Subtype Of Leukemia Research Articles

Artificial intelligence for the detection of acute myeloid leukemia from microscopic blood images; a systematic review and meta-analysis

BackgroundLeukemia is the 11th most prevalent type of cancer worldwide, with acute myeloid leukemia (AML) being the most frequent malignant blood malignancy in adults. Microscopic blood tests are the most common methods for identifying leukemia subtypes. An automated optical image-processing system using artificial intelligence (AI) has recently been applied to facilitate clinical decision-making.AimTo evaluate the performance of all AI-based approaches for the detection and diagnosis of acute myeloid leukemia (AML).MethodsMedical databases including PubMed, Web of Science, and Scopus were searched until December 2023. We used the “metafor” and “metagen” libraries in R to analyze the different models used in the studies. Accuracy and sensitivity were the primary outcome measures.ResultsTen studies were included in our review and meta-analysis, conducted between 2016 and 2023. Most deep-learning models have been utilized, including convolutional neural networks (CNNs). The common- and random-effects models had accuracies of 1.0000 [0.9999; 1.0001] and 0.9557 [0.9312, and 0.9802], respectively. The common and random effects models had high sensitivity values of 1.0000 and 0.8581, respectively, indicating that the machine learning models in this study can accurately detect true-positive leukemia cases. Studies have shown substantial variations in accuracy and sensitivity, as shown by the Q values and I2 statistics.ConclusionOur systematic review and meta-analysis found an overall high accuracy and sensitivity of AI models in correctly identifying true-positive AML cases. Future research should focus on unifying reporting methods and performance assessment metrics of AI-based diagnostics.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#recordDetails, CRD42024501980.

Temporary Molecular Relapse of Myeloid Leukemias in the Setting of COVID-19 and Viral-Induced Immunosuppression

Acute promyelocytic leukemia (APML) is one of the most curable leukemia subtypes, where the majority of patients achieve complete remission and also deep molecular remission after therapy, characterized by a PCR-undetectable state. Similarly, chronic myelogenous leukemia (CML) is a leukemia where, thanks to effective targeted treatment with tyrosine kinase inhibitors (TKIs), deep remission detectable only by PCR has become part of the routine management of these patients. Here, we describe a patient who was PCR-negative after induction and consolidation with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) and stayed PCR-undetectable for 13 months post-consolidation, later experiencing molecular relapse following mild SARS-CoV-2 infection. The patient was able to reestablish molecular remission again without anti-leukemic therapy several weeks later. She remained PCR-negative for the next 42 months. Viral infection-triggered immunosuppression, as in our case, offers a possible explanation for the temporary loss of molecular remission seen in leukemia patients monitored by PCR. Our first case illustrates this period of convalescence from viral infection, which was maybe accompanied by loss of molecular response. Viral infections and temporary immunosuppression may be a culprit in cases where molecular responses are lost temporarily. This loss of the PCR-undetectable state may have implications for other cancer patients where PCR monitoring is used. Thus, our observation may have broader implications for other patients, especially those with CML. We further enforce these findings by describing a second patient with CML who experienced temporary molecular relapse in the setting of post-viral syndrome.

The efficacy and safety of nelarabine in relapsed or refractory T-cell acute lymphoblastic leukemia: a systematic review and meta-analysis.

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a subtype of acute lymphoblastic leukemia characterized by the proliferation of abnormal T-cell precursors. Nelarabine, a purine analog, has been approved as a targeted therapy for patients with refractory or relapsed T-ALL. This study aims to evaluate the efficacy and safety of Nelarabine, either as monotherapy or in combination with other therapies, in treating T-ALL. A systematic review and meta-analysis were conducted following PRISMA guidelines. We searched Cochrane CENTRAL, PubMed, and Google Scholar up to August 2024 for studies evaluating Nelarabine's efficacy and safety in T-ALL patients. The primary outcome was complete response (CR), with secondary outcomes focusing on adverse events (AEs). Data were analyzed using a random effects model, with statistical significance set at p ≤ 0.05. Sixteen studies involving 1,865 patients were included, with 1,345 receiving Nelarabine. The pooled analysis revealed a CR rate of 37.9% (95% CI: 20.5-55.4%, p < 0.001) for Nelarabine monotherapy. Significant adverse events included neutropenia at 29.1% (95% CI: 9.1-49.1%, p < 0.001), thrombocytopenia at 32.4% (95% CI: 14.8-50.0%, p < 0.001), peripheral motor neuropathy at 17.1% (95% CI: 4.2-30.1%, p = 0.001), and peripheral sensory neuropathy at 15.3% (95% CI: 5.8-24.9%, p = 0.003). For combination therapy, infections occurred in 65.0% (95% CI: 27.1-103.0%, p < 0.001) of patients, febrile neutropenia in 48.7% (95% CI: -8.8-106.3%, p < 0.001), peripheral motor neuropathy in 10.5% (95% CI: 7.9-13.0%, p < 0.001), and peripheral sensory neuropathy in 23.1% (95% CI: 10.6-35.7%, p < 0.001). Nelarabine shows significant efficacy in treating refractory or relapsed T-ALL, with notable CR rates. However, its use, both as monotherapy and in combination therapy, is associated with considerable adverse events, particularly neurotoxicity and hematologic toxicities, necessitating careful monitoring. Further research is needed to optimize its application across diverse patient populations and to better manage its associated toxicities.

Disseminated Intravascular Coagulation in Pediatric Acute Leukemia: Prevalence, Laboratory Features, and Prognostic Significance of ISTH Score.

Disseminated intravascular coagulation (DIC) is associated with acute leukemia. DIC prevalence and clinical consequences are complex and varies across acute leukemia subtypes. The International Society of Thrombosis and Hemostasis (ISTH) scoring system is used for the detection of overt DIC. Children of both sexes (1 day-18 years) with acute leukemia, suspected to have DIC and referred to hematology laboratory were included in the study. DIC score was calculated according to ISTH guidelines from laboratory values obtained within 24 h of admission and repeated after 2 weeks. The DIC cases were classified into overt DIC if ISTH score ≤ 5 and non-overt if ISTH score > 5. Sixty-two children diagnosed with acute leukemia and having the clinical and laboratory diagnostic features of DIC along with 48 age-matched healthy controls participated in the study. DIC was more frequently diagnosed in cases of AML (66.13%) compared to ALL (33.87%). Cases with T-ALL had DIC (19.4%) more frequently than B-ALL type (14.5%). Similarly, children with M5, M2, and M3 had DIC more frequently (16.1%, 15.58% and 14.28%, respectively) compared to other AML types. Overt DIC was observed in 71% of DIC cases with acute leukemia while non-overt DIC was diagnosed in 29% of them. Follow-up for 14 days of non-overt cases showed that 12 out of 18 patients progressed from non-overt to overt DIC with a significant increase in D-dimer and a decline in platelets count. The incidence of bleeding (35.4%) was higher than thrombosis (19.4%) among acute leukemia patients with DIC. An ISTH score ≤ 5 predicted increased intensive care unit (ICU) admission, death and end organ dysfunction with odds ratio of 4.28, 6.77, and 6.67, respectively. Based on receiver-operator analysis of DIC cases classified as overt and non-overt DIC based on ISTH score, D-Dimer was excellent predictor of overt DIC with the high sensitivity and specificity. ISTH score predicts death, ICU admission and organ dysfunction in children with acute leukemia. D-Dimer is an excellent predictor of overt DIC in acute leukemia.

RanBALL: An Ensemble Random Projection Model for Identifying Subtypes of B-Cell Acute Lymphoblastic Leukemia.

As the most common pediatric malignancy, B-cell acute lymphoblastic leukemia (B-ALL) has multiple distinct subtypes characterized by recurrent and sporadic somatic and germline genetic alterations. Identifying B-ALL subtypes can facilitate risk stratification and enable tailored therapeutic design. Existing methods for B-ALL subtyping primarily depend on immunophenotyping, cytogenetic tests and genomic profiling, which would be costly, complicated, and laborious. To overcome these challenges, we present RanBALL (an ensemble Ran dom projection-based model for identifying B - ALL subtypes), an accurate and cost-effective model for B-ALL subtype identification. By leveraging random projection (RP) and ensemble learning, RanBALL can preserve patient-to-patient distances after dimension reduction and yield robustly accurate classification performance for B-ALL subtyping. Benchmarking results based on >1700 B-ALL patients demonstrated that RanBALL achieved remarkable performance (accuracy: 0.93, F1-score: 0.93, and Matthews correlation coefficient: 0.93), significantly outperforming state-of-the-art methods like ALLSorts in terms of all performance metrics. In addition, RanBALL performs better than tSNE in terms of visualizing B-ALL subtype information. We believe RanBALL will facilitate the discovery of B-ALL subtype-specific marker genes and therapeutic targets to have consequential positive impacts on downstream risk stratification and tailored treatment design. To extend its applicability and impacts, a Python-based RanBALL package is available at https://github.com/wan-mlab/RanBALL .

Global assessment of leukemia care quality: insights from the quality of care index (QCI) from 1990 to 2021

While advancements in leukemia care have been made, the global quality of care remains a concern. This study utilizes a modified quality of care index (QCI) to assess the global status of leukemia care. We analyzed data from the global burden of disease (GBD) study spanning 1990-2021. The QCI was constructed using principal component analysis, based on the weighted variances of key indicators. We compared the original QCI with our modified version, analyzed QCI trends across different age groups and leukemia subtypes, identified key influencing factors using linear mixed models (LMM), and used spatial autocorrelation analysis to verify the autocorrelation of the socio-demographic index (SDI) region. Then we employed the bayesian age-period-cohort (BAPC) model to predict future QCI trends. Between 1990 and 2021, both the age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR) for leukemia exhibited a consistent decline. Our modified QCI method outperformed the original approach, particularly when the variance explained by the first principal component was below 80%, demonstrating higher correlation with the healthcare access and quality index (HAQI) (Pearson r=0.91 vs. 0.89) and improved explanatory power (R2=0.82 vs. 0.79). Over past three decades, QCI was highest in San Marino (97.72%) and lowest in Fiji (3.51%), with significant regional variations across SDI levels (F=133.40, p<2e-16). High-SDI regions had the highest QCI (78.50%; 95% confidence interval: 77.20%, 79.70%). QCI trends varied by age, peaking at 94.49% in the 15-19 age group in 2021 and declining to 0.44% in the 75-79 age group. LMM analysis identified sex, age, year, SDI region, and leukemia subtype as significant QCI determinants. Spatial autocorrelation analysis confirmed positive autocorrelation within SDI regions (Global Moran's I=0.87, p<2e-16). Projections suggest a generally fluctuating upward trend in QCI for leukemia, reaching 79.58% by2046. The QCI serves as an effective metric for evaluating the quality of leukemia care. Our findings reveal a strong association between leukemia QCI and regional economic and educational development. Age is a critical factor, with an aging population contributing to a potential decline in QCI. These results underscore the urgent need for targeted interventions to enhance health services for older adults and to improve care quality in economically disadvantaged regions. This study was supported by the National Natural Science Foundation of China (General Program) (No.82370176) and the Key Research and Development Program of Hubei Province (No. CZKYXM2023036JZ).

Unveiling the link between NADPH oxidase 2 activation and mitochondrial superoxide formation in leukemic cell killing induced by arsenic trioxide.

This study focused on the interplay between NADPH oxidase 2 (NOX 2) activation and mitochondrial superoxide (mitoO2.-) formation induced by clinically relevant concentrations of arsenic trioxide (ATO; As2O3) in acute promyelocytic leukemia (APL) cells. Carefully controlled inhibitor studies and small interfering RNA mediated downregulation of p47phox (a component of the NOX 2 complex) expression demonstrated that, in an APL cell line, ATO promotes upstream NOX 2 activation critically connected with the formation of mitoO2.- and with the ensuing mitochondrial permeability transition (MPT)-dependent apoptosis. Instead, acute myeloid leukemia (AML) cell lines respond to ATO with low NOX 2 activation, resulting in a state that is non-permissive for mitoO2.- formation. Consistently, through rescue experiments, we demonstrate that pharmacological stimulation of NOX 2 overcomes resistance in these cells, thereby initiating the same cascade of downstream events observed in APL cells. As a final note, several lines of evidence, including measurement of glutathione, catalase and glutathione peroxidase levels, indicated that the antioxidant machinery was similar in APL and AML cells. The results regarding nuclear factor erythroid 2 p45-related factor 2-dependent antioxidant responses were instead of more complex interpretation as NB4 cells appeared particularly responsive to ATO. Our findings allow a novel interpretation of the interplay between NOX 2 activation and mitoO2.- formation induced by ATO, ultimately steering leukemic cells towards MPT-dependent apoptosis. These mechanistic insights provide a rationale for the disparate responses of APL and AML cells to ATO, offering potential avenues for the development of therapeutic intervention tailored to specific leukemia subtypes.

Causal relationship between branched-chain amino acids and leukemia risk: insights from a two-sample Mendelian randomization study

ABSTRACT Background Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids involved in protein synthesis, energy metabolism, and immune regulation. While BCAAs are known to influence cancer biology, their role in leukemia remains unclear. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between BCAA levels and four leukemia subtypes: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). Methods Data from genome-wide association studies (GWAS) were used to select single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for BCAA levels. The inverse-variance weighted (IVW) method served as the primary analytical approach, with heterogeneity assessed via Cochran’s Q test and pleiotropy through MR-Egger intercept. Sensitivity analysis was performed using leave-one-out analysis. Results A significant inverse association was observed between total BCAA levels, leucine, valine, and ALL risk. Total BCAA levels showed an odds ratio (OR) of 0.16 (95% CI: 0.05–0.54, p=0.003), leucine 0.17 (95% CI: 0.04–0.61, p=0.007), and valine 0.21 (95% CI: 0.07–0.61, p=0.004). No significant associations were found for AML, CLL, or CML. Conclusion This study suggests that BCAAs, particularly leucine and valine, may protect against ALL, offering insights into leukemia metabolic regulation and potential targets for prevention and therapy.

Genetic subtypes of B-cell acute lymphoblastic leukemia in adults.

B-cell acute lymphoblastic leukemia (B-ALL) is a rare malignancy in adults with outcomes remaining poor, especially compared to children. Over the past two decades, extensive whole-genome studies have identified numerous genetic alterations driving leukemia, leading to the recognition of more than 20 distinct subtypes which are closely associated with treatment response and prognosis. In pediatric B-ALL, large correlation studies have made genetic classification a central component of risk-adapted treatment strategies. Notably, genetic subtypes are unevenly distributed according to age, and the spectrum of genetic alterations and their prognostic relevance in adult B-ALL have been less extensively studied, with treatment primarily based on the presence or absence of BCR::ABL1 fusion. This review provides an overview of genetic subtypes in adult B-ALL, including recent biological and clinical insights in well-established subtypes as well as data on newly recognized subtypes. Their relevance for risk classification, disease monitoring and therapeutic management, including in the context of B-cell-directed therapies, is discussed. This review advocates for continuing efforts to further improve our understanding of the biology of adult B-ALL to establish the foundation of future precision medicine in B-ALL.

Why implementing machine learning algorithms in the clinic is not a plug-and-play solution: a simulation study of a machine learning algorithm for acute leukaemia subtype diagnosis.

Artificial intelligence (AI) and machine learning (ML) algorithms have shown great promise in clinical medicine. Despite the increasing number of published algorithms, most remain unvalidated in real-world clinical settings. This study aims to simulate the practical implementation challenges of a recently developed ML algorithm, AI-PAL, designed for the diagnosis of acute leukaemia and report on its performance. We conducted a detailed simulation of the AI-PAL algorithm's implementation at the University Hospital Essen. Cohort building was performed using our Fast Healthcare Interoperability Resources (FHIR) database, identifying all initially diagnosed patients with acute leukaemia and selected differential diagnoses. The algorithm's performance was assessed by reproducing the original study's results. The AI-PAL algorithm demonstrated significantly lower performance in our simulated clinical implementation compared to prior published results. The area under the receiver operating characteristic curve for acute lymphoblastic leukaemia dropped to 0.67 (95% CI: 0.61-0.73) and for acute myeloid leukaemia to 0.71 (95% CI: 0.65-0.76). The recalibration of probability cutoffs determining confident diagnoses increased the number of confident positive diagnosis for acute leukaemia from 98 to 160, highlighting the necessity of local validation and adjustments. The findings underscore the challenges of implementing ML algorithms in clinical practice. Despite robust development and validation in research settings, ML models like AI-PAL may require significant adjustments and recalibration to maintain performance in different clinical settings. Our results suggest that clinical decision support algorithms should undergo local performance validation before integration into routine care to ensure reliability and safety. This study was supported by the DFG-cofounded UMEA Clinician Scientist Program and the Ministry of Culture and Science of the State of North Rhine-Westphalia.

The expressions of myeloid differentiation and non-lineage specific differentiation antigens among FAB subtypes of acute myeloid leukemia in Iraqi patients

Background. Acute myeloid leukemia (AML) is a complex malignant disorder showing various subtypes with myeloid differentiation and non-lineage specific differentiation antigens (CD markers) expressions. Aim. The aim of this study is to evaluate the expression of myeloid and lymphoid antigens in relation to different French‑American‑British classification (FAB subtypes). Method. Three hundred and forty-four acute myeloid leukemia patients diagnosed based on blast percentage underwent bone marrow aspirate or whole blood collection, and flow cytometry was used to identify blast cells. Results. The expressions of myeloid differentiation antigens in AML patients were commonly observed; CD33 (73.3%), CD13 (68.3%), CD117 (67.4%), CD64 (54.6%), and cMPO (52.9%) in AML cases, with a significant difference in positivity (p-value &lt; 0.05) among FAB classes (M0, M1, M2, M3, M4, M5, and M7). The expression of non-myeloid-associated antigen HLA-DR (34.01%) and CD34 (42.15%) showed high prevalence among FAB subtypes of AML. Regarding CD36 (13.3%), CD35 (13.08%), IREM2 (9.9%), and CD123 (9.01%), the expression was lower than HLA-DR and CD34, with no expression of CD38 in AML patients. A significant difference in expression and distribution of CD markers among AML subclasses was found (p&lt;0.05). Conclusion. A large number of AML cases showed CD33 (73.3%), CD13 (68.3%), and CD117 (67.4%) expressions; these markers give two scores in diagnosis and highly distribution in AML subtype. Although no other leukemia subtypes were found to be linked to AML instances, AML blasts exhibited abnormal lymphoid characteristics, whereby the most prevailing lymphoid marker that was aberrantly expressed in AML was CD7. T-cell markers were more prevalent than B-cell markers.

Long-read epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.

Acute Myeloid Leukemia (AML) is an aggressive cancer with dismal outcomes, vast subtype heterogeneity, and suboptimal risk stratification. In this study, we harmonized DNA methylation data from 3,314 patients across 11 cohorts to develop the Acute Leukemia Methylome Atlas (ALMA) of diagnostic relevance that predicted 27 WHO 2022 acute leukemia subtypes with an overall accuracy of 96.3% in discovery and 90.1% in validation cohorts. Specifically, for AML, we also developed AML Epigenomic Risk , a prognostic classifier of overall survival (OS) (HR=4.40; 95% CI=3.45-5.61; P<0.0001), and a targeted 38CpG AML signature using a stepwise EWAS-CoxPH-LASSO model predictive of OS (HR=3.84; 95% CI=3.01-4.91; P<0.0001). Finally, we developed a specimen-to-result protocol for simultaneous whole-genome and epigenome sequencing that accurately predicted diagnoses and prognoses from twelve prospectively collected patient samples using long-read sequencing. Our study unveils a new paradigm in acute leukemia management by leveraging DNA methylation for diagnostic and prognostic applications.

Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022.

In 2022, leukemia ranked as the second most common hematological malignancy after non-Hodgkin lymphoma worldwide. However, updated global estimates of leukemia incidence by subtype are unavailable. We estimated leukemia incidences for different leukemia subtypes by country, world region, and human developmental index using data from the Cancer Incidence in Five Continents databases combined with the GLOBOCAN 2022 estimates of leukemia in 185 countries. We estimated sex-specific age-standardized rates (ASRs) per 100 000 for children (0-19 years) and adults (20+ years). In adults, the most common leukemia worldwide was AML (males:38%, ASR = 3·1; females:43%, ASR = 2·4), followed by CLL (males:28%, ASR = 2·2; females:24%, ASR = 1·3). In very high HDI countries, the ASR of CLL was higher than the ASR of AML among males (5·2 versus 4·3, respectively) and similar among females (2·9 and 3·0, respectively). In children, the most common leukemia was ALL (boys:70%, ASR = 2·4; girls:68%, ASR = 1·8) followed by AML (boys:22%, ASR = 0·76; girls:25%, ASR = 0·65). ALL proportions varied across world sub-regions from 57to78% among boys, and from 49 to 80% among girls. Our findings suggest clear geographical patterns of leukemia subtypes in adults and children. Further research into underlying causes that explain these variations is needed to support cancer control strategies for prevention and plan national healthcare needs.

Abstract A017: IGF2BP1 is essential for ETO2/GLIS2 leukemogenesis via stabilization of primitive myeloid transcriptional programs

Abstract Certain subtypes of pediatric leukemia continue to have dismal cure rates despite advances in targeted therapy. One such disease is acute megakaryoblastic leukemia (AMKL) with a rearrangement of ETO2/GLIS2 (also known as CBFA2T3/GLIS2.) Based on our preliminary data utilizing CRISPR/Cas9 screens in vivo in patient-derived xenografts, we have nominated IGF2BP1 as a potential vulnerability in ETO2/GLIS2-rearranged AMKL. For our discovery phase, we utilized a patient-derived E2G2r AMKL which successfully engrafts in NSGS mice. We created a stable Cas9-expressing subclone using lentiviral transduction followed by FACS enrichment and limiting dilution transplants. We then generated a custom library targeting the top 100 overexpressed genes between E2G2r leukemias versus other leukemia PDXs which we previously characterized, including eight transcription factors with motifs enriched in differentially expressed genes, as well as eight pan-essential positive controls. Mice were sacrificed at humane endpoints, and spleens and bone marrow underwent PCR amplification for gRNA sequences followed by sequencing and analysis with MAGeCK-VISPR (Wei L, et al. Genome Biol 2015). We observed the dropout of 38 genes with a false discovery rate &amp;lt; 0.25, including all positive control gRNAs. Among the most significantly depleted genes was the RNA binding protein IGF2BP1. We subsequently characterized phenotypic changes using shRNAs in the E2G2r cell line M07e and ETO2/GLIS2-transformed CD34+ umbilical cord blood cells. Notably, we observed impaired cell growth with IGF2BP1 knockdown in both cell lines as well as the parent xenograft. We also generated M07e lines expressing a degron (FKBPF36V, aka “dTAG”, Nabet et al. Nat Chem Biol 2018) knocked in at the endogenous IGF2BP1 locus and observed similar phenomena. Through flow cytometry of M07e following IGF2BP1 depletion, we observed changes in the leukemic immunophenotype as well, suggesting perturbation of megakaryocyte differentiation potential. To determine the mechanism underlying our observations, we performed enhanced UV crosslinking with IP and sequencing (Blue SM et al. Nat Protoc 2022) against both IGF2BP1 and m6A residues based on the putative role of IGF2BP1 as an m6A reader. We observed binding of IGF2BP1 predominantly in 3’UTRs, as well as the presence of m6A-modified bases at IGF2BP1 binding sites. Gene ontology (GO) analysis of IGF2BP1-bound transcripts demonstrated enrichment for GO terms pertaining to embryonic hematopoiesis and megakaryocyte maturation/development. We further evaluated global changes in gene expression following IGF2BP1 loss, and performed RNAseq 72 hours following shRNA-mediated knockdown. GO analysis showed that downregulated genes were highly enriched for E2F-mediated transcriptional programs. We hypothesize that IGF2BP1 regulates myeloid developmental transcripts essential for E2G2r leukemogenesis, likely via stabilization in an m6A-dependent fashion, and thus may represent a selective therapeutic target. Work is ongoing to further elucidate this proposed mechanism. Citation Format: Jason Clark, Mark Wunderlich, Jing Chen, Daniel Starczynowski, Lynn Lee. IGF2BP1 is essential for ETO2/GLIS2 leukemogenesis via stabilization of primitive myeloid transcriptional programs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A017.

Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.

Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.

Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia.

Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-ALL. The relationship between the type of IKZF1 alteration, disease subtype and outcome are incompletely understood. Leukemia subtype and genomic alterations were determined using transcriptome and genomic sequencing and SNP microarray in 688 pediatric patients with B-ALL in St. Jude Total Therapy 15 and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2- rearranged, BCR::ABL1- like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration ( P < 0.0001) . IKZF1 deletions of exon 4-7 ( P = 0.0002), genomic IKZF1 plus with any IKZF1 deletion ( P = 0.006) or with focal IKZF1 deletion ( P = 0.0007), and unfavorable genomic subtypes ( P < 0.005) were independently adversely prognostic factors. Associations of genomic IKZF1 plus and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. Genomic IKZF1 plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and predict response in patients with B-ALL.

Revumenib for patients with acute leukemia: a new tool for differentiation therapy.

Treatment of acute leukemia is gradually moving away from a "one-size-fits-all" approach, as scientific and clinical advances expand the arsenal of available targeted therapies. One of the recent additions is the group of menin inhibitors; oral, selective, small molecules that disrupt the interaction between the chromatin adapter menin, and an epigenetic regulator, the lysine methyltransferase 2A (KMT2A) complex. Two susceptible leukemia subtypes have been identified: (i) acute myeloid leukemia with a mutation in nucleophosmin 1 (NPM1), and (ii) any acute leukemia, myeloid or lymphoid, with a translocation resulting in the rearrangement of KMT2A. These leukemias share a distinct genetic expression, maintained by the KMT2A-menin interaction. Together they account for approximately 40% of patients with acute myeloid leukemia and 10% of patients with acute lymphoblastic leukemia. This spotlight review follows the journey of revumenib, as a representative of menin inhibitors, from bench to bedside. It focuses on the pathophysiology of leukemias sensitive to menin inhibition, delineation of how this understanding led to targeted drug development, and data from clinical trials. The important discovery of resistance mechanisms is also explored, as well as future directions in the use of menin inhibitors for treating leukemia.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Precision Medicine for Acute Lymphoblastic Leukemia in Children: A Review.

The clinical outcome for children diagnosed with acute lymphoblastic leukemia is a testimony to the success of modern medicine. Over the past few decades, survival has climbed from ∼10% to >90% for certain subgroups. Yet, the outcome for those with relapsed disease is often poor, and survivors struggle with a multitude of healthcare issues, some of which are lifelong. In recent years, the advent of the widespread sequencing of tumors has made available patients with previously unrecognized subtypes of leukemia, who have the potential to benefit from the addition of targeted therapies. Indeed, the promise of precision medicine, encompassing a person's environment, genetics and lifestyle, is likely to have profound impact on further tailoring therapies that are likely to improve outcomes, diminish toxicity and ultimately pave the pathway for a healthier population.

Breast relapse of myeloid sarcoma and SARS-CoV-2 infection following hematopoietic stem cell transplantation in mixed-phenotype acute leukemia: a case report

Abstract Background Mixed-phenotype acute leukemia is a rare, high-risk subtype of acute leukemia. Myeloid sarcoma is a localized tumor formed by the proliferation and infiltration of primitive or immature myeloid cells outside the bone marrow. It is often an extramedullary manifestation of acute myeloid leukemia, and imaging lacks specificity, leading to potential misdiagnosis. Case Presentation A female patient diagnosed with mixed-phenotype acute leukemia achieved complete remission after chemotherapy and allogeneic hematopoietic stem cell transplantation. However, a relapse occurred in the breast after transplantation. The patient achieved local control through mastectomy and removal of the axillary lymph nodes on the affected side. Unfortunately, during the subsequent course of chemotherapy, the patient died of a severe pulmonary infection caused by coronavirus disease 2019. Conclusion Continuous treatment and monitoring of mixed-phenotype acute leukemia patients are essential, especially for those with extramedullary manifestations (such as breast involvement).