Acute Lymphoid Leukemia Research Articles

A Biological Perspective: Epidemiology of Acute Leukemia in Souss Massa

Acute leukemia is a type of blood cancer characterized by the rapid and uncontrolled proliferation of abnormal immature cells in the bone marrow. It is divided into two main forms: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Common symptoms include severe fatigue, paleness, easy bleeding and bruising, frequent infections, bone and joint pain, as well as swollen lymph nodes. Acute lymphoid and myeloid leukemias account for 10 to 15% of malignant hematological disorders and are rare conditions, with the majority having a poor prognosis, except for a few specific forms. Acute myeloid leukemias (AML) have a consistent incidence over time, ranging from 2.5 to 3.5 per 100,000 population per year in Western countries. We conducted a retrospective descriptive study on the medical records of patients with acute leukemia between January 2023 and June 2024 (6 months), classified according to the criteria of the Franco-American-British (FAB) group. During this period, 68 cases of acute leukemia were diagnosed. The age of the patients ranged from 4 years to 87 years, with a mean age of 26 years. The male-to-female sex ratio was 1.40, favoring males. Acute leukemias were observed across all age groups. Cytological and cytochemical examination of bone marrow smears showed a predominance of acute myeloid leukemias at 64.7% (n=44), with 24 cases of acute lymphoblastic leukemias (35.3%). The study results provide valuable insights into the demographic and clinical characteristics of patients with acute leukemias. No precise statistics on acute leukemia have been conducted to date in our region. Our study could serve as a foundation for future research in this area. Indeed, the new WHO classification utilizes a comprehensive approach that incorporates cytological, cytogenetic, immunophenotypic, and molecular biology data to classify acute leukemias with both diagnostic and prognostic objectives. Outside of these distinguishing features, ...

A prospective, longitudinal study of health-related quality of life and contributing factors and its impact on medication adherence to oral anticancer agents in real-world patients with leukemia.

270 Background: Suboptimal rates of non-adherence have been reported in leukemia patients taking oral anticancer agents (OAAs), largely attributed to treatment-related symptoms (TRS). This survey was conducted to describe the complex relationship between adherence, TRS, and health-related quality of life (HRQOL). Methods: This is a single arm, observational, prospective, longitudinal study. Patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL) on OAAs completed a telephone survey, which included Wilson’s 3-item medication adherence measure, the PROMIS 10-item Global Health Scale (domains: overall QOL, physical/mental/social health), and assessment of TRS using PRO-CTCAE. This survey was repeated three times, two to three months apart. Optimal adherence was defined as greater than 90% per Wilson’s measure. Spearman’s correlation, chi-square tests, as appropriate, to evaluate the association between medication adherence and HRQOL. Results: 77 patients completed the first survey, of which 60.3% were male, with an average age of 62 years old. Diagnoses were: CML (n=28), CLL (n=19), AML (n=19), and ALL (n=11). Optimal adherence rates declined from 70.2% in the 1 st survey to 55% by the 3 rd survey, whereas HRQOL measures remained stable over time. Most patients (92.2%, n= 71) reported at least one TRS with 42.25% (n= 30) reporting ≥6 symptoms. Patients without TRS were more likely to be adherent than those with symptoms (100% vs. 67%, p=0.17). Specifically, patients with no pain were associated with higher adherence (p= 0.084). Those who rated their mental health and overall quality of life (QOL) as ‘excellent,’ ‘very good,’ or ‘good’ had numerically a higher adherence rate (73% with optimal adherence) than those rating it as ‘fair’ or ‘poor,’ (59-61% had optimal adherence), although not statistically significant. The number of TRS reported from PRO-CTCAE significantly affected patients’ reported QOL: patients reporting 0-5 number of TRS were more likely to report higher QOL (‘excellent,’ ‘very good,’ or ‘good’) than those reporting ≥6 TRS (p = 0.0004). Conclusions: Adherence rates in leukemia patients on OAAs were suboptimal and declined over time. TRS were common and inversely associated with HRQOL, even though adherence was not strongly correlated: patients with high adherence still reported fair or poor HRQOL. Given the numerous and varied factors contributing to non-adherence and HRQOL issues in leukemia patients, a multi-modality support program is essential.

Clinical and Nutritional Aspects and Outcomes of Covid-19 in Cancer and Non-Cancer Pediatric Patients

The SARS-CoV-2 virus has been the subject of study by several researchers worldwide since 2020; however, there are points to be clarified. This study aimed to analyze the clinical and nutritional aspects of hospitalized cancer and non-cancer pediatric patients and the association with COVID-19 outcomes. This is a cohort study of hospitalized children and adolescents with a laboratory diagnosis of COVID-19. Patients were assessed according to the presence or absence of previous oncological diseases. Sociodemographic, clinical and nutritional data were investigated during the course of the infection. Outcomes included Intensive Care Unit (ICU) admission, longer length of stay (14 days), criticality, and death. Oncological disease was found in 16 (19.3%) patients, most of whom had B-type acute lymphoid leukemia. In Poisson regression, adjusted for age and comorbidity, an association was found between oncological disease and length of stay ≥14 days (RR 4.30; 95% CI 1.46 − 15.6; p = 0.013), COVID-19 criticality (RR 3.82; 95% CI 1.66 − 30.9; p = 0.010) and death (RR 3.42; 95% CI 0.94 − 9.96; p = 0.035). The research revealed that cancer patients had longer hospital stays, were more likely to have the severe form of COVID-19, and had a 3.42 times greater risk of dying.

Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial.

Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood. To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor. This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months. National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers. Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkin's and non-Hodgkin's lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available. Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (∼25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective. Cumulative incidence of transplantation by Search Prognosis arm. Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113). A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor. Trial Registration: NCT#03904134.

Risk factors for red blood cell alloimmunization in patients with hematologic malignancy.

Patients with hematologic malignancy have a higher risk of developing red blood cell (RBC) alloimmunization which can delay blood transfusion. Information on the risk factors for alloimmunization in this group is still limited. This study aimed to determine the prevalence and predictors of RBC alloimmunization among these patients. Electronic medical records of the patients with acute myeloid leukaemia (AML), acute lymphoid leukaemia (ALL), multiple myeloma (MM) and lymphoma from a tertiary care hospital between January 2018 and December 2022 were retrospectively reviewed. Clinical, demographic and transfusion history data of the included patients were analysed. Of the 983 patients with hematologic malignancy, 798 were included in the study. The prevalence of RBC alloantibodies in this population was 4.8% (38 patients). The alloimmunization rate of each subgroup was as followed: AML 9.1%, ALL 2.9%, MM 3.8% and lymphoma 2.5%. The most common alloantibodies were anti-Mia, anti-E and anti-Lea. The majority (29/38, 76.3%) of alloimmunization had a single alloantibody. RBC autoantibody was detected in 10 patients. The detection of autoantibodies and having AML were independently associated with RBC alloimmunization (adjusted odds ratio [aOR] 13.41, 95% confidence interval [CI] 2.00-89.72, p = 0.007 and aOR 11.44, 95% CI 2.02-64.72, p = 0.006, respectively). The prevalence of RBC alloimmunization in the patients with hematologic malignancy was 4.8%. The alloimmunization rate of the AML subgroup was higher than those of other hematologic malignancies. The detection of autoantibodies and the AML diagnosis were identified as potential risk factors for RBC alloimmunization.

Circular RNA as a Biomarker for Diagnosis, Prognosis and Therapeutic Target in Acute and Chronic Lymphoid Leukemia.

Circular RNAs (circRNAs) are single-stranded RNAs that have received much attention in recent years. CircRNAs lack a 5' head and a 3' poly-A tail. The structure of this type of RNAs make them resistant to digestion by exonucleases. CircRNAs are expressed in different cells and have various functions. The function of circRNAs is done by sponging miRNAs, changing gene expression, and protein production. The expression of circRNAs changes in different types of cancers, which causes changes in cell growth, proliferation, differentiation, and apoptosis. Changes in the expression of circRNAs can cause the invasion and progression of tumors. Studies have shown that changes in the expression of circRNAs can be seen in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL). The conducted studies aim to identify circRNAs whose expression has changed in these leukemias and their more precise function so that these circRNAs can be identified as biomarkers, prediction of patient prognosis, and treatment targets for ALL and CLL patients. In this study, we review the studies conducted on the role and function of circRNAs in ALL and CLL patients. The results of the studies show that there is a possibility of using circRNAs as biomarkers in the identification and treatment of patients in the future.

KMT2A oncoproteins induce epigenetic resistance to targeted therapies.

Chromosomal translocations involving the Lysine-Methyl-Transferase-2A ( KMT2A ) locus generate potent oncogenic fusion proteins (oncoproteins) that disrupt regulation of developmental gene expression. By profiling the oncoprotein-target sites of 36 broadly representative KMT2A -rearranged leukemia samples, including three samples that underwent a lymphoid-to-myeloid lineage-switching event in response to therapy, we find the genomic enrichment of the oncoprotein is highly variable between samples and subject to dynamic regulation. At high levels of expression, the oncoproteins preferentially activate either an acute lymphoblastic leukemia (ALL) program, enriched for pro-B-cell genes, or an acute myeloid leukemia (AML) program, enriched for hematopoietic-stem-cell genes. The fusion-partner-specific-binding patterns over these gene sets are highly correlated with the prevalence of each mutation in ALL versus AML. In lineage-switching samples the oncoprotein levels are reduced and the oncoproteins preferentially activate granulocyte-monocyte progenitor (GMP) genes. In a sample that lineage switched during treatment with the menin inhibitor revumenib, the oncoprotein and menin are reduced to undetectable levels, but ENL, a transcriptional cofactor of the oncoprotein, persists on numerous oncoprotein-target loci, including genes in the GMP-like lineage-switching program. We propose KMT2A oncoproteins promote lineage-switching events through dynamic chromatin binding and can induce epigenetic lesions, marked by ENL, that support resistance to targeted therapies.

Exploratory case–control study on childhood cancer near the Mar Menor lagoon Region of Murcia (Spain) 2000 to 2018

The Mar Menor, Europe’s largest saltwater lagoon in the Mediterranean basin (Murcia, southeastern Spain), is an ecosystem facing severe pollution, anoxia events, and marine biodiversity loss. This exploratory study examines the association between residential proximity to the Mar Menor and childhood cancer incidence in Murcia from 2000 to 2018. In our case–control study of 594 cancer cases and 3564 controls, matched by birth year and sex, participants were categorized by proximity to the lagoon (G1 ≥ 20 km, G2 = 10–20 km, G3 = 2–10 km, G4 = ≤ 2 km). Odds ratios (ORs) and 95% confidence intervals (95%CI) were adjusted for sociodemographic and environmental covariates. Analysis of distance as a continuous variable indicated a decrease both in all types of cancer and lymphoid acute leukemia risk with greater distance (OR = 0.99; 95% CI 0.98–0.99), while as a categorical variable, it revealed a non-linear pattern. Specifically, the risk did not increase for those living within 2 km of the lagoon (OR = 0.87; 95% CI 0.52–1.37), whereas increased risks were observed in the 2–20 km range within Campo de Cartagena (G2; OR = 1.32; 95% CI 1.01–1.73 and G3; OR = 1.43; 95% CI 1.00–2.02). This suggests modulating factors near the lagoon may counterbalance risks from broader environmental contamination. These findings highlight the complexity of environmental health dynamics and the importance of detailed research to guide public health strategies and urban planning for environmental and child health protection.

Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia.

Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.

Impact of Race and Ethnicity on Outcomes After Umbilical Cord Blood Transplantation

BackgroundUmbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients. ObjectiveTo compare outcomes by social determinants of health. Study DesignWe designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). ResultsFor 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults.Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes. ConclusionsOS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children.

The DNA Methyltransferase Inhibitor 5-Aza-4'-thio-2'-Deoxycytidine Induces C>G Transversions and Acute Lymphoid Leukemia Development.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.

Impact of protein energy malnutrition on hospitalized patients with acute myeloid and lymphoid leukemia: A United States population-based cohort study.

6548 Background: Acute leukemia poses a significant burden to the society and the healthcare system. Advances in chemotherapeutics and hematopoietic stem cell transplantation (HSCT) have increased survival in these patients. Protein energy malnutrition (PEM) frequently complicates the clinical picture in patients with cancer, however data on the impact of PEM in patients with acute myeloid and lymphoid leukemia is limited. Methods: We utilized the 2020 National Inpatient Sample (NIS) Database in conducting this retrospective cohort study. We identified patients with acute leukemia (myeloid and lymphoid) and PEM using appropriate ICD-10 diagnostic codes. We stratified patients with acute leukemia based on the presence or absence of PEM. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of &lt;0.05 was considered statistically significant. The aim of this study was to investigate the impact of PEM on in-hospital mortality, hospital length of stay (LOS), and total hospitalization charge among patients with acute leukemia. Results: We identified a total of 30995 hospitalized patients with acute leukemia, of which 13.06% (4050/30995) had comorbid PEM. The overall in-hospital mortality among patients with acute leukemia was 8.95% (2775/30995). Among those with co-morbid PEM, the mortality rate was significantly higher at 12.47% (505/4050, p&lt;0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, PEM was found to be an independent predictor of increased in-hospital mortality (adjusted OR 1.50; 95% (confidence interval [CI], 1.18 -1.91); p=0.001), longer LOS (coefficient 10.50; CI 8.59 -12.41; p&lt;0.001), and higher total hospitalization charge ($208,308; CI $147,516- $269,100; p&lt;0.001). Conclusions: Our analysis demonstrated that PEM was widely prevalent in hospitalized patients with acute leukemia and significantly worsened outcomes including increased in-hospital mortality, LOS, and cost of healthcare utilization. A proactive approach for prevention and early management of cancer associated malnutrition is required. Further prospective multicentric studies are needed to better describe these associations.

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.

Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenograftsand controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.

Lymphoglandular bodies as useful morphological clue in diagnosis of Lymphoid malignancies- A Case Report

Lymphoglandular bodies, observed as round basophilic cytoplasmic fragments on Giemsa stain, are linked with lymphoid malignancies, aiding in distinguishing lymphomas from other small round cell tumors. This case report underscores the diagnostic significance of Lymphoglandular bodies in Acute lymphoid leukemia diagnosis through bone marrow biopsy. We present a case of a 21-year-old male with chest pain and weakness. The bone marrow biopsy revealed a monomorphic cell population with a high nuclear cytoplasmic ratio, prompting immunomarker analysis that confirmed the presence of blasts as lymphoblasts, leading to the diagnosis of Acute lymphoid leukemia. The identification of Lymphoglandular bodies in bone marrow biopsy facilitated the diagnosis, as peripheral blood examination did not indicate the presence of blasts suggestive of leukemia. Literature on the role of Lymphoglandular bodies in lymphoma diagnosis is limited, with more emphasis on cytological preparations. Lymphoglandular bodies serve as an adjunct in differentiating between lymphoma and non-lymphoma malignancies, being more frequently associated with Malignant lymphoma. The study aim to prove Lymphoglandular bodies as useful morphological clue in diagnosis of Lymphoid malignancies.

IL-15 gene mutation as a molecular risk factor in acute lymphoid leukemia.

The present study investigated the relationship between single nucleotide polymorphisms in the interleukin (IL)-15 gene located (exon 8) on the chromosomal location 4q31.21 and acute lymphoblastic leukaemia (ALL) risk in Iraqi patients. A total of 78 (49 male -29 female) primary ALL (62B-cell, 16 T-cells lineages cases and 30 healthy control subjects (median age 11, age range were 4-21.5), were enrolled at the Nanakaly Hospital of Erbil Province between February 2021 and January 2022. The genotype analysis was performed using polymerase chain reaction (PCR) and Sanger DNA sequencing. The IL15 homozygous rs10833 (100%) and rs2291596 (63.6%) genotypes indicated high frequencies and were associated with a risk of developing ALL, while the remaining 16 novel mutations indicated in low frequency (9.1%) except for the 97270G>GT genotype (18.2%). High expression levels were noted for different clusters of differentiation (CD) biomarkers between both subtypes of ALL, including, CD10, CD19, CD22, CD79a, CD99, terminal deoxynucleotidyl transferase (TdT), and human leukocyte antigen DR (HLA-DR) isotype in B-cells lineages, while, CD2, CD3, CD5, CD7, CD13, CD117 and TdT are more specific to T-cells lineages. On the other hand, significant changes were noted in certain hematological parameters including red blood cells (RBCs), haemoglobin (g/dl), haematocrite (HCt %), red blood cell distribution width (RDW %), and platelet counts (PLT- 109/L) compared with those of healthy subjects. Finally, it was concluded that various novel mutations were recorded with different subtypes of ALL diseases, and mild anemia was observed among patients. Future studies will be towered to associate these mutations with prognosis and therapeutic response of diseases.

Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling.

Naturally occurring gain-of-function (GOF) mutants have been identified in patients for a variety of cytokine receptors. Although this constitutive activation ofcytokine receptors is strongly associated with malignant disorders, ligand-independent receptor activation is also a useful tool in synthetic biology e.g. to improve adoptive cellular therapies with genetically modified T-cells. Balanced Interleukin (IL-)7 signaling via a heterodimer of IL-7 receptor (IL-7Rα) and the common γ-chain (γc) controls T- and B-cell development and expansion, whereas uncontrolled IL-7 signaling can drive acute lymphoid leukemia (ALL) development. The ALL-driver mutation PPCL in the transmembrane domain of IL-7Rα is a mutational insertion of the four amino acids proline-proline-cysteine-leucine and leads to ligand-independent receptor dimerization and constitutive activation. We showed here in the cytokine-dependent pre-B-cell line Ba/F3 that the PPCL-insertion in a synthetic version of the IL-7Rα induced γc-independent STAT5 and ERKphosphorylation and also proliferation of the cells and that booster-stimulation by arteficial ligands additionally generated non-canonical STAT3 phosphorylation via the synthetic IL-7Rα-PPCL-receptors. Transfer of theIL-7Rα transmembrane domain with the PPCL insertion intonatural and synthetic cytokine receptor chains of the IL-6, IL-12 and Interferon families also resulted in constitutive receptor signaling. In conclusion, our data suggested that the insertion of the mutated PPCL IL-7Rα transmembrane domain is an universal approach to generate ligand-independent, constitutively active cytokine receptors.

Association between direct acting agents used for chronic hepatitis C virus infection and the occurrence of acute leukaemia – A disproportionality analysis

BACKGROUND AND AIMSA recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODSWe conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTSWe identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSIONThis study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.

A Structural In Silico Analysis of the Immunogenicity of L-Asparaginase from Penicillium cerradense.

L-asparaginase is an essential drug used to treat acute lymphoid leukemia (ALL), a cancer of high prevalence in children. Several adverse reactions associated with L-asparaginase have been observed, mainly caused by immunogenicity and allergenicity. Some strategies have been adopted, such as searching for new microorganisms that produce the enzyme and applying protein engineering. Therefore, this work aimed to elucidate the molecular structure and predict the immunogenic profile of L-asparaginase from Penicillium cerradense, recently revealed as a new fungus of the genus Penicillium and producer of the enzyme, as a motivation to search for alternatives to bacterial L-asparaginase. In the evolutionary relationship, L-asparaginase from P. cerradense closely matches Aspergillus species. Using in silico tools, we characterized the enzyme as a protein fragment of 378 amino acids (39 kDa), including a signal peptide containing 17 amino acids, and the isoelectric point at 5.13. The oligomeric state was predicted to be a homotetramer. Also, this L-asparaginase presented a similar immunogenicity response (T- and B-cell epitopes) compared to Escherichia coli and Dickeya chrysanthemi enzymes. These results suggest a potentially useful L-asparaginase, with insights that can drive strategies to improve enzyme production.

First-Line Respiratory Support for Children With Hematologic Malignancy and Acute Respiratory Failure.

To characterize trends in noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) use over time in children with hematologic malignancy admitted to the PICU with acute respiratory failure (ARF), and to identify risk factors associated with NIV failure requiring transition to IMV. Retrospective cohort analysis using the Virtual Pediatric Systems (VPS, LLC) between January 1, 2010 and December 31, 2019. One hundred thirteen North American PICUs participating in VPS. Two thousand four hundred eighty children 0-21 years old with hematologic malignancy admitted to participating PICUs for ARF requiring respiratory support. None. There were 3013 total encounters, of which 868 (28.8%) received first-line NIV alone (NIV only), 1544 (51.2%) received first-line IMV (IMV only), and 601 (19.9%) required IMV after a failed NIV trial (NIV failure). From 2010 to 2019, the NIV only group increased from 9.6% to 43.1% and the IMV only group decreased from 80.1% to 34.2% (p < 0.001). The NIV failure group had the highest mortality compared with NIV only and IMV only (36.6% vs. 8.1%, vs. 30.5%, p < 0.001). However, risk-of-mortality (ROM) was highest in the IMV only group compared with NIV only and NIV failure (median Pediatric Risk of Mortality III ROM 8.1% vs. 2.8% vs. 5.5%, p < 0.001). NIV failure patients also had the longest median PICU length of stay compared with the other two study groups (15.2 d vs. 6.1 and 9.0 d, p < 0.001). Higher age was associated with significantly decreased odds of NIV failure, and diagnosis of non-Hodgkin lymphoma was associated with significantly increased odds of NIV failure compared with acute lymphoid leukemia. For children with hematologic malignancy admitted to the PICU with ARF, NIV has replaced IMV as the most common initial therapy. NIV failure rate remains high with high-observed mortality despite lower PICU admission ROM.

Complications of total-body irradiation in allogeneic bone marrow transplantation: A review article

Hematopoietic stem cell transplantation commonly known as bone marrow transplantation (BMT) or allogeneic BMT (using healthy blood stem cells from a donor) is the preferred therapeutic option for numerous blood-related conditions, both malignant and non-malignant. It is often the sole therapy strategy and essential for relapsed and refractory hematologic malignancies. There have studies regarding BMT on regimen containing total body irradiation (TBI) and a regimen without TBI. It is expected that TBI-based conditioning regimens provide better antitumor effects than chemotherapy regimens. The primary objective of TBI is to eradicate the recipient's bone marrow, facilitating the successful engraftment of donor bone marrow. Acute lymphoid leukemia (ALL) is the principal indication for TBI in bone marrow transplantation. Other diseases including Hodgkin’s lymphoma, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), multiple myeloma (MM), etc., may benefit from TBI-based regimens; however, TBI use is associated with many side effects.The main complications of patients who underwent TBI-containing conditioning regimens in bone marrow transplantation are vomiting and nausea, with frequencies of approximately 66% and 35%, respectively. However, these events are easily managed. Acute complications include stomatitis, diarrhea, loss of appetite, temporary loss of taste, rash and asthenia. Moreover, veno-occlusive disease, interstitial pneumonitis, lung side effects, growth hormone deficiency, neurological side effects, cataracts, renal toxicity, endocrine impairments, and infertility are other complications in patients who underwent TBI-containing conditioning regimens in bone marrow transplantation. In review article, a complication of total-body irradiation in allogeneic bone marrow transplantation was assessed.