCT and underwent HCT between 2002 and 2021. Regarding Ph‐positive ALL, patients with p210 transcripts were excluded because there was concern that this group might include patients with de novo CML‐BP.Although most of the outcomes were comparable, in patients with positive MRD at HCT, de novo CML‐BP was significantly associated with superior disease‐free survival (DFS) (hazard ratio [HR] 0.6, p = .0032), overall survival (HR 0.66, p = .027), and a lower risk of relapse (HR 0.48, p = .0051). In subgroup analyses, BCR::ABL1 mutation status had a significant interaction with the disease (p for interaction = .0027). De novo CML‐BP seemed to be associated with superior disease‐free survival in a BCR::ABL1 mutation‐positive cohort, whereas this association was not observed in a mutation‐negative cohort.Considering previous reports that showed inferior outcomes for de novo CML‐BP compared to Ph‐positive ALL, the data suggested that allogeneic HCT could overcome the poor prognosis of de novo CML‐BP. These findings highlight the importance of distinguishing de novo CML‐BP from Ph‐positive ALL. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to identify the impact of the COVID-19 pandemic on the frequency, clinical characteristics and outcomes of patients with acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Methods: This retrospective cohort study included all patients treated at Sultan Qaboos University Hospital in Muscat, Oman with AML or ALL from January 2017 to December 2021. Data were obtained from the electronic medical record, and patients diagnosed before the start of the COVID-19 pandemic were compared with those diagnosed during the pandemic using appropriate statistical tests. Results: A total of 151 patients with ALL (n = 58) and AML (n = 93) were included, of whom 78 were diagnosed before the COVID-19 pandemic and 73 during the pandemic. The rate of acute leukaemia increased during the pandemic (P = 0.039). The clinical characteristics and molecular profiles were similar between the 2 periods, except for platelet count which was higher during the pandemic compared to before the pandemic (median platelet count: 55 × 109/L versus 47 × 109/L; P = 0.02). No significant difference was found in the number of FLT3-positive AML; however, the number of NPM1-mutated AML cases was higher during the pandemic (P = 0.02). The number of Philadelphia-positive ALL cases remained consistent between the 2 time periods. The complete remission (P = 0.48) and the overall survival rates were similar (P >0.05). Conclusion: Except for an increased rate of acute leukaemia and a lower platelet count, the COVID-19 pandemic did not impact the presentation and outcomes of acute leukaemia. [ABSTRACT FROM AUTHOR]

Background: Although BRAF V600E mutations are common in solid tumors and select hematologic neoplasms, they are reported less frequently in myeloid malignancies. Of the cases of BRAF V600E-mutant acute myeloid leukemia (AML) that have been described, most display monocytic morphology and concurrent KMT2A rearrangement. Strikingly, all cases have been associated with poor survival. Case Presentation: Here, we report two cases of AML, one diagnosed in an elderly male with metastatic lung adenocarcinoma and hepatocellular carcinoma and the other diagnosed in a young boy previously treated for B-cell acute lymphoblastic leukemia. Peripheral blood NGS revealed oncogenic mutations in BRAF p.V600E (VAF = 33%), TET2 p.M508Cfs*25 (VAF = 48%), TET2 p.C211* (VAF = 49%), ZRSR2 p.R295* (VAF = 71%), BRAF p.N581S (VAF = 6%), and EZH2 c.118-2A>G, p.? (VAF = 4%) in case 1 and BRAF p.V600E (VAF = 1%) and KRAS p.G12A (VAF = 28%) in case 2. Cytogenetic workup revealed a complex karyotype in case 1 and an abnormal karyotype with non-clonal aberrations and KMT2A (MLL) rearrangement in case 2. Morphologically, both patients were found to have AML with monocytic features. The post-mortem examination of case 2 also revealed extensive solid organ infiltration, consistent with a monocytic leukemia. Both patients died within days of diagnosis, demonstrating the lethality of this molecular subgroup of AML. Conclusions: Our cases add to the literature, highlighting the poor prognosis of patients diagnosed with BRAF-mutant AML. Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms. [ABSTRACT FROM AUTHOR]

Background/Objectives: Infections remain the leading cause of mortality among neutropenic patients with haematologic malignancies, making effective infection management crucial. Achieving a sufficient neutrophil count is essential for the elimination of pathogens. Granulocyte concentrate (GC) can be a treatment option for neutropenic patients with severe infections. This study aimed to evaluate the efficacy, safety, and impact on survival of GC transfusions in neutropenic children with severe infections treated over the past 13 years in a single centre. Methods: The retrospective study analysed clinical data from 60 children (median age 9.5 years) who received GC transfusions at our centre. Granulocytes were collected by apheresis from donors stimulated with granulocyte colony-stimulating factor. The majority of the patients (70%) were diagnosed with acute leukaemia. The main indications for GC were severe pneumonia (45%) and bacterial sepsis (38.33%). Results: The patients received 1 to 29 GC transfusions for 1 to 70 days, with a median time of administration of 3 days. Neutrophil counts increased to >1000/µL within a median of 5 days. GCs were well tolerated by most patients. One patient presented symptoms of anaphylaxis, the other acute lung injury related to transfusions, and alloimmunisation was reported in one patient. Of the patients analysed, 78.33% survived the infection that justified GC administration. We did not observe significant differences in survival depending on the aetiology of the infection. Conclusions: Based on our research, GC appears to be a beneficiary for neutropenic children with severe infections and reduces infection mortality rates. However, further well-designed randomised trials are needed to define its role in this setting. [ABSTRACT FROM AUTHOR]

CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in "ScFvkh" design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10−10 M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by damage to organs and cells, initially mediated by tissue-binding autoantibodies and immune complexes. Lymphomas have been frequently reported, but the association of SLE with acute leukemia is rare and likely coincidental. We report a case of a 40-year-old female admitted for an etiological diagnosis of fever and dyspnea with peripheral edema. She had a history of SLE diagnosed 2 years prior and had been on immunosuppressive therapy since then. Hematological investigations showed leukocytosis, anemia, and thrombocytopenia. Further diagnostic testing could not be done as she passed away 3 days after acute leukemia was diagnosed. This case highlights the challenges of diagnosing hematological malignancies in immunosuppressed SLE patients where symptoms may be obscured. [ABSTRACT FROM AUTHOR]

Summary: Autologous chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment of lymphoid malignancies, leading to the approval of CD19‐CAR T cells for B‐cell lymphomas and acute leukaemia, and more recently, B‐cell maturation antigen‐CAR T cells for multiple myeloma. The long‐term follow‐up of patients treated in the early clinical trials demonstrates the possibility for long‐term remission, suggesting a cure. This is associated with a low incidence of significant long‐term side effects and a rapid improvement in the quality of life for responders. In contrast, other types of immunotherapies require prolonged treatments or carry the risk of long‐term side effects impairing the quality of life. Despite impressive results, some patients still experience treatment failure or ultimately relapse, underscoring the imperative to improve CAR T‐cell therapies and gain a better understanding of their determinants of efficacy to maximize positive outcomes. While the next‐generation of CAR T cells will undoubtingly be more potent, there are already opportunities for optimization when utilizing the currently available CAR T cells. This review article aims to summarize the current evidence from clinical, translational and fundamental research, providing clinicians with insights to enhance their understanding and use of CAR T cells. [ABSTRACT FROM AUTHOR]

Summary: Addition of molecular data to prognostic models has improved risk stratification of myelodysplastic neoplasms (MDS). However, the role of molecular lesions, particularly in the group of low‐risk disease (LR‐MDS), is uncertain. We evaluated a set of 227 patients with LR‐MDS. Overall survival (OS) and probability of leukaemic progression were the main endpoints. RUNX1 was associated with lower OS and SF3B1 with a reduced risk of death (HR: 1.7, 95% CI, 1.1–2.9; p = 0.05; and HR: 0.23, 95% CI 0.1–0.5; p < 0.001; respectively). TP53 and RUNX1 mutations were predictive covariates for the probability of leukaemic progression (p < 0.001). Blast percentage, neither analysed as categorical (<5% vs. 5%–9%; HR: 1.3, 95% CI, 0.7–2.9; p = 0.2) nor as a continuous variable (HR: 1.07, 95% CI, 0.9–1.1; p = 0.07), had impact on survival or probability of progression (sHR: 1.05, 95% CI, 0.9–1.1; p = 0.2). These results retained statistical significance when analysis was restricted to the definition of LR‐MDS according to the WHO 2022 and ICC classifications (<5% blasts). Thus, with the incorporation of molecular data, blast percentage happens to lose clinical significance both for survival and probability of progression in the group of patients with LR‐MDS. [ABSTRACT FROM AUTHOR]

Summary: Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome‐wide association study (GWAS) and a transcriptome‐wide association study (TWAS) in 260 patients of European‐descent from the DFCI 05–001 ALL trial, with validation in 101 patients of European‐descent from the DFCI 11–001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05–001 trial (p = 1.7 × 10−8). In DFCI 11–001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta‐analysis of the two cohorts (meta‐p = 2.4 × 10−6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta‐p = 2.3 × 10−3). Our findings highlight the genetic influence on treatment‐related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment. [ABSTRACT FROM AUTHOR]

Summary: Rearrangement of NUTM1 gene (NUTM1r) is one of the most frequent aberrations occurring in infants (younger than 1 year at diagnosis) with B‐cell precursor Acute Lymphoblastic Leukaemia (BCP‐ALL). In this study we had the unique opportunity to analyze the umbilical cord blood (UCB) sample from one infant patient with NUTM1r BCP‐ALL. Herein we reported for the first time that NUTM1r infant ALL arise prenatally, as both the patient‐specific CUX1::NUTM1 fusion gene, as well as two IG/TR leukaemic markers were already present and detectable in the patient's UCB at birth. Our results clearly demonstrate the prenatal origin of NUTM1r infant BCP‐ALL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is a hematopoietic disorder that mainly affects the child population, and it is characterized by the presence of lymphoid progenitor or precursor cells with different genetic alterations. The origin of this disease is controversial, since some authors assumed that leukemic transformation occurs in a lymphoid progenitor, and there is also evidence that suggests the existence of leukemic initiating cells (LIC). PTL, DMAPT, and PU-H71 are agents that have been shown to eliminate bulk and stem cells from myeloid leukemias, but this effect has not been analyzed in lymphoblastic leukemias. In this study, we evaluated the effect of these compounds in different populations from pediatric B-ALL. For this, bone marrow samples from pediatric patients without treatment were obtained and cultured in the presence or absence of PTL, DMAPT, and PU-H71. The viability and apoptosis index were analyzed by flow cytometry in different hematopoietic subpopulations. These observations indicate that PTL and DMAPT are able to reduce B-ALL cells with a minimum effect in normal hematopoietic and non-hematopoietic cells. In contrast, PU-H71 was able to reduce the leukemic population and had a minimal effect in normal cells. These results present evidence that PTL and DMAPT are able to abrogate in vitro different populations of B-ALL and could represent a possibility of treatment, as well as prevent disease progression or relapse. [ABSTRACT FROM AUTHOR]

This study investigates acute myeloid leukemia/lymphoblastic leukemia (AML/ALL) through a 14-year analysis (2009–2022) of 46 autopsied cases (age >12 years). B-ALL was the dominant subtype (34.8%). Liver and spleen were the common sites of active leukemia (63% cases). Symptoms like dyspnea and altered sensorium associated significantly with heart (p =.031) and brain leukostasis (p =.006). Measurable residual disease (MRD) negativity correlated with disease-free status outside the bone marrow, while MRD-positive cases displayed leukemic infiltrates. Infections were identified in 23 autopsied cases, notably linked to post-induction and post-transplant fatalities. Surprisingly, 18 of these 23 cases had unexpected infections mainly fungal (13 cases) with Aspergillus species as the most common. Diagnostic discrepancies were identified in 48% of cases. Malignant infiltration (46%) and infections (25%) were the leading causes of death. This research sheds light on leukemia in extra-medullary tissues, uncovers novel clinical-pathological associations, and highlights overlooked therapy side effects, offering insights for future case management. [ABSTRACT FROM AUTHOR]

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in KMT2A-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance. [ABSTRACT FROM AUTHOR]

Summary: Olverembatinib is a novel orally administered third-generation tyrosine kinase inhibitor (TKI) with definitive responses in T315I-mutant chronic myeloid leukemia (CML) patients. However, its value in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remained unclarified. In this multiple-center study, 20 patients with de novo Ph + ALL were treated with olverembatinib-based regimens as frontline therapy. All patients acquired complete remission (CR) after induction. 85% of patients achieved complete molecular response (CMR) within three months, contributed mainly by the addition of blinatumomab. A total of 45% of patients experienced mild hematological treatment-related adverse events (TRAEs). Olverembatinib-based treatment led to promising outcomes in de novo Ph + ALL patients but warranted further studies to investigate the best-combined strategy. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia presenting de novo in the blast phase (CML-BP) is a rare diagnosis among pediatric malignancies. We report on a 16-year-old male who presented with CML-BP lymphoid at diagnosis. He was treated with shortened acute lymphoblastic leukemia induction plus the tyrosine kinase inhibitor (TKI) imatinib followed by dasatinib. After achieving molecular remission (MR), hematopoietic stem cell transplantation (HSCT) was performed early after diagnosis. Despite prophylactic dasatinib, he relapsed 3 months later with the kinase domain mutation T315I. Multiple therapeutic approaches including ponatinib, blinatumomab, a 2nd HSCT from a different donor, donor lymphocyte infusions, and high-dose asciminib all resulted in subsequent relapse. Another molecular response was achieved by combining ponatinib plus asciminib with chemotherapy. In this situation, CD19-directed CAR-T cells (Kymriah®) were administered for compassionate use and tolerated without adverse events. Compared to all prior therapies, CAR T-cells maintained remission. After 12 months of follow-up, complete B-cell aplasia and low numbers of CAR-T cells are detectable in the peripheral blood, potentially mediating long-term disease control. [ABSTRACT FROM AUTHOR]

The association between cytokine receptor-like factor 2 (CRLF2) and clinical outcomes in acute lymphoblastic leukemia (ALL) has been a topic of ongoing debate, with divergent findings. This article intended to investigate the influence of CRLF2 alterations on ALL prognosis. Following the PRISMA 2020 guidelines, this meta-analysis was conducted. Hazard ratio (HR) values and confidence intervals (CIs) were the primary statistical measures used. Data heterogeneity was judged using the chi-square test and I2 statistic. Publication bias was appraised with funnel plots, Begg's test, and Egger's test. 16 studies with 6771 patients were finally screened out. CRLF2 over-expression (CRLF2 OE) was associated with poorer event-free survival (EFS) (HR = 1.70, 95% CI = 1.18–2.44, P = 0.004) and relapse-free survival (RFS) (HR = 1.70, 95% CI = 1.28–2.24, P = 0.000) in pediatric ALL. Patients with CRLF2-deregulation (CRLF2-d), also known as CRLF2 rearrangement, exhibited shorter overall survival (OS) (HR = 2.22, 95% CI = 1.49–3.32, P = 0.000), EFS (HR = 1.93, 95% CI = 1.43–2.60, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53–3.18, P = 0.000) compared to those without CRLF2-d. Subgroup analysis of multivariate HRs and corresponding CIs indicated that childhood with CRLF2 OE had a shorter RFS (HR = 1.70, 95% CI = 1.28–2.24, P = 0.006), and CRLF2-d was identified as an independent prognostic biomarker for OS (HR = 2.22, 95% CI = 1.49–3.32, P = 0.000), EFS (HR = 1.95, 95% CI = 1.44–2.64, P = 0.000), and RFS (HR = 2.2, 95% CI = 1.53–3.18, P = 0.000) in pediatric ALL patients. Both CRLF2 OE and CRLF2-d are associated with poor prognosis in ALL patients. [ABSTRACT FROM AUTHOR]

Biosensors are powerful tools for real-time monitoring of metabolic state. Low reactive oxygen species (ROS) level and high reductive capacity favor repopulation and chemotherapy resistance of leukemia cells. Either glycolysis or oxidative phosphorylation driven by fatty acid and glutamine supports the development of acute leukemia. Fatty acid synthesis and certain amino acids promote the progression of acute leukemia. Redox metabolism plays a central role in the cellular metabolism network, involves catabolic and anabolic reactions of diverse biomass, and determines the redox state of cells. It can be quantitatively and conveniently measured in living cells and organisms with genetically encoded fluorescent sensors, providing novel insights that cannot be readily acquired via conventional metabolic assays. Here, we review the recent progress on the regulation of leukemogenesis via redox metabolism, especially redox biosensor-based findings. In general, low reactive oxygen species levels and high reductive capacity promote leukemogenesis and chemotherapy resistance in leukemia cells, and acute leukemia cells rewire metabolism of glucose, fatty acids, and some amino acids, together with oxidative phosphorylation, to fuel energy production, support biomass-related synthesis, and survive oxidative stress. In summary, redox metabolism is a potential target for the development of novel therapies for leukemia or beneficial dietary regimens for patients with refractory and relapsed leukemia. [ABSTRACT FROM AUTHOR]