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High hyperdiploid karyotype with ≥ 49 chromosomes (which will be referred to as HHK) is rare in acute myeloid leukemia (AML). The European leukemia network (ELN) excluded those harboring only numerical changes (with ≥ 3 chromosome gains) from CK and listed them in the intermediate risk group, while the UK National Cancer Research Institute Adult Leukaemia Working Group classification defined ≥ 4 unrelated chromosome abnormalities as the cutoff for a poorer prognosis. Controversies occurred among studies on the clinical outcome of HHK AML, and their molecular characteristics remained unstudied. We identified 1.31% (133/10,131) HHK cases within our center, among which 48 cases only had numerical changes (NUM), 42 had ELN defined adverse abnormalities (ADV) and 43 had other structural abnormalities (STR). Our study demonstrated that: (1) No statistical significance for overall survival (OS) was observed among three cytogenetic subgroups (NUM, STR and ADV) and HHK AML should be assigned to the adverse cytogenetic risk group. (2) The OS was significantly worse in HHK AML with ≥ 51 chromosomes compared with those with 49–50 chromosomes. (3) The clinical characteristics were similar between NUM and STR group compared to ADV group. The former two groups had higher white blood cell counts and blasts, lower platelet counts, and mutations associated with signaling, while the ADV group exhibited older age, higher chromosome counts, higher percentage of myelodysplastic syndrome (MDS) history, and a dominant TP53 mutation. [ABSTRACT FROM AUTHOR]

• A rare NUP98::PRRX1 fusion gene in therapy-related acute myeloid leukemia. • NUP98::PRRX1 fusion gene may be caused by topoisomerase-Ⅱ inhibitors. • BCL2 inhibitors may have selective efficacy in patients with NUP98::PRRX1 fusion gene. Therapy-related acute myeloid leukemia (t-AML) is increasingly recognized as a treatment complication in patients receiving chemotherapy, radiotherapy, or immunosuppressive agents for primary neoplasms. NUP98::PRRX1 fusion gene, caused by t(1;11)(q23;p15), is a rare recurrent cytogenetic alteration in leukemia, and only seven cases with NUP98::PRRX1 were reported so far. A 53-year-old female patient was diagnosed with t-AML after 20 months of complete remission (CR) from diffuse large B-cell lymphoma (DLBCL). Conventional karyotype, fluorescence in situ hybridization (FISH), and DNA/RNA next-generation sequence (NGS) were used to detect genetic abnormalities. Abnormal karyotype of 46, XX, t(1;11)(q25;p15), del(7)(q22) was revealed. NUP98 gene rearrangement and del(7)(q22) were verified by FISH. Further, RNA NGS detected NUP98::PRRX1 fusion transcript, and DNA NGS detected KRAS gene mutation. The patient achieved CR after a combined chemotherapy regimen containing BCL-2 inhibitor and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but she died of leukemia recurrence 14 months later. Novel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance. [ABSTRACT FROM AUTHOR]

Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1 , wherein the karyotype revealed t(2; 2 ;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21). [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy and allogeneic stem cell transplantation (allo-SCT). Hematological relapse in patients who have attained complete remission (CR) after chemotherapy remains a significant cause of mortality, so remission maintenance in AML is a major challenge. Maintenance with histamine dihydrochloride associated with low-dose interleukin-2 (HDC/LD-IL-2), both administered by subcutaneous injections, has been approved for patients in CR who are not candidates for upfront allo-SCT. Clinical studies showed that HDC/LD-IL-2 significantly and sustainably improved leukemia-free survival with a good safety profile, and that patients less than 60 years old in CR after one induction and/or with a normal karyotype would particularly benefit from the association. The immunomodulatory action of HDC/LD-IL-2 is mediated by the expansion of the NK cell population and a concomitant improvement in NK cell functionality. Immunotherapy with HDC/LD-IL-2 may represent an emerging treatment option for remission maintenance in AML. The treatment and management of acute myeloid leukemia (AML) has improved in recent decennia by targeted therapy for subgroups of patients, expanded indications for allogeneic stem cell transplantation (allo-SCT) and surveillance of residual or arising leukemia. However, hematological relapse among patients who have attained complete remission (CR) after the initial courses of chemotherapy remains a significant cause of morbidity and mortality. Here, we review an immunotherapeutic option using histamine dihydrochloride and low-dose interleukin-2 (HDC/LD-IL-2) for remission maintenance in AML. The treatment is approved in Europe in the post-consolidation phase to avoid relapse among patients in CR who are not candidates for upfront allo-SCT. We present aspects of the purported anti-leukemic mechanism of this regimen, including translation of preclinical results into the clinical setting, along with relapse prevention in subgroups of patients. We consider that HDC/LD-IL-2 is a conceivable option for younger adults, in particular patients with AML of normal karyotype and those with favorable responses to the initial chemotherapy. HDC/LD-IL-2 may form an emerging landscape of remission maintenance in AML. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This is a case of an elderly patient diagnosed with acute myeloid leukemia (AML). While morphological findings, including numerous long, slender, cigar‐shaped Auer rods, suggested AML with t(8;21), cytogenetic and FISH analysis revealed abnormalities in chromosome 11 and the KMT2A (MLL) gene. The patient also exhibited double minutes, typically seen in AML and linked to a complex karyotype and poor prognosis. Correlating morphological findings with molecular genetics and cytogenetics is crucial for accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

• Genetic mutation score (GMS) could be a biomarker of normal karyotype acute myeloid leukemia (AML) relapse. • GMS nomogram (GMSN) was a model that integrated GMS, measurable residual disease, and clinical factors. • GMSN exhibited superior predictive potential for relapse of normal karyotype AML. Risk stratification for normal karyotype acute myeloid leukemia (NK-AML) remains unsatisfactory, which is reflected by the high incidence of leukemia relapse. This study aimed to evaluate the role of gene mutations and clinical characterization in predicting the relapse of patients with NK-AML. A prognostic system for NK-AML was constructed. A panel of gene mutations was explored using next-generation sequencing. A nomogram algorithm was used to build a genomic mutation signature (GMS) nomogram (GMSN) model that combines GMS, measurable residual disease, and clinical factors to predict relapse in 347 patients with NK-AML from four centers. Patients in the GMS-high group had a higher 5-year incidence of relapse than those in the GMS-low group (p < 0.001). The 5-year incidence of relapse was also higher in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001). The 5-year disease-free survival and overall survival rates were lower in patients in the GMSN-high group than in those in the GMSN-intermediate and -low groups (p < 0.001) as confirmed by training and validation cohorts. This study illustrates the potential of GMSN as a predictor of NK-AML relapse. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management, and prognosis prediction is much more important than before. Disease classifications and risk group classifications, such as the WHO classification, the international consensus classification (ICC), and the European LeukemiaNet (ELN) classification, were revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different; therefore, in this review, we emphasize well-known genetic subtypes in childhood AML, including core-binding factor AML (CBF AML), KMT2Ar (KMT2A/11q23 rearrangement) AML, normal karyotype AML with somatic mutations, unbalanced cytogenetic abnormalities AML, NUP98 11p15/NUP09 rearrangement AML, and acute promyelocytic leukemia (APL). Current risk group classification, the management algorithm in childhood AML, and novel treatment modalities such as targeted therapy, immune therapy, and chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed. [ABSTRACT FROM AUTHOR]

We report a case of a 20-year-old man who presented with splenomegaly, hyperleukocytosis, anemia, and thrombocytopenia. A diagnosis of acute myeloid leukemia (AML) with LRRFIP1::FGFR1 rearrangement with complex karyotype was determined. Chromosome analysis showed a male karyotype: 46,XY,i(1)(q10),t(2;8)(q37;p11.2),der(5)t(1;5) (p22;q13)[17]46,XY [3]. Fluorescence in situ hybridization (FISH) analysis using the Cytocell FGFR1 break apart/amplification probe detected FGFR1 rearrangement with t(2:8) in 126/200 cells analyzed. Other FISH probes including 1p36/ 1q25 probes, del(5q) deletion probe, TLX3 break apart probe, and PDGFRB break apart probe were also utilized to confirm the other karyotypic abnormalities. Next-generation sequencing (NGS) SureSelectXT Custom DNA Target Somatic Detection detected RUNX1 gene mutation. NGS Archer FusionPlex (RNA) confirmed the LRRFIP1::FGFR1 rearrangement. This is the second reported case of AML with LRRFIP1::FGFR1 rearrangement and the first with a complex karyotype. [ABSTRACT FROM AUTHOR]

Objectives: In myelodysplastic syndromes (MDS), neoplastic myeloblast (CD34+CD13+CD33+ cells) numbers often increase over time, leading to secondary acute myeloid leukemia (AML). In recent studies, blasts in some MDS patients have been found to express a megakaryocyte-lineage molecule, CD41, and such patients show extremely poor prognosis. This is the first study to evaluate whether myeloblasts transition to CD41+ blasts over time and to investigate the detailed immunophenotypic features of CD41+ blasts in MDS. Methods: We performed a retrospective cohort study, in which time-dependent changes in blast immunophenotypes were analyzed using multidimensional flow cytometry (MDF) in 74 patients with MDS and AML (which progressed from MDS). Results: CD41+ blasts (at least 20% of CD34+ blasts expressing CD41) were detected in 12 patients. In five of these 12 patients, blasts were CD41+ from the first MDF analysis. In the other seven patients, myeloblasts (CD34+CD33+CD41- cells) transitioned to megakaryoblasts (CD34+CD41+ cells) over time, which was often accompanied by disease progression (including leukemic transformation). These CD41+ patients were more frequently observed among patients with monosomal and complex karyotypes. CD41+ blasts were negative for the erythroid antigen, CD235a, and positive for CD33 in all cases, but CD33 expression levels were lower in three cases when compared with CD34+CD41- blasts. Among the five CD41+ patients who underwent extensive immunophenotyping, CD41+ blasts all expressed CD61, but two cases had reduced CD42b expression, three had reduced/absent CD13 expression, and three also expressed CD7. Conclusions: Myeloblasts become megakaryoblastic over time in some MDS patients, and examining the megakaryocyte lineage (not only as a diagnostic work-up but also as follow-up) is needed to detect CD41+ MDS. The immunophenotypic features revealed in this study may have diagnostic relevance for CD41+ MDS patients. [ABSTRACT FROM AUTHOR]

Background: Cytogenetic analysis continues to have an important role in the management of acute myeloid leukemia (AML) because it is essential for prognostication. It is also necessary to diagnose specific categories of AML and to determine the most effective form of treatment. Reports from South Asia are few because the availability of cytogenetic services is relatively limited. Methods: We performed a retrospective analysis of the cytogenetic findings in adults with AML seen consecutively in a single centre in India. The results were categorised according to the 2022 World Health Organisation (WHO), International Consensus Classification (ICC) and European LeukemiaNet (ELN) classifications. Results: There were 1791 patients aged 18–85 years (median age 42, 1086 males). Normal karyotypes were seen in 646 (36%) patients. The 1145 (64%) abnormal karyotypes comprised 585 (32.7%) with recurrent genetic abnormalities (RGA), 403 (22.5%) with myelodysplasia-related cytogenetic abnormalities (MRC), and 157 (8.8%) with other abnormalities. There were 567 (31.7%) patients with solitary abnormalities and 299 (16.7%) with two abnormalities. Among the 279 (15.6%) patients with ≥ 3 abnormalities, 200 (11.2%) had complex karyotypes (CK) as per the WHO/ICC and 184 (10.3%), as per the ELN definition. There were 158 (8.8%) monosomal karyotypes (MK). Patients with normal karyotypes had a higher median age (45 years) than those with abnormal karyotypes (40 years, p < 0.001), and those with ≥ 3 abnormalities (43 years), than those with fewer abnormalities (39 years, p = 0.005). Patients with CK (WHO/ICC) and monosomal karyotypes had a median age of 48 years. Those with RGA had a lower median age (35 years, p < 0.001) than MRC (46 years) or other abnormalities (44 years). The t(15;17) was the most common abnormality (16.7%),followed by trisomy 8 (11.6%), monosomy 7/del 7q (9.3%), t(8;21) (7.2%), monosomy 5/del 5q (6.7%) and monosomy 17/del 17p (5.2%). Conclusion: Our findings confirm the lower age profile of AML in India and show similarities and differences with respect to the frequencies of individual abnormalities compared to the literature. The frequencies of the t(15;17), trisomy 8 and the high-risk abnormalities monosomy 7 and monosomy 5/del 5q were higher, and that of the inv(16), lower than in most reports. [ABSTRACT FROM AUTHOR]

Background: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. Methods: This was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. Results: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. Conclusions: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need. Entospletinib with decitabine combination therapy was well tolerated in patients with acute myeloid leukemia who had TP53 mutations with or without a complex karyotype or had a complex karyotype without TP53 mutations. Remission rates were low, and overall survival was short. [ABSTRACT FROM AUTHOR]

Summary: To evaluate the prognostic impact of complex karyotype (CK) and/or monosomal karyotype (MK) in combination with various clinical factors on allogeneic stem cell transplantation (HSCT) outcomes of patients with acute myeloid leukaemia (AML), we analysed the registry database of adult AML patients who underwent allogeneic HSCT between 2000 and 2019 in Japan. Among 16 094 patients, those with poor cytogenetic risk (N = 3345) showed poor overall survival (OS) after HSCT (25.3% at 5 years). Multivariate analyses revealed that CK and/or MK (hazard ratio [HR], 1.31 for CK without MK; 1.27 for MK without CK; and 1.73 for both), age at HSCT ≥50 years (HR, 1.58), male sex (HR, 1.40), performance status ≥2 (HR, 1.89), HCT‐CI score ≥3 (HR, 1.23), non‐remission status at HSCT (HR, 2.49), and time from diagnosis to HSCT ≥3 months (HR, 1.24) independently reduced post‐HSCT OS among patients with poor cytogenetic risk AML. A risk scoring system based on the multivariate analysis successfully stratified patients into five distinct groups for OS. This study confirms the negative effects of CK and MK on post‐HSCT outcomes, and offers a powerful risk scoring system for predicting prognoses after HSCT among AML patients with unfavourable cytogenetics. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the characteristics of CCAAT/enhancer-binding protein a (CEBPA) mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype. Materials and Methods Based on updated knowledge of CEBPA mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort. Results Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.044; hazard ratio [HR], 2.419) and a trend in inferior RFS (p=0.186; HR, 1.838). Conclusion Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA. [ABSTRACT FROM AUTHOR]

This article discusses a case of a 71-year-old man who was admitted to the hospital with symptoms of complete heart block, anemia, and neutropenia. Further tests revealed the presence of undifferentiated-looking blasts in his blood and bone marrow, indicating a potential diagnosis of acute undifferentiated leukemia (AUL). However, additional genetic and cytogenetic testing revealed abnormalities associated with acute myeloid leukemia with myelodysplasia-related changes (AML-MR). This case highlights the challenges in accurately diagnosing and classifying certain types of leukemia and emphasizes the importance of comprehensive testing for accurate diagnosis and appropriate treatment. [Extracted from the article]

Background. Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods. The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). Results. The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion. S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to improve the understanding of complex karyotype acute mixed cell leukemia containing pseudo Chediak-Higashi granules. Methods: A case of acute mixed cell leukemia resembling AML1-ETO positive acute myeloid leukemia was reported. The results of morphological, immunophenotypic, and cytogenetic tests were analyzed by reviewing relevant literature. Results: The patient was a young boy with clinical manifestations of recurrent fever. Bone marrow smear: Granulocyte system hyperplasia is obvious, visible at each stage, primitive cells account for 12%. These cells are large in volume, mostly round or class round, with abundant cell mass, stained gray blue, unbalanced development of some nuclear plasma, abnormal cytoplasmic staining, and visible "sunrise red" -like changes. Typical Auer bodies, pseudo Chadiak-Higashi granules and phagocytic erythroid substances were observed. The nuclei are irregular in shape, distorted and depressed, with fine chromatin and prominent large nucleoli. Bone marrow was extracted 3 days later, the bone marrow smear showed 65% primitive cells. The morphology of primitive cells was similar to that of 3 days ago. The results of flow cytometry showed that the primary/naive T cells in the samples possessed nuclear cells. Flow cytometry showed two groups of abnormal cells. One group accounted for 3.87% of nuclear cells and was a primitive/naive T-cell phenotype, mainly expressing: CD34+, CD7+, CD5+, CD2dim+, MPO-, CCD3 + part, CD3-, CD4-, CD8 -, CD117 -, CD13-, CD33-, HLA - DR -, CD10-, CD11b-, CD56-. The other group which accounted for 79.8% of the nuclear cells was monocyte phenotype, mainly expressing: CD34-, CD117-, CD13+ small amount, CD33+, HLA-DR-, CD11b+, CD14+, CD15+, CD36+, CD56+, CD64+, CD4+, CD85J+, CD85K + part. It matched the immunophenotype of acute mixed cell leukemia (T/MMPAL). Immunophenotypic leukemia-related fusion genes were negative, and karyotype analysis results were 45, XY, T (11; 12)(p13; Q13), -12-17, + mar [12]/90 < n > 4, idem x 2 [6]/46, XY. Combined with the above results, acute mixed cell leukemia was diagnosed. Conclusions: The flow cytometry is the gold standard in the diagnosis of acute mixed cell leukemia. The diagnosis of acute mixed cell leukemia requires the combination of clinical manifestations, cellular morphology, immunology, cytogenetics and molecular biology, and the comprehensive diagnosis efficiency is obviously better than that of morphology. [ABSTRACT FROM AUTHOR]

PURPOSE: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML). METHODS: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases. RESULTS: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P <.0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P =.0018). Frequency of NPM1 , FLT3 , KRAS , and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML (NPM1 35% v 49%; P =.0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P =.0465; GATA2 9% v 2% P =.0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P =.020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P =.006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P =.070). CONCLUSION: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations. Clinical and molecular differences in therapy-related versus de novo AML with normal karyotype. [ABSTRACT FROM AUTHOR]

Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) patients with normal karyotype (NK-AML) have significant variabilities in outcomes. The European Leukemia Net stratification system and some prognostic models have been used to evaluate risk stratification. However, these common standards still have some limitations. The biological functions and mechanisms of Small Integral Membrane Protein 3 (SMIM3) have seldomly been investigated. To this date, the prognostic value of SMIM3 in AML has not been reported. This study aimed to explore the clinical significance, biological effects and molecular mechanisms of SMIM3 in AML. Methods: RT-qPCR was applied to detect the expression level of SMIM3 in bone marrow specimens from 236 newly diagnosed adult AML patients and 23 healthy volunteers. AML cell lines, Kasumi-1 and THP-1, were used for lentiviral transfection. CCK8 and colony formation assays were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to explore relevant signaling pathways. The biological functions of SMIM3 in vivo were validated by xenograft tumor mouse model. Survival rate was evaluated by Log-Rank test and Kaplan–Meier. Cox regression model was used to analyze multivariate analysis. The correlations between SMIM3 and drug resistance were also explored. Results: Through multiple datasets and our clinical group, SMIM3 was shown to be significantly upregulated in adult AML compared to healthy subjects. SMIM3 overexpression conferred a worse prognosis and was identified as an independent prognostic factor in 95 adult NK-AML patients. Knockdown of SMIM3 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. The reduced SMIM3 expression significantly suppressed tumor growth in the xenograft mouse model. Western blot analysis showed downregulation of p-PI3K and p-AKT in SMIM3-knockdown AML cell lines. SMIM3 may also be associated with some PI3K-AKT and first-line targeted drugs. Conclusions: SMIM3 was highly expressed in adult AML, and such high-level expression of SMIM3 was associated with a poor prognosis in adult AML. Knockdown of SMIM3 inhibited the proliferation of AML through regulation of the PI3K-AKT signaling pathway. SMIM3 may serve as a potential prognostic marker and a therapeutic target for AML in the future. [ABSTRACT FROM AUTHOR]

A next-generation-sequencing (NGS) myeloid mutation panel (siParadigm Diagnostic Informatics) identified a type A I NPM1 i frameshift mutation (p.W288fs, 19.0% variant allele frequency) as well as missense mutations in I DNMT3 i A (c.2645G>A, p.R882H, VAF: 46.1%), I IDH2 i (c.419G>A, p.R140Q, VAF: 40.3%) and the I FLT3 i JMD (c.1775T>G, p.V592G, VAF: 13.0%). Keywords: acute myeloid leukemia; FLT3; Precision medicine EN acute myeloid leukemia FLT3 Precision medicine 6079 6082 4 12/19/22 20221215 NES 221215 FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase involved in regulation of haematopoietic stem cell and progenitor cell proliferation and differentiation.[1] Activating mutations in I FLT3 i are found in 25%-35% of adults with acute myeloid leukaemia (AML), most commonly in-frame internal tandem duplications (ITD) within the intracellular juxtamembrane domain (JMD).[2] This domain, consisting of residues 572-603, serves an autoinhibitory function, in part by preventing the activation loop from unfolding into its active conformation.[3] I FLT3 i -ITD mutations cause a gain-of-function phenotype with increased proliferation and protection from apoptosis[4] and are associated with worse clinical outcomes.[5] Most other activating I FLT3 i mutations are found in the tyrosine kinase domain (TKD),[2] though rare activating JMD deletions have also been described.[[6]] We identified three patients with rare I FLT3 i JMD missense mutations (Table 1). In-house NGS myeloid mutation panel revealed I FLT3- i ITD, a type A I NPM1 i frameshift mutation (VAF: 35.4%) and missense mutations in I DNMT3A i (c.2645G>A, p.R882H, VAF: 26.3%) and the I FLT3 i JMD (c.1775T>G, p.V592G, VAF: 10.6%). Each of these findings was less pronounced among the I FLT3 i JMD missense mutants than in ITD- or TKD-expressing cell lines, suggesting that I FLT3 i JMD missense mutations result in more modest gain of function. [Extracted from the article]

Background: The SET-NUP214 fusion formed by cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13) is a rare gene rearrangement. This rearrangement has been reported mostly in T-cell acute lymphoblastic leukemia, but only rarely in acute myeloid leukemia (AML). The acute leukemia cases with the SET-NUP214 fusion gene show typical immunophenotype, karyotype, and poor treatment response. However, the cytogenetic or genetic changes in AML with SET-NUP214 fusion are not well understood. Methods: The diagnosis was made based on a combination of the morphology, immunophenotyping, multiplex reverse transcriptase-polymerase chain reaction, FISH, karyotype, Sanger sequencing, next-generation sequencing, and microarray analysis. Results: The author reports a rare case of AML with myelodysplasia-related changes, SET-NUP214 fusion gene, and complex karyotype that was resistant to induction chemotherapy, making diagnosis and treatment difficult. Conclusions: Further studies, including cytogenetic and molecular analyses, are needed to determine the pathophysiology and clinical significance for this rare gene rearrangement. [ABSTRACT FROM AUTHOR]

A number of studies have reported frequent incidence of c-kit gene mutations in association with core binding factor acute myeloid leukemia (CBF-AML). These genetic changes have become important prognostic predictors in patients with abnormal karyotype. Aim of this study was the detection of nucleotide alterations in newly diagnosed acute myeloid leukemia patients for three exons of c-kit gene, including cytogenetically normal patients. Thirty-one de novo AML patients were screened for any possible variations in exon 8, 11 and 17 sequences of c-kit proto-oncogene leading to amino acid substitutions or frame shift. Sanger sequencing method was employed followed by sequence analysis. Mutation data was then correlated with clinical and hematological parameters of patients and prognostic significance of genetic changes was assessed as well. The computational tools were then used to further understand the extent of damage caused by these mutations to c-kit protein. Fifteen (48.4%) mutant patients were observed with single, double or multiple mutations in one, two or all three exons studied. The analysis revealed eight new alterations which were not reported previously. Significant variation among mutant and non-mutant group of patients was observed with respect to FAB subtypes (x2 = 12.524, p = 0.029), Spleen size (x2 = 4.288, p = 0.038) and Red blood cell count (x2 = 8.447, p = 0.007). The survival analysis indicates poor overall and event free survival outcomes in mutant individuals. Furthermore, the in silico analysis suggests that changes in nucleotide sequences can possibly damage the protein structure and effect it's function. This study emphasizes the need to consider screening of c-kit gene alterations not only in CBF-AML but in cytogenetically normal AML patients as well. In current investigation the effect of mutation Arg420Gly on structure and function of c-kit protein was investigated, as this was the most observed substitution in present cohort. Various bioinformatics tools and techniques were employed, which determined that Arg420Gly is possibly non-pathogenic mutation. [ABSTRACT FROM AUTHOR]

Simple Summary: Differential diagnosis between Blastic pDC Neoplasm (BPDCN) and Acute Myeloid Leukemia with pDC expansion (pDC-AML) is particularly challenging, and genomic features can help in diagnosis. This review aims at clarifying recent data on genomics features because the past five years have generated a large amount of original data regarding pDC neoplasms. The genetic landscape of BPDCN is now well-defined, with important updates concerning MYC/MYC rearrangements, but also epigenetic defects and novel concepts in oncogenic and immune pathways. Concerning pDC-AML, they now appear to exhibit an original mutation landscape, especially with RUNX1 mutations, which is of interest for diagnostic criteria and for therapeutic purposes. We highlight here these two different profiles, which contribute to differential diagnosis between BPDCN and pDC-AML. This point is particularly important for the study of different therapeutic strategies between BPDCN and AML. Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective. [ABSTRACT FROM AUTHOR]

The CML patient developed myeloid blast crisis 18 months after the initial diagnosis of CML; the MPN-U patient developed accelerated phase of disease 24.1 months after initial diagnosis (Figure B S2 b ). Of the four patients alive at last follow-up, one patient had AML transforming from MDS with a follow-up time of 20.6 months and three were in complete remission including two patients who received allo-SCT. Keywords: acute myeloid leukaemia; EVI1; MECOM; MYC; myelodysplastic syndrome EN acute myeloid leukaemia EVI1 MECOM MYC myelodysplastic syndrome 604 608 5 07/27/22 20220801 NES 220801 I MYC i rearrangement can occur in various B-cell lymphomas, plasma cell neoplasm, rarely B or T cell lymphoblastic leukaemia, and blastic plasmacytoid dendritic cell neoplasm.1-6 However, the occurrence and significance of I MYC i rearrangement in other myeloid neoplasms have not been thoroughly investigated.7-13 Here, we assessed a cohort of 40 patients with 8q24/ I MYC i -rearranged myeloid neoplasms diagnosed from January 2009 through December 2020. [Extracted from the article]

• A novel karyotype of heptasomy 21 in an AML patient with complex karyotype. • Comprehensive genomic/genetic evaluation revealed several biomarkers with therapeutic implications. • Micronucleus formation may underlie the polysomy 21. Chromosomal aberrations are among the most important prognostic parameters in AML, and conventional cytogenetic analysis remains essential for risk stratification. In this report, we describe an adult male patient with a high percentage of circulating blasts, pathologically confirmed as AML with maturation. Cytogenetic analysis of a bone marrow sample revealed heptasomy 21 and trisomy 13 within a complex karyotype of 52,XY,der(2)t(2;13)(q33.3;q32.1),+13,+21,+21,+21,+21,+21 in all 20 cells examined, which was confirmed by metaphase FISH. Chromosomal microarray analysis (CMA) revealed complete loss of heterozygosity (LOH) of chromosome 21, supporting a common origin. In addition, LOH of chromosome 1p, trisomy 13, and partial tetrasomy of 13q and partial monosomy of 2q as a result of an unbalanced translocation between chromosomes 2 and 13 were observed. Molecular analysis identified two pathogenic missense variants: RUNX1 p.D198Y and SRSF2 p.P95R. The clonal allele ratio of RUNX1 p.D198Y was consistent with all copies of chromosome 21 in the leukemic clone carrying the mutation. Within the medical literature, there are no reports of heptasomy 21 for comparison; however, there are reports of AML with either polysomy 21 or trisomy 13. Our results suggest that even relatively 'common' AML aneuploidies may be associated with much more complex genomic changes, including loss of heterozygosity, which impact prognosis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) patients are at risk of bleeding due to disease-related lack of platelets and systemic coagulopathy. Platelets play a role in hemostasis. Leukemic blasts have been shown to alter platelet activation in vitro. Here we investigated biomarkers associated with thrombocytopenia in normal karyotype AML (NK-AML). From The Cancer Genome Atlas database, case-control study was performed between normal karyotype (NK) platelet-decreased AML (PD-AML, platelet count < 100 × 109/L, n = 24) and NK platelet-not-decreased AML (PND-AML, with platelet count ≥ 100 × 109/L, n = 13). Differentially expressed gene analysis, pathway analysis and modelling for predicting platelet decrease in AML were performed. DEG analysis and pathway analysis revealed 157 genes and eight pathways specific for PD-AML, respectively. Most of the eight pathways were significantly involved in G-protein-coupled receptor-related pathway, cytokine-related pathway, and bone remodeling pathway. Among the key genes involved in at least one pathway, three genes including CSF1R, TNFSF15 and CLEC10A were selected as promising biomarkers for predicting PD-AML (0.847 of AUC in support vector machine model). This is the first study that identified biomarkers using RNA expression data analysis and could help understand the pathophysiology in AML with low platelet count. [ABSTRACT FROM AUTHOR]

Background: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized. Case presentation: Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks. Conclusions: Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes. [ABSTRACT FROM AUTHOR]

Background: The goal is to assess the prognosis of cytogenetic abnormality, because cytogenetic abnormality is rarely encountered in clinical practice. Methods: We retrospectively report three cytogenetic abnormality cases with clinical, cytogenetic, and genetic characteristic. Results: All cases occurred within one month of birth and had prominent hepatosplenomegaly, including acute myeloid leukemia (case 1, case 2) and acute leukemia (case 3). Moreover, case 1 appeared as leukemia cutis at birth, case 2 was born with respiratory distress, and both showed hyperleukocytosis. The R-banded karyotype detected cytogenetic abnormality in three cases, case 1 with 46,XY,t(8;12)(q21;p13), case 2 with 47,XX,+21 and case 3 with 46,XY,t(6;X)(q22:p12), respectively. Especially in case 1, reverse transcription-polymerase chain reaction analysis showed MLL-AF10 rearranged. Conclusions: In our studies, all cases had not received chemotherapy and survived about 1 - 2 months. It suggests that cytogenetic disorders are closely related to disease development and likely result in fatal outcome if untreated. Thus, we proposed that a proper treatment decision is urgently needed in congenital leukemia. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment of pediatric acute myeloid leukemia (AML) is stratified according to multiple recurrent genetic aberrations, which require for detection of different diagnostic methods such as karyotyping and fluorescence in situ hybridization (FISH). The aim of this study was to analyze whether optical genome mapping (OGM), as a new all-in-one methodological approach, can identify all stratification-relevant genetic aberrations that were described by karyotyping. Therefore, frozen bone marrow and blood cells from 24 pediatric patients with AML, bi-lineage leukemia, and mixed-phenotype acute leukemia collected at diagnosis were analyzed by OGM. The results of OGM were compared with routine diagnostic results from karyotyping and FISH. We show that OGM has much potential to address limitations of cytogenetics and even identify new structural aberrations that can be useful for monitoring minimal residual disease (MRD) in patients without an MRD marker. Pediatric AML is characterized by numerous genetic aberrations (chromosomal translocations, deletions, insertions) impacting its classification for risk of treatment failure. Aberrations are described by classical cytogenetic procedures (karyotyping, FISH), which harbor limitations (low resolution, need for cell cultivation, cost-intensiveness, experienced staff required). Optical Genome Mapping (OGM) is an emerging chip-based DNA technique combining high resolution (~500 bp) with a relatively short turnaround time. Twenty-four pediatric patients with AML, bi-lineage leukemia, and mixed-phenotype acute leukemia were analyzed by OGM, and the results were compared with cytogenetics. Results were discrepant in 17/24 (70%) cases, including 32 previously unknown alterations called by OGM only. One newly detected deletion and two translocations were validated by primer walking, breakpoint-spanning PCR, and DNA sequencing. As an added benefit, in two cases, OGM identified a new minimal residual disease (MRD) marker. Comparing impact on risk stratification in de novo AML, 19/20 (95%) cases had concordant results while only OGM unraveled another high-risk aberration. Thus, OGM considerably expands the methodological spectrum to optimize the diagnosis of pediatric AML via the identification of new aberrations. Results will contribute to a better understanding of leukemogenesis in pediatric AML. In addition, aberrations identified by OGM may provide markers for MRD monitoring. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is characterized by blocked or aberrant differentiation of hematopoietic stem cells. The MECOM gene overexpression in hematopoietic progenitors induces myeloid differentiation block, resulting in increased self-renewal and survival of these transformed progenitors. However, its exact role in AML remains unclear. We aimed to estimate the prevalence of MECOM overexpression among pediatric AML patients, and assess its impact on clinical outcome. Real-time quantitative polymerase chain reaction and Livak method (2ΔΔCt) were used to determine relative MECOM expression level among 243 pediatric patients with AML. MECOM overexpression was considered if the cumulative relative expression was above 1 (2-ΔΔCt) and was designated as MECOMpos. Of 243 AML patients tested 57(23.5%) demonstrated MECOMpos. Patients with MECOMpos had significantly lower median age. The frequency of MECOMpos was significantly higher among AML patients with 11q23 abnormalities, complex karyotypes and among high- and intermediate-risk groups compared to low-risk group (p =.014). MECOMpos patients had significantly lower overall survival (OS) (38.7 vs. 78.9%, p <.001), event-free survival (EFS) (37.3% vs. 68.4%, p <.001), and had higher cumulative incidence of relapse (49.5% vs. 23.5%, p =.002) at 36 months compared to MECOMneg patients. Multivariate analysis revealed that MECOMpos was an adverse prognostic factor for OS (hazards ratio (HR) = 2.11, 95% confidence interval (CI) 1.24–3.60, p =.006) and EFS (HR= 1.71, 95% CI 1.07–2.75, p =.025). The logistic regression model showed that MECOMpos was an independent prognostic factor regardless of minimal residual disease status post first induction therapy in the intermediate-risk group (odds ratio 2.89; 95% CI 1.19–6.57, p =.018). The aberrant MECOM gene expression is an adverse prognostic factor, especially in patients without previously known cytogenetic risk factors. Our results suggest the potential benefit from pretreatment screening for MECOM gene overexpression in newly diagnosed AML patients for better risk stratification and treatment adjustment. [ABSTRACT FROM AUTHOR]

Recently, the WHO-5 and the ICC 2022 criteria have emphasized poor prognosis in AML/MDS patients with multi-hit TP53 mutations, whereas mutated TP53 plays a critical role in tumorigenesis, drawing substantial interest in exploring its biological behaviors. Diverse characteristics of TP53 mutations, including types, VAF, CNVs, allelic status, karyotypes, and concurrent mutations have been extensively studied. Novel potential targets and comprehensive treatment strategies nowadays are under swift development, owing to great advances in technology. However, accurately predicting prognosis of patients with TP53 -mutated myeloid neoplasms remains challenging. And there is still a lack of effective treatment for those patients. • In-depth exploration of characteristics of TP53 mutation, including types, VAFs, CNVs, allelic status, karyotypes, and concurrent mutations, provides a profound comprehension of in TP53 -mutated MNs. • The importance of TP53 multi-hit status in precisely predicting disease prognosis has been revealed by several studies. • Innovations and challenges coexist in treating TP53 -mutated MNs, navigating towards future potential therapies. [ABSTRACT FROM AUTHOR]

Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation. [ABSTRACT FROM AUTHOR]

The article explores Acute myeloid leukemia (AML) with inv(16)(p13q22)/t(16;16) (p13;q22) has distinct clinicopathologic features, including myelomonocytic leukemic cells, abnormal bone marrow eosinophils, and a relatively favorable prognosis.1,2 Most cases are classified as AML M4 with abnormal eosinophils (M4Eo) in the French-AmericanBritish (FAB) classification.

Acute myeloid leukemia (AML) presents as a heterogeneous blood cancer characterized by the proliferation of immature myeloid cells. We present the case of an 18-year-old female with AML whose symptoms include marked leukocytosis, anemia, as well as thrombocytopenia with spontaneous cerebellar and intracerebral bleeds. The bone marrow biopsy is hypercellular and is expunged by sheets of blast cells with dispersed chromatin, prominent nucleoli, highly irregular nuclei, and moderate cytoplasm. Chromosome analysis reveals an abnormal karyotype with a derivative trisomy 8 and a derivative chromosome 16. The karyotype is described as 47,XX,+der(8)add(8)(q24.3),der(16) inv(16)(p13.1q22)del(16)(q22)[21]/46,XX[1]. DNA FISH analysis reveals abnormalities for RUNX1T1 (8q21.3) and CBFB (16q22) genes. These findings align with that of conventional cytogenetics. The National Comprehensive Cancer Network guidelines for AML state that CBFB gene rearrangements indicate that the patient falls under the favorable risk category. However, AML with core binding factor molecular aberrations is a heterogeneous group and thus the interaction with further cytogenetic abnormalities may result in further pathogenesis. Clinical correlation was suggested. [ABSTRACT FROM AUTHOR]

Introduction In acute myeloid leukemia (AML), FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is a common driver mutation associated with high tumor burden and poor prognosis. This mutation is common in normal karyotype AML and such patients have high leukocyte count. The presence of this mutation can be predicted by certain hematological and immunophenotypic characteristics in day-to-day practice. Objective This study was undertaken to assess the strength of association between FLT3 gene mutation and hematological and immunophenotypic characteristics. Materials and Methods Morphological, hematological, immunophenotypic, and cytogenetic characteristics of FLT3 mutations recorded in 424 patients of AML in adults and children between 2016 and 2019 in a tertiary care cancer center in Western India. Blasts were classified according to French-American-British method. Tumor burden was assessed by serum lactate dehydrogenase (LDH) levels, leucocyte count, and peripheral smear blast percentage. Results Out of 424 cases, FLT3-ITD and FLT3-tyrosine kinase domain mutation were found in 72 and 25 AML patients, respectively. Patients with FLT3 mutation had high tumor burden, characterized by high leukocyte count (p < 0.001), peripheral blood (p = 0.01) and bone marrow (p = 0.03) blast percentage, and high serum LDH (mean 777.8 vs. 586; p = 0.10) compared with FLT3-negative patients. They also featured high platelet count (p < 0.001). Morphological, immunophenotypic, and cytogenetic characteristics also have been presented in the study. Conclusion Observations of the study suggest the presence of definitive hematological and immunophenotypic characteristics along with raised serum LDH levels serve as surrogate markers and indicators of FLT3 mutation in AML patients. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) frequently emerge in acute myeloid leukemia (AML), but the clinical features and molecular characteristics of IDH mutational status and other coexisting mutations have not been investigated in a large extensively characterized AML series. The aim of this study was to gain insight into the mutational profile of IDH‐mutated patients, such as the frequency and clinical characteristics of coexisting mutated genes. Materials and Methods: We investigated 485 newly diagnosed AML patients (range 18‐81 years). DNA was extracted from bone marrow samples at the time of diagnosis. All samples were investigated with a panel of 49 mutational genes using next‐generation sequencing (NGS). FLT3‐ITD, NPM1, and CEBPA mutations were detected by Sanger PCR sequencing. Results: We found 84 patients (17.3%) with IDH1 or IDH2 mutations. There were 40 IDH1R132, 15 IDH2R140Q, 17 IDH2R172K, and 12 uncommon mutations. No patient was found to have both IDH1 and IDH2 mutations. Patients with IDH2R140Q mutations were more frequently older and presented with significantly lower average platelet counts, while IDH2R172K‐mutated patients had significantly lower white blood cell (WBC) counts. On the background of IDH mutations, the presence of a normal karyotype showed a balanced distribution. The four most frequently coexisting mutated genes were NPM1, DNMT3A, TET2, and FLT3‐ITD. The majority of coexisting mutated genes were involved in regulating transcription and DNA methylation. IDH mutation status had no effect on the CR rate, regardless of other molecular abnormalities. Conclusion: Isocitrate dehydrogenases mutations are associated with a complex coexisting mutation cluster in AML. Future investigation is needed to reveal the association between IDH mutations and other genetic abnormalities, which may have an impact on the progression and prognosis of disease. [ABSTRACT FROM AUTHOR]

Objectives: This study seeks to further characterize the clinicopathologic spectrum of DDX41-mutated hematolymphoid malignancies.Methods: We identified DDX41 mutations from a cohort of known or suspected hematologic disorders and reviewed the corresponding clinical, genetic, phenotypic, and morphologic findings.Results: DDX41 mutations were identified in 20 (1.4%) of 1,371 cases, including 8 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 2 cases of therapy-related MDS/AML, 1 case of primary myelofibrosis, 1 case of chronic myeloid leukemia, 1 case of clonal cytopenia of uncertain significance (CCUS), 1 case of T-cell large granular lymphocytic leukemia (T-LGL), and 1 case of multiple myeloma. DDX41-mutated neoplasms were morphologically heterogeneous with a median cellularity of 20% (range, 10%-100%). Megakaryocyte dysplasia occurred in 7 (35%) of 20 cases and trilineage dysplasia in 1 (5%). Frequently comutated genes include a second, somatic DDX41 mutation (8/19, 42%) followed by mutations in TET2 (20%), DNMT3A (20%), ASXL1 (20%), and CUX1 (20%). Karyotypes were noncomplex in 17 (89%) of 19.Conclusions: This report extends the spectrum of DDX41-mutated disorders to include CCUS, T-LGL, and plasma cell disorders. The morphologic features are heterogeneous and nonspecific, highlighting the importance of DDX41 testing during routine workup of hematolymphoid neoplasms. [ABSTRACT FROM AUTHOR]

Objectives: TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods: Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results: A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion: In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation. [ABSTRACT FROM AUTHOR]

Double minute chromosomes (DMs) are rare in hematologic malignancies. We presented the cytogenetic characteristics and clinical features of the largest single-center cohort of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients with DMs. A total of 2576 AML patients and 1642 MDS patients were investigated, and 30 patients (AML = 19; MDS = 11) who had DMs were followed up. DMs were more common in primary AML (94.7%) and MDS (90.9%). Monosomal karyotypes (MK) were also the main cytogenetic characteristics, like complex karyotypes (CK). AML with myelodysplasia-related changes (AML-MRC) and MDS-refractory anemia with excess blasts (MDS-RAEB) was common in this cohort. We conclude that DMs-positive AML and DMs-positive MDS are associated with older age, complex karyotypes, monosomal karyotypes, TP53 deletion and TP53 mutations. DMs are a type of chromothripsis, which can be observed by the karyotype analysis. MYC and KMT2A were the most commonly amplified genes in DMs. Most patients with DMs presented an extremely poor prognosis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a clonal disorder of myeloid lineage precursors. Identification of cytogenetic aberrations is essential for classification and risk stratification of AML, with many demonstrating unique associations with various clinicopathologic features. One such abnormality is MYC amplification, a rare occurrence identified in less than 1% of AML patients. MYC is most commonly amplified in the form of double minutes, but may also occur via ring and marker chromosomes or homogeneously staining regions. Amplification of MYC often involves various chromosomal aberrations, including trisomies 4 and 6 and aneusomy of the sex chromosomes. In many cases, the presence of MYC amplicons is also associated with other negative prognostic factors, including complex karyotype and advanced age. Although MYC has been extensively investigated as a therapeutic target in various cancers, there are few studies examining the clinical significance of MYC amplification in AML. In this review, we explore recurrent cytogenetic abnormalities and demographic characteristics associated with amplification of MYC in patients with AML and discuss their diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Introduction: Residual disease (RD) detected using multiparametric flow cytometry (MFC) is an independent predictive variable of relapse in acute myeloid leukaemia (AML). However, RD thresholds and optimal assessment time points remain to be validated. Material and methods: We investigated the significance of RD after induction therapy in paediatric AML with normal karyotype between June 2008 and June 2018. Bone marrow samples from 73 patients were collected at the end of the first (BMA‐1) and second (BMA‐2) induction courses to monitor RD using MFC. Results: Presence of RD after BMA‐1 and/or BMA‐2 correlated with poor relapse‐free (RFS) and overall survival at 0.1% RD cutoff level. Receiver operating characteristic curve showed that RD cutoff levels of 1.3% and 0.5% after BMA‐1 and BMA‐2, respectively, predicted events with the highest sensitivity and specificity. In multivariable analysis, RD after BMA‐2 was the strongest independent risk predictor for poor RFS (hazard ratio 2.934; 95% confidence interval: 1.106‐7.782; P =.031). Conclusions: Our study therefore suggests that an RD level ≥0.5% after BMA‐2 has a significant predictive impact on the prognosis of AML patients having normal karyotype and thus guide the stratification of treatment strategies. [ABSTRACT FROM AUTHOR]

The article presents lineage switch from NPM1-mutant acute myeloid leukemia to acute T-cell lymphoblastic leukemia with KMT2D and ARID2 mutant. Topics discussed include Leukemia is a group of clonal stem cell diseases characterized by the clonal proliferation of malignant hematopoietic stem cells and impairment of normal hematopoietic function; and the incidence rate of this conversion phenomenon is 6%-9%,1 the most common switch occurred.

Background: Chromosomal aberrations which occur in different hematologic malignancies are believed to be highly applicable for identifying the prognosis and treatment protocols. We conducted the present study to investigate the chromosomal and molecular abnormalities in bone marrow of acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and myelodysplastic syndrome patients. Method: We performed this cross-sectional study in molecular pathology and cancer research center of Mashhad University of Medical Sciences (MUMS), during 2017-2019; the total number of our cases was 252. We did all the molecular and cytogenetic tests on these patients. SPSS V.16 software was utilized for the analysis of our data. Results: In this research, the ALL patients were meaningfully younger than AML ones. There were significant associations between karyotype patterns and types of malignancy; normal diploid was more frequent in myelodysplastic syndrome (P<0.05). Among numerical abnormalities, trisomy 3 and monosomy 14 were the most prevalent ones. Conclusion: The results of similar studies from different areas with different ethnics would help to identify new parameters for prognosis determination. Cytogenetic analysis is highly applicable for leukemia diagnosis and prognosis. [ABSTRACT FROM AUTHOR]