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Evaluating the baseline survival outcomes of the six Global Initiative for Childhood Cancer index cancers in Africa.

Limited survival data for the six Global Initiative for Childhood Cancer (GICC) priority cancers are available in Africa. Management of pediatric malignancies in Africa is challenging due to lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment. Reporting of outcome data is problematic due to the lack of registries. With the aim of evaluating the feasibility of baseline outcomes for the six index cancers, we present a descriptive analysis of respective survival rates in Africa. The survival rates were between 18% (lower middle-income countries) to 82.3% (upper middle-income countries) for acute lymphoblastic leukemia, between 26.9% (low-income countries) to 77.9% (upper middle-income countries) for nephroblastoma, between 23% (low-income countries) to 100% (upper middle-income countries), for retinoblastoma, 45% (low-income countries) to 95% (upper middle-income countries) for Hodgkin lymphoma and 28% (low-income countries) to 76% (upper middle-income countries) for Burkitt lymphoma. Solutions to improve survival rates and reported outcomes include establishing and funding sustainable registries, training and to actively include all countries in consortia from different African regions.HighlightsContinental differences in childhood cancer management such lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment, present challenges to the achievement of Global Initiative for Childhood Cancer goals.The available data registries do not adequately inform on the true incidences and outcomes of childhood cancers in Africa.The pathophysiology of some childhood cancers in Africa are associated with high-risk prognostic factors.Outcomes can be improved by greater regional collaboration to manage childhood cancer based on local resources and tumor characteristics.Some individual countries have reached the Global Initiative for Childhood Cancer goals for single cancers and it should be possible for more African countries to follow suit.

Acute Myocardial Infarction in a 13-Year-Old Boy after Bone Marrow Transplantation.

Advances in bone marrow transplantation (BMT) present a unique opportunity for treating leukemia in children. It has also increased the risk of long-term complications in the lungs, genitourinary tract, and nervous system. Coronary artery disease is the most common type of heart disease in older adults, but is not generally acknowledged as a complication of BMT, especially in young patients. We report the occurrence of acute myocardial infarction in a 13-year-old boy, approximately 5 years after he received a half-matched related bone marrow transplant from his father for T-cell lymphoblastic leukemia. Acute myocarditis was suspected early in the clinical course on the basis of his age and clinical presentations, such as atypical chest pain and dyspnea. Follow-up coronary angiography revealed a total occlusion of the right coronary artery, as well as diffused lesions of the left main, anterior descending, and circumflex branch. Fortunately, he was discharged from the hospital in satisfactory general condition after complex treatment. Why Should An Emergency Physician Be Aware of This In this case, its rarity and poor clinical recognition were the main reasons for delayed diagnosis, which led to a delay to coronary angiography. Given the high mortality in cardiovascular complications among BMT recipients, the correct diagnostic assessment in such cases becomes particularly relevant.

Utilization of novel lectin-conjugated Au nanoparticles as Thomsen-Friedenreich onco-antigen target for in vitro cytotoxicity and apoptosis induction in leukemic cell line.

Leukemia is a tumor of blood-forming tissues including bone marrow and lymphatic nodes, which comprise biologically distinct subgroups. In the present study, Au NPs-PEG-Lectin was prepared as a drug targeting system for potential Thomsen-Friedenreich antigen (TF-Ag) presented on the surface of leukemic cells to induce cytotoxicity. Gold nanoparticles were prepared using citrate reduction method and conjugated with lectin via SH-PEG-COOH. The conjugate was characterized using UVVis spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Zeta potential, and Scanning electron microscopy (SEM) with subsequent applications for cytotoxicity, cell cycle analysis, and apoptosis. Immunophenotypically blood samples from patients with acute lymphoblastic leukemia (ALL) were positively expressed CD45, CD95 dim expression, and low CD176 (TF-Ag) expression. Samples of acute myeloid leukemia (AML) confirmed the expression of all markers. Au NPs-PEG-Lectin conjugate showed an average size of 35.82 nm with zeta potential of -27.33 with accelerated lectin release from the conjugate at acidic pH. Au NPs-PEG-Lectin demonstrated the highest and most significant cytotoxic activity against HL-60 and K562 with IC

Leukemia cutis in T-cell acute lymphoblastic leukemia a 3-year follow-up case report.

Leukemia cutis (LC) is the infiltration of neoplastic leukocytes in the skin that can be observed in various types of leukemia including chronic lymphocytic leukemia, acute myeloid leukemia, and, occasionally, acute lymphoblastic leukemia. LC is considered an unfavorable prognostic factor in previous studies, and most patients die within 1 year after diagnosis. Herein, we report an uncommon case in which a patient presented with LC as the initial symptom of T-cell acute lymphoblastic leukemia (T-ALL) and remained in excellent clinical condition during a 3-year follow-up after treatment. A 50-year-old Chinese woman manifested with multiple infiltrated purplish plaques and tumors over the face, trunk, and lower extremities for more than 5 months, accompanied by recurrent fever and arthralgia. The diagnosis of T-ALL with LC was established by skin biopsy and bone marrow examination. After treatment with chemotherapy and allogeneic stem cell transplantation, the patient achieved complete remission and remained in good health for 3 years. To our knowledge, this is the first described case of a favorable evolution after a 3-year follow-up. Although uncommon, LC can be the first indication of the presence of T-ALL. This case highlights that early recognition of possible LC and access to treatment may benefit future patients with T-ALL and improve the prognosis of this aggressive disorder.

Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia.

Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for leukemia patients. These markers have been used in diagnosis, risk-stratification and targeted therapy application. Recent studies have indicated that numerous regulatory RNAs, such as long non-coding RNAs (lncRNAs), have a role in tumor initiation and progression. When it comes to leukemia, data for lncRNA involvement in its etiology, progression, diagnosis, treatment and prognosis is limited. The aim of this review is to summarize research data on lncRNAs in different types of leukemia, on their expression pattern, their role in leukemic transformation and disease progression. The usefulness of this information in the clinical setting, i.e., for diagnostic and prognostic purposes, will be emphasized. Finally, how particular lncRNAs could be used as potential targets for the application of targeted therapy will be considered.

Spectrum of Genetic Mutations in Korean Pediatric Acute Lymphoblastic Leukemia.

The wide application of next-generation sequencing (NGS) technologies has led to the discovery of multiple genetic alterations in pediatric acute lymphoblastic leukemia (ALL). In this work, we aimed to investigate the mutational spectrum in pediatric ALL. We employed a St. Mary’s customized NGS panel comprising 67 leukemia-related genes. Samples were collected from 139 pediatric ALL patients. Eighty-five patients (61.2%) harbored at least one mutation. In B-cell ALL, the RAS pathway is the most involved pathway, and the three most frequently mutated genes were NRAS (22.4%), KRAS (19.6%), and PTPN11 (8.4%). NRAS and PTPN11 were significantly associated with a high hyperdiploidy karyotype (p 0.018 and p < 0.001, respectively). In T-cell ALL, the three most frequently mutated genes were NOTCH1 (37.5%), FBXW7 (16.6%), and PTEN (6.2%). Several pairs of co-occurring mutations were found NRAS with SETD, NRAS with PTPN11 in B-cell ALL (p 0.024 and p 0.020, respectively), and NOTCH1 with FBXW7 in T-cell ALL (p < 0.001). The most frequent newly emerged mutation in relapsed ALL was NT5C2. We procured comprehensive genetic information regarding Korean pediatric ALL using NGS technology. Our findings strengthen the current knowledge of recurrent somatic mutations in pediatric ALL.

Preclinical Evaluation of CRISPR-Edited CAR-NK-92 Cells for Off-the-Shelf Treatment of AML and B-ALL.

Acute myeloid leukemia (AML) and B-cell acute lymphocytic leukemia (B-ALL) are severe blood malignancies affecting both adults and children. Chimeric antigen receptor (CAR)-based immunotherapies have proven highly efficacious in the treatment of leukemia. However, the challenge of the immune escape of cancer cells remains. The development of more affordable and ready-to-use therapies is essential in view of the costly and time-consuming preparation of primary cell-based treatments. In order to promote the antitumor function against AML and B-ALL, we transduced NK-92 cells with CD276-CAR or CD19-CAR constructs. We also attempted to enhance cytotoxicity by a gene knockout of three different inhibitory checkpoints in NK cell function (CBLB, NKG2A, TIGIT) with CRISPR-Cas9 technology. The antileukemic activity of the generated cell lines was tested with calcein and luciferase-based cytotoxicity assays in various leukemia cell lines. Both CAR-NK-92 exhibited targeted cytotoxicity and a significant boost in antileukemic function in comparison to parental NK-92. CRISPR-Cas9 knock-outs did not improve B-ALL cytotoxicity. However, triple knock-out CD276-CAR-NK-92 cells, as well as CBLB or TIGIT knock-out NK-92 cells, showed significantly enhanced cytotoxicity against U-937 or U-937 CD19tag AML cell lines. These results indicate that the CD19-CAR and CD276-CAR-NK-92 cell lines cytotoxic performance is suitable for leukemia killing, making them promising off-the-shelf therapeutic candidates. The knock-out of CBLB and TIGIT in NK-92 and CD276-CAR-NK-92 should be further investigated for the treatment of AML.

Entropy Measurements for Leukocytes Surrounding Informativeness Evaluation for Acute Lymphoblastic Leukemia Classification.

The study of leukemia classification using deep learning techniques has been conducted by multiple research teams worldwide. Although deep convolutional neural networks achieved high quality of sick vs. healthy patient discrimination, their inherent lack of human interpretability of the decision-making process hinders the adoption of deep learning techniques in medicine. Research involving deep learning proved that distinguishing between healthy and sick patients using microscopic images of lymphocytes is possible. However, it could not provide information on the intermediate steps in the diagnosis process. As a result, despite numerous examinations, it is still unclear whether the lymphocyte is the only object in the microscopic picture containing leukemia-related information or if the leukocytes surroundings also contain the desired information. In this work, entropy measures and machine learning models were applied to study the informativeness of both whole images and lymphocytes surroundings alone for Leukemia classification. This work aims to provide human-interpretable features marking the probability of sickness occurrence. The research stated that the hue distribution of images with lymphocytes obfuscated alone is informative enough to facilitate 93.0% accuracy in healthy vs. sick classification. The research was conducted on the ALL-IDB2 dataset.

Reliable Flow-Cytometric Approach for Minimal Residual Disease Monitoring in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia after CD19-Targeted Therapy.

We aimed to develop an antibody panel and data analysis algorithm for multicolor flow cytometry (MFC), which is a reliable method for minimal residual disease (MRD) detection in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated with CD19-directed therapy. The development of the approach, which was adapted for the case of possible CD19 loss, was based on the additional B-lineage marker expression data obtained from a study of primary BCP-ALL patients, an analysis of the immunophenotypic changes that occur during blinatumomab or CAR-T therapy, and an analysis of very early CD19-negative normal BCPs. We have developed a single-tube 11-color panel for MFC-MRD detection. CD22- and iCD79a-based primary B-lineage gating (preferably consecutive) was recommended. Based on patterns of antigen expression changes and the relative expansion of normal CD19-negative BCPs, guidelines for MFC data analysis and interpretation were established. The suggested approach was tested in comparison with the molecular techniques

A Comprehensive Overview of Recent Advances in Epigenetics in Pediatric Acute Lymphoblastic Leukemia.

Recent years have brought a novel insight into our understanding of childhood acute lymphoblastic leukemia (ALL), along with several breakthrough treatment methods. However, multiple aspects of mechanisms behind this disease remain to be elucidated. Evidence suggests that leukemogenesis in ALL is widely influenced by epigenetic modifications. These changes include DNA hypermethylation, histone modification and miRNA alteration. DNA hypermethylation in promoter regions, which leads to silencing of tumor suppressor genes, is a common epigenetic alteration in ALL. Histone modifications are mainly caused by an increased expression of histone deacetylases. A dysregulation of miRNA results in changes in the expression of their target genes. To date, several hundred genes were identified as suppressed by epigenetic mechanisms in ALL. What is promising is that epigenetic alterations in ALL may be used as potential biomarkers for classification of subtypes, predicting relapse and disease progression and assessing minimal residual disease. Furthermore, since epigenetic lesions are potentially reversible, an activation of epigenetically silenced genes with the use of hypomethylating agents or histone deacetylase inhibitors may be utilized as a therapeutic strategy for ALL. The following review summarizes our current knowledge about epigenetic modifications in ALL and describes potential uses of epigenetics in the clinical management of this disease.

Go with the Flow-Early Assessment of Measurable Residual Disease in Children with Acute Lymphoblastic Leukemia Treated According to ALL IC-BFM2009.

Measurable residual disease (MRD) is a well-known tool for the evaluation of the early response to treatment in patients with acute lymphoblastic leukemia (ALL). In respect to predicting the relapse the most informative cut-off and time point of MRD measurement during therapy were evaluated in our study. Between 1 January 2013 and 31 December 2019, multiparametric flow cytometry (MFC) MRD was measured in the bone marrow of 140 children with ALL treated according to the ALL IC-BFM2009 protocol. The MRD cut-off of 0.1% and day 33, end of induction, were the most discriminatory for all patients. Patients with negative MRD on day 15 and 33 had a higher 5-year overall survival-OS (100%) and a higher relapse-free survival-RFS rate (97.6%) than those with positive levels of MRD (≥0.01%) at both time points (77.8% and 55.6%,

The Influence of the Gut Microbiome in Paediatric Cancer Origin and Treatment.

Knowledge of the complexity of the gut microbiota is expanding, and its importance in physiological processes and disease development is widely studied. The aim of this review is to present the most relevant and recent research on the associations between gut microbiota and oncologic disease. Recently, a number of associations between the gut microbiome and neoplasms-regarding tumorigenesis, prognosis and therapeutic efficacy-have been reported. The effects of the gut microbiome on these processes are via the direct and indirect immunomodulating effects of bacteria. Studies have been done mainly in adult populations, where its effect on immunomodulating therapies was unambiguous. In paediatric populations, however, due to the low number of cases and the complex therapeutic approaches, there have been only a few studies. Among them, children with acute lymphoblastic leukaemia were mainly involved. Significant alterations in the abundance of certain bacteria were associated with altered therapeutic responses. Regarding solid tumours, studies with low case numbers have been reported no significant discoveries have been described so far. In the future, studies with larger cohorts are needed in order to better understand the associations between bacteria and neoplasms and to improve prognosis in the paediatric oncologic population.

Acute Lymphoblastic Leukemia and Invasive Mold Infections A Challenging Field.

Acute lymphoblastic leukemia (ALL) patients comprise a highly immunocompromised group due to factors associated either with the treatment or the disease itself. Invasive mold infections (IMIs) are considered to be responsible for higher morbidity and mortality rates in patients with hematologic malignancies, including ALL. Defining the exact incidence of IMIs in ALL patients has been rather complicated. The available literature data report a highly variable incidence of IMIs, ranging from 2.2% to 15.4%. Although predisposing factors for IMIs in the setting of ALL are ill-defined, retrospective studies have indicated that a longer duration of neutropenia, treatment with high-dose corticosteroids, and a lack of antimold prophylaxis are associated with an increased risk of IMIs. Additionally, the influence of novel ALL treatments on the susceptibility to fungal infections remains obscure however, initial data suggest that these treatments may induce prolonged neutropenia and thus an increased risk of IMIs. Administering primary antimold prophylaxis in these patients has been challenging since incorporating azole antifungal agents is troublesome, considering the drug-to-drug interactions (DDIs) and increased toxicity that may occur when these agents are coadministered with vincristine, a fundamental component of ALL chemotherapy regimens. Isavuconazole, along with several novel antifungal agents such as rezafungin, olorofim, and manogepix, may be appealing as primary antimold prophylaxis, given their broad-spectrum activity and less severe DDI potential. However, their use in ALL patients needs to be investigated through more clinical trials. In summary, this review outlines the epidemiology of IMI and the use of antifungal prophylaxis in ALL patients.

A multicenter study of ICU resource utilization in pediatric, adolescent and young adult patients post CAR-T therapy.

Tisagenlecleucel is associated with remarkable outcomes in treating patients up to the age of 25 years with refractory B-cell acute lymphoblastic leukemia (ALL). Yet, due to unique and potentially life-threatening complications, access remains limited to higher-resource and certified centers. Reports of inequity and related disparities in care are emerging. In this multicenter study of ALL patients admitted for anti-leukemia therapy, who required pediatric intensive care (ICU) support (n 205), patients receiving tisagenlecleucel (n 39) were compared to those receiving conventional chemotherapy (n 166). The median time to ICU transfer was 6 (0-43) versus 1 (0-116) days, respectively (p < 0.0001). There was no difference in the use of vasopressor, ionotropic, sedating, andor paralytic agents between groups, but use of dexamethasone was higher among tisagenlecleucel patients. Patients receiving tisagenlecleucel were more likely to have cardiorespiratory toxicity (p 0.0002), but there were no differences in diagnostic interventions between both groups andor differences in ICU length of stay andor overall hospital survival. Toxicities associated with tisagenlecleucel are generally reversible, and our findings suggest that resource utilization once admitted to the ICU may be similar among patients with ALL receiving tisagenlecleucel versus conventional chemotherapy. As centers consider improved access to care and the feasibility of tisagenlecleucel certification, our study may inform strategic planning.

Blinatumomab for treating pediatric B-lineage acute lymphoblastic leukemia A retrospective real-world study.

Blinatumomab was shown to be safe and effective for consolidation therapy in B-cell acute lymphoblastic leukemia (B-ALL). This study aimed to investigate the effectiveness and safety of blinatumomab in pediatric B-ALL patients in a real-world setting. This was a retrospective, observational study that included patients who initiated blinatumomab treatment between October 1, 2020 and June 20, 2022. Patients with B-ALL diagnosis, age below 18 years, and at least one blinatumomab treatment cycle were included. Treatment-related toxicities were assessed. Totally 23 pediatric patients were included in this study, with a median age of 6 years (range, 2 to 11 years). Blinatumomab therapy was applied for MRD-positive (disease ≥0.01%, These encouraging results suggest blinatumomab in pediatric B-ALL patients with MRD

Therapy-related B-lymphoblastic leukemia after multiple myeloma.

New therapies for multiple myeloma have improved outcomes, but are associated with therapy-related hematologic malignancies. We report eight patients with therapy-related B-lymphoblastic leukemias (t-B-ALL) in the setting of therapy for multiple myeloma, which included lenalidomide maintenance. A subset of patients had pancytopenia and low-level marrow involvement by acute leukemia, an unusual finding in de novo B-ALL. One patient died of chemotherapy complications the other seven responded. No patient died of B-ALL (median follow up of 1.0 years). Our series suggests that t-B-ALL is clonally unrelated to myeloma, presents with diverse cytogenetic abnormalities, and responds well to B-ALL therapy.

Characterisation of children and adolescents with acute lymphoblastic leukaemia who presented without peripheral blood blasts at diagnosis.

Of 1003 children with acute lymphoblastic leukaemia (ALL), 147 (14.7%) presented without peripheral blood blasts (PBB). While absence of PBB was not independently associated with survival outcomes when compared to those with PBB, patients without PBB had distinct genetic and clinical characteristics. Notably, we identified a novel genotype-phenotype relationship, in that the patients without PBB had a significantly higher incidence of hyperdiploid B-ALL, accounting for almost half of all patients without PBB (46.9% vs. 22.7%, p < 0.001). Further, absence of PBB was associated with decreased rates of leukaemia involvement of the central nervous system (p < 0.001).

TPENTPGS (T2) combo dramatically reduces Philadelphia chromosome-positive pro-lymphoblastic B leukemia in BALBc mice.

Acute lymphoblastic leukemia (ALL) is hematological neoplasia that affects human beings from early life to adulthood. Although ALL treatment has been effective, an important percentage of ALL patients are resilient to treatment. Therefore, there is an urgent need for testing a new combination of compounds for the treatment of this disease. Recently, combined TPEN and TPGS (T2 combo) have shown selective cytotoxic effects in vitro leukemia cells such as Jurkat, K562, and BaF3 cells. In this study, we aimed to test the effect of combined TPEN and TPGS agents (T2 combo) at a fixed dose (TPEN 5 mgkg TPGS 100 mgkg) on leukemic BaF3-BCR-ABL P210 BALB-c mice model. We found that 4 successive 2-day apart intravenous injections of T2 combo showed a statistically significant reduction of BaF3 BCR-ABL leukemia cells (- 69%) in leukemia BALBc mice (n 6) compared to untreated leukemia group (n 6). Moreover, the T2 combo was innocuous to non-leukemia BALBc mice (n 3) compared to untreated non-leukemia mice (control, n 3). After treatments (day 42), all mice were left to rest until day 50. Outstandingly, the leukemia BALBc mice treated with the T2 combo showed a lower percentage of BaF3-BCR-ABL P210 cells (- 84%) than untreated leukemia BALBc mice. Furthermore, treatment of leukemia and non-leukemia mice with T2 combo showed no significant tissue alterationdamage according to the histopathological analysis of brain, heart, liver, kidney, and spleen samples however, T2 combo significantly reduced the number of leukocytes in the bone marrow of treated leukemia mice. We conclude that the T2 combo specifically affects leukemia cells but no other tissueorgans. Therefore, we anticipate that the T2 combo might be a potential pro-oxidant combination for the treatment of leukemia patients.

Pharmacogenomics in hematological malignancy.

Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new causative variants associated with drug response have been reported by genome-wide association studies (GWASs). Additionally, therapeutic response has been predicted using a model of multiple single-nucleotide polymorphisms. In acute lymphoblastic leukemia (ALL), the genetic variants of NUDT15 associated with therapeutic response to 6-mercaptopurine (6-MP) have been reported by GWASs, and the frequency of NUDT15 variants was higher in Asians. Then, several reports on NUDT15 genetic variants associated with 6-MP-induced toxicities and the tolerable doses and outcomes of 6-MP therapy for ALL have been published in Asian countries. The drugs used in treating hematological malignancies have reported new genetic variants associated with its therapeutic response. However, the association between these genetic variants has not been validated in other populations. Here, we reviewed recent reports on the association between the genetic variants and response to drugs used in treating hematological malignancies, such as 6-MP, cytarabine, methotrexate, and vincristine.

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.

Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsedrefractory (rr) leukemia is poorly described. We identified patients with rr CD19 ALLlymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30% 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P .334) or neighborhood opportunity (P .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P .006 adjusted hazard ratio HR, 2.3 95% confidence interval CI, 1.3-4.1). There was no difference in hazard of death (P .545 adjusted HR, 1.2 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted.

ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1 and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1- like B-ALL signature genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1- like B-ALL. We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

Corpus Callosum Infarct in the Background of Varicella-Zoster Infection A Report of a Rare Case.

Infarctions of the corpus callosum are rare due to a rich blood supply. Corpus callosum derives its blood supply from four vessels from the anterior and posterior circulation and for this reason, they have a rare, atypical presentation. There is scarce literature regarding this pathology. Corpus callosum infarcts usually present with non-specific signs and symptoms. Here, we describe a case of corpus callosum infarction in a 5-year-old boy who was a known case of acute lymphoblastic leukaemia. He presented with disseminated varicella infection and developed tonic-clonic seizures. MRI brain was performed and a diagnosis of corpus callosum infarct was made. The patient was treated conservatively.

CDKN1A is a target for phagocytosis-mediated cellular immunotherapy in acute leukemia.

Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that tumor cell phagocytosis drives the pro-inflammatory activation of TAMs and identify a key role for the cyclin-dependent kinase inhibitor CDKN1A (p21). Through the transcriptional repression of Signal-Regularity Protein α (SIRPα), p21 promotes leukemia cell phagocytosis and, subsequently, the pro-inflammatory reprogramming of phagocytic macrophages that extends to surrounding macrophages through Interferon γ. In mouse models of human T-cell acute lymphoblastic leukemia (T-ALL), infusion of human monocytes (Mos) engineered to overexpress p21 (p21TD-Mos) leads to Mo differentiation into phagocytosis-proficient TAMs that, after leukemia cell engulfment, undergo pro-inflammatory activation and trigger the reprogramming of bystander TAMs, reducing the leukemic burden and substantially prolonging survival in mice. These results reveal p21 as a trigger of phagocytosis-guided pro-inflammatory TAM reprogramming and highlight the potential for p21TD-Mo-based cellular therapy as a cancer immunotherapy.

Altered microRNA expression profile is linked to T-cell exhaustion-related pathways in pediatric patients with acute lymphoblastic leukemia.

Although the phenotype and functions of exhausted T cells in several cancers have been identified, the involved molecular mechanisms remain to be further elucidated. In this regard, we have recently reported that the immunoregulatory cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T In this study, we aimed to further explore whether similar dysregulation in miRNA expression is linked to T cell exhaustion and dysfunctionality in B cell ALL patients. Peripheral blood samples from pediatric patients with ALL were recruited before and after induction chemotherapy as well as from healthy donors. Affymetrix microarray platform was used for miRNA profiling, and qRT-PCR was used to validate the expression of certain miRNAs that are related to T cell exhaustion. Bioinformatics analysis was performed to explore whether the dysregulated miRNAs were linked to T-cell exhaustion related pathways. A total of 516 miRNAs were dysregulated in ALL patients as compared to the healthy donor. Furthermore, among the total analyzed miRNAs, 10 were found to be linked to the key genes implicated in three exhaustion-related pathways TGF-β, FOXO, and MAPK, as revealed by miR-pathway analysis. Moreover, qRT-PCR analysis showed similar expression pattern to those obtained by microarray analysis. Our pilot study suggests the implication of certain miRNAs in T cell exhaustion pathways via targeting the specific key genes in those pathways.

Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia A Single-Arm, Multicenter, Phase II Trial.

We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia. This phase II trial enrolled 225 evaluable patients age ≤ 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design. Complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all negative for minimal residual disease. Their overall 12-month event-free survival (EFS) was 73.5% (95% CI, 67.3 to 80.3). Relapse occurred in 43 patients (24 with CD19 CD19-CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse.

Risk Factors for Readmission Following Febrile Neutropenia in Pediatric Oncology Patients.

Febrile neutropenia is the most common reason for admission from the emergency department for pediatric oncology patients. We identified pediatric inpatients age 1 to 21 years with an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis code of malignancy and either fever with neutropenia or fever alone over a 6-year period (2007-2012) using the PHIS database. We evaluated factors associated with readmission within 7 days after index hospitalization. There were 4029 index hospitalizations among 2349 patients in 6 hospitals, 294 encounters (7.3%) were followed by readmission within 7 days. Factors associated with increased odds of readmission included being in the lowest quartile for median household income (odds ratio OR1.64, P0.009), diagnosis of acute lymphoblastic leukemia (OR1.37, P0.016), lack of anerobic coverage during index hospitalization (OR1.48, P0.026), and absolute neutrophil count <200 cellsμL at discharge from index hospitalizations (OR1.55, P0.008). Patients who required readmission had a longer median length of stay and greater hospitalization costs during the index hospitalization. There was a trend towards increasing hospitalization rates for febrile neutropenia over time. While absolute neutrophil count is incorporated into many risk stratification strategies for fever management, further work should focus on addressing socioeconomic factors which may impact readmission rates.

Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis.

The BCL-2 family of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1, can mediate survival of some types of cancer. DT2216 is a PROteolysis-TArgeting Chimera (PROTAC) that degrades BCL-XL specifically and is in phase 1 trials. We sought to define the frequency and mechanism of resistance to DT2216 in T-cell acute lymphoblastic leukemia (T-ALL) cell lines. We measured cell survival and protein levels of BCL-XL, BCL-2, MCL-1 and the pro-apoptotic BIM in 13 distinct T-ALL cell lines after exposure to varying concentrations of DT2216. We identified concentrations of DT2216 which were cytotoxic to each T-ALL cell line. These concentrations have no correlation with the initial protein levels of BCL-XL, BCL-2, MCL-1 or BIM in each cell line. However, there was a correlation between survival to DT2216 and the efficiency of degradation of BCL-XL by DT2216. Only one cell line, SUP-T1, had significant resistance to DT2216, defined as an IC50 above what is achievable in murine tumors in vivo. Resistance to DT2216 is rare in a wide variety of T-ALL cells but when it occurs is correlated with decreased BCL-XL degradation. Resistance to DT2216 in T-ALL is not predicted by initial BCL-XL or BIM protein levels, or BCL-2 or MCL-1 levels before or after treatment. These data imply that a phase 2 clinical trial of DT2216 in T-ALL should be widely available and not limited to a subset of patients.

Interstitial pneumonitis associated with dasatinib treatment for chronic myeloid leukemia or acute lymphoblastic leukemia case series and a literature review.

Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.

Diagnostically misleading aberrant terminal deoxynucleotidyl transferase expression in germ cell tumors.

Terminal deoxynucleotidyl transferase (TdT) is a unique type of DNA polymerase predominantly expressed in precursor lymphoid cells and acute lymphoblastic leukemia. It participates in the junctional diversity of T-cell receptors and immunoglobulins. Recently, aberrant TdT expression was found in seminomas. Here, we evaluated the expression of TdT in our cohort of germ cell tumors (GCTs) with two anti-TdT antibody clones. We included 173 cases of testicular GCTs, 5 ovarian dysgerminomas, and one gonadoblastoma in the study. Tissue microarrays containing representative tumor samples were constructed and subsequently stained with anti-TdT monoclonal rabbit antibody EP266 (Dako) and TdT rabbit polyclonal antibody (Cell Marque). Expression was assessed with the H-score. No specific nuclear reaction was observed for the polyclonal anti-TdT antibody. The H-score values varied between the histological subtypes for the EP266 antibody. Positive nuclear staining was consistently seen in germ cell neoplasia in situ , seminoma, dysgerminoma, and embryonal carcinoma. Pure tumors had higher TdT H-scores than the mixed ones. Teratomas, yolk sac tumors, and choriocarcinomas were almost uniformly negative. Our study confirms that aberrant expression of TdT by testicular and ovarian GCTs exemplifies a potential diagnostic pitfall in histopathological diagnostics.

The association between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia A meta-analysis.

The aim of this meta-analysis was to determine the relationship between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia comprehensively. PubMed, EMBASE, Scopus, Web of Science, the Cochrane Library, Global Index Medicus, Clinicaltrials.gov, ProQuest, and Open Grey databases were used to find relevant papers. Using the STATA 16.0 and CMA 3.0 software, the significance of relationships between microRNA polymorphisms and childhood acute lymphoblastic leukemia risk was evaluated using odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for five genetic models. The results of the meta-analysis showed that there was no significant association between the polymorphism of miR-146a rs2910164 and childhood acute lymphoblastic leukemia risk in different genetic models. Also, in the sensitivity analysis, removing Xues study from the analysis indicated that both the homozygote and recessive models are significantly affected. Additionally, there was a statistically significant relationship between the polymorphisms of pri-miR-34bc rs4938723 (in the homozygote and recessive models) and miR-612 rs12803915 (in the allele and dominant models) and childhood acute lymphoblastic leukemia risk. These findings suggest that the rs4938723 and rs12803915 polymorphisms may have a role in the development of childhood acute lymphoblastic leukemia.

Multifocal Extramedullary Relapse With Neuroleukemiosis in a Case of Early T-Cell Precursor ALL 18F-FDG PETCT Findings.

Early T-cell precursor ALL (acute lymphoblastic leukemia) is a rare type of childhood and adult T-cell ALL. Disease recurrence is common within 2 years from the time of initial diagnosis. Outcomes of relapse have been characterized through risk stratification schemes, and one of the major determinants of overall survival is the overall tumor burden and sites of relapse. Although testicular recurrence is common Peripheral nerve as a site of recurrence is relatively rare. We present a case of early T-cell ALL on maintenance therapy with multifocal relapse on FDG PETCT in the cervical lymph nodes, the testis, and the left sciatic nerve. Bone marrow and flow cytometry confirmed the relapse.

Mercaptopurine induced myelosuppression in a child with a

Mercaptopurine (6-MP) is the backbone of the consolidation and maintenance therapy for paediatric acute lymphoblastic leukaemia (ALL). Nevertheless, it can cause critical myelosuppression. Predicting adverse reactions to 6-MP often involves the investigation of pharmacogenetic variants in particular thiopurine S-methyltransferase ( We present a six-year-old male child of Indian origin with persistent cytopenia after treatment. This prompted targeted sequencing of the genes Since the Individuals with the

Enhanced Thermostability and Molecular Insights for l-Asparaginase from

l-Asparaginase has gained much attention for effectively treating acute lymphoblastic leukemia (ALL) and mitigating carcinogenic acrylamide in fried foods. Due to high-dose dependence for clinical treatment and low mitigation efficiency for thermal food processes caused by poor thermal stability, a method to achieve thermostable l-asparaginase has become a critical bottleneck. In this study, a rational design including free energy combined with structural and conservative analyses was applied to engineer the thermostability of l-asparaginase from

Functional inhibition of MEF2 by CEBP is a possible mechanism of leukemia development by CEBP-IGH fusion gene.

CEBPA-IGH, a fusion gene of the immunoglobulin heavy-chain locus (IGH) and the CCAAT enhancer-binding protein α (CEBPα) gene, is recurrently found in B-ALL cases and causes aberrant expression of CEBPα, a master regulator of granulocyte differentiation, in B cells. Forced expression of CEBPα in B cells was reported to cause loss of B-cell identity due to the inhibition of Pax5, a master regulator of B-cell differentiation however, it is not known whether the same mechanism is applicable for B-ALL development by CEBPA-IGH. It is known that a full-length isoform of CEBPα, p42, promotes myeloid differentiation, whereas its N-terminal truncated isoform, p30, inhibits myeloid differentiation through the inhibition of p42 however, the differential role between p42 and p30 in ALL development has not been clarified. In the present study, we examined the effect of the expression of p42 and p30 in B cells by performing RNA-seq of mRNA from LCL stably transfected with p42 or p30. Unexpectedly, suppression of PAX5 target genes was barely observed. Instead, both isoforms suppressed the target genes of MEF2 family members (MEF2s), other regulators of B-cell differentiation. Similarly, MEF2s target genes rather than PAX5 target genes were suppressed in CEBP-IGH-positive ALL (n 8) compared with other B-ALL (n 315). Furthermore, binding of both isoforms to MEF2s target genes and the reduction of surrounding histone acetylation were observed in ChIP-qPCR. Our data suggest that the inhibition of MEF2s by CEBPα plays a role in the development of CEBPA-IGH-positive ALL and that both isoforms work co-operatively to achieve it.

A damage-associated molecular patterns-related gene signature for the prediction of prognosis and immune microenvironment in children stage III acute lymphoblastic leukemia.

Immunogenic cell death (ICD)-mediated immune response provides a strong rationale to overcome immune evasion in acute lymphoblastic leukemia (ALL). ICD will produce damage-associated molecular patterns (DAMPs) in tumor microenvironment. However, there are few studies on the application of DAMPs-related molecular subtypes in clinically predicting stage III of ALL prognosis. The current study is to identify the DAMPs-associated genes and their molecular subtypes in the stage III of ALL and construct a reliable risk model for prognosis as well as exploring the potential immune-related mechanism. We used Target and EBI database for differentially expressed genes (DEGs) analysis of the stage III pediatric ALL samples. Three clusters were identified based on a consistent clustering analysis. By using Cox regression and LASSO analysis, we determined DEGs that attribute to survival benefit. In addition, the Gene Set Enrichment Analysis (GSEA) was performed to identify potential molecular pathways regulated by the DAMPs-related gene signatures. ESTIMATE was employed for evaluating the composition of immune cell populations. A sum of 146 DAMPs-associated DEGs in ALL were determined and seven transcripts among them were selected to establish a risk model. The DAMPs-associated gene signature significantly contributed to worse prognosis in the high-risk group. We also found that the high-risk group exhibited low immune cell infiltration and high expression of immune checkpoints. In summary, our study showed that the DAMPs-related DEGs in the stage III of children ALL could be used to predict their prognosis. The risk model of DAMPs we established may be more sensitive to immunotherapy prediction.

The treatment of acute lymphoblastic leukemia in Jehovahs Witnesses and patients who cannot accept blood products.

Jehovahs Witnesses cannot accept blood products based upon religious beliefs, and when they present with acute leukemia, the ideal treatment strategy can be controversial. We present six cases of Jehovahs Witnesses with acute lymphoblastic leukemia and show that complete remission can be achieved without using anthracycline in 83% (56) of patients. We also report, for the first time in this population, that the use of agents with novel mechanisms of action, such as blinatumomab and nelarabine, is associated with minimal myelosuppression and can produce durable responses, with 2 of 6 patients still alive in CR3 at 4.9 and 6.6 years.

Gastrointestinal cancer occurs as extramuscular manifestation in FSHD1 patients.

Facioscapulohumeral dystrophy type1 (FSHD1) patients with a shortened D4Z4 repeat containing the DUX4 gene have a broad spectrum of clinical manifestations. In addition, high expression of DUX4 protein with an aberrant C terminus is frequently identified in B cell acute lymphoblastic leukemia. We investigated clinical manifestations in 31 FSHD1 patients and 30 non-affected individuals. Gastrointestinal cancers (gastric and colorectal cancers) increased after the age of 40 years and were more frequently observed in FSHD1 patients (n 10) than in non-affected individuals (n 2, p 0.0217), though the incidence of cancers occurring in non-gastrointestinal tissues of FSHD1 patients was the same as that of non-affected individuals (p > 0.999). These comorbidities of FSHD1 patients were not associated with D4Z4 repeat number. Our results suggest that gastrointestinal cancers are among the extramuscular manifestations of adult FSHD1 patients, and do not depend on D4Z4 repeat number.

Incidence, treatment and outcome of central nervous system relapse in adult acute lymphoblastic leukaemia patients treated front-line with paediatric-inspired regimens A retrospective multicentre Campus ALL study.

Within the Campus ALL network we analyzed the incidence, characteristics, treatment and outcome of a central nervous system (CNS) relapse in 1035 consecutive adult acute lymphoblastic leukemia (ALL) patients treated frontline with pediatric-inspired protocols between 2009 and 2020. Seventy-one patients (6.8%) experienced a CNS recurrence, more frequently in T- (28278 10%) than in B-ALL (43757 5.7%) (p 0.017). An early CNS relapse-< 12 months from diagnosis-was observed in 41 patients. In multivariate analysis, risk factors for early CNS relapse included T-cell phenotype (p <0.001), hyperleucocytosis >100 × 10

Hypoxia regulates CD9 expression and dissemination of B lymphoblasts.

Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1α (HIF1α), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1α signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis.

Disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia.

Fusarium is a polyphyletic genus of plant pathogens, members of which can cause opportunistic human infections with varying superficial and systemic presentations, including disseminated infections which typically occur in immunocompromised patients and have a poor prognosis. Treatment is challenging due to intrinsic resistance to many antifungal agents, and antifungal susceptibility testing is therefore essential. Early suspicion, isolation of the organism, and prompt initiation of management are crucial to improving survival. We present a case of disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia, successfully treated with liposomal amphotericin B, voriconazole, flucytosine, and terbinafine.

High-grade desmoplastic infantile astrocytoma in a 1-year-old child with Downs syndrome a case report.

Downs syndrome is the most common chromosomal abnormality in humans. It has been associated with central nervous system tumors such as primary acute lymphoblastic leukemia and germinomas, but desmoplastic infantile astrocytoma has not yet been reported with Downs syndrome. Desmoplastic infantile astrocytoma is a rare intracranial tumor that mostly occurs in the first 2 years of life. It usually presents as a large, aggressive tumor with both solid and cystic components. Genetically, it has been linked to the BRAF V600E mutation. Despite the rapid growth pattern, it usually has a favorable prognosis after neurosurgical excision. The presence of this extremely rare, genetically linked tumor, and its combination with Downs syndrome, the most common human genetic defect, makes this a very novel clinical presentation. It also raises a very research-worthy question of an undiscovered link between these two genetic disorders. In this case, we report a 1-year-old Pakistani origin male child with Downs syndrome, who presented with progressive macrocephaly and developmental regression over the last 2 months. He was unable to sit by himself, and had lost his handgrip bilaterally. Downs Syndrome was diagnosed soon after birth, based on typical facial features and presence of palmar crease, and later confirmed karyotypically for Trisomy 21. Upon presentation, initial blood tests did not show any abnormality. Magnetic resonance imaging of the brain was done, and showed a mixed intensity cystic mass with solid dural component posteriorly in the right parieto temporo occipital region. Craniotomy was performed, and about 85% of the tumor mass was excised. Histological examination and immunochemistry confirmed the suspected radiological diagnosis of desmoplastic infantile astrocytoma. After surgical excision, our patient gradually reacquired his previously regressed developmental milestones. Unfortunately, the remaining mass, which could not be excised due to its attachment to the highly vascular dura mater, showed regrowth on repeat brain magnetic resonance imaging. As his parents did not consent to further surgery, chemotherapy was offered as the next treatment option to prevent tumor regrowth. This case report highlights the need for more case data and research to understand desmoplastic infantile astrocytoma, and their genetic correlation with Downs syndrome. From a clinical standpoint, since desmoplastic infantile astrocytoma has a good postresection prognosis in a majority of early-diagnosed clinical cases, pediatricians, radiologists, and pathologists should consider desmoplastic infantile astrocytoma in their initial differential diagnosis in Downs syndrome patients with macrocephaly and developmental regression during the first 2 years of life.

Follow our path with asparaginase activity one technique, but different uses in clinical practice.

Acute lymphoblastic leukemia is the most common childhood malignancy. One of the drugs used in the treatment is Asparaginase, and monitoring of its activity levels enables better outcomes. Since 2018, our laboratory has been working to establish a regular analysis of activity. This implementation allowed to qualify care by detecting silent inactivation and also establishing desensitization as a safe way to overcome the lack of Erwinia. We were able to monitor children aged 0 to 18 years who were being treated with PEG-ASNase. The activity was assessed on days 7 (90 samples) and 14 (52 samples) after ASNase infusions. 142 samples were analyzed. 95.7% reached an adequate activity level (≥ 0.1 IUmL). Patients treated with ASNase can develop allergic reactions. With the activity monitoring, is possible to circumvent situations like these and implement desensitization protocols for patients who had clinical hypersensitivity without inactivation. Desensitization induces temporary unresponsiveness to drug antigens, allowing the patients to proceed with the prescribed chemotherapy. We have received samples from four patients being treated with different desensitization protocols. Patients tolerated the protocols well. Only one had a grade 2 reaction during the infusion and activity < 0.1 IUmL, which resulted in the switch to Erwinia. The dose adaptation is a possible and more recent use of ASNase monitoring and we were able to confirm the feasibility of PEG-ASNase desensitization protocols.

In vivo PDX CRISPRCas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance.

Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of cancer patients. To gain mechanistic insights, we developed a model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) of acute lymphoblastic leukemia with widely-used cytotoxic drugs for 18 consecutive weeks. In two distinct PDX samples, tumors initially responded to treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, replicate tumors developed different mutations in TP53 and individual sets of chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven by a combination of stochastic and deterministic processes. Transcriptome and proteome showed shared dysregulations between replicate tumors providing putative targets to overcome resistance. In vivo CRISPRCas9 dropout screens in PDX revealed broad dependency on BCL2, BRIP1 and COPS2. Accordingly, venetoclax re-sensitized derivative tumors towards chemotherapy, despite genomic heterogeneity, demonstrating direct translatability of the approach. Hence, despite the presence of multiple resistance-associated genomic alterations, effective rescue treatment for polychemotherapy-resistant tumors can be identified using functional testing in preclinical models.

Blockade of FGF2FGFR2 partially overcomes bone marrow mesenchymal stromal cells mediated progression of T-cell acute lymphoblastic leukaemia.

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which combined with fibroblast growth factor receptor 2 (FGFR2) on leukaemia cells, resulting in activation of PI3KAKTmTOR signalling pathway in leukaemia cells. In vitro blocking the interaction between FGF2 and FGFR2 with BGJ398 (infigratinib), a FGFR1-3 kinase inhibitor, or knockdown FGF2 in MSCs by interference caused deactivation of PI3KAKTmTOR pathway and dysregulations of genes associated with cell cycle and apoptosis in ALL cells, leading to decrease of leukaemia cells. In mouse model received BGJ398, overall survival was extended and dissemination of leukaemia cells in BM, spleen, liver and peripheral blood was decreased. After subcutaneous injection of primary human T-ALL cells with MSCs, tumour growth was suppressed when FGF2FGFR2 was interrupted. Thus, inhibition of FGF2FGFR2 interaction appears to be a valid strategy to overcome BM-MSCs mediated progression of T-ALL, and BGJ398 could indeed improve outcomes in T-ALL, which provide theoretical basis of BGJ398 as a BM microenvironment based therapeutic strategy to control disease progression.

Isolation of an obscure fungus, Parengyodontium album, from the blood of a severely neutropenic patient The first reported case from Malaysia.

Parengyodontium album is a very rarely encountered opportunistic fungal pathogen. A severely neutropenic 11-year-old boy with acute T-cell lymphoblastic leukemialymphoma was febrile and lethargic during his admission for elective chemotherapy. No cutaneous lesion or obvious source of infection was noted, and clinical examination was otherwise unremarkable. A blood specimen was sent for culture and fungal elements were visualized. Amphotericin B was administered empirically while awaiting fungal identification. Morphologically, a hyaline mould with thin septate hyphae plus smooth-walled conidiophores and conidiogenous cells arranged in whorls of up to four was cultured. Internal transcribed spacer region sequencing identified the fungus conclusively as P. album. Repeat blood culture was also positive for the same fungus. Following a two-week course of amphotericin B, fungemia clearance was attained.

Efficacy of tixagevimab-cilgavimab in preventing SARS-CoV-2 for patients with B-cell malignancies.

COVID-19 still represents a major issue for patients with lymphoid malignancies, especially those on therapy, because of immune suppression and suboptimal responses to vaccination. Davis et al report on their experience with double dose tixagevimab-cilgavimab preexposure prophylaxis in a cohort of 251 patients with chronic lymphocytic leukemia, B-cell lymphomas, multiple myeloma, or B-cell acute lymphoblastic leukemia, 63% of whom had received 3 doses of the SARS-CoV-2 vaccine. Breakthrough infections within 3 months occur despite passive immunization, affecting 11% in this series however, hospitalization rates are low, and mortality was avoided, suggesting benefit from this strategy.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy.

The development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval CI, 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32 95% CI, 1.62-32.98 P .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

Hypodiploidy has Unfavorable Impact on Survival in Pediatric Acute Myeloid LeukemiaAn I-BFM Study Group collaboration.

Hypodiploidy, defined as modal number (MN) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed 2000 to 2015 from fourteen childhood AML groups from the international Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(821) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs 45 (n66), 44 (n10), and 43 (n5). The most frequent chromosomes lost were 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52% for the hypodiploid cohort. Children with MN≤44 (n15) had inferior EFS (21%) and OS (33%) compared to children with MN45 (n66, EFS 37%, OS 56%). Adjusted Hazard ratios were to 4.9 (p0.001) and 6.1 (p0.003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5, p0.42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in patients treated with SCT in CR1.

A murine model for human earlyimmature T-cell precursor acute lymphoblastic leukemia (EITP ALL).

Earlyimmature T cell precursor acute lymphoblastic leukemia (EITP ALL) represents a subset of human leukemias distinct from other T-ALL, and associated with poor prognosis. Clinical studies have identified chromosomal translocations involving the

Oral-visceral iatrogenic Kaposi sarcoma following treatment for acute lymphoblastic leukemia a case report and review of the literature.

There have hardly been any reported cases of children presenting with Kaposi sarcoma as a second malignancy following treatment for acute lymphoblastic leukemia outside a transplant setting. We report a case of a 5-year-old boy of Bantu origin, which, to our knowledge, could be only the second reported case of oral-visceral Kaposi sarcoma after acute lymphoblastic leukemia treatment. The patient presented with a 1-month history of progressive, non-painful, soft tissue oral mass, 1 month after completing treatment for high-risk acute lymphoblastic leukemia. He was successfully treated for Kaposi sarcoma on a two-drug regimen (bleomycin and vincristine) with good clinical response. Visceral Kaposi sarcoma as a second malignancy may occur after pediatric acute lymphoblastic leukemia treatment, but its rarity makes it unlikely to raise suspicion among clinicians, thus precluding early diagnosis and treatment. We recommend routine evaluation for Kaposi sarcoma lesions in children undergoing long-term surveillance following treatment for childhood acute leukemia.

Imaging Findings in Children Presenting with CNS Nelarabine Toxicity.

Nelarabine is a nucleoside analog critical for the treatment of patients with T-cell acute lymphoblastic leukemialymphoma. However, clinical peripheral and central neurologic adverse events associated with nelarabine administration have been reported. Neuroimaging of brain neurotoxicity has only been described in very few reports in pediatric patients so far. Six children with diagnosed T-cell acute lymphoblastic leukemia who clinically experienced possible, probable, or definite nelarabine-induced toxicity and underwent spine andor brain MR imaging were reviewed. Neuroimaging findings showed a mixture of patterns including features of acute toxic leukoencephalopathy (seen in 6 cases), posterior reversible encephalopathy syndrome (2 cases), involvement of deep gray structures (1 case) and brainstem (2 cases), cranial and spinal neuropathy (2 cases each), and myelopathy (2 cases). Even though neuroimaging findings are nonspecific, the goal of this article was to alert the pediatric neuroradiologists, radiologists, and clinicians about the possibility of nelarabine-induced neurotoxicity and its broad neuroimaging spectrum.

Extracellular vesicles derived from human bone marrow stem cells inhibit acute lymphoblastic leukemia cell growth by inhibiting MAPK pathway via the miR-29b-3pGDF15 axis.

Acute lymphoblastic leukemia (ALL) is a common hematologic neoplastic disease. This study discussed the effect of extracellular vesicles (EVs) released from bone marrow mesenchymal stem cells (BMSC) on ALL cells and the mechanism. BMSCs-EVs were isolated by differential centrifugation and identified. The effect of BMSCs-EVs on ALL cell proliferation and apoptosis was evaluated. The expression of miR-29b-3p in ALL cells and EVs was detected. The uptake of EVs by ALL cells was observed. The effect of miR-29b-3p on ALL cell proliferation and apoptosis was assessed after silencing miR-29b-3p. The targeting relation of miR-29b-3p and GDF15 was analyzed by bioinformatics website and dual-luciferase assay. The role of GDF15 in proliferation and apoptosis of ALL cells was further confirmed and Western blot assay was performed to measure MAPK pathway-related protein levels. BMSCs-derived EVs inhibited proliferation and promoted apoptosis of ALL cells, as shown by the up-regulation of Caspase 3 and Bax expressions and down-regulation of Bcl-2 expression. EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p expression in ALL cells, and inhibited GDF15 expression. Silencing of miR-29b-3p or overexpression of GDF15 partially reversed the effect of EVs. EVs inhibited the MAPK pathway through the miR-29b-3pGDF15 axis. BMSCs-EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p, and inhibited GDF15 to suppress the MAPK pathway and further inhibit proliferation and promote apoptosis of ALL cells.

Expression analysis of circulating miR-22, miR-122, miR-217 and miR-367 as promising biomarkers of acute lymphoblastic leukemia.

The role of serum-based biomarkers such as microRNAs in cancer diagnosis has been extensively established. This study aimed to determine the expression levels of bioinformatically selected miRNAs and whether they can be used as biomarkers or a new therapeutic target in patients with acute lymphoblastic leukemia (ALL). The expression levels of serum miR-22, miR-122, miR-217, and miR-367 in 21 ALL patients and 21 healthy controls were measured using quantitative real-time PCR. The receiver operating characteristic (ROC) curve and the associated area under the curve (AUC) was used to assess candidate miRNAs diagnostic value as a biomarker. The results showed that miR-217 was markedly decreased in patients with ALL compared to controls. Moreover, miR-22, miR-122, and miR-367 were found to be upregulated. Furthermore, ROC analysis showed that serum miR-217 and miR-367 could differentiate ALL patients from healthy individuals, while miR-22 has approximate discriminatory power that requires further investigation. These results provide promising preliminary evidence that circulating miR-217 and miR-367 could be considered potent diagnostic biomarkers and therapeutic goals in this disease.

Successful Treatment of Prolonged, Severe Coronavirus Disease 2019 Lower Respiratory Tract Disease in a B cell Acute Lymphoblastic Leukemia Patient With an Extended Course of Remdesivir and NirmatrelvirRitonavir.

A patient with B-cell acute lymphoblastic leukemia (ALL) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had persistent, progressive pneumonia with viremia after 5 months of infection despite monoclonal antibodies, intravenous (IV) remdesivir and prolonged oral steroids. Twenty days of nirmatrelvirritonavir and 10 days of IV remdesivir led to full recovery.

Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia patients enrolled in measurable residual disease-oriented trials.

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinical-biological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A NKRAS MSH2 U2AF1 gene mutations that identified refractoryresistant patients. Mutations in the DMNT3A gene were also found in the nonleukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day 35 of induction therapy. The combined WOG signature and MRD on day 35 allowed risk-stratification of T-ALL into standard or high-risk groups with significantly different 5-year overall survival (OS) (95% confidence interval CI) of 52% (37-67 %) and 17% (1-33%), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.

B and T cell acute lymphoblastic leukemia evade chemotherapy at distinct sites in the bone marrow.

Persistence of residual disease after induction chemotherapy is a strong predictor of relapse in acute lymphoblastic leukemia (ALL). The bone marrow microenvironment may support treatment escape. Using 3D fluorescence imaging of 10 primary ALL xenografts we identify sites of predilection in the bone marrow for resistance to induction with dexamethasone, vincristine and doxorubicin. We detect B-cell precursor ALL cells predominantly in the perisinusoidal space at early engraftment and after chemotherapy. The spatial distribution of T-ALL cells was more widespread with contacts to endosteum, nestin pericytes and sinusoids. Dispersion of T-ALL cells in the bone marrow increased under chemotherapeutic pressure. A subset of slowly dividing ALL cells was transiently detected upon short-term chemotherapy, but not at residual disease after chemotherapy, challenging the notion that ALL cells escape treatment by direct induction of a dormant state in the niche. These lineage-dependent differences point to niche interactions that may be more specifically exploitable to improve treatment.

Adult mixed phenotype acute leukemia (MPAL) Bmyeloid MPAL

Myeloperoxidase (MPO) is considered a specific marker of myeloidnon-monocytic lineage in the diagnosis of mixed phenotype acute leukemia (MPAL). However, the clinical significance of isolated dim MPO expression in otherwise typical B lymphoblastic leukemia (B-ALL referred to as Bmyeloid MPAL We compared flow cytometric immunophenotype and clinicopathological findings among cases of Bmyeloid MPAL Cases of Bmyeloid MPAL This is the first study to investigate the clinical significance of adult Bmyeloid MPAL

Case report A rare case of coexisting Waldenstrom Macroglobulinemia and B-cell acute lymphoblastic leukemia with KMT2D and MECOM mutations.

Waldenstrom Macroglobulinemia (WM) is a rare and indolent lymphoma of B-cell origin characterized by elevated monoclonal IgM, with MYD88L265P mutation and CXCR4 mutation as common molecular alterations. B-cell Acute Lymphoblastic Leukemia (B-ALL) is clinically heterogeneous, characterized by abnormal proliferation and aggregation of immature lymphocytes in the bone marrow and lymphoid tissue. WM and ALL are hematologic malignancies of B-cell origin with completely different clinical manifestations and biological features. KMT2D and MECOM mutations are very rare in ALL and usually indicate poor disease prognosis. The coexistence of WM and ALL with KMT2D and MECOM mutations have not been reported. A 74-year-old female patient was diagnosed with WM in July 2018 and received four cycles of chemotherapy of bortezomib and dexamethasone. In November 2018, she received immunomodulator thalidomide as maintenance therapy. In November 2020, Brutons Tyrosine Kinase inhibitors (BTKi) has been introduced into the Chinese market and she took zanubrutinib orally at a dose of 80 mg per day. The disease remained in remission. In December 2021, she presented with multiple enlarged lymph nodes throughout the body. Bone marrow and next-generation sequencing (NGS) suggested the coexistence of WM and B-ALL with KMT2D and MECOM mutations. The patient was treated with zanubrutinib in combination with vincristine and dexamethasone, after which she developed severe myelosuppression and septicemia. The patient finally got remission. Due to the patients age and poor status, she refused intravenous chemotherapy and is currently treated with zanubrutinib. The coexistence of WM and B-ALL is very rare and has not been reported. The presence of both KMT2D and MECOM mutations predicts a poor prognosis and the possibility of insensitivity to conventional treatment options. BTKi achieves its anti-tumor effects by inhibiting BTK activation and blocking a series of malignant transformations in B-cell tumors. In addition, it also acts on T-cell immunity and tumor microenvironment. Combination therapy based on BTKi may improve the prognosis of this patient.

EBV-positive mucocutaneous ulcer presenting as a nasopharyngeal tumor in an immune suppressed patient.

We describe an unusual presentation of EBV-associated mucocutaneous ulcer presenting as a large tumor of the nasopharynx in an immune suppressed child. This condition is newly characterized and has not been well-studied in the otolaryngology literature. Our patient is a 12-year-old female undergoing chemotherapy for T-cell acute lymphoblastic leukemia who presented with progressively severe headaches, nasal obstruction, facial painpressure, photophobia, fever and otalgia associated with neutropenia and refractory to empiric antibiotic therapy. Bedside nasal endoscopy and imaging revealed signs of acute sinusitis and a large nasopharyngeal mass suspicious for neoplasm. The mass was eccentric to the right and distending the right fossa of Rosenmuller. She underwent endoscopic sinus surgery and biopsy of her nasopharyngeal mass. Pathologic analysis of the nasopharyngeal mass revealed EBV-positive mucocutaneous ulcer. This is an unusual presentation of a rare entity. EBV-positive mucocutaneous ulcer warrants awareness among otolaryngologists and is not well-described in our literature.

The Impact of Intensified CNS-Directed Therapy on Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation.

Findings from St Jude Total Therapy Study 16 (Total 16) showed early intensification of triple intrathecal therapy (ITT) improved CNS disease control for children with newly diagnosed acute lymphoblastic leukemia (ALL) at the greatest risk of CNS relapse. We examined the impact of this treatment on end-of-therapy neurocognitive outcomes. Between 2007 and 2017, 400 (83.5%) of 479 eligible patients treated with Total 16 risk-directed chemotherapy completed protocol-directed neurocognitive testing at the end of therapy. Intensified ITT was defined as ≥ 21 cumulative doses for patients with low-risk ALL (n 70194) and ≥ 27 doses for those with standard-to-high risk ALL (n 81206). Compared with age-normative expectations, the overall group had significantly lower estimated intelligence quotient ( Standard-to-high risk patients treated with intensified ITT are at moderately increased risk for neurocognitive problems. The findings suggest a threshold effect for ITT exposure, which can inform the design of future clinical trials and approaches to neurocognitive monitoring and intervention.

DasatinibPrednisone Induction Followed by BlinatumomabDasatinib in Ph Acute Lymphoblastic Leukemia.

Novel treatment strategies are needed for the treatment of Philadelphia chromosome positive (Ph) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph or Ph-like ALL (with dasatinib sensitive fusions mutations) were eligible and could be newly diagnosed or relapsed refractory. Induction therapy consisted of dasatinib prednisone. Patients not achieving response by Day 56 proceeded to blinatumomab re-induction therapy. Patients achieving response with induction or re-induction therapy proceeded to blinatumomab dasatinib post-remission therapy for 3 cycles followed by dasatinib prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at Days 28, 56, 84, and at additional time points based on response parameters. Measurable residual disease (MRD) was assessed centrally by 8 color flow cytometry at Day 28. Twenty-four eligible patients with newly diagnosed Ph ALL were enrolled with a median age of 73 years (range 65-87). This combination was safe and feasible. With a median of 2.7 years of follow up, 3-year overall survival and disease-free survival were 87% (95% CI 64%-96%) and 77% (95% CI 54%-90%), respectively. Although longer follow up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial is registered at www.clinicaltrials.gov as NCT02143414.

FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells.

Non-canonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow and tonsil donors, performed RNA-seq, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a cancer driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript utilized an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the bone marrow. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we utilized gain- and loss-of-function approaches and identified an FBXW7β-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the TNF superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis and responses to anti-cancer therapies.

A Therapeutically Targetable NOTCH1-SIRT1-KAT7 Axis in T-cell Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which the histone deacetylase SIRT1 is overexpressed downstream of a NOTCH1-bound enhancer. SIRT1 loss impaired leukemia generation, whereas SIRT1 overexpression accelerated leukemia and conferred resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, pharmacologic or genetic inhibition of SIRT1 resulted in significant antileukemic effects. Global acetyl proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene-expression profiling revealed metabolic changes together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a nonacetylatable KAT7-mutant partly rescued SIRT1 loss-induced proliferation defects. Overall, our results uncover therapeutic targets in T-ALL and reveal a circular feedback mechanism balancing deacetylaseacetyltransferase activation with potentially broad relevance in cancer. We identify a T-ALL axis whereby NOTCH1 activates SIRT1 through an enhancer region, and SIRT1 deacetylates and activates KAT7. Targeting SIRT1 shows antileukemic effects, partly mediated by KAT7 inactivation. Our results reveal T-ALL therapeutic targets and uncover a rheostat mechanism between deacetylaseacetyltransferase activities with potentially broader cancer relevance. This article is highlighted in the In This Issue feature, p. 1.

Real-world utility of early measurable residual disease assessments by multi-parametric flow cytometry in adult patients with B-lymphoblastic leukemia receiving Hyper-CVAD induction chemotherapy.

Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p .426) or overall survival (OS) (p .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p ·005) and OS (p .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.

B7-H3 targeted CAR-T cells show highly efficient anti-tumor function against osteosarcoma both in vitro and in vivo.

Osteosarcoma (OS) mainly happens in children and youths. Surgery, radiotherapy and chemotherapy are the common therapies for osteosarcoma treatment but all their anti-tumor effects are limited. In recent years, a new cellular therapy, CAR-T, a cellular immunotherapy with genetically engineered T cells bearing chimeric antigen receptor targeting specific tumor-associated antigen, has been proved to be an effective therapy against acute lymphoblastic leukemia. Thus, CAR-T is a potentially effective therapy for osteosarcoma treatment. A CAR gene targeting B7-H3 antigen was constructed into lentiviral vector through molecular biology techniques. Then, the CAR gene was transferred to T cells through lentiviral delivery system, and the CAR-T cells were largely expanded using in vitro culture technology. The in vitro anti-tumor effect of CAR-T cells was evaluated through Real Time Cell Analysis system (RTCA) and ELISA assay. The in vivo anti-tumor capabilities of CAR-T cells were evaluated using the patient-derived xenografts (PDX) model of osteosarcoma. The third-generation CAR-T cells we constructed could target the B7-H3 antigen, and the phenotype of CAR-T cells was consistent with normal T cells The CAR-T cells showed superior antitumor effects both in vitro and in vivo. Our study showed that B7-H3 targeted CAR-T cells had high anti-tumor efficacy against osteosarcoma both in vitro and in vivo, which proved that B7-H3 targeted CAR-T therapy is potentially effective for osteosarcoma treatment.

Fever Characteristics and Impact on Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy.

Fever is a hallmark symptom of cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell therapy. Fever characteristics and the impact of fever on safety and efficacy post CAR T are not well understood. We sought to explore the impact of fever and its characteristics on safety and efficacy post CAR T-cell therapy. We reviewed 40 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and March 2022. We evaluated all patients who developed fever after CAR T infusion and analyzed the association of fever with toxicity (CRS and neurotoxicity) and efficacy (overall response (ORR) and complete response (CR) at day 90 post CAR T infusion). Fever was defined as per Lee criteria (equal to or greater than 38°C). CRS and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy grading system. Fever occurred in 75% (3040) of patients. Rates of all grade and grade 3 CRS and ICANS were 75%, 2%, 33% and 10%, respectively. Fever occurred within 24 and 72 hours after CAR T infusion in 40% and 53% of patients, respectively. Fifty percent of patients received tocilizumab (toci) for CRS. After the first dose of toci, fever recurred in 38% of the patients, of which 67% had recurrence within 24 hours. Day 90 CR rates were 43% and 10% in patients with and without fever, respectively (Table 3). While fever is common after CAR T-cell therapy, early-onset and higher magnitude do not appear to affect safety or efficacy of CAR T. Absence of fever may affect response to CAR T.

An Efficient Detection and Classification of Acute Leukemia using Transfer Learning and Orthogonal Softmax Layer-based Model.

For the early diagnosis of hematological disorders like blood cancer, microscopic analysis of blood cells is very important. Traditional deep CNNs lead to overfitting when it receives small medical image datasets such as ALLIDB1, ALLIDB2, and ASH. This paper proposes a new and effective model for classifying and detecting Acute Lymphoblastic Leukemia (ALL) or Acute Myelogenous Leukemia (AML) that delivers excellent performance in small medical datasets. Here, we have proposed a novel Orthogonal SoftMax Layer (OSL)-based Acute Leukemia detection model that consists of ResNet 18-based deep feature extraction followed by efficient OSL-based classification. Here, OSL is integrated with the ResNet18 to improve the classification performance by making the weight vectors orthogonal to each other. Hence, it integrates ResNet benefits (residual learning and identity mapping) with the benefits of OSL-based classification (improvement of feature discrimination capability and computational efficiency). Furthermore, we have introduced extra dropout and ReLu layers in the architecture to achieve a faster network with enhanced performance. The performance verification is performed on standard ALLIDB1, ALLIDB2, and CNMC2019 datasets for efficient ALL detection and ASH dataset for effective AML detection. The experimental performance demonstrates the superiority of the proposed model over other compairing models.

One novel ACOT7-NPHP4 fusion gene identified in one patient with acute lymphoblastic leukemia a case report.

Acute lymphoblastic leukemia (ALL) is a type of heterogeneous hematopoietic malignancy that accounts for approximately 20% of adult ALL. Although ALL complete remission (CR) rate has increased to 85-90% after induction chemotherapy, 40-50% of patients eventually relapsed. Therefore, it is necessary to improve the outcomes of ALL via accurate diagnosis and individualized treatments, which benefits in part from molecular biomarkers. Here, we identified a new fusion gene, Acyl-CoA Thioesterase 7-Nephrocystin 4 (ACOT7-NPHP4), in a 34-year-old patient with ALL. The fusion gene contributed to chemoresistance to doxorubicin and acted as a new molecular marker. A 34-year-old male patient was diagnosed with ALL (common B cell) based on clinical manifestations and laboratory results. Although the patient received two cycles of the hyper-CVAD-L regimen as chemotherapy, the induction treatment failed. Because of the refusal of further treatments, the patient died of rapid progression of ALL one month later. Finally, a new fusion transcript, ACOT7-NPHP4, was detected in the patients lymphoblastic leukemia cells via RNA sequencing. This is the first report of a patient with ALL carrying an ACOT7-NPHP4 fusion gene. These findings may help understand the impact of ACOT7-NPHP4 in clinical molecular monitoring and drug resistance to doxorubicin furthermore, its leukemogenesis will be essential to explore in future.

Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy, characterized by cell subsets, enriched with leukemia-initiating cells (LIC). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of -Catenin in T-ALL, we performed co-Immunoprecipitation (Co-IP) followed by liquid-chromatography mass spectrometry. Here, we report that a non-canonical functional interaction of β-Catenin with the Forkhead-Box-O3 (FOXO3) transcription factor positively regulates LIC related genes including the Cyclin-dependent-kinase-4 (CDK4), which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-Catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. Additionally, gene expression data at the single-cell level of leukemic cells of primary patients at the diagnosis and minimal residual disease (MRD) up to 30 days from the standard treatments reveal that the expression of β-Catenin and FOXO3 dependent genes is present in the CD82CD117 cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). These findings highlight key functional roles for β-Catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL.

Targeting CD38 for acute leukemia.

Acute leukemia (AL) is a hematological malignancy, and the prognosis of most AL patients hasnt improved significantly, particularly for relapsed or refractory (RR) AL. Therefore, new treatments for RR adult acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are urgently necessary. Novel developments have been made in AL treatment, including target and immune therapies. CD38 is one of the targets due to its high expression in many hematological malignancies, including multiple myeloma, ALL and a subset of AML. Consequently, targeting CD38 therapies, including CD38 monoclonal antibodies (mAbs), bispecific antibodies, and CAR-T cell therapy, exhibit promising efficacy in treating multiple myeloma without significant toxicity and are being explored in other hematological malignancies and nonhematological diseases. Herein, this review focuses on targeting CD38 therapies in ALL and AML, which demonstrate sound antileukemic effects in acute leukemia and are expected to become effective treatment methods.

Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia.

Chimeric antigen receptor T cells targeting CD19 (CART-19) have shown remarkable efficacy for relapsedrefractory (RR) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We investigated whether prior use of inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, may impact CAR T-cell manufacturing or efficacy via pre-CART-19 depletion of the B-cell compartment. In this international, retrospective analysis, 39 children and young adults receiving InO before (n 12) andor after (n 27) T-cell apheresis as bridging therapy to CART-19 treatment were analyzed. Median age at infusion was 13 years (range 1.4-23 years). Thirty-four out of 39 patients (87.2%) obtained complete remission. With a median follow-up of 18.2 months after CART-19 infusion, 12-month event-free survival (EFS) was 53.3% (95% confidence interval (CI) 38.7-73.4) and overall survival (OS) was 77.8% (95% CI 64.5-93.9). Seventeen patients (44%) relapsed with a median of 159 days (range 28-655) after CART-19 infusion. No difference in day 28 minimal residual disease negative complete response rate, 12-month OSEFS, or incidence of CD19-positive or -negative relapses was observed among patients receiving InO before or after apheresis. Compared to published data for patients treated with CART-19 therapy without prior InO exposure, response and OSEFS for patients treated with InO prior to CART-19 are similar.

Relapsed Childhood Acute Lymphoblastic Leukemia Experience from a Single Tertiary Center in Thailand.

The outcomes of relapsed childhood acute lymphoblastic leukemia (ALL) in developed countries have improved over time as a result of risk-adapted, minimal residual disease-directed therapy, hematopoietic stem cell transplantation, and immunotherapy. There are few studies that have examined survival in relapsed childhood ALL in resource-limited countries. Therefore, this study aimed to assess the prognostic factors and survival outcome of relapsed childhood ALL in a major tertiary center in Southern Thailand. The medical records of patients with ALL aged <15 years between January 2000 and December 2019 were retrospectively reviewed. The Kaplan-Meier method was used to depict the overall survival (OS). A total of 472 patients with ALL were enrolled and relapsed ALL was found in 155 (32.8%) patients. Of these, 131 (84.5%) and 24 (15.5%) had B-cell and T-cell phenotypes, respectively. One hundred thirteen (72.9%) and 42 (27.1%) patients had early and late relapses, respectively. The most common site of relapse was bone marrow in 102 patients (65.8%). One hundred twenty-eight (82.6%) patients received treatment while 27 (17.4%) patients refused treatment. The 5-year OS of all relapsed patients was 11.9%. The 5-year OS among the patients with early relapse was significantly lower than in the patients with late relapse (5.3% vs. 29.1%, respectively, p <0.0001). Site and immunophenotype were not associated with survival of relapsed ALL. The median survival times among the patients who received and refused relapse chemotherapy were 11.8 and 3.1 months, respectively (p <0.0001). The relapse rate accounted for one third of patients with ALL with the 5-year OS of 12%. Early relapse and those who refused treatment were associated with poor survival outcome.

Quality of life of long-term childhood acute lymphoblastic leukemia survivors Comparison with healthy controls.

Improved treatment landscape has led to better outcomes for paediatric acute lymphoblastic leukemia (ALL) survivors. As the number of survivors increase, we need to elucidate the long-term quality of life (QoL) and domains of complaints in these patients. Furthermore, the main priorities of these patients need to be clarified. We assessed long-term QoL outcomes of survivors of childhood ALL compared to matched population controls. QoL data were collected from survivors recruited in France and Belgium between 2012 and 2017, including the Short Form Health Survey (SF-12) and the Quality of Life Systemic Inventory (QLSI). The Wilcoxon test was used to compare SF-12 scale scores between survivors and matched population controls. For the QLSI, comparisons were mainly descriptive. One hundred and eighty-six survivors (mean age 27.6 years range 18.1-52.8) at follow-up completed QoL measures, amongst whom 180 were matched to controls. Overall, survivors had higher QoL on all SF12 scale scores, indicating that they had better functioning compared to controls. Statistically significant differences on the SF12 were observed for Vitality, Social Functioning, Role Limitations due to Emotional Problems and Mental Health scales. QLSI outcomes suggested that survivors were happier than controls with Couple and Social Relations. Controls were unhappiest compared to survivors with Money, Love life, Self-esteem, Nutrition and Paid Work. Our findings suggest that survivors of childhood ALL have better QoL outcomes on some domains compared to the general population, specifically around social and emotional functioning, and that they tend to prioritize their relationships more. Interventions for improving QoL outcomes, might build on existing positive experiences with family, friends and partners.

Asparaginase activity monitoring in pediatric acute lymphoblastic leukemia A cross-sectional nationwide study in Spain.

A cross-sectional nationwide study was designed to assess national compliance with international consensusguidelines of monitoring asparaginase levels in children with acute lymphoblastic leukemia (ALL) treated with asparaginase in routine clinical practice. An ad hoc questionnaire was designed and completed by staff physicians from Hemato-Oncology Units throughout Spain. A total of 39 physicians (64% pediatricians) with a mean (SD) age 43.5 (7.9) years and 15.3 (17.6) years of professional activity participated in the study. They accounted for 90% of hospitals in which children with ALL are treated in Spain. A total of 19 participants (48.7%) reported that asparaginase levels were routinely monitored (own center in 2 cases 10.5%, another hospital in 17 cases 89.5%). Asparaginase was not monitored in 51.3% of the cases, mostly (80%) because unavailability of testing. When asparaginase was monitored, 68% of participants reported that this was done in all asparaginase-treated patients and 84% in all phases of the disease (induction, consolidation, re-induction, maintenance) with a time interval of 7 days for the pegylated form, 48 h for Erwinia asparaginase and 14 days for maintenance with the pegylated form. All participants reported that they modified treatment according to results of testing, with a limit of total depletion of ≥100 IUL. Levels <100 or 20 IUL were considered indicative of hypersensitivity by 46% of physicians. There is still a gap between what is recommended and what is done in clinical practice, with more than 50% of centers not monitoring the level of asparaginase activity in pediatric ALL. Protocols for asparaginase testing in daily practice should be implemented.

Comprehensive molecular characterization of a rare case of Philadelphia chromosome-positive acute myeloid leukemia.

The Philadelphia chromosome (Ph) resulting from the t(922) translocation generates the oncogenic BCRABL1 fusion protein that is most commonly associated with chronic myeloid leukemia (CML) and Ph-positive (Ph) acute lymphoblastic leukemia (ALL). There are also rare instances of patients (≤1%) with newly diagnosed acute myeloid leukemia (AML) that harbor this translocation (Paietta et al.,

Protective Effect of Neonatal Hepatitis B Vaccine Against HBV Breakthrough Infection in Children with Leukemia A Real-world Study.

Hepatitis B vaccine is the most effective preventive measure against hepatitis B virus (HBV) infection. However, the risk of HBV breakthrough infection in fully immunized children (neonatal hepatitis B immunization) who receive immunosuppressive therapy and transfusion of blood components is not well characterized. In this real-world study, we aimed to investigate the immune protection conferred by neonatal hepatitis B vaccine in children with acute lymphoblastic leukemia (ALL) who were treated with immunosuppressive therapy and blood component transfusions. Children with ALL who had received all three doses of neonatal hepatitis B vaccine were included in this study. HBV seromarkers were detected before and after the initiation of immunosuppressive therapy. A total of 1,011 children with ALL who were fully vaccinated against hepatitis B in infancy before the initiation of immunosuppressive therapy were eligible for inclusion. HBV infection was detected in four of 410 children (0.98%) with an HBsAg test after the initiation of immunosuppressive therapy. The median interval from treatment initiation was 19 months. Three doses of neonatal hepatitis B vaccine conferred adequate protection. In endemic regions, there is a low risk of HBV breakthrough infection in fully immunized children with immunosuppressive therapy.

Renal Ultrasonographic Abnormalities at Initial Presentation of Children Diagnosed with Acute Lymphoblastic Leukemia and Long-Term Renal Functions and Prognosis in Survivors.

The kidney is a vulnerable organ for acute lymphoblastic leukemia (ALL), by the disease, and various associated clinical pictures. This retrospective study aims to document renal ultrasound abnormalities in children with newly diagnosed ALL as well as to investigate the correlation between renal findings and clinicallaboratorysurvival data. All children (age <18 years) with ALL were included in the study. An increase in sizenephromegaly (NM) or hyperechogenicity (HE) of the kidneys at first admission was accepted as a pathological renal abnormality. The clinicallaboratory findings, survival, and long-term renal functions were compared between patients with and without NMHE. The incidence of NM±HE was 12% in 163 patients. Enlargement of spleen, liver, or both and, hypercreatininemia was independently correlated with the presence of NMHE. After the induction therapy, ultrasound findings were resolved in all patients, and NMHE did not influence ALL prognosis. All survivors had normal renal functions in long term. The renal ultrasound abnormalities are not uncommon in children with leukemia at admission, without a negative impact on leukemia prognosis and on long-term renal functions.

Residential proximity to croplands at birth and childhood leukaemia.

Domestic and parental occupational pesticide exposures are suspected of involvement in the occurrence of childhood acute leukaemia (AL), but the role of exposure to agricultural activities is little known. In a previous ecological study conducted in France, we observed an increase in acute lymphoblastic leukaemia (ALL) incidence rate with increasing viticulture density in the municipalities of residence at diagnosis. This study aimed to test the hypothesis that residential proximity to croplands at birth increases the risk of childhood AL, with a particular focus on vineyards. We identified all the primary AL cases diagnosed before the age of 15 years in the cohorts of children born in the French municipalities between 1990 and 2015. We estimated crop densities in each municipality of residence at birth using agricultural census data, for ten crop types. Variations in standardized incidence ratios (SIR) were evaluated with Poisson regression models, for all AL, ALL and acute myeloid leukaemia (AML), separately. Among the 19,809,700 children born and residing in mainland France at birth in 1990-2015, 8,747 AL cases (7,236 ALL and 1,335 AML) were diagnosed over the period. We did not evidence any statistically significant positive association between total crop density or any specific crop density in the municipality of residence at birth and all AL, ALL or AML. Interestingly, we observed a higher ALL incidence rate in the municipalities with the highest viticulture densities (SIR 1.25 95%CI 1.01-1.54). Adjusting for the main potential confounders did not change the results. Our study does not support the hypothesis that residential proximity to croplands, particularly vineyards, around birth plays a role in childhood leukaemia. The slightly higher ALL incidence rate in children born in the municipalities with the highest viticulture densities may reflect the previously-observed association at diagnosis.

Treatment-Associated Acute Lymphoblastic Leukemia Following Autologous Hematopoietic Stem Cell Transplant and Lenalidomide Maintenance in Patients With Multiple Myeloma.

Secondary malignancies including leukemia are an increasing concern in patients with prior primary malignancies treated with alkylating agents or topoisomerase II inhibitors. These can also be referred to as therapy-related leukemia. Therapy-related leukemia most commonly results in myelodysplastic syndrome or acute myeloid leukemia. The alkylating agent can cause chromosomal aberrations typically manifest as deletions in chromosome 11 or loss of part of complete loss of chromosomes 5 and 7. Conversely, acute lymphoblastic leukemia (ALL) has been described following maintenance therapy with immunomodulatory (IMiD) drugs pomalidomide, thalidomide, and lenalidomide. We present a case of a 71-year-old man with a history of multiple myeloma (MM) maintained on lenalidomide after stem cell transplant who presented with treatment-associated ALL. At time of leukemic presentation, chromosomal analysis showed a near-triploid clone consistent with masked double low hyplodiploidy which is associated with a poor prognosis. The patient had a deletion of the long arm of chromosome 5 which has been described in prior case reports with ALL secondary to lenalidomide therapy. There are explicit mechanisms in the literature, which have been attributed to development of ALL after exposure to thalidomide or lenalidomide. At time of submission, there are 20 cases described in the literature linking ALL to IMiD drugs. We describe a case and review the mechanisms of lenalidomide-associated ALL.

Viral Infection Profile in Children Treated for Acute Lymphoblastic Leukemia-Results of Nationwide Study.

Viral infections can be a serious complication of therapy in children with acute lymphoblastic leukemia (ALL). In this study, we focused on the incidence and the profile of viral infection in children with ALL treated in 17 pediatric oncology centers in Poland in the two-year periods of 2018-2019 and 2020-2021. We also compared the frequency of viral infections in 2018-2019 to that in 2020-2021. In 2020-2021, a total of 192 children with ALL had a viral infection during intensive chemotherapy. A total number of 312 episodes of viral infections were diagnosed. The most common infections detected in the samples were COVID-19 (23%), rhinovirus (18%), and respiratory syncytial virus (14%). COVID-19 and BK virus infections were the reason for the death 1% of all patients. In 2018-2019, a total of 53 ALL patients who had a viral infection were reported and 72 viral events were observed, mainly adenovirus (48.6%), rotavirus (31.9%), and herpes zoster (8.3%). No deaths were reported during this period. The cumulative incidence of viral infections in 2018-2019 was 10.4%, while for 2020-2021, it was 36.7%. In conclusion, a high incidence of COVID-19 infection was observed among pediatric patients with ALL in Poland. The mortality rate in our material was low. The viral profile in ALL children undergoing chemotherapy can be useful for clinicians to improve prophylactic and therapeutic strategies.

The Protective Effects of Nutraceutical Components in Methotrexate-Induced Toxicity Models-An Overview.

There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkins lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota.

Customized Deep Learning Classifier for Detection of Acute Lymphoblastic Leukemia Using Blood Smear Images.

Acute lymphoblastic leukemia (ALL) is a rare type of blood cancer caused due to the overproduction of lymphocytes by the bone marrow in the human body. It is one of the common types of cancer in children, which has a fair chance of being cured. However, this may even occur in adults, and the chances of a cure are slim if diagnosed at a later stage. To aid in the early detection of this deadly disease, an intelligent method to screen the white blood cells is proposed in this study. The proposed intelligent deep learning algorithm uses the microscopic images of blood smears as the input data. This algorithm is implemented with a convolutional neural network (CNN) to predict the leukemic cells from the healthy blood cells. The custom ALLNET model was trained and tested using the microscopic images available as open-source data. The model training was carried out on Google Collaboratory using the Nvidia Tesla P-100 GPU method. Maximum accuracy of 95.54%, specificity of 95.81%, sensitivity of 95.91%, F1-score of 95.43%, and precision of 96% were obtained by this accurate classifier. The proposed technique may be used during the pre-screening to detect the leukemia cells during complete blood count (CBC) and peripheral blood tests.

Association between Dysfunction of the Nucleolar Stress Response and Multidrug Resistance in Pediatric Acute Lymphoblastic Leukemia.

Approximately 20% of pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relapse or are refractory to chemotherapy despite the low frequency of

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas.

The aim of this review is to highlight mechanisms of immunosuppression for each agent, along with pooled analyses of infectious complications from the available medical literature. Rituximab confers no increase in grade ≥3 infectious risks, except in the case of patients with advanced-stage non-Hodgkin lymphoma. Gemtuzumab ozogamicin links with high rates of grade ≥3 infections which, however, are comparable with historical cohorts. Pembrolizumab exhibits a favorable safety profile in terms of severe infections. Despite high rates of hypogammaglobulinemia (HGG) with blinatumomab, low-grade ≥3 infection rates were observed, especially in the post-reinduction therapy of relapsed B-acute lymphoblastic leukemia. Imatinib and nilotinib are generally devoid of severe infectious complications, but dasatinib may slightly increase the risk of opportunistic infections. Data on crizotinib and pan-Trk inhibitors entrectinib and larotrectinib are limited. CAR T-cell therapy with tisagenlecleucel is associated with grade ≥3 infections in children and is linked with HGG and the emergence of immune-related adverse events. Off-label therapies inotuzumab ozogamicin, brentuximab vedotin, and venetoclax demonstrate low rates of treatment-related grade ≥3 infections, while the addition of bortezomib to standard chemotherapy in T-cell malignancies seems to decrease the infection risk during induction. Prophylaxis, immune reconstitution, and vaccinations for each targeted agent are discussed, along with comparisons to adult studies.

The Proliferating Cell Nuclear Antigen (PCNA) Transcript Variants as Potential Relapse Markers in B-Cell Acute Lymphoblastic Leukemia.

Leukemia is the most common childhood malignancy in Mexico, representing more than 50% of all childhood cancers. Although treatment leads to a survival of up to 90% in developing countries, in our country, it is less than 65%. Additionally, 30% of patients relapse with poor prognosis. Alternative splicing plays an important role in transcriptome diversity and cellular biology. This mechanism promotes an increase in the assortment of proteins with potentially distinct functions from a single gene. The proliferating cell nuclear antigen (PCNA) gene encodes two transcripts for the same protein of 261 amino acids, which is associated with several important cellular processes and with several types of cancer. However, the diversity of the transcript variants expressed in this condition is not clear. Then, we used microarray gene expression to identify changes in the exon expression level of PCNA. The data were validated using RT-PCR and Sanger sequencing, and three additional transcripts (PCNAV3, PCNAV4, and PCNAV5) were identified. Computational analyses were used to determine the potential proteins resulting, their structure, and interactions with PCNA native protein and themselves. Additionally, the PCNA transcript variants were inhibited using specific siRNA, determining that their inhibition contributes to the malignant characteristics in vitro. Finally, we quantified the PCNA transcript variants in acute lymphoblastic leukemia samples and identified their expression in this disease. Based on the clinical characteristics, we determined that PCNAV2 and PCNAV4 are expressed at significantly low levels in relapsed B-ALL patients. We conclude that the low expression of PCNAV2 and PCNAV4 could be a potential molecular marker of relapse in acute lymphoblastic leukemia patients.

Significant Contribution of Interleukin-18 Genotypes to Childhood Acute Lymphocytic Leukemia Risk in Taiwanese.

Evidence has shown that interleukin-18 (IL-18) has both antitumor and pro-tumor effects in various types of leukemia. The current study aimed at investigating the contribution of IL-18 polymorphisms to the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan. IL-18 promoter -656 (rs1946519), -607 (rs1946518), and -137 (rs187238) genotypes of 266 childhood ALL cases and 266 controls were determined by polymerase chain reaction-restriction fragment length polymorphism methodology. The distributions of genotypic and allelic frequencies of IL-18 rs1946519, rs1946518 or rs187238, were not significantly different between childhood ALL cases and controls (all p>0.05). However, in the stratification analysis among the cases, IL-18 rs187238 GC and CC genotypes were associated with increased childhood ALL risk and shorter survival (OR4.19 and 2.93, 95%CI2.04-8.64 and 1.19-7.23, p0.0001 and 0.0250, respectively). No association was found with rs1946519 and rs1946518 (all p>0.05). IL-18 rs187238 GC and CC genotypes can serve as predictors for childhood ALL prognosis among Taiwanese. Validation in larger and various populations can greatly extend the feasibility of this novel predictor.

The kinetics of blast clearance are associated with copy number alterations in childhood B-cell acute lymphoblastic leukemia.

We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance A - early slow responders (n105), B - patients with persistent leukemia (n24), C - fast responders with the low but detectable disease at the end of induction (n66) that corresponded with the patients clinical features, the microdeletion profile,the presence of gene fusions and patients survival. Low incidence of large CNAs and chromosomal numerical aberrations occurred in cluster A which included ALL samples showing recurrent microdeletions within the genes encoding transcription factors (i.e., IKZF1, PAX5, ETV6, and ERG), DNA repair genes (XRCC3 and TOX), or harboring chromothriptic pattern of CNAs. Low hyperdiploid karyotype with trisomy 8 or hypodiploidy was predominantly observed in cluster B. Whereas cluster C included almost exclusively high-hyperdiploid ALL samples with concomitant mutations in RAS pathway genes. The pattern of CNAs influences the kinetics of leukemic cell clearance and selected aberrations affecting DNA repair genes may contribute to BCP-ALL chemoresistance.

StatPearls

Non-Hodgkin lymphoma (NHL) is a neoplasm of the lymphoid tissues originating from B cell precursors, mature B cells, T cell precursors, and mature T cells. Non-Hodgkin lymphoma comprises various subtypes, each with different epidemiologies, etiologies, immunophenotypic, genetic, clinical features, and response to therapy. It can be divided into two groups, indolent and aggressive, based on the diseases prognosis. The most common mature B cell neoplasms are Follicular lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, Mantle cell lymphoma, marginal zone lymphoma, and primary CNS lymphoma. The most common mature T cell lymphomas are Adult T cell lymphoma and mycosis fungoides. The treatment of NHL varies greatly, depending on tumor stage, grade, type of lymphoma, and various patient factors (e.g., symptoms, age, performance status). The natural history of these tumors shows significant variation. Indolent lymphomas present with waxing and waning lymphadenopathy for many years, whereas aggressive lymphomas have specific B symptoms such as weight loss, night sweats, and fever and can result in deaths within a few weeks if untreated. Lymphomas that usually have indolent presentations include follicular lymphoma, chronic lymphocytic leukemiasmall lymphocytic lymphoma, and splenic marginal zone lymphoma. Aggressive lymphomas include diffuse large B cell lymphoma, Burkitt lymphoma, precursor B and T cell lymphoblastic leukemialymphoma, adult T cell leukemialymphoma, and certain other peripheral T cell lymphomas. Up to two-thirds of patients present with peripheral lymphadenopathy. Rashes on the skin, increased hypersensitivity reactions to insect bites, generalized fatigue, pruritus, malaise, fever of unknown origin, ascites, and effusions are less common presenting features. Approximately half of the patients develop extranodal disease (secondary extranodal disease) during the course of their disease, while between 10 and 35 percent of patients have primary extranodal lymphoma at diagnosis. Primary gastrointestinal (GI) tract lymphoma may present with nausea and vomiting, aversion to food, weight loss, fullness of the abdomen, early satiety, and visceral obstruction-related symptoms. Patients may even present with features of acute perforation and gastrointestinal bleeding and, at times with features of malabsorption syndrome. Primary central nervous system (CNS) lymphoma may present with headaches, spinal cord compression features, lethargy, focal neurologic deficits, seizures, and paralysis.

StatPearls

The production of abnormal leukocytes defines leukemia either as a primary or secondary process. Based on the rapidity of proliferation, they can be classified as acute or chronic, and myeloid or lymphoid based on the cell of origin. Predominant subtypes are acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), involving the myeloid lineage acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) involving the lymphoid chain. Other less common variants such as mature B-cell and T-cell leukemias, NK cell-related leukemias, to name a few, arise from mature white blood cells. However, with the advent of next-generation sequencing (NGS) and the identification of various biomarkers, the World Health Organization (WHO) classification was updated in 2016, bringing multiple changes to the traditional classification for acute leukemias and myeloid neoplasms. GLOBOCAN, a global observatory for cancer trends, showed a global incidence of 474,519 cases with 67,784 in North America. The Age-Standardized Rates are around 11 per 100,000, with a mortality rate of approximately 3.2. Many genetic risk factors have been identified, such as Klinefelter and Down syndromes, ataxia telangiectasia, Bloom syndrome, and telomeropathies such as Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome germline mutations in RUNX1, CEBPA, to name a few. Viral infections associated with Epstein Barr virus, human T-lymphotropic virus, ionizing radiation exposure, radiation therapy, environmental exposure with benzene, smoking history, history of chemotherapy with alkylating agents, and topoisomerase II agents have also been implicated in the development of acute leukemias. Symptoms are nonspecific and can include fever, fatigue, weight loss, bone pain, bruising, or bleeding. Definitive diagnoses often require bone marrow biopsy, the results of which help the hematologists and stem cell transplant physicians regarding the selection of treatment options ranging from chemotherapy to allogeneic stem cell transplantation. The prognosis is variable depending on the leukemia subtype in question.

Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia.

Genome editing of allogeneic T cells can provide off-the-shelf alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator-like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3 long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsedrefractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 10

Socio-economic outcomes among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies Results of the 58LAE study.

The objective of this study is to evaluate the socio-economic outcomes of survivors of childhood acute lymphoblastic leukaemia (ALL). Childhood ALL adult survivors, enrolled in EORTC trials between 1971 and 1998 in France and Belgium, were invited to fill out a questionnaire with information about their socio-economic situation (living with a partner, having a university degree, having a job, working part time and history of having a paid job). The outcomes were compared with two matched control populations. Among 1418 eligible patients, 507 (35.8%) participated, including 39 (8%) and 61 (12%) patients who received a haematopoietic stem cell transplantation (HSCT) and a cranial radiotherapy (CRT), respectively. The median time to follow-up was 20 years, and median age was 25 years. Survivors showed a socio-economic level at least as good as controls. HCST and CRT were associated with a higher probability of not obtaining a bachelor degree (respectively OR 3.49, 95% CI 1.46-8.35 and OR 2.31, 95% CI 1.04-5.15), HSCT was associated with unemployment (OR 2.89, 95% CI 1.09-7.65) and having a relapse was associated with a higher probability of not having a partner (OR 1.88, 95% CI 1.01-3.51) adjusting for confounders. Childhood ALL survivors showed a high level of socio-economic participation. HCST and CRT were associated with poorer functioning.

Targeting amino acid metabolism in cancer.

Metabolic rewiring is a characteristic hallmark of cancer cells. This phenomenon sustains uncontrolled proliferation and resistance to apoptosis by increasing nutrients and energy supply. However, reprogramming comes together with vulnerabilities that can be used against tumor and can be applied in targeted therapy. In the last years, the genetic background of tumors has been identified thoroughly and new therapies targeting those mutations tested. Nevertheless, we propose that targeting the phenotype of cancer cells could be another way of treatment aiming to avoid drug resistance and non-responsiveness of cancer patients. Amino acid metabolism is part of the altered processes in cancer cells. Amino acids are building blocks and also sensors of signaling pathways regulating main biological processes. In this comprehensive review, we described four amino acids (asparagine, arginine, methionine, and cysteine) which have been actively investigated as potential targets for anti-tumor therapy. Asparagine depletion is successfully used for decades in the treatment of acute lymphoblastic leukemia and there is a strong implication to apply it to other types of tumors. Arginine auxotrophic tumors are great candidates for arginine-starvation therapy. Higher requirement for essential amino acids such as methionine and cysteine point out promising targetable weaknesses of cancer cells.

United we stand, divided we fall. Multicentre standardization of measurable residual disease assessment in acute leukaemia is the way forward.

Assessment of measurable residual disease (MRD) using multiparameter flow cytometry in precursor B-cell acute lymphoblastic leukaemia (ALL) is routine. However, studies on the harmonization of laboratory techniques as well as on the interpretation of results are limited. Here, Ikoma-Colturato and colleagues from Brazil demonstrate multicentric standardization of B-ALL MRD using EuroFlow protocols. Commentary on Ikoma-Colturato et al., Multicentric standardization of minimalmeasurable residual disease in B-cell precursor acute lymphoblastic leukaemia using next-generation flow cytometry in a lowmiddle-level income country. Br J Haematol 2023200381-384.

Integrated clinical genotype-phenotype characteristics of early T-cell precursor acute lymphoblastic leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP-ALL patients are poorly understood. The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP-ALL. The median age was 43 years (range, 16-71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1-2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next-generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi-agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. Patients with ETP-ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers.

A case of acute lymphoblastic leukaemia disease with pancreatic mass as the first symptom confirmed by elastography combined with EUS-FNA.

Haematological diseases with pancreatic masses as the first symptom are clinically rare but should not be ignored. This case report describes a 60-year-old female patient with acute leukaemia that had a pancreatic mass as her first symptom. The patient was admitted and elastography combined with endoscopic ultrasound (EUS) guided fine needle aspiration biopsy (EUS-FNA) was used for diagnosis, treatment planning and determination of prognosis. The site selected for the EUS-FNA puncture was the caudal section of the pancreatic body and the posterior wall of the gastric body was used as the puncture point. The elastography view of the head of the pancreas was bluegreen with predominant blue colour. A 19 G puncture needle with a slow-draw core and two stitches of micro-negative pressure were used. Cytology detected heterotypic cells, pancreatic puncture histopathology, the presence of pancreatic alveolar structures and heterotypic tumour cells in the interstitium. Immunohistochemistry of the pancreatic puncture tissue showed B-cell lymphoblast-derived tumours and bone marrow puncture indicated acute lymphoblastic leukaemia. The patient was diagnosed with acute lymphoblastic leukaemia invading the pancreas and was treated with chemotherapy. After treatment, her condition was stable. Follow-up is ongoing and there have been no signs of tumour recurrence or metastasis.

Translocation t(119) in acute precursor B-cell lymphoblastic Leukaemia in paediatric patients- Pakistani population.

To determine the impact of translocation t(119) in paediatric patients diagnosed with precursor B-cell acute lymphoblastic leukaemia. The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data from January 2012 to January 2018 of paediatric patients diagnosed with precursor B-cell acute lymphoblastic leukaemia. Data of patients having t(119) translocation with or without complex karyotype formed group A, while data of patients without any cytogenetic abnormality formed the control group B. Relapse and event-free survival were calculated and the outcomes were compared between the groups. Data was analysed using SPSS 20. Of the 450 subjects whose data was analysed, 84(18.7%) were included 25(30%) in group A and 59(70%) were in group B. There were 21(84%) males and 4(16%) females in group A with mean age on presentation 3.68±0.6 years compared to 41(69.4%) males and 18(30.5%) females with mean age on presentation 4.0±0.92 (p>0.05). There were no differences between the groups in terms of baseline markers (p>0.05). The relapse and event-free survival rates were also not significantly different between the groups (p>0.05). There was no significant difference related to outcomes of precursor B-cell acute lymphoblastic leukaemia patients having t(119) translocation with or without complex karyotype and those without any cytogenetic abnormality, indicating that translocation t(119)-positive patients do not need treatment intensification.

Dual inhibition of EZH12 induces cell cycle arrest of B cell acute lymphoblastic leukemia cells through upregulation of CDKN1C and TP53INP1.

Disease-risk stratification and development of intensified chemotherapy protocols have substantially improved the outcome of acute lymphoblastic leukemia (ALL). However, outcomes of relapsed or refractory cases remain poor. Previous studies have discussed the oncogenic role of enhancer of zeste homolog 1 and 2 (EZH12), and the efficacy of dual inhibition of EZH12 as a treatment for hematological malignancy. Here, we investigated whether an EZH12 dual inhibitor, DS-3201 (valemetostat), has antitumor effects on B cell ALL (B-ALL). DS-3201 inhibited growth of B-ALL cell lines more significantly and strongly than the EZH2-specific inhibitor EPZ-6438, and induced cell cycle arrest and apoptosis in vitro. RNA-seq analysis to determine the effect of DS-3201 on cell cycle arrest-related genes expressed by B-ALL cell lines showed that DS-3201 upregulated CDKN1C and TP53INP1. CRIPSRCas9 knockout confirmed that CDKN1C and TP53INP1 are direct targets of EZH12 and are responsible for the antitumor effects of DS-3201 against B-ALL. Furthermore, a patient-derived xenograft (PDX) mouse model showed that DS-3201 inhibited the growth of B-ALL harboring MLL-AF4 significantly. Thus, DS-3201 provides another option for treatment of B-ALL.

Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia a single-arm, single-centre, phase 2 trial.

Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes. We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μgday by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients. Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years IQR 29-45 26 68% male 21 55% White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related. Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia. Amgen.

Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia.

The hematopoietic transcription factor Ikaros (

A Case of Daratumumab-Induced Significant Decrease in Donor-Specific HLA Antibodies and Remission Induction Before Haploidentical Stem Cell Transplantation in a Refractory B-ALL Patient.

To explore the method of eliminating donor-specific anti-HLA antibodies (DSA) in haploidentical stem cell transplantation (haplo-SCT). We present a refractory B-cell acute lymphoblastic leukemia (ALL) patient who had strongly positive DSA, but had no human leukocyte antigen-matched donor. Although CD38 expression on leukemia cells was negative, daratumumab combined with etoposide and venetoclax therapy was chosen for her. She achieved a significant decrease in DSA levels and complete remission on the combination therapy with daratumumab. She then received a haplo-SCT from a daughter as a donor and had a successful engraftment of donor stem cell. In haplo-SCT, strongly positive DSA levels, directed against donor HLA antigens, could be significantly reduced by daratumumab therapy before transplantation and successfully bridge subsequent haplo-SCT. Although CD38 expression is negative in leukemia cells, refractory B-ALL patients may still benefit from combination therapy with daratumumab. We need further clinical observation.