scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Approach to the diagnosis of aplastic anemia

22 Jun 2021-Blood Advances (American Society of Hematology)-Vol. 5, Iss: 12, pp 2660-2671
About: This article is published in Blood Advances.The article was published on 2021-06-22 and is currently open access. It has received 18 citations till now.
Citations
More filters
Journal ArticleDOI
TL;DR: In this article , the authors conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing, and the median culture time was 28 days (IQR 22−29 days).
Abstract: To avoid acquired variants found in the blood, cultured skin fibroblasts are a recommended DNA source for germline genetic testing in patients with hematologic disorders, but data are lacking regarding practicality and limitations. We conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing. We analyzed next-generation sequencing data from the targeted capture of 144 inherited cancer and bonemarrow failure genes to identify variants at heterozygous and subclonal variant allele frequencies. Sixteen (5%) biopsies failed to culture. Culture failure was more likely in samples with delays in culture initiation (OR = 4.3; p < 0.01) or a pathogenic variant in a telomere gene (OR = 42.6; p < 0.01). Median culture time was 28 days (IQR 22−29 days). Culture time was longer for subjects with prior allogeneic stem cell transplantation (+10.7%; p = 0.02) and shorter in subjects with a heterozygous pathogenic variant (−11.9%; p < 0.01), larger biopsy size (−10.6%; p < 0.01), or lymphoid malignancy (−8.4%; p < 0.01). Subclonal variants were identified in 10 (4%) and confirmed in five (56%) of eight with alternate samples available. Subclonal and discordant variants illustrate that germline testing from cultured skin fibroblasts requires phenotypic correlation and, in rare cases, follow-up studies for optimal interpretation.

6 citations

Journal ArticleDOI
TL;DR: In this article , a more precise and automated prediction model is proposed to distinguish these four types to accelerate the identification process for doctors, and the results showed 99.21% accuracy, 98.44% sensitivity, 99.30% precision and an F1 score of 98.84%.

5 citations

Journal ArticleDOI
TL;DR: An overview of the genetic causes of IBMFS has led to important advances in understanding DNA repair, telomere biology, ribosome biogenesis, and hematopoietic stem cell regulation.
Abstract: Patients with inherited bone marrow failure syndrome (IBMFS) can develop peripheral blood cytopenia, which can ultimately progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although some cases of IBMFS are diagnosed based on their typical presentation, variable disease penetrance and expressivity may result in diagnostic dilemmas. With recent advances in genomic evaluation including next-generation sequencing, many suspected cases of IBMFS with atypical presentations can be identified. Identification of the genetic causes of IBMFS has led to important advances in understanding DNA repair, telomere biology, ribosome biogenesis, and hematopoietic stem cell regulation. An overview of this syndromes is summarized in this paper.

3 citations

Journal ArticleDOI
TL;DR: A plethora of new drugs interfering with the proximal and terminal complement cascade are under recent development and the first proof-of-pinciple proximal complement inhibitor targeting C3 has been approved in 2021 as mentioned in this paper .
Abstract: For the last 20 years, therapy of paroxysmal nocturnal hemoglobinuria (PNH) relied—up until recently—on antibody based terminal complement inhibitionon. PNH pathophysiology—a mutational defect leading to partial or complete absence of complement‐regulatory proteins on blood cells—leads to intravascular hemolysis and consequences such as thrombosis and other sequelae. A plethora of new drugs interfering with the proximal and terminal complement cascade are under recent development and the first “proof‐of‐pinciple” proximal complement inhibitor targeting C3 has been approved in 2021. “PNH: where we stand” will try to give a brief account on where we came from and where we stand focusing on approved therapeutic options. The associated improvements as well as potential consequences of actual and future treatments as well as their impact on the disease will continue to necessitate academic and scientific focus on improving treatment options as well as on side effects and outcomes relevant to individual patient lives and circumstances in order to develop effective, safe, and available treatment for all hemolytic PNH patients globally.

2 citations

Journal ArticleDOI
TL;DR: It is demonstrated that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or trans-plant outcomes, and higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult AA patients.
Abstract: Acquired aplastic anemia (AA) is caused by autoreactive T cell–mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.

2 citations

References
More filters
Journal ArticleDOI
19 May 2016-Blood
TL;DR: The 2016 edition of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues represents a revision of the prior classification rather than an entirely new classification and attempts to incorporate new clinical, prognostic, morphologic, immunophenotypic, and genetic data that have emerged since the last edition.

7,147 citations

BookDOI
TL;DR: The biological basis of disease at genetic, molecular, cellular, and epidemiologic levels is discussed and tissue-specific interventions to arrest or cure autoimmune disease are discussed.
Abstract: = Abstract Since publication of the Third Edition in 1998, the understanding of the immune mechanisms underlying autoimmunity and autoimmune disease has significantly deepened and broadened. This Fourth Edition incorporates new material and combines common themes underlying inductive and effector mechanisms and therapies that relate generally to the autoimmune disorders. It discusses the biological basis of disease at genetic, molecular, cellular, and epidemiologic levels. New to This Edition: * Tissue-specific interventions to arrest or cure autoimmune disease * Bone marrow eradication and replacement * Both basic science and clinical medicine is covered * Boxed points to emphasize key features of each chapter.

1,058 citations

Journal ArticleDOI
06 Feb 2014-Blood
TL;DR: GATA2 deficiency unites susceptibility to MDS/AML, immunodeficiency, pulmonary disease, and vascular/lymphatic dysfunction, and monocytopenia, B, NK, and CD4 lymphocy topenia correlated with the presence of disease.

554 citations

Journal ArticleDOI
TL;DR: The authors thank Sally B. Killick, Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe and Anna Wood for their help.
Abstract: Sally B. Killick (Writing Group Chair), Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe, Anna Wood (BCSH Task Force Member), Judith C.W. Marsh on behalf of the British Society for Standards in Haematology. The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Northern Genetics Service, Newcastle upon Tyne, St Bartholomew’s Hospital, Barts Health NHS Trust, London, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, Addenbrooks Hospital, University of Cambridge, Cambridge, Leeds Teaching Hospitals, Leeds, Kings College Hospital NHS Foundation Trust, London, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Great Ormond Street Hospital for Children NHS Foundation Trust, London, West Hertfordshire NHS Trust, Watford.

464 citations

Journal ArticleDOI
TL;DR: A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment and might not necessarily have predicted the response to therapy and long-term survival among individual patients.
Abstract: BACKGROUND In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. METHODS We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. RESULTS Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. CONCLUSIONS Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.)

430 citations