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Blood May 2024The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid... (Review)
Review
The spectrum of myeloid disorders ranges from aplastic bone marrow failure characterized by an empty bone marrow completely lacking in hematopoiesis to acute myeloid leukemia in which the marrow space is replaced by undifferentiated leukemic blasts. Recent advances in the capacity to sequence bulk tumor population as well as at a single-cell level has provided significant insight into the stepwise process of transformation to acute myeloid leukemia. Using models of progression in the context of germ line predisposition (trisomy 21, GATA2 deficiency, and SAMD9/9L syndrome), premalignant states (clonal hematopoiesis and clonal cytopenia of unknown significance), and myelodysplastic syndrome, we review the mechanisms of progression focusing on the hierarchy of clonal mutation and potential roles of transcription factor alterations, splicing factor mutations, and the bone marrow environment in progression to acute myeloid leukemia. Despite major advances in our understanding, preventing the progression of these disorders or treating them at the acute leukemia phase remains a major area of unmet medical need.
Topics: Humans; Disease Progression; Preleukemia; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Animals; Precancerous Conditions; Mutation; Cell Transformation, Neoplastic
PubMed: 38498034
DOI: 10.1182/blood.2023020817 -
Hematology. American Society of... Dec 2023Atypical chronic myeloid leukemia (aCML) is included in the group of myelodysplastic/myeloproliferative neoplasms by the International Consensus Classification and has...
Atypical chronic myeloid leukemia (aCML) is included in the group of myelodysplastic/myeloproliferative neoplasms by the International Consensus Classification and has been renamed as MDS/MPN with neutrophilia by the fifth edition of World Health Organization classification. It is always characterized by morphologic identification of granulocytic dysplasia with >10% circulating immature myeloid cells, 2 distinguished features that differentiate this disease among the others. Somatic mutations may help to diagnose but are not specifically pathognomonic of the disease, with the most detected including ASXL1, SETBP1, NRAS, KRAS, SRSF2, and TET2 and with low-frequency CBL, CSF3R, JAK2, and ETNK1. The genomic landscape of aCML has been recently unravelling, revealing that SETBP1 and ETNK1 are usually not ancestral but secondary events associated with disease progression. Unfortunately, until now, no consensus on risk stratification and treatment has been developed: Mayo Clinic prognostic score identified as adverse events age >67 years, hemoglobin level <10 g/dL, and TET2 mutations. Although some possible genetic markers have been identified, allogeneic transplant remains the only curative strategy.
Topics: Humans; Aged; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myelodysplastic-Myeloproliferative Diseases; Mutation; Prognosis; Disease Progression
PubMed: 38066919
DOI: 10.1182/hematology.2023000448 -
Clinics in Laboratory Medicine Dec 2023Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms characterized by clonal hematopoiesis and abnormal maturation of hematopoietic cells, resulting in... (Review)
Review
Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms characterized by clonal hematopoiesis and abnormal maturation of hematopoietic cells, resulting in cytopenias. The transformation of MDS to acute myeloid leukemia (AML) reflects a progressive increase in blasts due to impaired maturation of the malignant clone, and thus MDS and many AML subtypes form a biological continuum rather than representing two distinct diseases. Recent data suggest that, in addition to previously described translocations, NPM1 mutations and KMT2A rearrangements are also AML-defining genetic alterations that lead to rapid disease progression, even if they present initially with less than 20% blasts. While some adult patients <20% blasts can be treated effectively with intensive AML-type chemotherapy, in the future, treatment of individual patients in this MDS/AML group will likely be dictated by genetic, biological, and patient-related factors rather than an arbitrary blast percentage.
Topics: Adult; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Mutation
PubMed: 37865509
DOI: 10.1016/j.cll.2023.07.001 -
Current Hematologic Malignancy Reports Oct 2023CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic... (Review)
Review
PURPOSE OF REVIEW
CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic and familial AML.
RECENT FINDINGS
Due to the recent advances in molecular testing and the prognostic role of CEBPA mutation in AML, the definition for AML with CEBPA mutation (AML-CEBPA) has significantly changed. This review provides the rationale for the updates on classifications, and the impacts on laboratory evaluation and clinical management for sporadic and familial AML-CEBPA patients. In addition, minimal residual disease assessment post therapy to stratify disease risk and stem cell transplant in selected AML-CEBPA patients are discussed. Taken together, the recent progresses have shifted the definition, identification, and management of patients with AML-CEBPA.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; CCAAT-Enhancer-Binding Proteins; Prognosis
PubMed: 37261703
DOI: 10.1007/s11899-023-00699-3 -
Blood Reviews Jul 2023MDS and AML are clonal hematopoietic stem cell disorders of increasing incidence, having a variable prognosis based, among others, on co-occurring molecular... (Review)
Review
MDS and AML are clonal hematopoietic stem cell disorders of increasing incidence, having a variable prognosis based, among others, on co-occurring molecular abnormalities. TP53 mutations are frequently detected in these myeloid neoplasms and portend a poor prognosis with known therapeutic resistance. This article provides a timely review of the complexity of TP53 alterations, providing updates in diagnosis and prognosis based on new 2022 International Consensus Classification (ICC) and World Health Organization (WHO) guidelines. The article addresses optimal testing strategies and reviews current and arising therapeutic approaches. While the treatment landscape for this molecular subgroup is under active development, further exploration is needed to optimize the care of this group of patients with unmet needs.
Topics: Humans; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Mutation; Myeloproliferative Disorders; Prognosis; Tumor Suppressor Protein p53
PubMed: 36841672
DOI: 10.1016/j.blre.2023.101055 -
Blood Jul 2023
Topics: Humans; Leukemia, Myeloid, Acute; Genomics
PubMed: 37410505
DOI: 10.1182/blood.2023020672 -
Clinics in Laboratory Medicine Dec 2023The genetic underpinnings of myeloid neoplasms are becoming increasingly well understood. The accessibility to sequencing technology, in particular next-generation... (Review)
Review
The genetic underpinnings of myeloid neoplasms are becoming increasingly well understood. The accessibility to sequencing technology, in particular next-generation sequencing (NGS), has highlighted the importance of gene mutations in myelodysplastic syndromes (MDS) in conjunction with traditional cytogenetics. With the relatively recent influx of molecular information to complement known cytogenetic abnormalities, the diagnosis, classification, and prognosis of MDS and acute myeloid leukemia (AML) have been increasingly refined, which has also led to therapeutic advancements. It has been shown that TP53 mutations have a significant impact in cases of MDS, as well as AML, and have led to TP53-defined myeloid disease. TP53 mutations are also now incorporated into prognostic scoring systems, as patients have been shown to have aggressive disease and poor outcomes. With the increased understanding of the importance of TP53 disruption in myeloid neoplasia, it is likely that the critical role of TP53 will continue to be highlighted by an individual's disease classification and personalized therapeutic management.
Topics: Humans; Mutation; Chromosome Aberrations; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Prognosis; Tumor Suppressor Protein p53
PubMed: 37865506
DOI: 10.1016/j.cll.2023.07.004 -
Cancer Cell Nov 2023Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop...
Chimeric antigen receptor (CAR) T cell therapies are limited by antigen escape and on-target/off-tumor toxicity. In addressing these challenges, Haubner et al. develop an "IF-BETTER" strategy. Their combinatorial chimeric co-stimulatory receptor with an attenuated CAR enhances acute myeloid leukemia (AML) killing while protecting healthy progenitors, highlighting the potential to leverage cooperative CAR designs.
Topics: Humans; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive
PubMed: 37832553
DOI: 10.1016/j.ccell.2023.09.015 -
Bulletin Du Cancer Nov 2023Myelodysplastic syndromes (MDS) are clonal stem cell diseases that primarily affect the elderly. They are classified into low- and high-risk MDS according to prognostic... (Review)
Review
Myelodysplastic syndromes (MDS) are clonal stem cell diseases that primarily affect the elderly. They are classified into low- and high-risk MDS according to prognostic scoring systems. In high-risk patients, treatment should aim to modify the course of the disease by preventing progression to acute myeloid leukemia, and thus improve survival. Stem cell transplantation remains the only curative treatment when possible, but this concerns a small minority of patients. Treatment is mainly based on hypomethylating agents (HMA). Our understanding of the biology of MDS has led to the development of drugs targeting key cellular processes such as apoptosis or post-translational modifications of proteins, the microenvironment and genetic mutations. Currently, new drugs are mainly tested in combination with HMAs in several clinical trials and, although none has yet obtained marketing authorization, many molecules seem promising.
Topics: Humans; Aged; Antimetabolites, Antineoplastic; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Marketing; Tumor Microenvironment
PubMed: 37407322
DOI: 10.1016/j.bulcan.2023.02.029 -
Expert Review of Anticancer Therapy 2023Patients with myeloid neoplasms such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) are generally older, and many are not eligible for... (Review)
Review
INTRODUCTION
Patients with myeloid neoplasms such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) are generally older, and many are not eligible for curative intent intensive therapies and/or allogeneic hematopoietic stem cell transplantation. While lower intensity, hypomethylating agent (HMA)-based therapies such as azacitidine+venetoclax have improved patient outcomes significantly, responses are not durable, and most patients die from disease-related complications. The approvals of oral HMAs such as cedazuridine-decitabine (C-DEC) and oral azacitidine (CC-486) have kindled the hope that myeloid malignancies may soon be treated with total oral therapy.
AREAS COVERED
We review all-oral therapies including the approvals of C-DEC and CC-486 in MDS and AML, respectively, in addition to emerging all-oral therapies, both monotherapy and combination, in higher-risk (HR) MDS and AML.
EXPERT OPINION
Oral HMAs have the potential to be a convenient and efficacy-equivalent treatment option for patients with HR-MDS or AML and improve their quality of life by reducing clinic visits for medication administration. Total-oral therapy combinations, largely including an oral HMA 'backbone,' are in the early phases of clinical development, and it is our hope that well-designed trials employing these agents may soon allow the identification of optimal regimens that deliver effective disease-directed therapy with good tolerability.
Topics: Humans; Quality of Life; Azacitidine; Myelodysplastic Syndromes; Decitabine; Leukemia, Myeloid, Acute
PubMed: 37470508
DOI: 10.1080/14737140.2023.2238897