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Determination of the Binding Epitope of an Anti-Mouse CCR9 Monoclonal Antibody (C

C-C chemokine receptor 9 (CCR9) is a receptor for C-C-chemokine ligand 25 (CCL25). CCR9 is crucial in the chemotaxis of immune cells and inflammatory responses. Moreover, CCR9 is highly expressed in tumors, including several solid tumors and T-cell acute lymphoblastic leukemia. Several preclinical studies have shown that anti-CCR9 monoclonal antibodies (mAbs) exert antitumor activity. Therefore, CCR9 is an attractive target for tumor therapy. In this study, we conducted the epitope mapping of an anti-mouse CCR9 (mCCR9) mAb, C

T cell functions and organ infiltration by leukemic T cells require cortactin.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties, and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to T cell receptor engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to T cell receptor and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system, suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.

Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsedrefractory B-ALL.

Murine chimeric antigen receptor T (CAR-T) cell therapy has demonstrated clinical benefit in patients with relapsedrefractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). However, the potential immunogenicity of the murine single-chain variable fragment domain may limit the persistence of CAR-T cell, leading to relapse. We performed a clinical trial to determine the safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell (hCART19) for RR B-ALL. Fifty-eight patients (aged 13-74 years) were enrolled and treated between February 2020 and March 2022. The endpoints were complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety. Overall, 93.1% (5458) of patients achieved CR or CR with incomplete count recovery (CRi) by day 28, with 53 patients having minimal residual disease negativity. With a median follow-up of 13.5 months, the estimated 1-year OS and EFS were 73.6% (95% CI 62.1% to 87.4%) and 46.0% (95% CI 33.7% to 62.8%), with a median OS and EFS of 21.5 months and 9.5 months, respectively. No significant increase in human antimouse antibodies was observed following infusion (p0.78). Duration of B-cell aplasia in the blood was observed for as long as 616 days, which was longer than that in our prior mCART19 trial. All toxicities were reversible, including severe cytokine release syndrome, which developed in 36% (2158) of patients and severe neurotoxicity, which developed in 5% (358) of patients. Compared with our prior mCART19 trial, patients treated with hCART19 had longer EFS without increased toxicity. Additionally, our data also suggest that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplantation or CD22-targeted CAR-T cell, following hCART19 therapy had a longer EFS than those without consolidation therapy. hCART19 has good short-term efficacy and manageable toxicity in RR B-ALL patients. NCT04532268.

Prophylactic or preemptive tyrosine kinase inhibitor therapy after allogeneic hematopoietic cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Prevention of disease relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia remains a major concern. Maintenance therapy with tyrosine kinase inhibitors (TKIs) after allo-HCT has been used to reduce the incidence of relapse. Two main strategies are employed for using TKIs after allo-HCT prophylactic TKI therapy, which is given before measurable residual disease (MRD) detection, and preemptive TKI therapy, which is given after MRD detection. These strategies both have advantages and disadvantages in terms of treatment efficacy, adverse events, adherence, and socioeconomic factors. In addition, many issues remain to be resolved because of the lack of large prospective studies on how to use TKIs after allo-HCT. These include indications for prophylactic and preemptive TKI therapy, timing of initiation, frequency of MRD monitoring, TKI selection, dose, and treatment duration. While the current available evidence is extremely limited, this article will discuss these issues after summarizing some representative and recent studies. It will also share a novel indicator that can be used to visualize the reversible transition between molecular relapse and remission by TKI therapy.

Venous thromboembolism in children with acute lymphoblastic leukemia in China a report from the Chinese Childrens Cancer Group-ALL-2015.

Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Childrens Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08-2.8, P 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n 120) and, symptomatic VTE, 58.49% (n 93), which was more common in patients aged 12-18 years (P 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n 147), 4.08% (n 6) had bleeding. The VTE recurrence rate was 5.03% (n 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P 0.02), with residual thrombus (P 0.006), or with short anticoagulation period (P 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

Early post-induction augmented therapy improves outcome in children and adolescents with T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all newly diagnosed ALL in children and adolescents and is associated with worse outcomes compared to pre-B ALL. We aimed to decrease T-ALL relapses by intensifying our regimen. Patients with T-ALL were treated using two different regimens before September 2014, patients were treated per St. Jude Total XV protocol subsequently, a major change was adopted by adding two intensive blocks FLAG and Reintensification. Cranial radiation was limited to patients with WBC ≥ 100 kμl at diagnosis andor patients with CNS2CNS3 status. Between June 2005 and April 2020, a total of 100 patients (76 males) were treated and followed up for a median of 70 months (range 14-181). Median age at diagnosis was 9 years (range 0.5-17.8). Forty-eight patients were diagnosed after September 2014 and received the augmented regimen their median follow up was 46 months (range 14-74). The 5-year-EFS estimates for patients who received the augmented regimen versus standard regimen were 87% ± 4.9% versus 67% ± 6.8% (p .03) and the 5-year-OS estimates were 87% ± 5.1% versus 71% ± 6.3% (p .06), respectively. Treatment related mortality (TRM) was reported in two patients treated per standard regimen but none for patients who received the augmented regimen. We implemented a novel approach with early intensification added to a backbone of modified St. Jude Total-XV regimen for patients with T-ALL that resulted in improved outcome with no treatment related mortality.

Spontaneous remission of acute lymphoblastic leukemia A series of nine cases and a review of literature.

To report a series of acute lymphoblastic leukemia (ALL) cases with spontaneous remission and provide presenting clinical and pathologic information and details of clinical course to raise awareness among oncologists and patients. We identified and analyzed nine patients with ALL and spontaneous remission. Review of literature reveals an additional nine previously reported cases with similar clinical course. All of these patients, ranging in age from 2 to 12 years of age, presented with inciting signs and symptoms of viral or bacterial infection. All of the patients showed varying percentages of lymphoblasts (.2% to 90%) in diagnostic bone marrow biopsy. All B-ALL cases shared a similar blast phenotype on flow cytometry with coexpression of CD19, CD10 and TdT and variable CD20 expression. All nine patients achieved spontaneous remission of their leukemia as confirmed by flow cytometry andor bone marrow biopsy without chemotherapeutic intervention. Time to remission from presentation ranged from 1 to 8 weeks. After remission, all patients redeveloped ALL, and time from remission to reemergence ranged from 2 to 24 weeks. Our series of cases and cases identified in literature show that ALL diagnosed with modern methods of flow cytometry and molecular analysis will recur within weeks to months from disappearance, usually with cytopenias, which provides a template for oncologic follow-up and testing in these patients.

Drug-Induced Cardiotoxicity in Children During the Past 30 Years A Bibliometric Study and Visualization Analysis.

BACKGROUND Drug-induced cardiotoxicity (DICT) is one of the most serious adverse drug reactions, which is an important safety issue in drug development and clinical practice. This study aimed to summarize the knowledge structure and to detect emerging trends, and provide ideas for future research on DICT in children using bibliometric methods. MATERIAL AND METHODS All publications on DICT in children were retrieved through the Web of Science Core Collection up to April 20, 2022. The document type was restricted to articles with the language set to English. CiteSpace and VOSviewer were used to conduct this bibliometric analysis. RESULTS A total of 298 articles were included, and the annual publications decreased since 2021. The United States was the leading country with the most publications (117), the highest centrality (0.39), and total citations (4055). The most influential institution was the University of British Columbia, while Carleton BC and Rassekh SR, both from Canada, were the most productive authors, but there was no leader in this field. The keywords with both high frequency and high centrality after excluding cardiotoxicity and children were acute lymphoblastic leukemia (Freq43, Central0.15), childhood cancer (Freq42, Central0.13), toxicity (Freq33, Central0.16), and breast cancer (Freq29, Central0.19). Adriamycin cardiotoxicity was the first burst keyword, while childhood cancer, oxidative stress, and cardiac dysfunction were emerging research hotspots. CONCLUSIONS Attention to DICT in children was insufficient. This study serves as a breakthrough point, providing a comprehensive overview of the knowledge structure, development landscape, and future opportunities in this field.

Puppet masters of B-cell progenitor acute lymphoblastic leukemia The preB cell receptor and the interleukin 7 receptor α.

B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is enriched for a preB cell phenotype, hinting at a specific vulnerability of this cell stage. Two signaling pathways via the preB cell receptor (preBCR) and the interleukin 7 receptor α (IL-7Rα) chain govern the balance between differentiation and proliferation at this stage and both receptor pathways are routinely altered in human BCP-ALL. Here, we review the immunobiology of both the preBCR as well as the IL-7Rα and analyze the human BCP-ALL spectrum in the light of these signaling complexes. Finally, we present a terminology for preBCR signaling modules that distinguishes a pro-proliferative phase-I module from a pro-differentiative phase-II module. This terminology might serve as a framework to better address shared oncogenic mechanics of preB cell stage BCP-ALL.

Ethnic disparities in childhood leukemia survival by border residence A Texas population-based analysis.

The US-Mexico border is a medically underserved region where survival disparities have been observed in adults diagnosed and treated for various malignancies. Studies examining survival disparities among children living in this region and diagnosed with cancer are lacking. The objective of this study was to evaluate the impact of border residence on survival among children with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and living near the Texas-Mexico border at the time of their diagnosis. The authors hypothesized that this group experiences inferior survival compared with patients with childhood leukemia living in nonborder areas. The authors conducted a retrospective survival analysis leveraging data from the Texas Cancer Registry. The study included patients aged birth to 19 years who were diagnosed with ALL or AML between 1995 and 2017. Cox proportional hazards models were used to evaluate the factors associated with the risk of death. Overall survival estimates were calculated using Kaplan-Meier methods. During the study period, there were 6002 children diagnosed with ALL and 1279 diagnosed with AML. Inferior 5-year overall survival was observed among children with ALL living along the border region compared with those living in nonborder areas (77.5% vs. 85.8%). In adjusted models, children with ALL living along the border experienced a 30% increased hazard of death versus children living in nonborder areas. In contrast, for children with AML, survival estimates did not vary by border versus nonborder residence. Living along the border was associated with inferior survival among children with ALL, but not among children with AML. Additional studies are urgently needed to identify the factors driving these disparities to effectively design multilevel interventions and influence state and national cancer control programs.

TKI Landscape for Ph ALL Expanding.

Preliminary phase III findings support using ponatinib, a third-generation tyrosine kinase inhibitor, as part of standard care for adults newly diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia. In the PhALLCON trial, ponatinib significantly outperformed imatinib, inducing deeper and more durable responses with no added toxicity.

Progress Against Cancer in Kuwait Trends in Incidence, Survival and Mortality.

To assess progress against cancer, trends in incidence, survival and mortality need to be interpreted simultaneously. Data were obtained from the Kuwait Cancer Registry (KCR) for all Kuwaiti children (0-14 years) and adults (15-99 years) diagnosed with one of 18 common cancers during 2000-2013, with follow-up for vital status to 31 December 2015. World-standardised average annual incidence and mortality rates were calculated for 2000-2004, 2005-2009, 2010-2013. Five-year net survival was estimated with the Pohar Perme estimator, corrected for background mortality using life tables of all-cause mortality. Survival estimates were agestandardised using the International Cancer Survival Standard weights. For liver cancer, five-year net survival increased from 11.4% to 13.4% for patients diagnosed between 2000-2004 and 2010-2013, while incidence and mortality rates fell from 5.5 to 3.6 and from 3.9 to 3.0 per 100,000, respectively. Similar patterns were seen for acute lymphoblastic leukaemia (ALL) and lymphoma in children. Survival and mortality remained stable for cancers of the lung, cervix and ovary, but incidence declined from 10.2 to 7.4, 4.9 to 2.4 and 5.8 to 4.3 per 100,000, respectively. For breast cancer, survival increased from 68.3% to 75.2%, while incidence and mortality rose from 45.6 to 58.7 and from 5.8 to 12.8 per 100,000, respectively. For colon cancer, incidence and mortality rates rose from 11.4 to 12.6 and from 2.3 to 5.4 per 100,000, respectively. Five-year survival fell from 64.8% to 50.2% between 2000-2004 and 2005-2009, before rising to 58.5% for 2010-2013. Increasing survival, alongside falling incidence and mortality rates, represents progress in cancer control, attributable to effective prevention (e.g. tobacco control and lung cancer) and early diagnostic activity (e.g. mammography for breast cancer), or better treatment (e.g. childhood ALL). The increasing prevalence of obesity, linked to rising incidence for breast and colon cancers, suggests the need for public health prevention campaigns.

Extensive Extramedullary Involvement at Presentation in B-Cell Acute Lymphoblastic Leukemia.

Extensive extramedullary involvement as presentation is uncommon in pediatric B-cell acute lymphoblastic leukemia. A 7-year-old boy was diagnosed with painless parotid gland enlargement. He had pancytopenia and significantly raised serum lactate dehydrogenase. Fine-needle aspiration cytology from the parotid was suggestive of lymphoid malignancy. Flow cytometry and bone marrow biopsy suggested B-cell acute lymphoblastic leukemia. 18F-FDG PETCT revealed extensive bone marrow disease and the involvement of the spleen, pancreas, kidneys, and the parotid, submandibular, and lacrimal glands. He had negligible physiological brain uptake.

Typing of acute leukemia by intelligent optical time-stretch imaging flow cytometry on a chip.

Acute leukemia (AL) is one of the top life-threatening diseases. Accurate typing of AL can significantly improve its prognosis. However, conventional methods for AL typing often require cell staining, which is time-consuming and labor-intensive. Furthermore, their performance is highly limited by the specificity and availability of fluorescent labels, which can hardly meet the requirements of AL typing in clinical settings. Here, we demonstrate AL typing by intelligent optical time-stretch (OTS) imaging flow cytometry on a microfluidic chip. Specifically, we employ OTS microscopy to capture the images of cells in clinical bone marrow samples with a spatial resolution of 780 nm at a high flowing speed of 1 m s

Analysis of

The rat sarcoma virus ( We retrospectively analyzed clinical characteristics, treatment, and outcomes of 93 ALL children during first induction chemotherapy in Anhui Provincial Childrens Hospital under the Chinese Childrens Leukemia Group-acute lymphoblastic leukemia 2018 (CCLG-ALL-2018). All genomic DNA samples were obtained from bone marrow mononuclear cells upon new diagnosis. Of 93 ALL children, 26 (27.9%) were positive for Newly diagnosed ALL in children with

Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of The The Advancements in

Treatment for a B-cell acute lymphoblastic leukemia patient carrying a rare

Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance andor treatment outcome to ALL

Double systemic cytokine release syndrome following sequential infusion of anti-CD22 and anti-CD19 chimeric antigen receptor T cells after autologous hematopoietic stem cell transplantation for a central diffuse large B-cell lymphoma patient A case report and literature review.

Chimeric Antigen Receptor T cell(CAR T-cell) therapy has been a great success in relapsedrefractory acute B lymphoblastic leukemia and B-cell lymphoma. At the same time, there are also related adverse reactions, especially cytokine release syndrome(CRS) and immune effector cell associated neurotoxicity syndrome(ICANS). However, Double CRS caused by CRA T cells are very rare. Here, we report a 33-year-male with secondary central diffuse large B-cell lymphoma(CNSL) who develpoed double CRS following sequential infusion of Anti-CD22 and Anti-CD19 CAR T cells after autologous hematopoietic stem cell transplantation(ASCT). On d5, the patient developed high fever, along with chilly sensation, shivering, headache, blood oxygen desaturation, shock, weakness, severe thirst, and heart rate decline. IL-6 and ferritin increased significantly. The patient was diagnosed with the first CRS (grade 3). On d36, the patient again had a persistent fever(T>39C) and limbs rash. IL-6 and ferritin again increased significantly on d38. After exclusion of infection, a diagnosis of double CRS was made. The patients symptoms were completely relieved after receiving tocilizumab, glucocorticoids, and other supportive treatments on d45.On d90, contrast-enhanced MR angiogram shows that the lesion basically disappeared, indicating the patient had achieved CR. At the end of the follow-up at d150, the patient was functioning normally without any sequelae. This is the first reported case worldwide where the patient with secondary CNSL suffered double CRS after CAR T-cell infusion. Our findings showed that it is important to increase awareness of early detection and diagnosis of double CRS and adopt appropriate treatment strategies.

Single-cell heterogeneity and dynamic evolution of Ph-like acute lymphoblastic leukemia patient with novel TPR-PDGFRB fusion gene.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a refractory and recurrent subtype of B-cell ALL enriched with kinase-activating rearrangements. Incomplete understanding of the heterogeneity within the tumor cells presents a major challenge for the diagnosis and therapy of Ph-like ALL. Here, we exhibited a comprehensive cell atlas of one Ph-like ALL patient with a novel TPR-PDGFRB fusion gene at diagnosis and relapse by using single-cell RNA sequencing (scRNA-seq). Twelve heterogeneous B-cell clusters, four with strong MKI67 expression indicating highly proliferating B cells, were identified. A relapse-enriched B-cell subset associated with poor prognosis was discovered, implicating the transcriptomic evolution during disease progression. Integrative single-cell analysis was performed on Ph-like ALL and Ph

KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPRCas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

Venous thromboembolism incidence associated with pegylated asparaginase (ASP) compared to the native L-ASP A retrospective analysis with an ASP-based protocol in adult patients with acute lymphoblastic leukaemia.

Venous thromboembolism (VTE) is a well-known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)-based chemotherapy, including the ASP-intensive Dana-Farber Cancer Institute (DFCI) 91-01 protocol for adults. Since 2019, native L-ASP is no longer available in Canada and was replaced by pegylated (PEG)-ASP. To determine whether the incidence of VTE has changed since switching from L-ASP to PEG-ASP, we conducted a single-centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L-ASP group (2011-2019) and 70 from the PEG-ASP group (2018-2021). During Induction, 10.29% (18175) of patients who received L-ASP developed VTE, whereas 28.57% (2070) of patients who received PEG-ASP developed VTE (p 0.0035 odds ratio OR 3.35, 95% confidence interval CI 1.51-7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18132) of patients had VTE on L-ASP while 34.37% (1132) of patients on PEG-ASP developed VTE (p 0.0096 OR 3.96, 95% CI 1.57-9.96 with multivariable analysis). We found that PEG-ASP is associated with a higher incidence of VTE compared to L-ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG-ASP.

Proteome Analysis of Adult Acute Lymphoblastic Leukemia by Two-dimensional Blue NativeSodium Dodecyl Sulfate Gel Electrophoresis.

Despite the significant progress in the treatment of Acute Lymphoblastic Leukemia (ALL) in children, it still remains as one of the most challenging malignancies in adults. Identification of new biomarkers may improve the management of adult ALL. Proteins expressed on the cell surface can be considered as disease-associated biomarkers with potential for diagnosis and targeted therapies. Thus, membrane proteome studies give essential information about the disease-related biomarkers. We applied 2-dimensional blue-native SDS-PAGE technique followed by MALDI-TOFTOF-mass spectrometry to study the cell membrane proteome of peripheral blood mononuclear cells of adult B-ALL patients in comparison to that of the healthy controls. Sixty seven differentially expressed protein spots were detected, among them 52 proteins were found to be up-regulated but the other 15 proteins were down-regulated in B-ALL. Five differentially expressed proteins, involved in energy metabolism pathways, were detected in B-ALL patients compared to the healthy control group. Differentially expressed proteins provide an insight into the molecular biology of B-ALL. Further studies must be done to confirm our data to be considered as potential targets for detection and treatment of B-ALL.

Neutropenia-related aspergillosis in non-transplant haematological patients hospitalised under ambient air versus purified air conditions.

To reduce the risk of invasive aspergillosis (IA), air purification by high-efficiency particulate air filtration and laminar air flow (HEPALAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non-transplant haematological patients is inconsistent. We sought to assess the incidence and outcome of pulmonary IA in non-transplant patients with life-threatening neutropenia by comparing an ambient air hospitalisation period (2008-2011) with a subsequent HEPALAF hospitalisation period (2012-2014). We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia-related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia-related hospitalisations under HEPALAF conditions. IA was defined using the 2008 EORTCMSG criteria. Within a 7-year study period, we observed one proven, three probable and 73 possible IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life-threatening neutropenia (1-10 days, 1.8% >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2% >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPALAF conditions (odds ratio OR, 0.368 95% confidence interval, 0.207-0.654 p < .001) and duration of neutropenia (OR, 1.043 1.023-1.062 per day p < .001) and anaemia (OR, 1.044 1.008-1.081 per day p .016). IA-associated fatal outcomes were non-significantly reduced under HEPALAF (OR, 0.077 0.005-1.151 p .063). The protective effect of HEPALAF was not seen under posaconazole prophylaxis (OR, 0.856 0.376-1.950 p .711). Implementation of HEPALAF was associated with a significant reduction in neutropenia-related IA in non-transplant haematological patients.

Stills disease in children and acute lymphoblastic leukemia, an exceptional association a case report.

Stills disease, also known as systemic juvenile idiopathic arthritis (SJIA), and acute lymphoblastic leukemia have similar clinical and biological features posing diagnostic and treatment challenges. Indeed, while Stills disease is a diagnosis of exclusion in rheumatology, polyarthritis associated with hyperleukocytosis and fever, which is characteristic of this disease, are often detected in early stages of acute lymphocytic leukaemias. We here report the case of a 4-year-old girl, treated for Stills disease, in whom the diagnosis of acute lymphoblastic leukemia was made after 2 months, based on bone marrow biopsy. La maladie de Still de l´enfant et la leucémie aigue lymphoblastique ont des similitudes cliniques et biologiques qui posent des problèmes de retard de diagnostic et de prise en charge. En effet, si la maladie de Still est un diagnostic d´exclusion en rhumatologie, la polyarthrite associée à l´hyperleucocytose en contexte fébrile qui la caractérise est souvent rencontrée au cours des leucémies aigues lymphoïdes au stade précoce. Nous rapportons le cas d´une fillette de 4 ans, traitée comme maladie de Still de l´enfant et chez qui le diagnostic de LAL a été posé au bout de 2 mois grâce à une biopsie de la moelle osseuse.

Thrombolytic treatment of right atrial thrombus in a patient with B cell acute lymphoblastic leukemia a case report.

Right atrial thrombus is a severe complication of central venous catheterization (CVC). Concomitant pulmonary embolism may aggravate the clinical picture by causing or increasing shortness of breath and decreasing effort capacity, palpitations, and tricuspid valve regurgitation. A 32-year-old female patient with

Detection of acute promyelocytic leukemia in peripheral blood and bone marrow with annotation-free deep learning.

While optical microscopy inspection of blood films and bone marrow aspirates by a hematologist is a crucial step in establishing diagnosis of acute leukemia, especially in low-resource settings where other diagnostic modalities are not available, the task remains time-consuming and prone to human inconsistencies. This has an impact especially in cases of Acute Promyelocytic Leukemia (APL) that require urgent treatment. Integration of automated computational hematopathology into clinical workflows can improve the throughput of these services and reduce cognitive human error. However, a major bottleneck in deploying such systems is a lack of sufficient cell morphological object-labels annotations to train deep learning models. We overcome this by leveraging patient diagnostic labels to train weakly-supervised models that detect different types of acute leukemia. We introduce a deep learning approach, Multiple Instance Learning for Leukocyte Identification (MILLIE), able to perform automated reliable analysis of blood films with minimal supervision. Without being trained to classify individual cells, MILLIE differentiates between acute lymphoblastic and myeloblastic leukemia in blood films. More importantly, MILLIE detects APL in blood films (AUC 0.94 ± 0.04) and in bone marrow aspirates (AUC 0.99 ± 0.01). MILLIE is a viable solution to augment the throughput of clinical pathways that require assessment of blood film microscopy.

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsedrefractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

The positive feedback loop of MAD2L1TYK2STAT3 induces progression in B-cell acute lymphoblastic leukaemia.

Mitotic arrest deficient 2 like 1 (MAD2L1) has been extensively studied in several malignancies however, its role in B-cell acute lymphoblastic leukaemia (B-ALL) remains unclear. The expression of MAD2L1 was evaluated by real-time quantitative polymerase chain reaction. The biological functions of MAD2L1 in B-ALL were explored through Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2-deoxyuridine assay (EDU), transwell assay, flow cytometry and xenograft models. The Western blotting and co-immunoprecipitation were utilized to evaluate the interplay between MAD2L1 and the TYK2STAT3 pathway. The luciferase reporter and chromatin immunoprecipitation (ChIP) assay were employed to identify interactions between STAT3 and MAD2L1. We demonstrated that MAD2L1 was markedly upregulated in B-ALL, and its expression level not only correlated with the relapse and remission of the condition but also with a poor prognosis. MAD2L1 promoted the proliferation, migration and invasion of B-ALL cells in vitro and in vivo, whereas MAD2L1 knockdown had the opposite effects. Mechanistically, MAD2L1 induces the progression of B-ALL by activating the TYK2STAT3 signaling pathway to phosphorylate. Interestingly, STAT3 induces the expression of MAD2L1 by binding directly to its promoter region, resulting in a positive-feedback loop of MAD2L1TYK2STAT3. This study uncovered a reciprocal loop of MAD2L1TYK2STAT3, which contributed to the development of B-ALL. Therefore, MAD2L1 can be considered a potential diagnostic biomarker as well as a novel therapeutic target for B-ALL.

Asparaginase therapy in patients with acute lymphoblastic leukemia expert opinion on use and toxicity management.

The addition of asparaginase to acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treatment regimens provides significant patient benefits. Asparaginase therapies vary in origin (

The emerging use of chemotherapy-free regimens in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Before the development of tyrosine kinase inhibitors (TKIs), the outcome of patients with a diagnosis of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia was dismal. Combinations of TKIs and chemotherapy improved survival rates, but allogeneic stem cell transplant was still relied on to avoid relapse in most cases. More recently, the chemotherapy-free combination of blinatumomab plus newer-generation TKIs has shown favorable results and may eliminate the need for allogeneic stem cell transplant. This review discusses the evolution of the treatment of Ph-positive acute lymphoblastic leukemia with chemotherapy-free regimens in the current era.

Comparison of the efficacy of second and third generation lentiviral vector transduced CAR CD19 T cells for use in the treatment of acute lymphoblastic leukemia both in vitro and in vivo models.

T cells genetically engineered to express a chimeric antigen receptor (CAR) specifically binding to a CD19 antigen has become the frontline of hematological malignancies immunotherapy. Their remarkable antitumor effect has exerted complete remission in treating B-cell malignancies. Although successful patient treatment has been shown, improvement to the structure of CAR to enhance its safety and efficacy profile is warranted. Transduction with a lentiviral vector (LVV) leading to the expression of CARs is also a critical step in redirecting T cells to target specific tumor antigens. To improve the efficacy of CD19 CARs in this study, the transduction ability of second and third generations LVV were compared. Ex vivo expansion of CD19 CARs T cells from healthy donors peripheral blood mononuclear cells was performed after transduction of T cells with second and third generations LVV. Transduction efficacy of transduced T cells was determined to show a higher percentage in the third generations LVV transduced cells, with no changes in viability and identity of cells characterized by immunophenotyping. Testing the cytotoxic capacity of third generations LVV-transduced T cells against target cells showed higher reactivity against control cells. Cytokine expression was detected on the CD19 CARs T cells, suggesting that these cells limit in vitro growth of B-cell leukemia via secretion of the pro-inflammatory cytokine IFN γ. To investigate whether the third generation LVV transduced T cells can limit CD19 lymphoma growth in vivo, an analysis of tumor burden in a mouse model assessed by bioluminescence imaging was performed. We found that, in the presence of CD19 CARs T cells, the level of tumor burden was markedly reduced. In addition, an increase in the length of survival in mice receiving CAR-CD19 T cells was also observed. This suggests that transduction with third generations LVV generate a functional CAR-CD19 T cells, which may provide a safer and effective therapy for B-cell malignancies.

Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Evolves from TP53-Mutated Clonal Hematopoiesis.

Low-hypodiploid acute lymphoblastic leukemia (LH-ALL) in both children and adults is characterized by biallelic TP53 alterations in virtually all cases. However, in contrast to a common germline origin of the TP53 mutations in pediatric cases, those in adult cases are mostly somatic and are derived from age-related clonal hematopoiesis (ARCH), highlighting the role of TP53-mutant ARCH in the development not only of myeloid leukemogenesis but also of LH-ALL in aged populations. See related article by Kim et al., p. 134 (4).

General condition and comorbidity of long-term survivors of adult acute lymphoblastic leukemia.

Cure rates in adult acute lymphoblastic leukemia (ALL) improved using pediatric-based chemotherapy and stem cell transplantation (SCT). However, limited data on health condition of cured adults are available whereas pediatric data cannot be transferred. The GMALL analyzed the health status in survivors of adult ALL retrospectively. Physicians answered a questionnaire on general condition (ECOG status) and comorbidity or syndrome occurrence observed after treatment. 538 patients with a median age of 29 (15-64) years at diagnosis were analyzed, median follow-up was seven (3-24) years. 31% had received SCT. ECOG status was 0-1 in 94%, 34% had not developed significant comorbidities. Most frequent comorbidities involved the neurologic system (27%), endocrine system (20%), skin (18%), Graft-versus-Host-Disease (15%), cardiac system (13%), fatigue (13%). SCT impacted ECOG status and comorbidity occurrence significantly. ECOG 0-1 was observed in 86% of SCT and 98% of non-SCT patients (p.

Acute promyelocytic leukemia with FIP1L1RARA fusion gene The clinical utility of transcriptome sequencing and bioinformatic analyses.

Acute promyelocytic leukemia (APL) is typically characterized by the presence of coagulopathy and the A Transcriptome analysis of six patients was performed by RNA-seq. The heat map was used for showing the RNA expression profile, the volcano plot for identifying differential expression genes (DEGs), and the KEGG Orthology-Based Annotation System (KOBAS) online biological information database for KEGG pathway enrichment analysis. Obvious differences between APL with A

A review on the role of LINC00173 in human cancers.

Long intergenic non-protein coding RNA 173 (LINC00173) is a long non-coding RNA with especial function in the tumorigenic process. Studies in different types of cancers support an oncogenic role for LINC00173 except for studies in B-cell precursor acute lymphoblastic leukemia, cervical cancer, pancreatic cancer and gastric cancer. In breast and lung cancers, both oncogenic and tumor suppressor roles have been reported for LINC00173. LINC00173 can serve as a molecular sponge for miRNAs. miR-218Etk, miR-511-5pVEGFA, miR-182-5pAGER, miR-765NUTF2, miR-765PLP2, miR-182-5pFBXW7, miR-338-3pRab25, miR‑641RAB14 and miR-1275BCL2 are examples of the miRNAmRNA axes being regulated by LINC00173 in the context of cancer. The current review provides a summary of different studies on the role of LINC00173 in these cancers.

Unexpected appearance of KMT2AMLLT10 fusion transcript in acute myeloid leukemia with t(511)(q31q23.3).

As an uncommon but nonrandom translocation in acute myeloid leukemia (AML) t(511)(q31q23) results in fusion between KMT2A at 11q23 and ARHGAP26 at 5q31. The 5q31 region has another KMT2A partner, AFF4, which was identified in acute lymphoblastic leukemia harboring ins(511)(q31q13q23). We report here a 65-year-old woman with AML M5b. G-banding and spectral karyotyping demonstrated 46,XX,t(511)(q31q23.3). Fluorescence in situ hybridization revealed not only separated 5 and 3 KMT2A signals but a faint 5 KMT2A signal. Reverse transcription polymerase chain reaction (RT-PCR), using a KMT2A sense primer and ARHGAP26 antisense primer, detected no band whereas RT-PCR with a AFF4 antisense primer revealed an amplified band. However, sequence analysis unexpectedly disclosed that KMT2A exon 6 was connected with MLLT10 exons 15 to 18. This may be due to cross-hybridization between MLLT10 exon 18 and AFF4 antisense primer derived from AFF4 exon 10 since both exons had eight identical bases (AAGCAGCT). The MLLT10 gene is located at 10p12.31 a faint 5 KMT2A signal was probably present at this locus. These findings indicate that in AML the 5 KMT2A fragment containing exons 1 to 6 may be cryptically inserted into MLLT10 intron 14 when a reciprocal translocation t(511)(q31q23.3) involving KMT2A occurred.

HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias Novel Molecules on the Horizon.

Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.

Phosphorylation of Thymidylate Synthase and Dihydrofolate Reductase in Cancer Cells and the Effect of CK2α Silencing.

Our previous research suggests an important regulatory role of CK2-mediated phosphorylation of enzymes involved in the thymidylate biosynthesis cycle, i.e., thymidylate synthase (TS), dihydrofolate reductase (DHFR), and serine hydroxymethyltransferase (SHMT). The aim of this study was to show whether silencing of the CK2α gene affects TS and DHFR expression in A-549 cells. Additionally, we attempted to identify the endogenous kinases that phosphorylate TS and DHFR in CCRF-CEM and A-549 cells. We used immunodetection, immunofluorescenceconfocal analyses, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), in-gel kinase assay, and mass spectrometry analysis. Our results demonstrate that silencing of the CK2α gene in lung adenocarcinoma cells significantly increases both TS and DHFR expression and affects their cellular distribution. Additionally, we show for the first time that both TS and DHFR are very likely phosphorylated by endogenous CK2 in two types of cancer cells, i.e., acute lymphoblastic leukaemia and lung adenocarcinoma. Moreover, our studies indicate that DHFR is phosphorylated intracellularly by CK2 to a greater extent in leukaemia cells than in lung adenocarcinoma cells. Interestingly, in-gel kinase assay results indicate that the CK2α isoform was more active than the CK2α subunit. Our results confirm the previous studies concerning the physiological relevance of CK2-mediated phosphorylation of TS and DHFR.

Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL).

The Hedgehog (HH) signaling network is one of the main regulators of invertebrate and vertebrate embryonic development. Along with other networks, such as NOTCH and WNT, HH signaling specifies both the early patterning and the polarity events as well as the subsequent organ formation via the temporal and spatial regulation of cell proliferation and differentiation. However, aberrant activation of HH signaling has been identified in a broad range of malignant disorders, where it positively influences proliferation, survival, and therapeutic resistance of neoplastic cells. Inhibitors targeting the HH pathway have been tested in preclinical cancer models. The HH pathway is also overactive in other blood malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). This review is intended to summarize our knowledge of the biological roles and pathophysiology of the HH pathway during normal T-cell lymphopoiesis and in T-ALL. In addition, we will discuss potential therapeutic strategies that might expand the clinical usefulness of drugs targeting the HH pathway in T-ALL.

Exploring Urban Green Spaces Effect against Traffic Exposure on Childhood Leukaemia Incidence.

Several environmental factors seem to be involved in childhood leukaemia incidence. Traffic exposure could increase the risk while urban green spaces (UGS) exposure could reduce it. However, there is no evidence how these two factors interact on this infant pathology. to evaluate how residential proximity to UGS could be an environmental protective factor against traffic exposure on childhood leukaemia incidence. A population-based case control study was conducted across thirty Spanish regions during the period 2000-2018. It included 2526 incident cases and 15,156, individually matched by sex, year-of-birth, and place-of-residence. Using the geographical coordinates of the participants home residences, a 500 m proxy for exposure to UGS was built. Annual average daily traffic (AADT) was estimated for all types of roads 100 m near the childrens residence. Odds ratios (ORs) and 95% confidence intervals (95% CIs), UGS, traffic exposure, and their possible interactions were calculated for overall childhood leukaemia, and the acute lymphoblastic (ALL) and acute myeloblastic leukaemia (AML) subtypes, with adjustment for socio-demographic covariates. We found an increment of childhood leukaemia incidence related to traffic exposure, for every 100 AADT increase the incidence raised 1.1% (95% CI 0.58-1.61%). UGS exposure showed an incidence reduction for the highest exposure level, Q5 (OR 0.63 95% CI 0.54-0.72). Regression models with both traffic exposure and UGS exposure variables showed similar results but the interaction was not significant. Despite their opposite effects on childhood leukaemia incidence individually, our results do not suggest a possible interaction between both exposures. This is the first study about the interaction of these two environmental factors consequently, it is necessary to continue taking into account more individualized data and other possible environmental risk factors involved.

The Landscape of Secondary Genetic Rearrangements in Pediatric Patients with B-Cell Acute Lymphoblastic Leukemia with t(1221).

The most frequent chromosomal rearrangement in childhood B-cell acute lymphoblastic leukemia (B-ALL) is translocation t(1221)(p13q22). It results in the fusion of the

Computer-Aided Diagnosis System for Blood Diseases Using EfficientNet-B3 Based on a Dynamic Learning Algorithm.

The immune systems overproduction of white blood cells (WBCs) results in the most common blood cancer, leukemia. It accounts for about 25% of childhood cancers and is one of the primary causes of death worldwide. The most well-known type of leukemia found in the human bone marrow is acute lymphoblastic leukemia (ALL). It is a disease that affects the bone marrow and kills white blood cells. Better treatment and a higher likelihood of survival can be helped by early and precise cancer detection. As a result, doctors can use computer-aided diagnostic (CAD) models to detect early leukemia effectively. In this research, we proposed a classification model based on the EfficientNet-B3 convolutional neural network (CNN) model to distinguish ALL as an automated model that automatically changes the learning rate (LR). We set up a custom LR that compared the loss value and training accuracy at the beginning of each epoch. We evaluated the proposed model on the C-NMCLeukemia dataset. The dataset was pre-processed with normalization and balancing. The proposed model was evaluated and compared with recent classifiers. The proposed models average precision, recall, specificity, accuracy, and Disc similarity coefficient (DSC) were 98.29%, 97.83%, 97.82%, 98.31%, and 98.05%, respectively. Moreover, the proposed model was used to examine microscopic images of the blood to identify the malaria parasite. Our proposed models average precision, recall, specificity, accuracy, and DSC were 97.69%, 97.68%, 97.67%, 97.68%, and 97.68%, respectively. Therefore, the evaluation of the proposed model showed that it is an unrivaled perceptive outcome with tuning as opposed to other ongoing existing models.

Pediatric Acute Myeloid Leukemia Post Cytotoxic Therapy-Retrospective Analysis of the Patients Treated in Poland from 2005 to 2022.

Acute P.myeloid leukemia post cytotoxic therapy (AML-pCT) is rare complication of cancer treatment in childhood. The objective of the study was to identify clinical characteristics and provide an analysis of the outcomes in pediatric AML-pCT. We retrospectively analyzed the data of 40 children with AML-pCT, treated from 2005 to 2020 within the Polish Pediatric Leukemia and Lymphoma Study Group. The most common primary malignancies were acute lymphoblastic leukemia (32.5%) and brain tumors (20%). The median latency period was 2.9 years (range 0.7-12.9). Probabilities of overall (OS), event-free (EFS), and relapse-free survival (RFS) in the whole cohort were 0.49 ± 0.08, 0.43 ± 0.08, and 0.64 ± 0.10, respectively. Significant improvements in outcomes were observed in patients treated from 2015-2022 (two induction cycles followed by stem cell transplantation-SCT in 69% of patients) compared to 2005-2014 (four induction cycles followed by SCT in 49% of patients). The probability of EFS increased from 0.30 ± 0.10 to 0.67 ± 0.12 (

Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC

IL-15 Prevents the Development of T-ALL from Aberrant Thymocytes with Impaired DNA Repair Functions and Increased NOTCH1 Activation.

We previously reported that NOD.

CAR-T What Is Next

The year 2017 was marked by the Food and Drug Administration (FDA) approval of the first two chimeric antigen receptor-T (CAR-T) therapies. The approved indications were for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in a second or later relapse. Since then, extensive research activities have been ongoing globally on different hematologic and solid tumors to assess the safety and efficacy of CAR-T therapy for these diseases. Limitations to CAR-T therapy became apparent from, e.g., the relapse in up to 60% of patients and certain side effects such as cytokine release syndrome (CRS). This led to extensive clinical activities aimed at overcoming these obstacles, so that the use of CAR-T therapy can be expanded. Attempts to improve on efficacy and safety include changing the CAR-T administration schedule, combining it with chemotherapy, and the development of next-generation CAR-T therapies, e.g., through the use of CAR-natural killer (CAR-NK) and CAR macrophages (CAR-Ms). This review will focus on new CAR-T treatment strategies in hematologic malignancies, clinical trials aimed at improving efficacy and addressing side effects, the challenges that CAR-T therapy faces in solid tumors, and the ongoing research aimed at overcoming these challenges.

Applicability of Seven Glomerular Filtration Rate Evaluation Formulas in Dose Adjustment of High Concentration of Methotrexate Chemotherapy in Children with ALL.

To investigate the diagnostic efficacy of seven glomerular filtration rate (GFR) evaluation formulas Schwartz2009, Schwartz1976, Counahan-Barratt, Filler, CKD-EPI One hundred and twenty-four children with ALL were included in the study. GFR determined by renal dynamic imaging (sGFR) was used as the standard to evaluate the accuracy, consistency of eGFR calculated by seven formulas and sGFR, and the diagnostic efficacy of each formula when the sGFR ≤85 mlmin boundary. All of the accuracy of eGFR estimated by Schwartz2009 were greater than 70% in the 0-3, >4 and ≤6, >6 and ≤9, >9 and ≤16 years old group and male group, and the consistency exceeded the professional threshold. When the sensitivity of the ROC curve sGFR ≤85 mlmin was 100% of CKD-EPI Schwartz2009 formula predicts the highest accuracy of eGFR in the 7 glomerular filtration rate. CKD-EPI 肾小球率过滤评估公式在儿童ALL高浓度甲氨蝶呤化疗剂量调整中的适用性研究. 探讨7种肾小球滤过率（GFR）评估公式Schwartz2009、Schwartz1976、Counahan-Barratt、Filler、CKD-EPI 纳入124例次儿童ALL患者为研究对象，以肾动态显像法测定的GFR（sGFR）作为标准，评估公式估算GFR（eGFR）与sGFR的准确性、一致性及sGFR≤85 mlmin界点的诊断效能. Schwartz2009公式估算0-3岁组、>4且≤6岁组、>6且≤9岁组、>9且≤16岁组及男性儿童组eGFR值准确性均大于70%，一致性均超出专业界限值；CKD-EPI 7种肾小球滤过率评估公式中Schwartz2009公式预测eGFR的准确性最高，CKD-EPI

Diagnosis Significance of the Levels of Cytokines IL-6, IL-10 and CXCL-13 in Cerebrospinal Fluid for Central Nervous System Infiltration of Lymphoma.

To evaluate the diagnostic value of the expression levels of cytokines interleukin-6(IL-6), interleukin-10 (IL-10) and chemokine （C-X-C motif） ligand-13 (CXCL-13) in cerebrospinal fluid (CSF) for central nervous system infiltration of lymphoma. Forty patients diagnosed as lymphoma or acute lymphoblastic leukemia in General Hospital of Northern Theater Command from July 2020 to July 2021 were collected and recorded their CSF indexes, including pressure, protein, Pandy test, nucleated cell count, glucose and chlorine content in CSF. The levels of cytokines IL-6, IL-10 and CXCL-13 were detected by Enzyme-linked immunosorbent assay. The patients were divided into CNSI (central nervous system infiltration) group and non-CNSI group, the average levels of IL-6, IL-10, CXCL-13 and IL-10IL-6 ratio in CNSI group were higher than those in non-CNS group, but the difference of IL-10IL-6 ratio between the two groups was statistically significant ( The levels of IL-6, IL-10 and CXCL-13 in CSF of lymphoma patients with CNS infiltration were higher than those in non-CNS infiltration group, and those in patients with protein elevated group are higher than those in the protein normal group. 脑脊液中细胞因子IL-6、IL-10和CXCL-13的表达水平对淋巴瘤中枢神经系统浸润的诊断意义. 探讨细胞因子白介素-6（IL-6）、白介素-10（IL-10）和趋化因子-13（CXCL-13）在脑脊液中的表达水平对于淋巴瘤中枢神经系统浸润的诊断价值. 收集2020年7月至2021年7月在北部战区总医院就诊的30例淋巴瘤患者、10例急性淋巴细胞白血病患者的脑脊液，记录其脑脊液指标（包括压力、蛋白、潘氏试验、有核细胞计数、葡萄糖含量、氯含量），应用酶联免疫吸附实验检测细胞因子IL-6、IL-10和CXCL-13的水平. 根据中枢浸润与否分为中枢浸润组（CNSI组）和非中枢浸润组（non-CNSI组），CNSI组的IL-6、IL-10、IL-10IL-6比值及CXCL-13表达水平均高于non-CNSI组，但仅IL-10IL-6比值在两组之间差异具有统计学意义（ 淋巴瘤发生中枢神经系统浸润患者的脑脊液中细胞因子IL-6、IL-10和CXCL-13的水平高于未发生中枢浸润者，且脑脊液蛋白升高患者的IL-6、IL-10和CXCL-13因子水平高于脑脊液蛋白正常患者.

Study on the Regulation of Chidamide on CD8

To explore the regulatory effect of chidamide on CD8 The expression levels of Chidamide upregulated In T-cell acute lymphoblastic leukemia, chidamide may increase the concentration of CXCL9 in the tumor microenvironment by up-regulating the expression of CXCL9 in tumor cells, leading to an increase in the number of CD8 西达本胺对急性T淋巴细胞白血病CD8 探讨西达本胺对急性T淋巴细胞白血病CD8 通过荧光定量PCR检测西达本胺处理的Jurkat细胞、淋巴细胞、与西达本胺处理的Jurkat细胞共培养的淋巴细胞的 西达本胺上调Jurkat细胞系 急性T淋巴细胞白血病中，西达本胺可能通过上调肿瘤细胞CXCL9的表达，增加肿瘤微环境中CXCL9的浓度，导致CD8

The Effect of SP1 on the Progression of T-cell Acute Lymphoblastic Leukemia.

To study the transcriptional regulation of SP1 on the scaffold protein ARRB1 and its influence on the progression of T-cell acute lymphoblastic leukemia (T-ALL). pGL3-ARRB1-luc, pCDNA3.1-SP1 and other transcription factor plasmids that might be combined were constructed, and the binding of transcription factors to the promoter of The expression of fluorescein were enhanced by co-transfection with pCDNA3.1-SP1 and pGL3-ARRB1-luc plasmids in HEK293T cell line ( Transcription factor SP1 promotes the transcription and expression of ARRB1 by binding the the promoter of 转录因子SP1对急性T淋巴细胞白血病进程的影响. 研究转录因子SP1对支架蛋白ARRB1的转录调节及其在急性T淋巴细胞白血病（T-ALL）中的作用. 构建pGL3-ARRB1-luc、pCDNA3.1-SP1及其他可能结合的转录因子质粒，采用双荧光素酶报告基因实验证明ARRB1启动子区与转录因子结合；利用慢病毒感染构建SP1过表达的稳定细胞株JK-SP1，RT-PCR及Western blot验证SP1与ARRB1表达的关系；进一步流式细胞术检测SP1对细胞凋亡、细胞周期以及细胞活性氧含量的作用。构建NCG小鼠异种移植模型，探讨SP1对白血病小鼠成模能力的影响. pGL3-ARRB1-luc、pCDNA3.1-SP1质粒共转入HEK293T细胞后，虫荧光素高表达（ 转录因子SP1通过直接结合于

Effect of

To discover the relationship between matrix remodeling associated 7 ( The expression of Database analysis showed that Knockdown of 发掘基质重塑相关7（ 通过BloodSpot数据库检索并分析 数据库分析显示 敲低

Clinical Study on the Relationship between Gene Mutation Profile and Prognosis in Pediatric Acute Lymphocyte Leukemia.

To analyze the gene mutation profile in children with acute lymphocyte leukemia (ALL) and to explore its prognostic significance. Clinical data of 249 primary pediatric ALL patients diagnosed and treated in the Department of Hematological Oncology of Wuhan Childrens Hospital from January 2018 to December 2021 were analyzed retrospectively. Next-generation sequencing (NGS) was used to obtain gene mutation data and analyze the correlation between it and the prognosis of children with ALL. 227 (91.2%) were B-ALL, 22 (8.8%) were T-ALL among the 249 cases, and 178 (71.5%) were found to have gene mutations, of which 85 (34.1%) had ≥3 gene mutations. NRAS(23.7%), KRAS (22.9%),FLT3(11.2%), PTPN11(8.8%), CREBBP (7.2%), Genetic mutations are prevalent in childhood ALL and mutations in 儿童急性淋巴细胞白血病患者基因突变谱与预后相关性的临床研究. 分析儿童急性淋巴细胞白血病（ALL）患者的基因突变谱，并探讨其对患儿预后的影响. 回顾性分析2018年1月至2021年12月于武汉儿童医院血液肿瘤科249例初诊ALL患儿的临床资料，采用靶向特异性二代测序（Next-generation sequencing, NGS）技术获得基因突变谱数据，并分析其与ALL患儿预后的相关性. 249例患儿中B-ALL 227例（91.2%），T-ALL 22例（8.8%）；178例（71.5%）患儿检测发现基因突变，其中85例（34.1%）患儿存在≥3种基因突变。突变率较高的基因依次为NRAS（23.7%）、KRAS（22.9%）、FLT3（11.2%）、PTPN11（8.8%）、CREBBP（7.2%）、 儿童ALL普遍存在基因突变，

Severe acute respiratory syndrome coronavirus-2 Alpha variant (B.1.1.7), original wild-type severe acute respiratory syndrome coronavirus 2, and cytomegalovirus co-infection in a young adult with acute lymphoblastic leukemia, case report, and review of the possible cytomegalovirus reactivation mechanisms.

Like other viral infections, severe acute respiratory syndrome coronavirus-2 infection could affect different human body systems, including host immune responses. Three years after its pandemic, we learn more about this novel coronavirus. As we expected, different co-infections with various organisms, such as viruses, bacteria, and even fungi, have been reported. However, concurrent infection with two severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus is extremely unusual. We have only a rudimentary understanding of such co-infections and their long-term consequences for patients with cancer. An 18-year-old young Iranian adult with acute lymphoblastic leukemia presented with abdominal pain, diarrhea, nausea, and vomiting following a recent history of severe acute respiratory syndrome coronavirus-2 infection. The patient never experienced respiratory symptoms, and the chest imaging study was normal on admission. His primary laboratory investigation revealed prerenal azotemia and severe abnormal liver function tests (blood urea nitrogen 32 mgdL, creatinine 1.75 mgdL, prothrombin time 66 s, partial thromboplastin time 44.5 s, international normalized ratio 5.14, total bilirubin 2.9 mgdL, and direct bilirubin 2.59 mgdL). Cytomegalovirus disease was diagnosed by polymerase chain reaction in his blood and stool samples. The patients gastrointestinal signs and symptoms improved shortly after receiving intravenous ganciclovir treatment. His gastrointestinal symptoms continued intermittently for weeks despite maintenance valganciclovir prescription, necessitating frequent hospitalizations. The patient was complicated by the recurrence of gastrointestinal symptoms during the sixth hospitalization, even though he had no respiratory symptoms, and the nasopharyngeal test revealed severe acute respiratory syndrome coronavirus-2 Wuhan strain for the first time. Remdesivir and valganciclovir were administrated due to persistent enteritis and evidence of intestinal tissue invasion by severe acute respiratory syndrome coronavirus 2 and cytomegalovirus on multiple intestinal biopsies, which led to partial clinical responses. Cytomegalovirus and severe acute respiratory syndrome coronavirus-2 fecal shedding continued for more than 6 months despite repeated antiviral therapy, and the Wuhan and Alpha strains were also detected in his nasopharyngeal samples through repeated sampling (confirmed by four nasopharyngeal sampling and multiple stool specimens and several intestinal biopsies). Finally, during the Delta-variant (B.1.617.2) outbreak in Iran, the patient was admitted again with febrile neutropenia and decreased level of consciousness, necessitating respiratory support and mechanical ventilation. During the Delta-variant peak, the patients nasopharyngeal sample once more tested positive for severe acute respiratory syndrome coronavirus 2. The patient died a few days later from cardiopulmonary arrest. The coronavirus disease 2019 pandemic has encountered patients with cancer with critical diagnostic and treatment challenges. Patients who are immunocompromised may co-infect with multiple severe acute respiratory syndrome coronavirus-2 strains and cytomegalovirus, and even with timely diagnosis and treatment, the prognosis may be poor.

BAX as the mediator of C-MYC sensitizes acute lymphoblastic leukemia to TLR9 agonists.

The prognosis of B-cell acute lymphoblastic leukemia (B-ALL) has improved significantly with current first-line therapy, although the recurrence of B-ALL is still a problem. Toll-like receptor 9 (TLR9) agonists have shown good safety and efficiency as immune adjuvants. Apart from their immune regulatory effect, the direct effect of TLR9 agonists on cancer cells with TLR9 expression cannot be ignored. However, the direct effect of TLR9 agonists on B-ALL remains unknown. We discussed the relationship between TLR9 expression and the clinical characteristics of B-ALL and explored whether CpG 685 exerts direct apoptotic effect on B-ALL without inhibiting normal B-cell function. By using western blot, co-immunoprecipitation, immunofluorescence co-localization, and chromatin immunoprecipitation, we explored the mechanism of the apoptosis-inducing effect of CpG 685 in treating B-ALL cells. By exploring the mechanism of CpG 685 on B-ALL, the predictive biomarkers of the efficacy of CpG 685 in treating B-ALL were explored. These efficiencies were also confirmed in mouse model as well as clinical samples. High expression of TLR9 in B-ALL patients showed good prognosis. C-MYC-induced BAX activation was the key to the effect of CpG oligodeoxynucleotides against B-ALL. C-MYC overexpression promoted P53 stabilization, enhanced Bcl-2 associated X-protein (BAX) activation, and mediated transcription of the BAX gene. Moreover, combination therapy using CpG 685 and imatinib, a BCR-ABL kinase inhibitor, could reverse resistance to CpG 685 or imatinib alone by promoting BAX activation and overcoming BCR-ABL1-independent PI3KAKT activation. TLR9 is not only a prognostic biomarker but also a potential target for B-ALL therapy. CpG 685 monotherapy might be applicable to Ph

Laboratory Aspects of Minimal Measurable Residual Disease Testing in B-Lymphoblastic Leukemia.

Minimal residual disease detection provides critical prognostic predictor of treatment outcome and is the standard of care for B lymphoblastic leukemia. Flow cytometry-based minimal residual disease detection is the most common test modality and has high sensitivity (0.01%) and a rapid turnaround time (24 hours). This article details the leukemia associated immunophenotype analysis approach for flow cytometry-based minimal residual disease detection used at St. Jude Childrens Research Hospital and importance of using guide gates and back-gating.

Novel and replicated clinical and genetic risk factors for toxicity from high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance. We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mgm Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958SLC19A1 and rs7317112ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283SLCO1B1 were found to be associated with a decreased risk for delayed clearance. These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

Functional damaging germline variants in ETV6, IKZF1, PAX5 and RUNX1 predisposing to B-cell precursor acute lymphoblastic leukemia.

Recent genome-wide studies have demonstrated that a significant proportion of children with cancer carry predisposing germline variants, with varying incidence according to cancer type. In general, there is a lower incidence of underlying germline predisposing variants among patients with B-cell acute lymphoblastic leukemia (B-ALL) compared to other types of cancer, but higher rates may be found in patients with specific leukemia subtypes. Two categories of ALL-predisposing variants have been described common polymorphisms, conferring low-penetrance ALL susceptibility, and rare variants, conferring high-penetrance ALL susceptibility. Variants in genes encoding hematopoietic transcription factors are an example of the latter, and include ETV6, IKZF1, PAX5 and RUNX1. Here, we present an overview of the germline variants detected in patients with B-ALL in these four genes and a summary of functional studies analyzing the impacts of these variants upon protein function, and hence their effects with regard to leukemia predisposition. Furthermore, we review specific clinical characteristics of patients with B-ALL, including specific features of the patient or family history and associated somatic genetic characteristics, which are suggestive of underlying germline alterations in one of these genes. This review may be of assistance in the interpretation of patient genetic germline findings, made even more challenging by the absence of a suggestive family history or by an unknown familial cancer history. Despite a low incidence of underlying germline alterations in ETV6, IKZF1, PAX5 and RUNX1 in patients with B-ALL, identification of an underlying ALL predisposition syndrome is relevant to the clinical management of patients and their relatives, as the latter are also at risk of developing cancer.

A secondary CD34 acute lymphoblastic leukemia unmasked and mobilized by G-CSF in an autologous stem cell donor with testicular cancer.

Late complications of chemotherapy include treatment-related secondary leukemias. We describe an unusual case of a new treatment-related acute lymphoblastic leukemia (t-ALL) that was unmasked and mobilized by G-CSF during autologous hematopoietic progenitor cell collection (HPCC) in a young man with testicular cancer. Electronic chart review of the patient medical history and pertinent laboratory findings. Patient CD34 and blast results were compared to 4249 autologous and 437 allogeneic HPCC performed between 2004 and 2022. In autologous donors, the %blast and %CD34 were compared by linear regression and paired t-test using commercial software. The patient was a 21-year-old male with relapsed testicular cancer referred for G-CSF cytokine-only mobilization and autologous HPCC. His pre-mobilization WBC count and differential were normal. On the day of HPCC, his WBC 37.9 KmcL with 12% blasts and 9.75% circulating CD34 cells. The patient was admitted 9 days after HPCC with a normal WBC count and 15% blasts. He was diagnosed with a pro-B t-ALL bearing an t(411)(q21q23) translocation and KMT2A-AF4 rearrangement. Upon review, this patient had the highest %CD34 among 4686 HPCC and was the only donor with %CD34 > 1% after a cytokine-only mobilization. We report a case of t-ALL that mimicked CD34 HPC and was mobilized by high-dose G-CSF. Up to 70% of secondary leukemias bear 11q23KMT2A rearrangements, which occur at the multipotent stem cell stage and can result in myeloid and lymphoid leukemias. Donors who have received past chemotherapy, especially with topoisomerase II inhibitors, are at increased risk for 11q23KMT2A leukemias.

Dasatinib-associated chylothorax in a pediatric patient with chronic myeloid leukemia a case report and literature review.

Dasatinib is an effective 2 An 11-year-old boy diagnosed with breakpoint cluster region-Abelson (BCR-ABL) fusion was treated with dasatinib. After 38 months, the patient was admitted for dyspnea characterized by decreased breath sounds on both lungs during physical examination. Computed tomography (CT) showed bilateral PE with local insufficiency of both lungs. Drug-induced chylothorax was presumed based on clinical manifestations, excluding other possible causes. Dasatinib was withdrawn, diuretics as well as steroids were given for supportive therapy and octreotide was administered to decrease fat absorption in the intestine. However, the chylous fluid did not decrease significantly. The patient was then being fasted. Unexpectedly, after fasted for two days, the chylous fluid became clear and the drainage volume was decreased. The patient was advised to use nilotinib. We followed up the patient for 8 months, and there was no recurrence of chylothorax. Our patient had a shorter treatment course for chylothorax than those in the literature. In addition to dasatinib withdrawal, fasting treatment was also utmost critical. We summarize the literature of known existing cases to improve the understanding of the side effects and management of dasatinib in the treatment of CML.

Cardiovascular morbidity following conventional therapy versus allogeneic hematopoietic stem cell transplantation after childhood, adolescent, and young adult leukemia in Finland.

Allogeneic hematopoietic stem cell transplantation (aHSCT) represents a therapeutic choice for high-risk and relapsed leukemia at a young age. In this retrospective population-based study, we evaluated cardiovascular complications after aHSCT (N 272) vs conventional therapy (N 1098) among patients diagnosed with acute lymphoblastic or acute myeloid leukemia below 35 years between 1985 and 2004. Additionally, siblings from a prior comparison group served as population controls (N 39 217). Childhood leukemia and aHSCT was associated with a 16-fold HR for developing arterial hypertension (HR 16.8, 95%CI 1.5-185.5) compared with conventional therapy. A 2-fold HR for any cardiovascular complication was observed after AYA leukemia and aHSCT vs conventional treatment (HR 2.7, 95% CI 1.4-5.1). After AYA leukemia and aHSCT, the HR of cardiac arrhythmia was significantly elevated vs conventional therapy (HR 14.4, 95% CI 1.5-125.2). Moreover, after aHSCT in childhood, elevated hazard ratios (HRs) were found for cardiomyopathy cardiac insufficiency (HR 105.0, 95% CI 10.0-1100.0), cardiac arrhythmia, and arterial hypertension (HR 20.1, 95%CI 2.5-159.7 and HR 20.0, 95%CI 4.1-97.4) compared with healthy controls. After adolescent and young adult (AYA) leukemia and aHSCT, markedly increased HRs were observed for cardiac arrhythmia (HR 29.2, 95%CI 6.6-129.2), brain vascular thrombosis atherosclerosis and cardiomyopathycardiac insufficiency (HR 23.4, 95%CI 7.1-77.4 and HR 19.2, 95%CI 1.5-245.2) compared with healthy controls. As the cumulative incidence for cardiovascular complications rose during the follow-up of childhood and AYA leukemia patients, long-term cardiovascular surveillance is warranted to optimize the quality of life after childhood and AYA leukemia following both conventional treatment and aHSCT.

Clinical Impact of Drug Adherence of Tyrosine Kinase Inhibitors in Children with Ph-Positive Acute Lymphoblastic Leukemia.

To explore the impact of ABL1-tyrosine kinase inhibitors (TKIs) adherence on the survival of chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) children and clarify the potential predictors of patients prognosis from TKIs intake practices. Ninety newly diagnosed Ph ALL patients who received TKIs were enrolled. We collected the baseline characteristics and adverse events (AEs) in all children moreover, TKIs adherence was measured by an eight-item Morisky medication adherence scale (MMAS-8). Progression-free survival (PFS) and overall survival (OS) analysis were performed, and risk factors for PFS and OS were evaluated. Among all patients, 69 cases were regarded as adherers, while 21 were non-adherers. The median duration of TKIs interruption was significantly prolonged in the non-adherence group than in the adherence group 13 (0-101) vs. 56 (11-128), p<0.001. Additionally, dose reduction occurred in 55.2% of non-adherers versus 23.0% of adherers (p0.002). The PFS and OS in adherers were significantly higher versus non-adherers (p0.020 and p0.039). MMAS-8 score was an independent risk factor for PFS (p0.010) and OS (p0.031). Among non-adherers, the median OS was only 23.1% (4.2-42%) in patients aged≤10-years-old versus 54.4% (38.8-70%) in adolescents. Most of the patients who experienced TKIs non-adherence suffered pancytopenia. TKIs adherence during treatment significantly influenced the survival of pediatric Ph ALL patients, and non-adherers with age≤10-years-old were more vulnerable to TKIs disruption. The cumulative TKIs dose should be especially emphasized to patients with age≤10-years-old, which may result in an inferior achievement of relevant treatment milestones.

Outcomes of adult patients with early T-cell precursor (ETP) acute lymphoblastic leukemialymphoma (ALL) and non-ETP T-ALL.

Early T-cell precursor (ETP) acute lymphoblastic leukemialymphoma (ALL) is generally considered to be a high-risk subtype. We retrospectively analyzed the clinical outcomes of adult patients diagnosed with ETP-ALL or other T-cell ALL (non-ETP T-ALL). The subjects were 82 patients (ETP-ALL n 18, non-ETP T-ALL n 64) for whom relevant immunophenotype data needed for classification were available. ETP-ALL patients were older (median age, 50.5 vs. 33.5 years, P 0.042) and had less mediastinal involvement (27.8 vs. 73.4%, P < 0.001). The rate of complete remission (CR) with the first induction therapy was significantly lower in the ETP group (33.3 vs. 64.0%, P 0.03), but the CR rate within 2 cycles of chemotherapy did not differ significantly (61.1 vs. 76.6%, P 0.232). The 3-year overall survival (OS) rate was also similar in both groups (43.2 vs. 45.8%, P 0.992). The ETP phenotype had no impact on survival in the transplant group or the non-transplant group. A multivariate analysis identified the male sex as a poor prognostic factor (HR 4.43, P < 0.01), but not the immunophenotype of ETP. The prognosis for adult patients with ETP-ALL was comparable to that of non-ETP T-ALL patients. However, further studies aimed at improving the remission rate for ETP-ALL are needed.

Pharmacokinetics and safety of dasatinib and its generic a phase I bioequivalence study in healthy Chinese subjects.

Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug. 32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of C The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile. This trial was registered in ClinicalTrials.gov (Number NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number CTR20181708).

Absence of terminal deoxynucleotidyl transferase expression in T-ALLLBL accumulates chromosomal abnormalities to induce drug resistance.

T-acute lymphoblastic leukemialymphoma (T-ALLLBL) is a malignant neoplasm of immature lymphoblasts. Terminal deoxynucleotidyl transferase (TDT) is a template-independent DNA polymerase that plays an essential role in generating diversity for immunoglobulin genes. T-ALLLBL patients with TDT

Nanotechnology-based diagnostics and therapeutics in acute lymphoblastic leukemia a systematic review of preclinical studies.

Cytogenetics and Molecular Genetics in Pediatric Acute Lymphoblastic Leukemia (ALL) and Its Correlation with Induction Outcomes.

Arathi Srinivasan

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCRABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

Clinical summary of pediatric acute lymphoblastic leukemia patients complicated with asparaginase-associated pancreatitis in SCCLG-ALL-2016 protocol.

Asparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P .017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR 1.009, 95% CI0.370-2.752, P .986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase.

Transferring measurable residual disease measurement in pediatric acute lymphoblastic leukemia from quantitative real-time PCR to digital droplet PCR.

Since the measurement of measurable residual disease (MRD) is part of clinical routine examination for children affected with acute lymphoblastic leukemia (ALL), continuous efforts are made to improve its method, applicability and accuracy. Whereas quantitative real-time polymerase chain reaction (qPCR) is considered as the gold standard for MRD detection and endowed with international guidelines for implementation and evaluation, these do not yet exist for digital droplet PCR (ddPCR). However, advantages are seen in droplet partitioning for MRD measurement to allow absolute quantification without depending on reference samples. In this study, 17 MRD targets of nine patients with childhood B-ALL were analyzed with qPCR and ddPCR, respectively. All patients were assigned to high risk group and had hematopoietic stem cell transplantation and CD19 antibody therapy for relapse prevention. Starting with the sequences and guidelines of qPCR and optimizing the protocol for ddPCR, the MRD targets could also be measured precisely with this novel method, using the same primer and probe sets as for qPCR. The already established MRD protocol of qPCR could be transferred to ddPCR and all 17 MRD targets were measured in dilution series reaching comparable Limit of detection levels with both PCR methods. With a given qPCR protocol and some experience in conventional MRD monitoring, it is conceivable to transfer the procedure of MRD measurement to ddPCR technology. Our data is in line with other studies which are summarized and discussed here as well to facilitate the transfer of MRD diagnostics to ddPCR.

Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia a systematic review and meta-analysis.

Chimeric Antigen Receptor (CAR) T cell therapy is an effective treatment approach for patients with relapsed or refractory acute lymphoblastic leukemia (RR B-ALL). However, identifying the factors that influence long-term response to this therapy is necessary to optimize patient selection and treatment allocation. We conducted a literature review and meta-analysis to investigate the use of autologous anti-CD19 CAR T cell therapy in both pediatric and adult patients with RR B-ALL, using several databases including MEDLINE, Cochrane Central, ScienceDirect, Web of Science, JournalsOvid, Embase, and clinicaltrial.gov. A total of 38 reports were analyzed, which enrolled 2134 patients. Time-to-event endpoints were estimated using reconstructed patient survival data. The study explored key modulators of response, including costimulatory domains, disease status, age, and lymphodepletion. The median overall survival and event-free survival were 36.2 months 95% CI 28.9, NR and 13.3 months 95% CI 12.2, 17, respectively. The overall response rate was 76% 95% CI 71, 81. The use of 4-1BB costimulatory domain in the CAR construct, administration of low-dose cyclophosphamide lymphodepletion, and pretreatment morphologic remission were associated with better overall survival, with hazard ratios of 0.72, 0.56, and 0.66, respectively. Morphologic remission and 4-1BB domain were associated with better event-free survival, with hazard ratios of 0.66 and 0.72, respectively. These findings suggest that CAR T cell therapy may offer long-term benefits to patients with RR B-ALL. However, further research is needed to optimize patient selection and better understand the impact of various factors on the outcome of CAR T cell therapy.

Safety of levofloxacin as an antibiotic prophylaxis in the induction phase of children newly diagnosed with acute lymphoblastic leukemia an interim analysis of a randomized, open-label trial in Brazil.

Despite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications. From May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 11 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days. Twenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia. The use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route.

Correlation of the surface expression of thymic stromal lymphopoietin receptor with the presence of CRLF2 gene rearrangements in children with B-lineage acute lymphoblastic leukemia.

In this study, we aimed to compare the immunophenotype of tumor cells in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harboring rearrangements of the CRLF2 gene with that in children without such aberrations with a specific focus on the surface expression of the related protein thymic stromal lymphopoietin receptor (TSLPR). We examined bone marrow samples from 46 patients with primary BCP-ALL who had CRLF2 rearrangements detected by FISH (CRLF2() cohort). A total of 140 consecutive patients with intact CRLF2 were included in a control CRLF2(-) cohort. TSLPR expression was studied by flow cytometry. The majority of CRLF2() patients were conventionally positive (≥20% positive cells) for TSLPR (33 of 46, 71.7%). Among the remaining children in this group, two were completely TSLPR-negative, seven had less than 10% TSLPR-positive cells, and four had between 10% and 20% TSLPR-positive cells. By contrast, the majority of CRLF2(-) patients had no TSLPR-positive cells (119 of 140, 85.0%), while in 15 cases (10.7%), the percentage of TSLPR-positive cells was below 10%, and in six cases (4.3%), it was between 10% and 20%. Receiver operator characteristic analysis revealed a threshold of only 1.6% TSLPR-positive cells for the effective prediction of the presence of CRLF2 rearrangement. Moreover, this threshold retained its predictive value when only children with low TSLPR positivity were studied. When surface TSLPR is detected at the diagnosis of BCP-ALL, close attention should be given to the search for chromosomal aberrations involving CRLF2 at any level of expression.

1,5-Anhydroglucitol promotes pre-B acute lymphocytic leukemia progression by driving glycolysis and reactive oxygen species formation.

Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression. The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model. We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinaseextracellular signal-regulated kinase (MAPKERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells. Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.

IgDFcδR is involved in T-cell acute lymphoblastic leukemia and regulated by IgD-Fc-Ig fusion protein.

T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Excessive IgD may play a role in T cell activation via IgD Fc receptor (FcδR). Here we aimed to investigate the effects of IgD in T-ALL and demonstrated the potential benefit by targeting IgDFcδR in T-ALL patients with IgD-Fc-Ig fusion protein. In T-ALL patients blood samples and cell lines, the level of IgD, the percentage of FcδR expressing cells and the binding affinity were determined by flow cytometry. T cell viability, proliferation and apoptosis were analyzed. A mouse xenograft model was used to evaluate the in vivo effect of IgD-Fc-Ig, an IgD-FcδR blocker. The levels of serum IgD and FcδR were abnormally increased in part of T-ALL patients and IgD could induce over-proliferation and inhibit apoptosis of T-ALL cells in vitro. FcδR was constitutively expressed on T-ALL cells. IgD-Fc-Ig showed similar binding affinity to FcδR and selectively blocked the stimulation effect of IgD on T-ALL cells in vitro. In vivo study exhibited that IgD-Fc-Ig may also have therapeutic benefit. IgD-Fc-Ig administration inhibited human T-ALL growth and extended survival in xenograft T-ALL mice. In conclusion, this work supports the idea of targeting IgDFcδR in T-ALL patients with excessive IgD. IgD-Fc-Ig fusion protein might be a potential biological drug with high selectivity for T-ALL treatment.

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California.

Residential use of pesticides has been associated with increased risk of childhood acute lymphoblastic leukemia (ALL). We evaluated determinants of glyphosate concentrations in house dust and estimated ALL risk in the California Childhood Leukemia Study (CCLS). The CCLS is a population-based case-control study of childhood leukemia in California. Among those < 8-years (no move since diagnosisreference date), we collected dust (2001-2007) from the room where the child spent the most time while awake and measured > 40 pesticides. Three-to-eight years later, we collected a second sample from non-movers. We used Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry to measure glyphosate (µgg dust) for 181 ALL cases and 225 controls and for 45 households with a second dust sample. We used multivariable Tobit regression to evaluate determinants of glyphosate concentrations. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated for ALL and quartiles of the concentration (first samples) using unconditional logistic regression. We computed the within- and between-home variance and intraclass correlation coefficient (ICC). Glyphosate was frequently detected (cases 98 % controls 99 %). Higher concentrations were associated with occupational pesticide exposure, nearby agricultural use, treatment for lawn weeds and beeswasps, and sampling season. Increasing concentrations were not associated with ALL risk (adjusted OR We observed higher concentrations in homes associated with expected predictors of exposure but no association with childhood ALL risk. Due to continuing use, potential exposure to young children is high. It will be important to evaluate risk in future studies with multiple dust measurements or biomarkers of exposure.

Novel extragenic genomic safe harbors for precise therapeutic T cell engineering.

Cell therapies that rely on engineered immune cells can be enhanced by achieving uniform and controlled transgene expression in order to maximize T cell function and achieve predictable patient responses. Although effective, current genetic engineering strategies that utilize g-retroviral, lentiviral and transposon-based vectors to integrate transgenes, unavoidably produce variegated transgene expression in addition to posing a risk of insertional mutagenesis. In the setting of chimeric antigen receptor (CAR) therapy, inconsistent and random CAR expression may result in tonic signaling, T cell exhaustion and variable T cell persistence. We report and validate herein an algorithm for the identification of extragenic genomic safe harbors (GSH) that can be efficiently targeted for DNA integration and support sustained and predictable CAR expression in human peripheral blood T cells. The algorithm is based on 7 criteria established to minimize genotoxicity by directing transgene integration away from functionally important genomic elements, maximize efficient CRISPRCas9-mediated targeting, and avert transgene silencing over time. T cells engineered to express a CD19 CAR at GSH6, which meets all 7 criteria, are curative at low cell dose in a mouse model of acute lymphoblastic leukemia, matching the potency of CAR T cells engineered at the TRAC locus, and effectively resist tumor rechallenge 100 days after their infusion. The identification of functional extragenic GSHs thus expands the human genome available for therapeutic precision engineering.

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia.

Components of the bone marrow microenvironment (BMM) have been shown to mediate the way in which leukemia develops, progresses and responds to treatment. Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells. While previous work has highlighted functional defects in the mesenchymal stem cell (MSC) population from the BMM of acute leukemias, thorough characterization and molecular profiling of MSCs in pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, has not been conducted. Here, we investigated the cellular and transcriptome profiles of MSCs isolated from the BMM of an immunocompetent BCR-ABL1

Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia.

Methotrexate (MTX) has an antitumor effect when used for the treatment of acute lymphoblastic leukemia (ALL). This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX. Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay. The serum MTX concentration was determined using homogeneous enzyme immunoassay. MTX-related toxicities were also evaluated. Renal toxicity was significantly associated with higher serum MTX concentrations at 24, 48, and 72 hours, and MTX elimination delay (

PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS12 hexamer stability.

Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), yet the underlying mechanisms are still elusive. Here, we demonstrate that

Superior Mediastinal Syndrome Misdiagnosed as Foreign Body Aspiration A Case Report.

Superior mediastinal syndrome is a life-threatening pediatric oncological emergency that requires high level of awareness and clinical suspicion to avoid misdiagnosis and devastating outcomes. Early diagnostic evaluation and management of underlying etiology are of utmost significance for optimal results. In children, it is most commonly caused by non-Hodgkins lymphoma and T-cell lymphoblastic leukemia. We report a case of a six-year-old boy with superior mediastinal syndrome secondary to T-cell acute lymphoblastic leukemia, initially misdiagnosed as foreign body aspiration and underwent a procedure with a life-threatening outcome.

Case report Hyperosmolar hyperglycemic syndrome secondary to PEG-asparaginase-induced hypertriglyceridemia and pancreatitis.

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (T-ALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreatitis and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase.

Spectrum and clinical features of gene mutations in Chinese pediatric acute lymphoblastic leukemia.

The 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85-90%, with a 10-15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL. We enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ A total of 381 gene mutations were identified in 66 different genes in 152219 patients. PIK3R1 mutation was more common in infants (P 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P 0.033, P 0.048, respectively). This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Genomic and proteomic characterization of Philadelphia-like B-lineage acute lymphoblastic leukemia A report of Indian patients.

The gold standard for the identification of Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) patients is gene expression profiling. Because of its diverse nature, its identification is extremely difficult and expensive. On the genomic and proteomic landscape of Ph-like ALL patients, there is a paucity of published literature from developing countries. The authors used digital barcoded nCounter NanoString gene expression profiling for its detection, followed by molecular and proteomic characterization using fluorescence in situ hybridization and liquid chromatography-tandem mass spectrometry (LC-MSMS). The authors found 32.05% Ph-like ALL patients and their median age at presentation was considerably higher than Ph-negative ALL cases (p .0306). Furthermore, we identified 20% CRLF2 overexpressed cases having 8.33% CRLF2-IGH translocation with concomitant R683S mutation and 8.33% CRLF2-P2RY8 translocation. In 80% of CRLF2 downregulated cases, we identified 10% as having JAK2 rearrangement. Minimal residual disease-positivity was more common in Ph-like ALL cases (55.55% vs. 25% in Ph-negative ALL cases). Immunoglobulin J chain (Jchain), small nuclear ribonucleoprotein SmD1 (SNRPD1), immunoglobulin κ constant (IGKC), NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 2 (NDUFA2), histone H2AX (H2AFX), charged multivesicular body protein 4b (CHMP4B), and carbonyl reductase (NADPH) (CBR1) proteins were identified to be substantially expressed in Ph-like ALL patients, using LC-MSMS. Gene enrichment analysis indicated that involvement of spliceosomal mediated messenger RNA splicing pathway and four microRNAs was statistically significant in Ph-like ALL patients. For the first time, we have described incidence, molecular, and proteomic characterization of Ph-like ALL, in developing nations. In developing countries, detecting Philadelphia (Ph)-like B-lineage acute lymphoblastic leukemia is complicated and challenging due to its diverse genetic landscape. There is no well-defined and cost-effective methodology for its detection. The incidence of this high-risk subtype is very high in adult cases, and there is an urgent need for its accurate detection. We have developed an online PHi-RACE classifier for its rapid detection, followed by delineating the genomic and proteomic landscape of Ph-like acute lymphoblastic leukemias for the first time in Indian patients.

Design, synthesis, and anticancer evaluation of 1-benzo1,3dioxol-5-yl-3-N-fused heteroaryl indoles.

A series of 1-benzo1,3dioxol-5-yl-indoles bearing 3-N-fused heteroaryl moieties have been designed based on literature reports of the activity of indoles against various cancer cell lines, synthesized via a Pd-catalyzed C-N cross-coupling, and evaluated for their anticancer activity against prostate (LNCaP), pancreatic (MIA PaCa-2), and acute lymphoblastic leukemia (CCRF-CEM) cancer cell lines. A detailed structure-activity relationship study culminated in the identification of 3-N-benzo1,2,5oxadiazole 17 and 3-N-2-methylquinoline 20, whose IC

Efficacy and safety of dual-targeting chimeric antigen receptor-T therapy for relapsed or refractory B-cell lymphoid malignancies a systematic review and meta-analysis.

Dual-targeting chimeric antigen receptor (CAR)-T cell therapy has been proposed as a potential solution for overcoming antigen escape during anti-CD19 CAR-T treatment. We performed this systematic review and meta-analysis to investigate the efficacy and safety of this novel treatment in patients with B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL). We systematically searched relevant literature based on databases (PubMed, Web of Science, Embase and Cochrane) and conference abstracts. The primary outcomes measured were the best objective response rate (ORR) or complete response (CR), 12-month overall survival (OS) and progression-free survival (PFS), cytokine release syndrome (CRS) and neurotoxicity. Fifteen registered prospective open-label clinical trials were included. Among the 260 patients with B-NHL, the pooled best ORR and CR were 77% (95% CI 0.71-0.82) and 52% (95% CI 0.40-0.63), respectively, and the pooled 12-month PFS and OS were 54.0% (95% CI 0.47-0.61) and 66.0% (95% CI 0.56-0.77), respectively. In the 159 patients with B-ALL, the combined best CR was observed to be 92% (95% CI 0.82-0.99) and the pooled 12-month PFS and OS were 65.0% (95% CI 0.51-0.77) and 73.0% (95% CI 0.56-0.92), respectively. Moreover, in B-NHL patients, grade ≥3 CRS was observed in 14.0% (95% CI 0.04-0.29) of these patients, and 5.0% (95% CI 0.02-0.08) showed grade ≥3 neurotoxicity in the case of B-ALL patients, grade ≥3 CRS and neurotoxicity occurred in 11.0% (95% CI 0.04-0.19) and 2.0% (95% CI 0.00-0.06), respectively. This study demonstrates the safety and clinical efficacy of dual-targeting CAR-T cell therapies in B-cell malignancies. Further well-designed randomized controlled trials are required to establish the role of dual-targeting CAR-T cell therapy in patients with B-cell malignancies.

Vincristine-induced ptosis in a leukemia patient treated with pyridoxine and pyridostigmine.

Blepharoptosis, commonly referred to as ptosis or eyelid sagging, is a condition where the upper eyelid droops over the eye. It can be congenital or acquired and is caused by the weakening of the eyelid muscles. We present a case of a 3-year-old boy with T-cell acute lymphoblastic leukemia who developed bilateral ptosis while on treatment with Berlin-Frankfurt Munster-98 protocol. The patient was diagnosed with bilateral ptosis due to vincristine, the primary agent in the induction phase of the protocol. The addition of the neuroregenerative agents and supportive measures led to marked improvement, followed by complete resolution within 3 weeks. Vincristine is an anticancer agent with known neurotoxicity, which has a significant role in treating hematological malignancies and sarcoma. In many studies, the addition of neuroregenerative agents such as pyridoxine and pyridostigmine has been noted to hasten recovery without any documented side effects. Similar findings were also drawn from our research due to Indias higher incidence of vincristine-induced neurotoxicity. It is essential to promptly diagnose and manage symptoms at the earliest to prevent the risk of permanent nerve damage and inferior quality of life for the patient.

Case report Ponatinib as a bridge to CAR-T cells and subsequent maintenance in a patient with relapsedrefractory Philadelphia-like acute lymphoblastic leukemia.

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsedrefractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy.

Switching from salvage chemotherapy to immunotherapy in adult B-cell acute lymphoblastic leukemia.

About one-half of adults with acute B-cell lymphoblastic leukemia (B-ALL) who do not achieve molecular complete remission or who subsequently relapse are not cured by current chemo- or targeted therapies. Previously, the sole therapeutic option for such persons was a hematopoietic stem cell transplant. Recently, several immune therapies including monoclonal antibodies, bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cells (CARs) have been shown safe and effective in this setting. In this manuscript, we summarize data on US FDA-approved immune therapies of advanced adult B-ALL including rituximab, blinatumomab, inotuzumab ozogamicin, tisagenlecleucel and brexucabtagene autoleucel. We consider the results of clinical trials focusing on efficacy, safety, and quality of life (QoL). Real-world evidence is presented as well. We also briefly discuss pharmacodynamics, pharmacokinetics, and pharmacoeconomics followed by risk-benefit analyses. Lastly, we present future directions of immune therapies for advanced B-ALL in adults.

Acute kidney injury and delayed methotrexate clearance in an adult patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia treated with imatinib.

A female patient in her early 30s was treated with imatinib and high-dose methotrexate (HD-MTX) for Philadelphia chromosome-positive acute lymphoblastic leukaemia. The patient developed delayed MTX clearance and grade 3 acute kidney injury characterised by elevated creatinine (114% increase from baseline). After intensified calcium folinate rescue therapy and hydration, the MTX serum level was appropriately decreased 72 hours after the start of MTX infusion, and renal function returned to normal. Medication analysis by a clinical pharmacist suggested that the concomitant treatment with imatinib likely contributed to the delayed MTX clearance and caused the acute kidney injury.

Disseminated Cunninghamella elegans Infection Diagnosed by mNGS During Induction Therapy in a Child With Intermediate-risk Acute Lymphoblastic Leukemia A Case Report and Review of Literature.

We described a 14-year-old girl with acute lymphoblastic leukemia who developed disseminated mucormycosis during induction therapy. Disseminated Cunninghamella elegans infection was confirmed by histopathology, microbiological culture, and metagenomic next-generation sequencing analysis of skin tissue, blood, and cerebrospinal fluid. Subsequently, the patient received a combination of liposomal amphotericin B, posaconazole, and caspofungin for antifungal treatment, but eventually died because of severe fungal pneumonia, respiratory failure, and septic shock. Moreover, case reports of pulmonary mucormycosis in children published since 1959 were reviewed. In summary, metagenomic next-generation sequencing is an effective diagnostic method for Cunninghamella with high speed and sensitivity.

Physical Inactivity as an Early Sign of Frailty in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia.

Young adult survivors of childhood leukemia have been reported with increased likelihood of age-related comorbidities compared with the general population. We compared the prevalence of frailty in young adult survivors of childhood acute lymphoblastic leukemia (n58, median age23 y, median survival time18 y) with age-matched and sex-matched controls without history of cancer. Frailty phenotypes were determined using Fried frailty model. Association between frailty status and cardiometabolic conditions, systemic inflammation, and T-cell immunophenotype changes were also examined. Frailty and prefrailty were more common among survivors compared with controls (58.6% vs. 34.5%, P0.019). Physical inactivity (39.7%) was the most frequently observed frailty criterion among the survivors. Prevalence of cardiometabolic conditions was comparable between the robust and frailprefrail survivors. Robust survivors had a higher level of T-cell activation than the prefrailfrail survivors (P<0.05), but no significant difference was observed for systemic inflammatory markers (IL-6 and C-reactive protein) and percentage of terminally differentiated T cells. Signs of frailty, especially physical inactivity, was detected in childhood acute lymphoblastic leukemia survivors early in their third decade of life. Survivors who were prefrailfrail also had altered T-cell activation however, the role of such changes in T-cell phenotype in the etiology of frailty warrant further investigation.

Low Expression of BRCA1 as a Potential Relapse Predictor in B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood hematological malignancy worldwide. Treatment outcomes have improved dramatically in recent years despite this, relapse is still a problem, and the potential molecular explanation for this remains an important field of study. We performed microarray and single-cell RNA-Seq data mining, and we selected significant data with a P -value<0.05. We validated BRCA1 gene expression by means of quantitative (reverse transcription-polymerase chain reaction.) We performed statistical analysis and considered a P -value<0.05 significant. We identified the overexpression of breast cancer 1, early onset (BRCA1 P -value2.52 -134 ), by means of microarray analysis. Moreover, the normal distribution of BRCA1 expression in healthy bone marrow. In addition, we confirmed the increases in BRCA1 expression using real-time (reverse transcription-polymerase chain reaction and determined that it was significantly reduced in patients with relapse ( P -values0.026). Finally, we identified that the expression of the BRCA1 gene could predict early relapse ( P -values0.01). We determined that low expression of BRCA1 was associated with B-cell acute lymphoblastic leukemia relapse and could be a potential molecular prognostic marker.

Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia a case study.

Although Philadelphia chromosome-positive acute leukemia (Ph -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are universal events during treatment with first-generation and second-generation TKIs. The present third-generation TKI has a dose-dependent, increased risk of serious cardiovascular events and the sensitivity is poor for patients with ≥2 mutations accompanied by the T315I mutation. Thus, novel and well-tolerated TKIs should be explored. This study analyzes the efficacy and advert effects of olverembatinib, a novel third TKI, in the treatment of newly diagnosed adult Ph -ALL in induction therapy. Four adult patients with newly diagnosed Ph -ALL were treated with olverembatinib as the first-line treatment. For induction therapy, these patients received 40 mg of oral olverembatinib quaque omni die for 28 days, 1 mgkgd of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mgd at days 1, 8 and 15. After induction therapy, these patients received median or high-dose of cytarabine and methotrexate combined with oral olverembatinib as consolidation therapy. Then the allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed. All patients reached complete remission with a complete cytogenetic response after induction therapy. Two patients reached major molecular remission and one with complete molecular remission. Before allo-HSCT, all the patients achieved complete molecular remission. All the patients have survived disease-free for 3-6 months. No severe advert effects were observed. It is well-tolerated and effective for olverembatinib in the treatment of newly diagnosed adult patients with Ph -ALL. A prospective study should be performed to further testify the role.

Safety and Efficacy of Alendronate to Treat Osteopenia in Children During Therapy for Acute Lymphoblastic Leukemia A Retrospective Cohort Study of Sequential Outcomes.

Low bone mineral density is encountered in children with acute lymphoblastic leukemia (ALL) before, during, and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. Sixty-nine children with ALL received alendronate for a mean of 87 weeks after dual-energy x-ray absorptiometry. Dual-energy x-ray absorptiometry was repeated following the completion of alendronate, and 5 to 9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral density (LS aBMD) Z scores were obtained. The mean LS aBMD Z score rose from -1.78 to-0.47 (P <0.0001). There was a modest median loss of LS aBMD subsequently in the 32 subjects on long-term follow-up. Almost 80% (N172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who received alendronate, which was almost uniformly well tolerated, 769 (10.3%) relapsed compared with 1989 (21.3%) who did not receive the drug. Alendronate appears to be well tolerated and moderately effective in osteopenic children with ALL. Whether it offers protection against relapse of leukemia needs further study.

Use of blinatumomab and CAR T-cell therapy in children with relapsedrefractory leukemia A case series study.

The 5-year event-free survival rate for childhood acute lymphoblastic leukemia (ALL) has increased to more than 85%. However, the 5-year overall survival rate in children with relapsedrefractory ALL did not exceed 50%. In the past decade, immunotherapies (such as blinatumomab and chimeric antigen receptor T-cell therapy) were approved for relapsedrefractory B-ALL, transforming the treatment environment for children with relapsedrefractory ALL. This study aimed to explore how immunotherapy can be incorporated into salvage regimens for pediatric patients with relapsedrefractory ALL by retrospectively analyzing the diagnosis and treatment process of seven children with relapsedrefractory leukemia and observing the side effects of the two strategies and long-term survival. The clinical features and treatment responses of patients aged <14 years with relapsedrefractory leukemia who received immunotherapy (including Chimeric Antigen Receptor T cell treatment and blinatumomab) at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between February 2014 and April 2022 were retrospectively analyzed. Seven children underwent immunotherapy. Five patients received immunotherapy and sequential allogeneic hematopoietic stem cell transplantation (HSCT), whereas the other two received only immunotherapy. Five patients achieved complete remission (71.4%). None of the patients had severe cytokine release syndrome. However, one developed grade 3 immune effector cell-associated neurotoxicity syndrome with prior leukoencephalopathy. The median follow-up period was 541 days (range, 186-3,180 days). No deaths were related to treatment. Three patients relapsed, two had CD19-negative recurrences, and the third showed CD19 antigen reduction. One patient died after disease progression, whereas the other died of HSCT-related complications. One patient abandoned the treatment after relapse and was lost to follow-up. Blinatumomab and CAR T-cell therapy showed excellent remission rates and manageable toxicity in pediatric patients with relapsedrefractory leukemia. However, the duration of the remission was limited. Therefore, further prospective randomized clinical studies should be conducted to improve the long-term efficacy of immunotherapy.

Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia an analysis by the Acute Leukemia Working Party of the EBMT.

In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy Cy was used in 2105 cases while TBI 12 Gy Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBICy conditioning was associated with a reduced risk of relapse (HR 0.69, p 0.049) and increased risk of grade 2-4 acute graft-versus-host disease (GVHD, HR 1.57, p 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBICy as compared to TBIFlu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBICy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBIFlu and therefore should probably be considered a preferable regimen.

Total Body Irradiation Versus Chemotherapy Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplant A Systematic Review and Meta-Analysis.

Allogeneic hematopoietic stem cell transplant (HSCT) is indicated in pediatric patients with acute lymphoblastic leukemia (ALL) who have relapsed or are at a very high risk of relapse during first complete remission. Two types of myeloablative conditioning are employed before allogeneic HSCT total body irradiation (TBI)-based regimens and chemotherapy (CHT) alone. This study compares the efficacy and safety of TBI-based regimens and CHT-based conditioning in pediatric, adolescent, and young adult patients with ALL (0-24 years old). TBI-based and CHT-conditioning regimens were evaluated in 4262 and 1367 patients, respectively, from 15 studies. Compared to CHT alone, TBI-based regimens were associated with better overall survival (OS), relative risk (RR) 1.21, better event-free survival (RR 1.34), and a reduced risk of relapse (RR 0.69). Both approaches had comparable risk of acute graft-versus-host disease (GVHD), grades 3 to 4 acute GVHD, chronic GVHD, and nonrelapse mortality (NRM). In the subgroup analysis for patients in first complete remission, TBI-based regimens and CHT alone had comparable OS and NRM. Our results demonstrate the superiority of TBI-based regimens compared to CHT alone in pediatric patients with ALL.

Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia secondary analyses of eight Childrens Oncology Group cohort trials.

Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status. Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Childrens Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease. Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 65·6%), followed by Hispanic patients (4354 20·6%), non-Hispanic Black patients (1517 7·2%), non-Hispanic Asian (n1071 5·1%), and non-Hispanic other (n338 1·6%). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1% hazard ratio HR 1·37, 95% CI 1·26-1·49 p<0·0001) among Hispanic patients and 81·8% (79·3-84·0 HR 1·45, 1·28-1·65 p<0·0001) among non-Hispanic Black patients. Non-hispanic Asian patients had a 5-year event-free survival of 88·1% (95% CI 85·5-90·3%) and non-Hispanic other patients had a survival of 82·8% (76·4-87·6%). Inferior event-free survival among Hispanic patients was substantially attenuated by disease prognosticators and insurance status (HR decreased from 1·37 1·26-1·49 p<0·0001 to 1·11 1·00-1·22 p0·045). The increased risk among non-Hispanic Black patients was minimally attenuated (HR 1·45 1·28-1·65 p<0·0001 to 1·32 1·14-1·52 p<0·0001). 5-year overall survival was 93·6% (91·5-95·1%) in non-Hispanic Asian patients, 93·3% (92·8-93·7%) in non-Hispanic White patients, 89·9% (88·7-90·9%) in Hispanic, 89·7% (87·6-91·4%) in non-Hispanic Black patients, 88·9% (83·2-92·7%) in non-Hispanic other patients. Disparities in overall survival were wider than event-free survival (eg, among non-Hispanic other patients, the HR for event-free survival was 1·43 1·10-1·85 compared with 1·74 1·27-2·40 for overall survival). Disparities were restricted to patients with B-cell acute lymphocytic leukaemia, no differences in event-free survival or overall survival were seen in the T-cell acute lymphocytic leukaemia group. Substantial disparities in outcome for B-cell acute lymphocytic leukaemia persist by race and ethnicity, but are not observed in T-cell acute lymphocytic leukaemia. Future studies of relapsed patients, access to and quality of care, and other potential aspects of structural racism are warranted to inform interventions aimed at dismantling racial and ethnic disparities. National Cancer Institute and St Baldricks Foundation.