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Blood Jul 2021VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic disease of adulthood caused by somatic mutations in UBA1 in hematopoietic... (Review)
Review
VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic disease of adulthood caused by somatic mutations in UBA1 in hematopoietic progenitor cells. Patients develop inflammatory and hematologic symptoms. Myeloid-driven autoinflammation and progressive bone marrow failure lead to substantial morbidity and mortality. Effective medical treatments need to be identified. Reports in the current issue of Blood describe novel UBA1 genetic variants, treatment options, and insight into disease pathophysiology. VEXAS syndrome represents a prototype for a new class of diseases.
Topics: Erythroid Cells; Genes, X-Linked; Genetic Diseases, Inborn; Humans; Male; Mutation; Myeloid Cells; Myeloproliferative Disorders; Syndrome; Ubiquitin-Activating Enzymes
PubMed: 33971000
DOI: 10.1182/blood.2021011455 -
Expert Review of Clinical Immunology Feb 2023VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in... (Review)
Review
INTRODUCTION
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in the gene. The various clinical manifestations of VEXAS broadly divided into inflammatory or haematological. VEXAS defines a new disease category - the hematoinflammatory disorders triggered by somatic mutations restricted to blood but causing systemic inflammation with multi-organ involvement and associated with aberrant bone marrow status. VEXAS causes significant morbidity and reduced life expectancy, but the optimum standard of care remains undefined.
AREAS COVERED
This review describes the discovery of VEXAS, relevant genetic causes and immunopathology of the disease. A detailed account of its various clinical manifestations and disease mimics is provided. Current treatment and management options are discussed.
EXPERT OPINION
New rare variants in and VEXAS-like negative cases are reported. Consensus diagnostic criteria might be required to define VEXAS and its related disorders. Investigation of sporadic, VEXAS-like cases will require the application of deep sequencing using DNA obtained from various cellular or tissue locations. Prospective studies are needed to define the optimal supportive and treatment options for patients with varying disease severity and prognosis. VEXAS-specific hematopoietic stem cell transplant selection criteria also require development.
Topics: Humans; Consensus; Inflammation; Mutation; Myelodysplastic Syndromes
PubMed: 36537591
DOI: 10.1080/1744666X.2023.2157262 -
American Journal of Hematology Mar 2022Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative... (Review)
Review
DISEASE OVERVIEW
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years).
DIAGNOSIS
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 10 /L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.
RISK-STRATIFICATION
Molecularly integrated prognostic models include the Groupe Français des Myélodysplasies, Mayo Molecular Model (MMM), and the CMML specific prognostic model. Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 10 /L, hemoglobin <10 g/dL, platelet count <100 × 10 /L, and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups: high (≥3 risk factors), intermediate-2 (2 risk factors), intermediate-1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.
RISK-ADAPTED THERAPY
Hypomethylating agents such as 5-azacitidine and decitabine are commonly used, with overall response rates of ~40%-50% and complete remission rates of ~7%-17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality.
Topics: Chromosome Aberrations; Disease-Free Survival; Humans; Leukemia, Myelomonocytic, Chronic; Neoplasm Proteins; Risk Assessment; Risk Factors; Survivors
PubMed: 34985762
DOI: 10.1002/ajh.26455 -
La Clinica Terapeutica 2022The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone.... (Review)
Review
The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone. We can find bone marrow edema in many musculoskeletal diseases such as Inflammatory and Rheumatic diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis (BMLs) and Bone Marrow Edema Syndromes (BMES). This classification is based on pathophysiological, histological and clinical differences despite the same imaging evidence. The distinction is useful also in terms of treatment. Bisphosphonates in association with NSAIDs or corticosteroids are the main therapy while TNF-a Inhibitors are used for the specific inflammatory origin. Bone marrow edema has become an important aspect to consider in the diagnostic path of the main musculoskeletal diseases. This paper starts from a systematic review of literature. We chose the most decisive contributions in order to develop a better description of the pathogenetic features about this "new" evidence.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow; Bone Marrow Diseases; Diphosphonates; Edema; Humans; Magnetic Resonance Imaging; Male; Osteoarthritis, Knee
PubMed: 36155729
DOI: 10.7417/CT.2022.2459 -
Medicina (Kaunas, Lithuania) Sep 2023Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins... (Review)
Review
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal hematopoietic disorder characterized by the lack of glycosylphosphatidylinositol-anchored proteins (GPI-APs) as a consequence of somatic mutations in the phosphatidylinositol glycan anchor biosynthesis class A () gene. Clinical manifestations of PNH are intravascular hemolysis, thrombophilia, and bone marrow failure. Treatment of PNH mainly relies on the use of complement-targeted therapy (C5 inhibitors), with the newest agents being explored against other factors involved in the complement cascade to alleviate unresolved intravascular hemolysis and extravascular hemolysis. This review summarizes the biology and current treatment strategies for PNH with the aim of reaching a general audience with an interest in hematologic disorders.
Topics: Humans; Hemoglobinuria, Paroxysmal; Hemolysis; Complement System Proteins; Thrombophilia; Glycosylphosphatidylinositols; Biology
PubMed: 37763731
DOI: 10.3390/medicina59091612 -
Annals of Laboratory Medicine May 2022Myelodysplastic syndrome (MDS) is a diverse hematological malignancy with a wide spectrum of presentations and implications. Treatment strategies for patients with MDS... (Review)
Review
Myelodysplastic syndrome (MDS) is a diverse hematological malignancy with a wide spectrum of presentations and implications. Treatment strategies for patients with MDS heavily rely on prognostic scoring systems, such as the revised international prognostic scoring system (IPSS-R). Bone marrow fibrosis (BMF) has been identified as an independent risk factor for poor survival in patients with MDS, irrespective of the IPSS-R risk category. However, BMF is not widely included in scoring systems and is not always considered by clinicians when making treatment decisions for patients. In this review, we discuss the available literature about the presentation and prognosis of patients with MDS and concurrent BMF. The prognostic impact of BMF should be factored in when deciding on transplant candidacy, especially for intermediate-risk patients.
Topics: Humans; Myelodysplastic Syndromes; Primary Myelofibrosis; Prognosis; Risk Factors
PubMed: 34907099
DOI: 10.3343/alm.2022.42.3.299 -
Hematology. American Society of... Dec 2021Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid...
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit-erythroid and colony forming unit-erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.
Topics: Adult; Anemia, Diamond-Blackfan; Bone Marrow; Bone Marrow Transplantation; Child, Preschool; Disease Management; Female; Humans; Infant; Male; Mutation; Ribosomal Proteins
PubMed: 34889440
DOI: 10.1182/hematology.2021000314 -
Annals of Hematology Aug 2023Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow,... (Review)
Review
Myeloid sarcoma (MS) is a distinct entity among myeloid neoplasms defined as a tumour mass of myeloid blasts occurring at an anatomical site other than the bone marrow, in most cases concomitant with acute myeloid leukaemia (AML), rarely without bone marrow involvement. MS may also represent the blast phase of chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, the clinical and molecular heterogeneity of AML, as highlighted by the 2022 World Health Organization (WHO) and International Consensus (ICC) classifications, indirectly define MS more as a set of heterogeneous and proteiform diseases, rather than a homogeneous single entity. Diagnosis is challenging and relies mainly on histopathology, immunohistochemistry, and imaging. Molecular and cytogenetic analysis of MS tissue, particularly in isolated cases, should be performed to refine the diagnosis, and thus assign prognosis guiding treatment decisions. If feasible, systemic therapies used in AML remission induction should be employed, even in isolated MS. Role and type of consolidation therapy are not univocally acknowledged, and systemic therapies, radiotherapy, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered. In the present review, we discuss recent information on MS, focusing on diagnosis, molecular findings, and treatments also considering targetable mutations by recently approved AML drugs.
Topics: Humans; Sarcoma, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37286874
DOI: 10.1007/s00277-023-05288-1 -
JAMA Jan 2023VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic... (Observational Study)
Observational Study
IMPORTANCE
VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.
OBJECTIVE
To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.
EXPOSURES
Exome sequencing was performed.
MAIN OUTCOMES AND MEASURES
Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.
RESULTS
In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).
CONCLUSIONS AND RELEVANCE
This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
Topics: Female; Humans; Male; Biopsy; Electronic Health Records; Prevalence; Myelodysplastic Syndromes; Ubiquitin-Activating Enzymes; Mutation; Retrospective Studies; Exome; Middle Aged; Skin Diseases, Genetic; United States
PubMed: 36692560
DOI: 10.1001/jama.2022.24836 -
Haematologica Jul 2022Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an...
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by sustained peripheral blood monocytosis and an inherent risk for transformation to acute myeloid leukemia (15-30% over 3-5 years). While CMML is morphologically classified into CMML-0, 1 and 2 based on peripheral blood and bone marrow promonocyte/blast counts, a more clinically relevant classification into dysplastic and proliferative subtypes, based on the presenting white blood cell count, is helpful in prognostication and therapeutics. CMML is a neoplasm associated with aging, occurring on the background of clonal hematopoiesis, with TET2 and SRSF2 mutations being early initiating events. The subsequent acquisitions of ASXL1, RUNX1, SF3B1 and DNMT3A mutations usually give rise to dysplastic CMML, while ASXL1, JAK2V617F and RAS pathway mutations give rise to proliferative CMML. Patients with proliferative CMML have a more aggressive course with higher rates of transformation to acute myeloid leukemia. Allogeneic stem cell transplant remains the only potential cure for CMML; however, given the advanced median age at presentation (73 years) and comorbidities, it is an option for only a few affected patients (10%). While DNA methyltransferase inhibitors are approved for the management of CMML, the overall response rates are 40-50%, with true complete remission rates of <20%. These agents seem to be particularly ineffective in proliferative CMML subtypes with RAS mutations, while the TET2mutant/ASXL1wildtype genotype seems to be the best predictor for responses. These agents epigenetically restore hematopoiesis in responding patients without altering mutational allele burdens and progression remains inevitable. Rationally derived personalized/targeted therapies with disease-modifying capabilities are much needed.
Topics: Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Mutation; Myelodysplastic-Myeloproliferative Diseases; Prognosis
PubMed: 35236051
DOI: 10.3324/haematol.2021.279500