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Acute Myeloid Leukemia Research

Works Count: 96582

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Description

This cluster of papers focuses on the diagnosis, management, and genomic classification of Acute Myeloid Leukemia (AML). It covers topics such as prognostic factors, clonal hematopoiesis, FLT3 mutations, epigenetic landscapes, therapeutic trials, and the role of hematopoietic stem cells in AML.

Keywords

Acute Myeloid Leukemia; AML; Genomic Classification; Myeloid Neoplasms; Prognostic Factors; Clonal Hematopoiesis; FLT3 Mutations; Epigenetic Landscapes; Therapeutic Trials; Hematopoietic Stem Cells

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

2013-05-02

T J Ley , Christopher A. Miller , Li Ding +7 more

Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the … Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.).

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Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study

2000-12-15

Marilyn L. Slovak , Kenneth J. Kopecky , Peter A. Cassileth +7 more

The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial

1998-10-01

David Grimwade , Helen M. Walker , Fiona Oliver +7 more

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International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes

1997-03-15

Peter L. Greenberg , Christopher Cox , Michelle M. LeBeau +7 more

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The Human Hematopoietic Colony-Stimulating Factors

1987-06-05

Steven C. Clark , Robert Kamen

The complementary DNAs and genes encoding the four major human myeloid growth factors—granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3—have all been molecularly cloned. These DNA clones … The complementary DNAs and genes encoding the four major human myeloid growth factors—granulocyte colony-stimulating factor, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3—have all been molecularly cloned. These DNA clones have proved valuable for studying the molecular biology of these important regulatory molecules as well as for the large-scale production of the recombinant growth factor proteins. These advances have led to a much better understanding of the role of the myeloid growth factors in regulating hematopoiesis in vivo that should soon find practical application in clinical medicine.

Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

2015-05-01

David P. Steensma , Rafael Bejar , Siddhartha Jaiswal +4 more

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Age-related mutations associated with clonal hematopoietic expansion and malignancies

2014-10-19

Mingchao Xie , Charles Lu , Jiayin Wang +7 more

Clinical and biological implications of driver mutations in myelodysplastic syndromes

2013-09-13

Elli Papaemmanuil , Moritz Gerstung , Luca Malcovati +7 more

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The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate

2010-02-22

Patrick S. Ward , Jay Patel , David R. Wise +7 more

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Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell

1997-07-01

Dominique Bonnet , John E. Dick

Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds.

1978-05-01

Steven Collins , Francis W. Ruscetti , Robert E. Gallagher +1 more

A human leukemic cell line (designated HL-60) has recently been established from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia. This cell line displays distinct morphological and … A human leukemic cell line (designated HL-60) has recently been established from the peripheral blood leukocytes of a patient with acute promyelocytic leukemia. This cell line displays distinct morphological and histochemical commitment towards myeloid differentiation. The cultured cells are predominantly promyelocytes, but the addition of dimethyl sulfoxide to the culture induces them to differentiate into myelocytes, metamyelocytes, and banded and segmented neutrophils. All 150 clones developed from the HL-60 culture show similar morphological differentiation in the presence of dimethyl sulfoxide. Unlike the morphologically immature promyelocytes, the dimethyl sulfoxide-induced mature cells exhibit functional maturity as exemplified by phagocytic activity. A number of other compounds previously shown to induce erythroid differentiation of mouse erythroleukemia (Friend) cells can induce analogous maturation of the myeloid HL-60 cells. The marked similarity in behavior of HL-60 cells and Friend cells in the presence of these inducing agents suggests that similar molecular mechanisms are involved in the induction of differentiation of these human myeloid and murine erythroid leukemic cells.

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Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program

2003-10-09

J Gäbert , Emmanuel Beillard , Vincent H. J. van der Velden +7 more

Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

2008-04-30

Richard F. Schlenk , Konstanze Döhner , Jürgen Krauter +7 more

Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein α gene … Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein α gene (CEPBA), the myeloid–lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients.

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Clinical Effect of Point Mutations in Myelodysplastic Syndromes

2011-06-30

Rafael Bejar , Kristen E. Stevenson , Omar Abdel‐Wahab +7 more

Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype … Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems.

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AML1, the Target of Multiple Chromosomal Translocations in Human Leukemia, Is Essential for Normal Fetal Liver Hematopoiesis

1996-01-01

Tsukasa Okuda , Jan M. van Deursen , Scott W. Hiebert +2 more

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A cell initiating human acute myeloid leukaemia after transplantation into SCID mice

1994-02-01

Tsvee Lapidot , Christian Sirard , Josef Vormoor +7 more

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

2012-01-01

Li Ding , Timothy J. Ley , David E. Larson +7 more

The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of clonal evolution, with chemotherapy appearing to have a role in both patterns. Many … The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of clonal evolution, with chemotherapy appearing to have a role in both patterns. Many patients with acute myeloid leukaemia (AML) achieve remission, but it is often short-lived and the returned disease is usually refractory to therapy. Genome sequencing of eight patients with AML before and after relapse reveals two major patterns of tumour cell evolution. The founding clone survives chemotherapy in all patients, and, in one clonal pattern, it acquires new mutations and expands at relapse. In the other, a subclone surviving from the original tumour expands and then acquires new mutations. Comparisons of relapse-specific and primary tumour mutations point to an increase in transversions, implying DNA damage caused by cytotoxic chemotherapy. This work demonstrates that the AML genome in an individual patient presents a moving target, and highlights the importance of striving to eradicate both the founding clone and all of its subclones. Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level1,2 . To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

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The World Health Organization (WHO) classification of the myeloid neoplasms

2002-09-18

James W. Vardiman , Nancy L. Harris , Richard D. Brunning

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Mutation inTET2in Myeloid Cancers

2009-05-27

François Delhommeau , Sabrina Dupont , Véronique Della Valle +7 more

The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined.We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, … The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined.We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice.We initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed.Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.

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Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B

2002-05-15

Lewis R. Silverman , Erin P. Demakos , Bercedis L. Peterson +7 more

PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza … PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m 2 /d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P < .001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P = .007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P = .001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P = .03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes

2009-04-09

James W. Vardiman , Jüergen Thiele , Daniel A. Arber +7 more

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Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia

2012-03-14

Jay P. Patel , Mithat Gönen , María E. Figueroa +7 more

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a … Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

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Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet

2009-10-31

Hartmut Döhner , Elihu H. Estey , Sergio Amadori +7 more

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World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting—Airlie House, Virginia, November 1997

1999-12-01

Nancy L. Harris , Elaine S. Jaffe , J Diébold +5 more

PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell … PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms. DESIGN: Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification. RESULTS: The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of each of these features varies among diseases, and there is no one gold standard. The WHO classification applies the principles of the REAL classification to myeloid and histiocytic neoplasms. The classification of myeloid neoplasms recognizes distinct entities defined by a combination of morphology and cytogenetic abnormalities. At the CAC meeting, which was organized around a series of clinical questions, participants reached a consensus on most of the questions posed. They concluded that clinical groupings of lymphoid neoplasms were neither necessary nor desirable. Patient treatment is determined by the specific type of lymphoma, with the addition of grade within the tumor type, if applicable, and clinical prognostic factors, such as the International Prognostic Index. CONCLUSION: The WHO classification has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment of hematologic malignancies.

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study

2009-02-22

Pierre Fenaux , Ghulam J. Mufti , Eva Hellström‐Lindberg +7 more

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Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

2014-11-26

Giulio Genovese , Anna K. Kähler , Robert E. Handsaker +7 more

Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.

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DNMT3AMutations in Acute Myeloid Leukemia

2010-11-10

Timothy J. Ley , Li Ding , Matthew J. Walter +7 more

The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding … The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations.A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis.DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.).

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Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

2002-06-15

Christian Thiede , Christine Steudel , Brigitte Mohr +7 more

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Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome

2009-08-06

Elaine R. Mardis , Li Ding , David J. Dooling +7 more

The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.We used massively parallel DNA sequencing to obtain a very … The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known.We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome.We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis.By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.

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Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials

2010-04-13

David Grimwade , Robert K. Hills , Anthony V. Moorman +6 more

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Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)

2002-08-01

John C. Byrd

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

2014-11-26

Siddhartha Jaiswal , Pierre Fontanillas , Jason Flannick +7 more

The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood … The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.

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Proposed Revised Criteria for the Classification of Acute Myeloid Leukemia

1985-10-01

John M. Bennett

Position Papers1 October 1985Proposed Revised Criteria for the Classification of Acute Myeloid LeukemiaA Report of the French-American-British Cooperative GroupJOHN M. BENNETT, M.D., DANIEL CATOVSKY, M.D., MARIE T. DANIEL, M.D., GEORGE … Position Papers1 October 1985Proposed Revised Criteria for the Classification of Acute Myeloid LeukemiaA Report of the French-American-British Cooperative GroupJOHN M. BENNETT, M.D., DANIEL CATOVSKY, M.D., MARIE T. DANIEL, M.D., GEORGE FLANDRIN, M.D., DAVID A. G. GALTON, M.D., HARVEY R. GRALNICK, M.D., CLAUDE SULTAN, M.D.JOHN M. BENNETT, M.D.Search for more papers by this author, DANIEL CATOVSKY, M.D.Search for more papers by this author, MARIE T. DANIEL, M.D.Search for more papers by this author, GEORGE FLANDRIN, M.D.Search for more papers by this author, DAVID A. G. GALTON, M.D.Search for more papers by this author, HARVEY R. GRALNICK, M.D.Search for more papers by this author, CLAUDE SULTAN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-103-4-620 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe first proposals for the morphologic classification of the acute leukemias by the French-American-British (FAB) group (1) were put forward in the hope that they might serve as a basis for a generally acceptable system of classification. Such a system would permit comparisons between series of cases, show prognostic differences between different categories, and provide a framework of reference for persons working in different biological disciplines who use material from patients with leukemia.In the last 7 years the FAB proposals have been accepted by many groups involved in cooperative clinical trials with both acute myeloid leukemia and acute lymphoblastic...References1. BENNETTCATOVSKYDANIEL JDM. Proposals for the classification of the acute leukaemias: French-American-British Cooperative Group. Br J Haematol. 1976;33:451-8. CrossrefMedlineGoogle Scholar2. SECOND INTERNATIONAL WORKSHOP ON CHROMOSOMES IN LEUKEMIA, 1979. Morphological analysis of acute promyelocytic (M3) and t(8;21). Cancer Genet Cytogenet. 1980;2:97-8. CrossrefGoogle Scholar3. THIRD INTERNATIONAL WORKSHOP ON CHROMOSOMES IN LEUKEMIA, 1980. Clinical significance of chromosomal abnormalities in acute lymphoblastic leukemia. 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Hypocellular acute leukemia. Am J Med. 1982;72:391-5. CrossrefMedlineGoogle Scholar31. CATOVSKYDECARDULLOO'BRIEN DSLM. Cytochemical markers of differentiation in acute leukemia. Cancer Res. 1981;41( 11 pt 2):4824-32. MedlineGoogle Scholar32. PARKINARTHURABRAMSON JDC. Acute leukemia associated with the t(4;11) chromosome rearrangement: ultrastructural and immunologic characteristics. Blood. 1983;119:1321-31. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Rochester, New York; London England Paris and Creteil France Bethesda Maryland▸From the University of Rochester Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York; Medical Research Council Leukaemia Unit, Royal Postgraduate Medical School, London, England; Institut de Recherches sur les Leucemies et les Maladies du Sang, Hopital Saint-Louis, Paris, France; Hematology Service, National Institutes of Health, Bethesda, Maryland; and Service Central d'Hematologie-Immunologie, Hopital Henri Mondor, Creteil, France. 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2004-08-14

Ursula Creutzig , Gertjan J.L. Kaspers

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2005-01-19

Brunangelo Falini , Cristina Mecucci , Enrico Tiacci +7 more

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2012-06-29

Peter L. Greenberg , Heinz Tuechler , Julie Schanz +7 more

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2016-04-12

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2016-06-08

Elli Papaemmanuil , Moritz Gerstung , Lars Bullinger +7 more

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2016-11-29

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2017-06-21

Siddhartha Jaiswal , Pradeep Natarajan , Alexander J. Silver +7 more

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2017-06-23

Richard M. Stone , Sumithra J. Mandrekar , Ben L. Sanford +7 more

Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted … Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

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Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

2018-10-26

Courtney D. DiNardo , Keith W. Pratz , Vinod Pullarkat +7 more

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Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

2020-08-12

Courtney D. DiNardo , Brian A. Jonas , Vinod Pullarkat +7 more

Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b … Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.

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Acute Myeloid Leukemia

2015-09-16

Hartmut Döhner , Daniel J. Weisdorf , Clara D. Bloomfield

Many recent biologic insights have shed light on the nosology of acute myeloid leukemia. Although this new knowledge has not yet had a major influence on the treatment of the … Many recent biologic insights have shed light on the nosology of acute myeloid leukemia. Although this new knowledge has not yet had a major influence on the treatment of the disease, strategies under investigation may improve outcomes.

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2001-12-03

Scott A. Armstrong , Jane Staunton , Lewis B. Silverman +7 more

Myelodysplastic Syndromes

2013-07-01

Peter L. Greenberg , Eyal C. Attar , John M. Bennett +7 more

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid … The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.

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Proposals for the classification of the myelodysplastic syndromes

1982-06-01

John M. Bennett , Daniel Catovsky , MT Daniel +4 more

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

2022-06-22

Joseph D. Khoury , Éric Solary , Oussama Abla +7 more

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within … The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

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International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

2022-06-29

Daniel A. Arber , Attilio Orazi , Robert P. Hasserjian +7 more

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Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN

2022-07-07

Hartmut Döhner , Andrew H. Wei , Frederick R. Appelbaum +7 more

Abstract The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. … Abstract The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.

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KRAS mutation status critically determines the clinical outcome of patients with KMT2A-rearranged acute myeloid leukemia.

2025-07-01

Yibo Wu , Xiaolin Yuan , Xiaoyu Lai +7 more | PubMed

KMT2A(11q23)-rearranged acute myeloid leukemia (KMT2A-r AML) represents a clinically aggressive subtype with heterogeneous outcomes. Current evidence remains inconclusive regarding the prognostic relevance of fusion partners in 11q23/KMT2A-rearranged AML. The comprehensive … KMT2A(11q23)-rearranged acute myeloid leukemia (KMT2A-r AML) represents a clinically aggressive subtype with heterogeneous outcomes. Current evidence remains inconclusive regarding the prognostic relevance of fusion partners in 11q23/KMT2A-rearranged AML. The comprehensive mutational landscape and prognostic implications of co-occurring driver mutations remain poorly characterized. A comprehensive clinicogenomic analysis of 159 de novo KMT2A-r AML patients was conducted to assess the correlation between molecular profiles and clinical outcomes. Notably, the KMT2A::MLLT4 subgroup exhibited significantly higher KRAS mutation frequencies compared to other rearrangement groups (p < .05). Survival analysis revealed that the KMT2A::MLLT4 cohort demonstrated trends toward inferior overall survival (OS) and increased cumulative incidence of relapse (CIR) relative to other rearrangement subgroups. Stratified by mutational status, patients with KRAS mutations exhibited significantly inferior 2-year OS rates (24.6% vs. 50.5%; p = .001) and higher 2-year CIR (56.3% vs. 34.6%; p = .018) compared to KRAS wild-type counterparts. This adverse prognostic association remained in the transplanted cohort (OS: 32.3% vs. 73.5%; p < .001; CIR: 73.6% vs. 23.0%; p < .001). In contrast, mutations in NRAS, FLT3 did not demonstrate statistically significant associations with OS or CIR in either the overall cohort or transplant subgroup. Multivariable Cox regression confirmed KRAS mutation as an independent adverse prognostic factor for both 2-year OS (hazard ratio [HR], 0.51; 95% CI, 0.31-0.84; p = .008) and CIR (HR, 1.80; 95% CI, 1.04-3.12; p = .037) in the overall cohort. This association persisted in the transplanted patients subgroup (OS: HR, 0.18; 95% CI, 0.06-0.52; p = .001; CIR: HR, 3.89; 95% CI, 1.05-14.37; p = .042). These results demonstrate the independent prognostic value of KRAS mutations across treatment modalities, including both conventional chemotherapy and hematopoietic stem cell transplantation.

KIT amplitude-based multiplex droplet digital polymerase chain reaction outperforms direct sequencing for sensitive KIT D816 genotyping in core binding factor acute myeloid leukemia

2025-06-25

Shumpei Mizuta , Noriko Bandai , Saya Yoshida +7 more | Laboratory Medicine

Abstract Introduction The prognosis of acute myeloid leukemia is stratified by genetic abnormalities; however, the detection sensitivity varies by method. The KIT D816 mutation is frequently found in core binding … Abstract Introduction The prognosis of acute myeloid leukemia is stratified by genetic abnormalities; however, the detection sensitivity varies by method. The KIT D816 mutation is frequently found in core binding factor leukemia and is associated with a poor prognosis. In this study, we aimed to investigate the performance of multiplex droplet digital polymerase chain reaction (ddPCR) for detecting KIT D816 mutations and propose the practical mutation analysis method for clinical laboratory testing. Methods We evaluated the detection limit of ddPCR using mixed probes for HEX-labeled wild-type and FAM-labeled mutations (D816V, D816Y, and D816H) by analyzing plasmid mixtures containing these sequences. We compared the frequency of KIT mutations detected by direct sequencing and ddPCR in 20 patients with core binding factor leukemia. Results Multiplex ddPCR successfully discriminated between mutation types based on plot positions on a 2-dimensional map, with a detection limit of 0.1%. The frequency of D816 mutations was 42.5% using ddPCR and 20% using direct sequencing. Most patients with KIT D816 mutation require hematopoietic stem cell transplantation for chimeric gene clearance. Discussion Amplitude-based multiplex ddPCR efficiently provides sensitive and accurate genotyping of KIT D816 and has potential applications for other genetic abnormalities.

MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion

2025-06-25

Jennifer Yeung , Sophia Y Philbrook , Emma Uible +7 more

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in … Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A, TET2, and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-kB, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88-L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88-L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88-L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-kB activation and reversed Myd88-L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.

The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia

2025-06-25

H.A. Yu , Junshik Hong , Dong‐Yeop Shin +1 more | Leukemia

Clinical management of <scp>CMML</scp>—State of the art

2025-06-24

Kathrin Nachtkamp , F. Schulz , Norbert Gattermann +1 more | British Journal of Haematology

Summary Chronic myelomonocytic leukaemias (CMML) are myeloid neoplasms characterized by a sustained increase in monocyte counts in the peripheral blood, accompanied by dysplasia, abnormal proliferation, chromosomal anomalies and somatic mutations … Summary Chronic myelomonocytic leukaemias (CMML) are myeloid neoplasms characterized by a sustained increase in monocyte counts in the peripheral blood, accompanied by dysplasia, abnormal proliferation, chromosomal anomalies and somatic mutations of haematopoietic cells. More than 95% of CMML patients harbour somatic mutations. CMML must be separated from other myeloid neoplasms and reactive monocytosis. The clinical presentation of CMML varies, but most frequently shows signs and symptoms of haematopoietic insufficiency or myeloproliferation. Robust instruments are available for assessing the prognosis of patients with CMML, such as the CMML‐specific prognostic scoring system molecular. Treatment options for patients with CMML are still inadequate and generally less effective than those for other myeloid neoplasms. The only curative approach is allogeneic stem cell transplantation. This article explains essential aspects of CMML pathophysiology and provides an overview of diagnostic considerations, prognostic assessment and therapeutic options.

Advances in the role of the IGF signaling system in myelodysplastic syndromes and acute myeloid leukemia

2025-06-24

Yifan Wang , Xinyu Dong , Shandong Tao +7 more | Frontiers in Oncology

The insulin-like growth factor (IGF) signaling system comprises functionally specific ligands (IGF-I and IGF-II), receptor (IR), and binding proteins (IGFBP). IGFs are activated by binding to their receptor, IGF-IR, which … The insulin-like growth factor (IGF) signaling system comprises functionally specific ligands (IGF-I and IGF-II), receptor (IR), and binding proteins (IGFBP). IGFs are activated by binding to their receptor, IGF-IR, which is a tyrosine kinase receptor. This activation initiates signaling cascades such as PI3K/Akt and MAPK/ErK pathways, which are essential for cell proliferation, differentiation, and survival. Growing evidence links the IGF system to various hematological disorders, yet comprehensive reviews on its role in Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are limited. To advance understanding in this area, we aim to summarize the emerging evidence on the involvement of IGF signaling in the pathogenesis of MDS and AML. Specifically, we highlight how dysregulation of IGF-I, IGF-IR, and IGFBPs contributes to disease progression, encompassing clonal hematopoietic abnormalities, ineffective hematopoiesis in MDS, and the development of AML. The potential therapeutic implications of targeting the IGF signaling pathway, including the role of NVP-AEW541 and NVP-ADW742 effectively suppressing AML cell proliferation and enhancing chemotherapy sensitivity, are also explored. By integrating current findings, this review provides novel insights into the mechanistic role of IGF signaling in MDS and AML and its therapeutic implications, thereby guiding future research and potential clinical applications. Given the challenges, such as pathway redundancy and therapy resistance, further investigations are necessary to validate IGF-targeted therapies and optimize their clinical utility in hematologic malignancies.

Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes

2025-06-24

Clifford M. Csizmar , Anuya Ajit Natu , Mark E. Gurney +7 more | Leukemia

Rethinking Cytarabine Dosing in Consolidation Therapy for Patients with AML

2025-06-24

Joshua T. Weinreb , Omar Abdel‐Wahab | NEJM Evidence

Long-term outcomes of patients with refractory cytopenia of childhood under observation only

2025-06-24

Beatrice Drexler , Stephan Schwarz‐Furlan , Irith Baumann +7 more | Blood Advances

Pretreatment expression of miR-191a may predict response to the induction chemotherapy based on cytarabine in acute myeloid leukemia patients – a single-center pilotal study

2025-06-24

Agnieszka Szymczyk , Sylwia Chocholska , Katarzyna Radko +2 more | PLoS ONE

Background Acute myeloid leukemia (AML) is associated with the accumulation of acquired genetic disorders. Moreorver chromosomal and molecular changes are independent prognostic factors that are taken into account to determine … Background Acute myeloid leukemia (AML) is associated with the accumulation of acquired genetic disorders. Moreorver chromosomal and molecular changes are independent prognostic factors that are taken into account to determine prognosis and treatment. MicroRNAs are novel gene regulators, which have been recognized to play an important role in pathological leukemogenesis. This study is aimed to analyze the possible role of micro RNAs as a markers predicting the outcome to induction chemotherapy based on cytarabine. Materials and methods The expression of miR-34a, miR-191, miR-199a and miR-199b in previously separated bone marrow cells was assessed at the moment of diagnosis in 44 AML patients with use of qRQ-PCR technique. Assessment of response to induction therapy was based on criteria for response to treatment proposed by European LeukemiaNet (ELN). Results Only the expression level of miR-191a out of all analyzed microRNAs was significantly associated with the induction chemotherapy response. We detected also significantly higher expression of miR-191 in FLT3-ITD negative group in comparison to FLT3-ITD positive subjects. For miR-34a, miR-199a and miR-199b, no relationship was found between their expression and FLT3-ITD , NPM1 and CEBPA mutations. It was also shown that in the group of patients with low miR-191 expression, the number of myeloblasts was higher (p < 0.05). Conclusions These results may prove an important role of miR-191a expression as a predictor of response to the induction chemotherapy based on cytarabine, even in cases when other risk factors are absent.

Intermediate-Dose Cytarabine as Postinduction AML Therapy

2025-06-24

Mathilde Hunault , Cécile Pautas , Sarah Bertoli +7 more | NEJM Evidence

We conducted a randomized controlled trial to compare intermediate doses (IDAC) with high doses of cytarabine (HDAC) as postinduction therapy in patients 18 to 60 years of age with newly … We conducted a randomized controlled trial to compare intermediate doses (IDAC) with high doses of cytarabine (HDAC) as postinduction therapy in patients 18 to 60 years of age with newly diagnosed acute myeloid leukemia (AML). The main objectives were to evaluate noninferiority in overall survival (OS) after IDAC and safety. Patients 18 to 60 years of age with newly diagnosed AML, except those with core-binding factor, acute promyelocytic, Philadelphia chromosome-positive, or post-myeloproliferative neoplasm AML, were eligible. After the induction course, we randomly assigned patients to either IDAC (1500 mg/m2/12 hours) or HDAC (3000 mg/m2/12 hours). Patients with intermediate- and adverse-risk AML were eligible for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. The primary end point was OS in a predefined per-protocol analysis population. The primary analyses were performed in 1132 randomly assigned patients, with a noninferiority outcome adjusted on the European Leukemia Net (ELN) 2022 risk group, the use of induction anthracycline, the response to induction, and HSCT as a function of time following treatment. At 5 years, OS was estimated at 59.3% (95% confidence interval [CI], 55.0 to 63.3) in the IDAC group versus 57.5% (95% CI, 53.3 to 61.5) in the HDAC group (adjusted hazard ratio, 0.96; 95% CI, 0.80 to 1.15; noninferiority test, P=0.0042). A preplanned analysis was unable to detect any interaction between IDAC or HDAC treatment effect and patient subgroups, including those defined by the ELN 2022 risk group or response to induction prior to random assignment. In addition, the severity of chemotherapy-induced myelosuppression and the incidence of related adverse events were lower after IDAC. Our trial shows noninferior outcomes in patients 18 to 60 years of age with newly diagnosed AML treated with low- versus high-dose cytarabine; this occurred with similar or lower toxicities. (Funded by the Regional Clinical Research Office, Angers and others; EudraCT number, 2014-000699-24; ClinicalTrials.gov number, NCT02416388.).

Feasibility of allogeneic stem cell transplantation (HSCT) in patients with acute myeloid leukemia previously treated with CPX-351: report from a single center

2025-06-23

Sabrina Giammarco , Patrizia Chiusolo , Elisabetta Metafuni +6 more | Annals of Hematology

Case report: Clinical characteristics and genetic analysis of a familial platelet disorder associated with RUNX1 gene mutation

2025-06-23

Hua Zhou , Jing Zhao , Xiaoyan Gu | Frontiers in Hematology

Objective To explore the clinical and genetic mutation characteristics of familial platelet disorder with acute myeloid leukemia tendency (FPD/AML) caused by RUNX1 germline mutations. Methods The clinical data and gene … Objective To explore the clinical and genetic mutation characteristics of familial platelet disorder with acute myeloid leukemia tendency (FPD/AML) caused by RUNX1 germline mutations. Methods The clinical data and gene mutation results of a child with FPD/AML and family members admitted to Changzhou Children’s Hospital on 8 September 2022 were analyzed. Results A 1-year and 11-month-old male patient had recurrent thrombocytopenia for 1 year, with scattered bleeding points throughout the body. Blood routine tests showed thrombocytopenia, and peripheral blood smears and bone marrow cytology tests showed no significant abnormalities. The gene sequencing results showed that the patient carried a frameshift mutation in RUNX1: c.494delG (p.G165Vf*11). Sanger sequencing, which was used for family verification analysis, revealed that the mutation in the patient was inherited from his mother, and his grandmother had similar clinical symptoms. Conclusions These findings expand the spectrum of RUNX1 variants linked to familial platelet disorders. The familial platelet disorder (FPD) associated with this gene is clinically rare and has the potential to undergo malignant transformation. Continuous monitoring of biological evolution is essential, and early intervention and treatment may be warranted.

Features of SRSF2-mutated patients with chronic myelomonocytic leukemia in a national (ABCMML) and international cohort (cBioPortal)

2025-06-23

Marc Tölly , Klaus Geißler | Wiener Medizinische Wochenschrift

The big data derived from major international collaborations now make it possible to validate findings from traditional national patient cohorts in order to demonstrate consistency. In this study, we compared … The big data derived from major international collaborations now make it possible to validate findings from traditional national patient cohorts in order to demonstrate consistency. In this study, we compared findings in SRSF2-mutated patients of the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) with the CMML cohort documented in cBioPortal. It has been consistently shown in both CMML cohorts that SRSF2 mutations are not associated with shorter overall survival and acute myeloid leukemia-free survival. Regarding phenotypic features, it was found that SRSF2 mutations were significantly associated with higher hemoglobin values in the ABCMML and cBioPortal cohorts. The number of platelets was significantly lower in SRSF2-mutated patients in both CMML cohorts, but there were no differences regarding leukocytes and circulating blasts. Data validation using two independent CMML cohorts ensures the quality standards for clinical decision-making.

[Retracted] In vivo and in vitro effects of heme oxygenase‑1 silencing on the survival of acute myelocytic leukemia‑M2 cells

2025-06-23

Sixi Wei , Yating Wang , Qixiang Chai +3 more | Experimental and Therapeutic Medicine

[This retracts the article DOI: 10.3892/etm.2015.2209.]. [This retracts the article DOI: 10.3892/etm.2015.2209.].

Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia

2025-06-23

Richard J. Marrero , Vivek M. Shastri , Deedra Nicolet +7 more | JAMA Network Open

Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior … Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts. To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts. This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025. Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols. ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status. The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P < .001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P = .04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients. In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.

Overview of Acute Myeloid Leukemia with TP53 Mutation: Single Center, Real-Life Data

2025-06-23

Selin Küçükyurt , Hacer Berna Afacan Öztürk , Lale Aydın Kaynar +7 more | Hitit Medical Journal

Objective: Acute myeloid leukemia (AML) with TP53 mutations represents a distinct and high-risk molecular subgroup characterized by aggressive disease progression, chemoresistance, and poor survival outcomes. This study provides a single-center … Objective: Acute myeloid leukemia (AML) with TP53 mutations represents a distinct and high-risk molecular subgroup characterized by aggressive disease progression, chemoresistance, and poor survival outcomes. This study provides a single-center analysis of clinical characteristics, treatment responses, and survival outcomes in a real-world cohort of patients with TP53-mutated AML. Material and Method: A retrospective observational study was conducted at Ankara Etlik City Hospital, analyzing nine patients diagnosed with TP53-mutated AML between January 2023 and January 2024. Patients were treated with intensive or less intensive induction regimens based on patient-related factors. Cytogenetic and molecular abnormalities were recorded, alongside treatment responses were assessed per the European Leukemia Net 2022 guidelines. The primary endpoint was overall survival. Results: The median age at diagnosis was 65 years, with 55.5% female patients. Complex karyotypes were observed in 66.7% of cases, and multi-hit TP53 mutations were identified in two patients. A complete response was achieved in 75% of patients treated with intensive induction therapy (7+3), while a complete or partial response was achieved in 60% of patients receiving the azacitidine-venetoclax regimen. Six patients died within 12 months, predominantly due to infection, while the three surviving patients underwent for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The median overall survival (OS) of the entire cohort was 9 months. Patients with TP53-mutated AML who underwent allo-HSCT exhibited significantly prolonged OS (p=0.01). Conclusion: The prognosisof TP53-mutated AML remains particularly poor, highlighting an urgent need for the development of novel therapeutic approaches to improve patient outcomes. While allo-HSCT offers a potential survival benefit, effective bridging therapies and post-transplant management are critical for improving outcomes in this high-risk population

CIC‐Rearrangements in Pediatric Acute Erythroid Leukemia/Erythroblastic Sarcoma

2025-06-23

Alexandra L. Chang‐Graham , Thien Nguyen , Jean Oak +2 more | Pediatric Blood & Cancer

Clinical Characteristics and Treatment Outcomes of Acute Myeloid Leukemia in Adolescent and Young Adult versus Adult Patients: A Single-Center Experience in Qatar

2025-06-23

Shehab Fareed , Abdulrahman Al‐Mashdali , Hawraa Shwaylia +7 more | Clinical Hematology International

Acute myeloid leukemia (AML) presents differently across age groups, with unique challenges in the adolescent and young adult (AYA) populations. This study compares clinical characteristics and outcomes between AYA and … Acute myeloid leukemia (AML) presents differently across age groups, with unique challenges in the adolescent and young adult (AYA) populations. This study compares clinical characteristics and outcomes between AYA and adult AML patients in Qatar. We conducted a retrospective analysis of 151 AML patients treated at the National Center for Cancer Care and Research, Qatar, between 2017-2021. Patients were divided into AYA (15-39 years, n=73) and adults (≥40 years, n=78) groups. Clinical characteristics, cytogenetic profiles, treatment approaches and survival outcomes were compared between groups. AYA patients (median age 30 years) showed distinct characteristics compared to adults (median age 53.9 years). AYA patients had lower platelet counts (62,900/mm³ versus 96,500/mm³, p=0.016) and higher blast percentages in peripheral blood and bone marrow (60% versus 40%, p=0.02). Core binding factor rearrangements were more common in AYA patients (32% versus 12%, p=0.03), while adult patients had more diploid karyotypes (55% versus 36%). AYA patients received more intensive therapy, with higher rates of FLAG-Ida salvage therapy (34% versus 15%) and allogeneic transplantation (32% versus 15%, p=0.01). While transplantation significantly improved survival in adults, its impact was less pronounced in AYA patients. Median overall survival was comparable between groups (23.14 versus 24.08 months, p=0.09). Our study reveals distinct biological and clinical characteristics between AYA and adult AML patients in Qatar. Despite receiving more intensive therapy, AYA patients showed comparable survival outcomes to adults, suggesting the need for age-specific treatment approaches. The differential impact of transplantation between age groups highlights the importance of personalized treatment strategies. These findings contribute to understanding age-specific differences in AML and may help optimize treatment approaches for both populations.

NPM1-Mutated AML: Deciphering the Molecular and Clinical Puzzle in the Era of Novel Treatment Strategies

2025-06-23

Michael D. Diamantidis , Maria Vlachou , Anastasia Katsikavela +3 more | Cancers

The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes … The aberrant localization of the mutated nucleophosmin (NPM1) protein in the cytoplasm is the hallmark of the development of acute myeloid leukemia (AML); the gene, located in the nucleolus, codes for a protein that normally shuttles between the nucleus and the cytoplasm of the normal hematopoietic cells. Patients harboring NPM1 mutations are diagnosed as having NPM1-mutated AMLs, which are types of leukemia with distinct clinical and laboratory characteristics. The essential diagnostics for investigating NPM1-mutated AMLs, the interactions with concomitant mutations affecting prognosis and the therapeutic interventions that the treatment of such patients requires are discussed in this review. Novel investigational agents in current clinical trials are also highlighted, along with the roles of exportin 1 (XPO1), menin-KMT2A inhibitors and immunotherapy in NPM1-mutated AMLs. This review focuses on critically evaluating the available data and aims to reveal the secrets of NPM1-mutated AMLs.

Comparable response rates of venetoclax 50 mg with posaconazole versus venetoclax 400 mg despite lower pharmacokinetic exposure in newly diagnosed acute myeloid leukemia: less is enough

2025-06-22

Rudra Narayan Swain , Smita Pattanaik , Arihant Jain +4 more | Leukemia & lymphoma/Leukemia and lymphoma

Early identification of TP53 mutations and TP53 allelic state in myelodysplastic neoplasms and acute myeloid leukemia via point‐of‐care p53 immunohistochemistry

2025-06-21

Shyam A. Patel , Salwa Khedr , Carmelina Gordon +7 more | Cancer

Abstract Background The prolonged turnaround time for next‐generation sequencing (NGS) results may be a barrier to the timely selection of therapeutics in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) … Abstract Background The prolonged turnaround time for next‐generation sequencing (NGS) results may be a barrier to the timely selection of therapeutics in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with mutated TP53 . Biomarker validation for early detection of TP53 mutation may have a significant impact on clinical decision‐making. Methods In this study, p53 immunohistochemistry (IHC) (index test) and TP53 NGS (referent test) were performed on 145 bone marrow specimens from 82 unique patients with TP53 ‐mutant MDS or AML to validate IHC as an early surrogate for NGS, and to assess the prognostic relevance of IHC. Results p53 IHC testing was able to correctly identify 95.5% of patients with TP53 ‐mutant MDS and 100% of patients with TP53 ‐mutant AML in this cohort. The mean p53 stain positivity was higher for AML compared to MDS (28% ± 3.67% vs. 8.8% ± 1.61%; p < .001), as well as for multihit TP53 compared to monoallelic TP53 . Bootstrap analysis with 2000 iterations showed that a p53 IHC of 7% was the threshold best associated with multihit TP53 . False‐negative results were obtained with IHC in all TP53 sole nonsense or frameshift mutations. IHC positivity was inversely correlated with overall survival (OS), with the highest quintile of p53 positivity showing a median OS of just 2.53 months. Conclusions IHC is a useful biomarker for the early detection of TP53 ‐mutant MDS or AML and for prediction of TP53 allelic state. The results suggest a role for IHC across global markets, especially in geographic areas with inaccessibility to NGS testing.

Bimekizumab

2025-06-21

| Reactions Weekly

Mesenchymal stem cells in the bone marrow microenvironment: a double-edged sword for AML

2025-06-21

Mohamed J. Saadh , Nassim Fard , Ahmed Hussein +5 more | Journal of Cancer Research and Clinical Oncology

Mesenchymal stem cells (MSCs) play a pivotal role in supporting acute myeloid leukemia (AML) cell survival, proliferation, and drug resistance through various mechanisms, including the release of soluble factors, direct … Mesenchymal stem cells (MSCs) play a pivotal role in supporting acute myeloid leukemia (AML) cell survival, proliferation, and drug resistance through various mechanisms, including the release of soluble factors, direct cell-cell interactions, and the creation of a leukemia-supportive niche. Conversely, MSCs also demonstrate potential inhibitory effects on AML, including the induction of apoptosis, cell cycle arrest, and the modulation of immune responses. These contrasting effects highlight the complexities of MSC-AML interactions and emphasize the need for further research to understand their therapeutic potential fully. Targeting MSCs represents a promising avenue for AML treatment. Strategies aimed at modifying MSC-mediated support of AML cells, such as inhibiting pro-survival signaling pathways, disrupting the leukemia-supportive niche, and enhancing the immune-stimulatory functions of MSCs, could offer novel therapeutic approaches. However, it is essential to acknowledge the limitations of current research. Further investigations are necessary to elucidate the precise mechanisms underlying the dual effects of MSCs in AML, to identify biomarkers that predict patient response to MSC-targeted therapies, and to develop strategies to overcome potential challenges associated with MSC-based interventions. In conclusion, understanding the multifaceted role of MSCs in AML pathogenesis is crucial for developing innovative therapeutic approaches. By harnessing the potential of MSCs and targeting their interactions with AML cells, we can explore novel strategies to improve treatment outcomes and enhance the overall management of this challenging hematological malignancy. This review underscores the intricate relationship between MSCs and AML within the bone marrow microenvironment.

Impact of ETV6 mutations on clinical outcomes in acute myeloid leukemia: a real-world retrospective cohort study

2025-06-21

Xue–Qian Li , Hong Wang , Haohao Han +6 more | Annals of Hematology

As a member of the ETS family, ETV6 has been demonstrated to be implicated with the molecular etiology of various hematopoietic diseases. However, the clinical impact of ETV6 mutations (ETV6mut) … As a member of the ETS family, ETV6 has been demonstrated to be implicated with the molecular etiology of various hematopoietic diseases. However, the clinical impact of ETV6 mutations (ETV6mut) in acute myeloid leukemia (AML) remains unclear. Hereon, we included 879 consecutive newly diagnosed AML patients in our institution to elucidate the prognostic impact of ETV6 mutation status. In the overall cohort, ETV6mut were found in 24 cases (2.7%) and were associated with lower hemoglobin levels. The predominant common mutation types were missense mutations (15/31, 48.4%) and frameshift mutations (14/31, 45.2%). ETV6 mutations often occurred in conjunction with U2AF1 and ASXL1 mutations. Moreover, ETV6mut was associated with a lower complete remission (CR) rate (45.8% vs. 69.1%, P = 0.015) and shorter OS (P = 0.048) compared to the ETV6 wild-type (ETV6wt) group. Notably, the achievement of CR did not contribute to survival benefit in AML with ETV6mut. In multivariate analysis, ETV6 mutation was shown to be an independent adverse factor for OS in AML patients (HR: 1.72, 95% CI: 1.03-2.89; P = 0.040). Taken together, our study shows a mutational profile of ETV6 in AML and suggests that ETV6 mutations are associated with poor prognosis in AML patients.

Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors

2025-06-20

Jaclyn Andricovich , Coen J. Lap , Alexandros Tzatsos | Blood

Identification and validation of ARF6 for a potential prognostic biomarker of acute myeloid leukemia

2025-06-20

Chike Zhang , Yang Liu , Xiaoshuang Yuan +6 more | Cancer Cell International

The small GTPase ADP-ribosylation factor 6 (ARF6) is key in cell membrane transport and cytoskeleton remodeling. It has been proven to drive the occurrence and development of a variety of … The small GTPase ADP-ribosylation factor 6 (ARF6) is key in cell membrane transport and cytoskeleton remodeling. It has been proven to drive the occurrence and development of a variety of tumors. The subject of this study is to investigate the expression characteristics, prognostic value, and mechanism of action of ARF6 in acute myeloid leukemia (AML). We investigated ARF6 expression and prognostic significance using data from databases such as Genotype-Tissue Expression, The Cancer Genome Atlas Program, Gene Expression Omnibus database, and Cancer Cell Line Encyclopedia. Then we validated ARF6 expression in AML using clinical samples and cell lines. Subsequently, functional enrichment analysis of ARF6-related differential genes was carried out to explore the potential mechanism of ARF6 in the occurrence and development of AML. The expression level of ARF6 and its function and mechanism on AML cells were investigated by in vitro cell experiments. Our findings revealed that ARF6 was upregulated in most tumors compared with matched samples from healthy individuals, and its overexpression was significantly relevant to poor survival outcomes. In AML, ARF6 expression showed correlations with age, white blood cell count, French-American-British classification, and treatment outcomes. High ARF6 expression emerged as an independent prognostic factor in Cox regression analysis. Pathway enrichment analysis denoted that ARF6 mainly contributed to cell proliferation, cell adhesion, and immune regulation, and its expression level correlated with immune cell infiltration in AML. In addition, protein-protein interaction network analysis showed that ARF6 was associated with TLR4, ITGAX, ITGAM, FCGR3A, CD86, and CD4. Experimental validation demonstrated elevated ARF6 expression in AML patient samples, and the utilization of ARF6 inhibitors in AML cells resulted in the inhibition of cell proliferation, arrest of the cell cycle, and increase of apoptosis through the PI3K/AKT/NF-κB pathway. To sum up, our results suggest that high expression of ARF6 may serve as a potential marker for poor prognosis in AML by the PI3K/AKT/NF-κB pathway. This study provides novel insights into potential targeted therapies for AML, aiming to improve the prognosis of patients with this aggressive malignancy.

Clinical significance of the transcription factor (SOX11) expression in the bone marrow of acute myeloid leukemia patients

2025-06-20

Rania S Abdel Aziz , Enas Radwan , Abdelhamid Fouad +2 more | World Journal of Clinical Oncology

BACKGROUND The prognosis for acute myeloid leukemia (AML) remains poor, underscoring the need for a deeper understanding of its underlying molecular mechanisms. AIM To assess the significance of SOX11 gene … BACKGROUND The prognosis for acute myeloid leukemia (AML) remains poor, underscoring the need for a deeper understanding of its underlying molecular mechanisms. AIM To assess the significance of SOX11 gene expression in the clinical features, response to treatment, and survival outcomes of adult patients with AML. METHODS This retrospective study enrolled 102 adults with AML. SOX11 gene expression in bone marrow samples was measured using real-time PCR. Data were correlated to the patients’ clinical features, response to treatment, and survival rates. RESULTS Increased SOX11 expression was significantly associated with the presence of the FLT3-ITD mutation (P < 0.001), the FAB-M2 subtype (P = 0.008), and cytogenetic abnormalities (P = 0.011). However, no significant association was found between SOX11 expression and other clinical laboratory parameters, complete remission, disease-free survival, or overall survival. CONCLUSION SOX11 expression may serve as a marker to identify specific subsets of AML patients who could benefit from intensive targeted chemotherapy.

Alisertib inhibits acute myeloid leukemia cell growth by inhibiting STAT3 activation

2025-06-20

Pang-Ting Cheng , Ho Lin , Yu-Chiao Cheng +6 more | Toxicology and Applied Pharmacology

State-wise disparities and temporal trends in acute myeloid leukemia (AML) in the United States of America (USA)

2025-06-20

Rupayan Kundu , Kriti Soni , Ritabrata Kundu +1 more | Leukemia & lymphoma/Leukemia and lymphoma

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. We utilized Global Burden of Diseases 2021 data to assess age-standardized incidence rates (ASIR), age-standardized death rates (ASDR) … Acute myeloid leukemia (AML) is the most common acute leukemia in adults. We utilized Global Burden of Diseases 2021 data to assess age-standardized incidence rates (ASIR), age-standardized death rates (ASDR) per 100,000 population, and annual percentage changes (APC) of ASIR and ASDR of AML across USA states. Statistical modeling, including 2 two-sample t-test, was done. In 2021, the USA reported 21,533 AML cases (ASIR: 3.85) and 16,648 deaths (ASDR: 2.91). Both ASIR and ASDR increased from 1990 to 2021, particularly among individuals aged 70 years and older. In 2021, Kentucky and West Virginia had the highest ASIR and ASDR, respectively. From 1900 to 2021, metabolic risks related to AML death increased, while behavioral and occupational risks related to death declined. The growing AML burden in the USA, especially among older adults, underscores the need for age-sensitive care, preventive strategies targeting modifiable risks like obesity and smoking, and equitable healthcare access across states.

Impact of fludarabine dose on outcome after allo-HSCT with reduced intensity conditioning for older patients with AML

2025-06-19

Guillaume Dachy , Myriam Labopin , Gèrard Socié +7 more | Bone Marrow Transplantation

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia

2025-06-19

Shellaina J. V. Gordon , Florian Perner , Laura MacPherson +7 more | Cancer Discovery

Abstract Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range … Abstract Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

Radiotherapy for Orbital Myeloid Sarcoma as Extramedullary Relapse in a Pediatric Acute Myeloid Leukemia Patient Post-haploidentical Bone Marrow Transplantation

2025-06-19

M Ghafouri , Ramesh Boggula , C. Nagle +2 more | Cureus

Extramedullary Relapse of CBFA2T3::GLIS2-Positive Megakaryoblastic Leukemia Mimicking Secondary Ewing Sarcoma: An Exemplary Case for the Diagnostic Trap

2025-06-19

Svetlana Lebedeva , Ekaterina Mikhailova , Sophia Bogacheva +7 more | International Journal of Molecular Sciences

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a … In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of CBFA2T3::GLIS2-positive AMKL is the RAM immunophenotype, which looks very similar to that of solid-tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of CBFA2T3::GLIS2-positive AMKL, excluding solid tumors may be challenging. We report a case of a girl with isolated extramedullary CBFA2T3::GLIS2-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presented significant challenges owing to their overlapping histological features (small, round blue-cell morphology and similar growth patterns). The tumor cells' immunophenotype completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the CBFA2T3::GLIS2 fusion, but no Ewing sarcoma-specific EWSR1, FUS and CIC fusion transcripts were found. Thus, extramedullary CBFA2T3::GLIS2-positive AMKL relapse was confirmed. The presented case demonstrates the difficulties in differential diagnosis between AMKL relapse and the development of a secondary tumor.

TET2 mutation does not impact the prognosis of adult acute myeloid leukemia patients receiving a hematopoietic stem cell transplantation in first remission: similar outcome following matched sibling and unrelated versus haploidentical donor transplants in a multi-center retrospective analysis from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

2025-06-19

Lin Li , Yishan Ye , Jacques‐Emmanuel Galimard +7 more | Haematologica

Not available. Not available.

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells

2025-06-19

Kellen Gil , Jamie Borg , Rosana Moreira Pereira +7 more | Haematologica

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem … Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3’s mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.

Understanding therapy-related AML: genetic insights and emerging strategies for high-risk patients

2025-06-19

Joaquín Jerez , Céline Hernandez , Caterina Hill | Frontiers in Hematology

Therapy-related acute myeloid leukemia (t-AML) is a complex clinical entity characterized by its association with prior exposure to cytotoxic agents or radiotherapy. Recent analyses have unveiled the intricate molecular landscape … Therapy-related acute myeloid leukemia (t-AML) is a complex clinical entity characterized by its association with prior exposure to cytotoxic agents or radiotherapy. Recent analyses have unveiled the intricate molecular landscape of t-AML, revealing a heterogeneous genetic profile marked by mutations in TP53, PPM1D, and other genes. While t-AML does not constitute a distinct molecular entity, its prognostic impact is integrated into current risk classifications, with particular emphasis on TP53 mutations. Treatment strategies should be guided by the underlying biology of the disease rather than solely by clinical history. The significance of t-AML lies in its role as a qualifying condition rather than an independent disease entity. Its association with germline mutations and clonal hematopoiesis of indeterminate potential represents an emerging and promising field for developing preventive and monitoring strategies. The standard therapeutic approach for t-AML has evolved, with promising alternatives emerging. The CPX-351 regimen has demonstrated superior outcomes compared to conventional 3 + 7 induction therapy in selected patients. The incorporation of Venetoclax, both in combination with hypomethylating agents and in high- or low-intensity chemotherapy regimens, has shown efficacy in high-risk AML, including t-AML cases; however, its validity must be confirmed in prospective studies. Allogeneic hematopoietic stem cell transplantation remains a crucial consolidation strategy. Participation in clinical trials is of paramount importance to optimize management strategies for this high-risk AML subset.

Effect of the IDH1 inhibitor combined with hypomethylating agents on acute myeloid leukemia

2025-06-19

Yan Cheng , Hongwei Wu | Tumori Journal

Objective: Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This … Objective: Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This study delves into the mechanism of IVO with hypomethylating agents (HMAs) (azacitidine or decitabine) for treating IDH1-mutated AML through the PI3K/AKT pathway. Methods: IDH1 R132H -mutated MOLM-13 (IDH1 R132H -MOLM-13) cells were constructed. The effects of the drugs, both individually and in combination, on IDH1 R132H -MOLM-13 cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry, with combination index (CI) values calculated using CompuSyn software. IDH1 , DNMT1 , PI3K and AKT gene mRNA levels, and the PI3K/AKT pathway- and histone lysine methylation-related protein levels in IDH1 R132H -MOLM-13 cells were determined by RT-qPCR and Western blot. Results: IDH1 R132H -mutated MOLM-13 cells (IDH1 R132H -MOLM-13) were successfully constructed. The IDH1 inhibitor, either as a monotherapy or combined with HMAs, effectively inhibited IDH1 R132H -MOLM-13 cell proliferation, and the combination therapy exhibited synergistic effects (CI < 1). The combination therapy increased cell proportion in the G2/M phase and apoptotic rate. Both treatment modalities reduced IDH1 , DNMT1 , PI3K and AKT mRNA levels and histone lysine methylation levels (H3K4me3, H3K9me3, H3K27me3); besides, PI3K and AKT phosphorylation levels were reduced, with the reductions being more significant in cells undergoing combination therapy. The indexes did not differ significantly between cells undergoing the two modalities of combined treatments. Conclusion: The IDH1 inhibitor with HMAs suppressed IDH1 R132H -MOLM-13 cell proliferation and viability and decreased the methylation level by repressing the phosphorylation of the PI3K/AKT pathway, showing a synergistic inhibitory effect.

Beyond Standard Protocols: Real-world Challenges and Innovative Solutions in Pediatric Leukemia Management - “Experience from a Tertiary Oncology Center Integrating MRD-guided Therapy and Novel Agents”

2025-06-19

Shweta Pathak , C. Charles Jain , Vidya Kumari Saurav - +4 more | International Journal For Multidisciplinary Research

Background: Pediatric acute leukemias represent a heterogeneous group of malignancies with variable prognoses. Although survival rates have improved significantly with risk-adapted protocols and advances in supportive care, management becomes complicated … Background: Pediatric acute leukemias represent a heterogeneous group of malignancies with variable prognoses. Although survival rates have improved significantly with risk-adapted protocols and advances in supportive care, management becomes complicated in the presence of comorbidity, age-related challenges, or rare molecular subtypes. Objective: To present three pediatric cases—infantile AML, ALL in a child with Down syndrome, and APML with differentiation syndrome—demonstrating diagnostic dilemmas, therapeutic challenges, and the potential of modified regimens. Methods: Retrospective descriptive case series at a tertiary pediatric oncology unit, examining clinical profiles, treatment adaptations, and outcomes. Results: All patients achieved remission. Two required significant modifications due to toxicity or preexisting conditions. Integration of MRD-guided strategies, novel therapeutic agents like azacitidine and venetoclax, and aggressive management of complications led to favorable outcomes. Conclusion: Personalized protocols, vigilant monitoring, and early recognition of complications are essential in pediatric leukemia care. Incorporation of newer agents may rescue patients where traditional therapies fail or are poorly tolerated.

Optimal timing of allogeneic hematopoietic stem cell transplant in MDS

2025-06-19

Kristin Rathje , Nicolaus Kröger | Leukemia & lymphoma/Leukemia and lymphoma

Myelodysplastic neoplasms (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, dysplasia, and a significant risk of progression to acute myeloid leukemia. Allogeneic hematopoietic stem cell transplant (HSCT) remains the … Myelodysplastic neoplasms (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, dysplasia, and a significant risk of progression to acute myeloid leukemia. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative therapy for MDS, particularly for higher-risk disease, but its success depends heavily on the timing of the procedure. This review explores the evolving evidence and decision models guiding the optimal timing of HSCT, balancing the risks of disease progression and transplant-related morbidity and mortality. Key considerations include advancements in disease-specific and transplant-specific risk stratification, such as the IPSS-M and transplant-specific scoring systems, which integrate clinical, cytogenetic, and molecular data to personalize timing decisions. Improvements in haploidentical HSCT and supportive care have expanded the feasibility and safety of HSCT for diverse patient populations, including the elderly. Prospective trials underscore the survival benefits of HSCT over non-transplant approaches for higher-risk MDS, while ongoing studies aim to address uncertainties in pretreatment, post-transplant maintenance therapy, and donor selection. By synthesizing these developments, this review provides practical insights into optimizing HSCT timing to improve outcomes for MDS patients.

Access to AlloTx for AML: the value of the social phenotype

2025-06-19

Gary J. Schiller | Blood

Impact of Time to Treatment Initiation on Quality of Response in Patients with Acute Myeloid Leukemia Receiving Intensive Chemotherapy

2025-06-18

Elisa Buzzatti , Giovangiacinto Paterno , Raffaele Palmieri +7 more | Cancers

Acute myeloid leukemia (AML) necessitates timely treatment, yet the impact of prolonged time to treatment (TTT) on clinical outcomes remains debated, especially its impact on achieving measurable residual disease (MRD) … Acute myeloid leukemia (AML) necessitates timely treatment, yet the impact of prolonged time to treatment (TTT) on clinical outcomes remains debated, especially its impact on achieving measurable residual disease (MRD) negativity, a powerful prognostic indicator in AML. This retrospective study analyzed 196 adult AML patients treated with intensive chemotherapy, evaluating the effect of TTT on outcome measures and quality of response. TTT was categorized arbitrarily into <8, 8-14, and >14 days. Results showed a median TTT of 11 days. Median overall survival (OS) was 414 days, with no significant differences among TTT groups (p = 0.48). Complete remission rate was 75.5%, with significantly higher rates in patients treated within 14 days (p = 0.004 and p = 0.006 for 8-14 and <8 days, respectively) compared to >14 days. MRD was assessed in 140 patients, with 35% achieving negativity, and no significant differences observed among TTT groups. This study suggests that a treatment delay of up to 14 days does not negatively impact OS or MRD negativity. This timeframe potentially allows for thorough patient evaluation, including detailed genetic profiling and comorbidity assessment, facilitating a more personalized and optimized therapeutic strategy.

Different Immunotherapeutic Combinations Enhance Specific T Cell Immune Responses Against Leukemic Cells, as well as Leukemic Progenitor and Stem Cells, in Acute Myeloid Leukemia

2025-06-18

Jochen Greiner , Patrick J. Schuler , Hubert Schrezenmeier +4 more | Research Square (Research Square)

<title>Abstract</title> Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukaemia (AML). Despite being shown to be effective in the context of stem cell … <title>Abstract</title> Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukaemia (AML). Despite being shown to be effective in the context of stem cell transplants for almost 50 years, further improvements are required to prevent relapse and its associated morbidity. The therapeutic use of immune checkpoint inhibition in AML is still under debate. We have shown some positive effects of it on cancer control <italic>ex vivo</italic>. We found that anti-programmed death-1 (PD-1) antibodies in combination with azacitidine (AZA) had the most pronounced effect on T-cell activation and control of leukemic progenitor/ stem cell growth. We identified which leukemia-associated antigen (LAA) stimulated the largest IFNg immune response by T cells from AML patients with and without the nucleophosmin 1 (NPM1) mutation and which immunotherapeutic strategy, either alone or in combination with anti-PD-1, could enhance immune responses against leukemic cells and leukemic progenitor/stem cells. Anti-PD-1 with AZA had a particularly strong effect with a mean colony reduction of 56% (range: 0-100%). Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells but also leukaemic progenitor/stem cells. Especially the combination of LAA-peptides with anti-PD-1 antibody and one further immunotherapeutic could be an interesting option for further clinical studies.

Genomic Profile and Clinical Outcomes in Acute Myeloid Leukemia with Monosomal Karyotype

2025-06-18

Collins Wangulu , Ehsan Bahrami Hezaveh , Mojgan Zarif +5 more | International Journal of Molecular Sciences

The biology of Monosomal Karyotype Acute Myeloid Leukemia (MK AML) remains unclear, and its mutational profile has not been exclusively assessed. We sought to determine the genomic profile of MK … The biology of Monosomal Karyotype Acute Myeloid Leukemia (MK AML) remains unclear, and its mutational profile has not been exclusively assessed. We sought to determine the genomic profile of MK AML patients and its correlation with overall survival (OS). We conducted a retrospective study involving 664 AML patients, identifying 156 (23.5%) with MK AML. The most common monosomies were -17 (41%) and -7 (37%), with 149 (95%) and 138 (88%) having myelodysplasia-related (MR) cytogenetics and complex karyotype (CK), respectively. Frequent mutations included TP53 (69%), DNMT3A (19%), TET2 (13%), and IDH1 (7%). Patients with MK AML with TP53 mutation (TP53 Mut) had shorter OS compared to those with TP53 wild-type (WT) (median OS, 3.9 versus 9.2 months, p = 0.002). Our validation study further supports this finding. There was no significant difference in OS related to the presence or absence of CK (p = 0.252), MR mutations (p = 0.252), DNMT3A (p = 0.264), TET2 (p = 0.264), and IDH1 (p = 0.183) alterations. Co-mutation with novel EPI6 and TAZI signature alterations did not significantly impact OS among MK AML TP53 Mut patients, suggesting that TP53 Mut remains the dominant driver of outcome in this subgroup. In conclusion, MK AML is a genotypically diverse and high-risk group, with MK AML TP53 Mut indicating worse prognosis.

Advances and challenges in the treatment of myelodysplastic syndromes

2025-06-18

Rohit Thalla , Ryan Mack , Jorgena Kosti-Schwartz +2 more | Experimental Hematology and Oncology

Abstract Myelodysplastic syndromes (MDS) is a heterogeneous group of pre-leukemic diseases characterized by peripheral blood cytopenia, morphologic dysplasia, and an increased risk of transformation to leukemia. MDS develop from genetically … Abstract Myelodysplastic syndromes (MDS) is a heterogeneous group of pre-leukemic diseases characterized by peripheral blood cytopenia, morphologic dysplasia, and an increased risk of transformation to leukemia. MDS develop from genetically mutant clonal hematopoietic stem and progenitor cells (HSPCs) which have defects in generating mature functional blood cells due to impaired differentiation and/or survival activities. In addition, mutant HSPCs also inhibit the generation of new blood cells from remaining healthy HSPCs. Thus, the complete elimination of mutant HSPCs is the optimal goal for MDS treatment. However, most current therapies for MDS are little more than palliative, primarily addressing cytopenia-related symptoms and improving the quality of life. Only the hypomethylating agents (HMA) lenalidomide and imetelstat reduced the mutational burden, and then only in a small subset of cases. Many HMA-based combination therapies failed to show benefits superior to single-agent HMA treatment in clinical trials. At the present time, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only cure for the minority of qualified patients who have HLA-matched donors. Novel effective treatments are urgently needed. Here we summarize the current standard therapeutic approaches for MDS patients and discuss major advances in MDS research and treatments. We also discuss major challenges and potential solutions to overcome these challenges for future MDS research and drug development.

MARCH1, transcriptionally regulated by POU2F2, facilitates acute myeloid leukemia progression via inducing MYCT1 degradation

2025-06-18

Jianing Liu , Jianan Xu , Rongcan Sun +7 more | Oncogene

E2f coordinates the cell cycle and cell fate of hematopoietic progenitors to drive stress myelopoiesis

2025-06-18

Annick Cachon , Glaucius Oliva , Eunsun Kim +7 more | bioRxiv (Cold Spring Harbor Laboratory)

ABSTRACT During inflammation, cytokines such as Tnfα, Il1β and Il6 stimulate hematopoietic stem and progenitor cells (HSPCs) to proliferate and accelerate the production of inflammatory cells from the myeloid lineage … ABSTRACT During inflammation, cytokines such as Tnfα, Il1β and Il6 stimulate hematopoietic stem and progenitor cells (HSPCs) to proliferate and accelerate the production of inflammatory cells from the myeloid lineage through a process called stress myelopoiesis. Genetic inactivation of repressors of cell cycle activity in HSPCs is sufficient to recapitulate stress myelopoiesis, suggesting that the cell cycle activity and cell fate decision of proliferative HSPCs are coordinated by a cell intrinsic mechanism. However, the nature of this mechanism remains unknown. Here, we show that E2f simultaneously regulates proliferation of HSPCs, repression of alternative cell fates via the activation of Suz12 / Ezh2 -containing PRC2 complex and promotion of the myeloid fate by enhancing the signaling activity of CD131, the common βchain receptor for βcytokines (i.e. Il3 and Gm-Csf). Accordingly, dual inhibition of Ezh2 and βcytokine signaling activity in a preclinical model of colitis represses stress myelopoiesis and restores colon homeostasis. Our results suggest that dual targeting of βcytokine signaling and Ezh2 activity represents a novel therapeutic strategy to repress the production of pro-inflammatory myeloid cells in a wide spectrum of inflammatory diseases.

Bone marrow microenvironment-responsive polymeric-drug/siRNA regulate leukemia stem cells assisting for prevention of AML relapse

2025-06-18

Shihong Cheng , Xiaohan Kong , Yiqiu Zhang +7 more | Biomaterials