Genetic Screening of Patients with Evans Syndrome: A Single Centre Analysis

Abstract Background: Evans syndrome (ES) is a rare disorder defined as the simultaneous or sequential presence of autoimmune haemolytic anemia and immune thrombocytopenia but it can also be considered as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying congenital immune dysregulation syndrome that, in some case, can benefit from specific treatments. Aims: The aim of this study is to investigate the clinical/immnunological characteristics and the underlying genetic background of a single centre cohort of patients with ES. Methods: Data were obtained from a retrospective charts' review of patients with a diagnosis of ES in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both hematologic and immunological disorders as congenital bone marrow failure syndromes, primary immunodeficiencies, and primary immune regulatory disorders. Results: Fourteen patients (23 males, 17 females) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine/40 (8%) patients had a family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 29/40 (72%) of cases, respectively. Seventeen out of 40 (42%) children fitted the ALPS diagnostic criteria. The remaining 15 (37%) and 9 (22%) were classified as having an ALPS-like phenotype and an isolated ES, respectively. Twenty patients (50%) were found to have an underlying genetic defect on TNFRSF13B, FAS, CTLA4, IKBGK, CARD11, LIG4, LRBA, STAT3, CASP10 and ADA2 genes. Table 1 shows the details of clinical/immunological characteristics of patients with or without a genetic diagnosis. No significant differences were noted between the two groups. Conclusions: This study shows that half of patients with ES have a genetic background, secondary to Primary Immunodeficiencies. Therefore, an immunological screening and an extended molecular evaluation should be offered to all patients, since specific genetic diagnosis may benefit from targeted treatments. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Inherited Failure Syndromes.

Blood ◽

10.1182/blood.v114.22.sci-10.sci-10 ◽

2009 ◽

Vol 114 (22) ◽

pp. SCI-10-SCI-10

Author(s):

Grover C. Bagby

Keyword(s):

Relative Risk ◽

Diagnostic Tests ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Genetic Diagnosis ◽

Hematopoietic Cells ◽

Dyskeratosis Congenita ◽

Inherited Disorders ◽

Hematopoietic Stem ◽

Diagnostic Certainty

Abstract Abstract SCI-10 Global and lineage-restricted bone marrow failure syndromes can be acquired or inherited. Each of the known inherited disorders was initially described by observant clinicians before the field had access to modern tools of molecular biology and genetics. Consequently until recently, diagnosis had depended entirely on a clinical context drawn from the medical and family history, careful physical examinations and a few laboratory tests, none of which were pathognomonic. Today, many of the mutated genes responsible for these phenotypes have been identified and diagnostic tests of good reliability are emerging. This presentation will review the advantages and pitfalls associated with the application of newer diagnostic tests for many of these diseases. The molecular genetic insights have provided additional clinically relevant lessons. For example, the diseases are not limited to patients with the “classic” phenotype and can be diagnosed initially in adulthood. A substantial fraction of patients with Fanconi anemia (FA), for example, does not exhibit the cutaneous or skeletal manifestations of the disease. Some FA patients have entirely normal hematopoiesis, including the responses of hematopoietic cells to mitomycin C or diepoxybutane (abnormalities of which are considered to be the diagnostic standard for this disease). Such patients are “mosaics” in which a single hematopoietic stem cell has corrected the defect on one mutant FA allele and gives it and its progeny such a competitive advantage that they repopulate the entire marrow. Establishing the diagnosis in such cases is essential because the patients remain at high risk for squamous cell carcinoma and because their non-hematopoietic cells remain hypersensitive to cross-linking agents. Between these syndromes there are some shared genetic dysfunctions. For example, cells from patients with dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia have genetic lesions that directly perturb ribosome biogenesis. Few of these disorders are caused by the inactivation of only one gene. There are at least 13 FA genes, more than 6 dyskeratosis congenita genes, more than one Shwachman-Diamond gene, more than 6 Diamond-Blackfan genes, and at least 7 genes for congenital neutropenia. Not surprisingly, some of these genes encode mutually interacting proteins (the most widely studied of these form a nuclear Fanconi interactome). While the identification of involved genes has advanced our levels of diagnostic certainty, the discoveries have posed many challenges and the list of unanswered questions is growing longer. The most cost-effective approaches to diagnosis are not perfectly defined and although mutation analysis is of profound research importance and required for certain management strategies (e.g. in vitro fertilization and pre-implantation genetic diagnosis) the clinical value of assigning patients to specific complementation groups or mutations has not yet been clearly demonstrated. Leading research questions for hematologists focusing on these disorders include: How do these disparate genetic lesions influence the function of hematopoietic stem cells so profoundly? What environmental influences play a role in marrow failure progression and do the mutant gene products interact biochemically with signals evolving from environmental cues? What accounts for the high relative-risk of myelodysplasia and acute leukemia in all of these disorders? Will effective gene therapy reduce the relative risk of MDS and AML? Hypotheses centering on each of these points are now being tested in a number of laboratories and some of them will be summarized in this presentation. Disclosures No relevant conflicts of interest to declare.

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Autoimmune Cytopenias and Covid-19 Vaccination: Relapse and Suggested Treatment

Blood ◽

10.1182/blood-2021-145532 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4141-4141

Author(s):

Gregorio Campos-Cabrera ◽

Francisco-Gerardo Torres-Salgado ◽

Salvador Campos-Cabrera ◽

Jose-Luis Campos-Villagomez ◽

Virginia Campos-Cabrera

Keyword(s):

Complete Remission ◽

Hemolytic Anemia ◽

Autoimmune Hemolytic Anemia ◽

De Novo ◽

Conflicts Of Interest ◽

High Dose ◽

Evans Syndrome ◽

Autoimmune Thrombocytopenia ◽

Platelet Counts ◽

Autoimmune Cytopenias

Abstract Introduction: There are "de novo" and relapsed autoimmune diseases in patients with COVID-19 that includes autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia among others (Hematology 2021;26:225-239 and Curr Rheumatol Rev 2021;17:193-204). There is scanty material about relapse of autoimmune hematological diseases after vaccination for COVID-19 (Blood Adv 2021;13:2794-2798). Material and methods: Adult patients 18 years or older with autoimmune thrombocytopenia, Evans syndrome and autoimmune hemolytic anemia who completed SARS-Cov2 vaccination. Results: Between December 2020 and June 2021 there were identified 53 patients with autoimmune hematological disease that completed SARS-Cov2 vaccination. Thirty-six with autoimmune thrombocytopenia, all were preexisting. Twelve with autoimmune hemolytic anemia, 5 secondaries to previous COVID-19 and 7 preexisting. Five with Evans syndrome, all preexisting. Twenty-three patients with autoimmune thrombocytopenia did not develop any fall in the platelet count. Ten patients had a fall of 50 % from basal counts and recovered spontaneously. Three patients developed counts below 30,000 with purpuric symptoms and needed treatment that consisted in two courses of dexamethasone 40 mg daily for four days every three weeks; all patients reached complete remission without any further treatment. All patients with Evans syndrome developed hemolysis and low platelet counts. Two patients maintained Hb levels above 10 and platelet counts above 50,000; both patients had spontaneously recovery. Three patients developed Hb levels below 7 with anemic syndrome and platelets below 50,000 but without purpuric syndrome; they received the same treatment as patients with autoimmune thrombocytopenia and reached complete remission too. All five patients with autoimmune hemolytic anemia secondary to COVID-19 developed Hb levels below 7 with anemic symptoms and needed treatment as described. The remaining 7 patients with preexisting autoimmune anemia developed hemolysis; five with Hb levels above 7 and recovery without any treatment; two had Hb levels below 7 and received the same treatment with full recovery and complete remission. Conclusions: Autoimmune cytopenias can be trigger by vaccines and viral infections by involving molecular mimicry and circulating immune complexes, including SARS-Cov2. The viral protein spike from SARS-Cov2 has mimicry between the Ankyrin-1 in the erythrocyte surface, and has been linked as one of the pathogenesis pathways of autoimmune hemolytic anemia secondary to COVID-19 (Br J Haematol 2020;190:e92-e93 and Blood 2020;136:suppl8,138001). Relapse of autoimmune cytopenias after vaccination with SARS-Cov2 involves stimulation of autoantibodies production from preexisting B cells. Although relapses were observed in the three kinds of patients, all with hemolytic component developed a drop in the hemoglobin levels, most of them needed treatment. It is important to notice that patients with hemolytic autoimmune anemia secondary COVID-19 had severe relapse, event that support the mimicry mentioned lines above. It is important to follow up closely this kind of patients after SARS-CoV2 vaccination, we suggest weekly complete blood counts, and a short courses of high dose dexamethasone can induce curable responses if treatment is advised. Disclosures No relevant conflicts of interest to declare.

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Links Between DNA Damage and Metabolism, Pathways Causing Bone Marrow Failure in Fanconi Anemia, and Therapeutic Implications

Blood ◽

10.1182/blood.v120.21.sci-3.sci-3 ◽

2012 ◽

Vol 120 (21) ◽

pp. SCI-3-SCI-3

Author(s):

Ketan J. Patel

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Genetic Defect ◽

Scientific Session ◽

Ethanol Exposure ◽

Southeast Asians ◽

Therapeutic Implications ◽

Blood Stem Cells

Abstract Abstract SCI-3 Recent work from my lab has discovered that metabolism generates reactive aldehydes. These reactive molecules are potent damagers of DNA. The consequences of this are revealed by the inactivation of enzymes that detoxify these aldehydes and the Fanconi anemia DNA repair pathway in mice and vertebrate cell lines. The scientific session presentation will discuss this work and recent unpublished research on how natural aldehydes damage blood stem cells. This work has consequences for understanding how metabolism and ethanol exposure can be genotoxic, particularly in the vast population of Southeast Asians carrying a genetic defect in aldehyde catabolism (“pink flushers”). It is also relevant to the emergence of bone marrow failure and leukemia in Fanconi anemia. Disclosures: No relevant conflicts of interest to declare.

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Metastatic Breast Cancer in a Patient with Fanconi Anemia

Blood ◽

10.1182/blood.v124.21.5164.5164 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5164-5164

Author(s):

Jeffrey Graham ◽

Debjani Grenier ◽

Arjuna Ponnampalam

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Fanconi Anemia ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Genetic Defect ◽

Susceptibility Gene ◽

Metastatic Breast ◽

Morphological Evidence ◽

Breast Cancer Susceptibility Gene

Abstract Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure, congenital malformations and a propensity for developing malignancies at an early age. The underlying genetic defect in FA creates a state of cellular hypersensitivity to many traditional chemotherapy agents, making the treatment of malignancies in this population particularly challenging. We describe a 42-year-old female who presented with a solitary mass in her left breast. Core biopsy revealed an invasive ductal carcinoma that did not express estrogen (ER) or progesterone receptors (PR), but did express human epidermal growth factor receptor 2 (HER2). Staging work-up revealed diffuse skeletal metastatic disease. At her initial consultation with medical oncology, she was discovered to be pancytopenic. Further history revealed a sibling with aplastic anemia and that she had undergone chromosomal breakage testing for FA in the past, which was subsequently confirmed to be positive. She underwent a bone marrow aspirate and biopsy that showed metastatic marrow infiltration by non-hematopoietic cells. In addition there was morphological evidence of dyserythropoiesis and cytogenetic abnormalities on karyotyping, features suggestive of FA. She was initially started on trastuzumab monotherapy. Low dose radiation therapy was added due to local tumor progression. Combined HER2 directed therapy was to be implemented, but was held due to a functional decline in the patient. To date, she has not received definitive genetic testing to determine which FA subgroup she belongs to. This case highlights two important aspects of FA. The first is the inherent increase in susceptibility to neoplasms in this group, including solid tumors such as breast cancer. The genes associated with FA are involved in deoxyribonucleic acid (DNA) repair pathways, including mutations in the breast cancer susceptibility gene, BRCA2. The second is the heightened sensitivity to the toxic effects of many standard chemotherapy and radiation treatments. This creates unique challenges in the treatment of malignancies in this population and stresses the importance of targeted therapies. Disclosures No relevant conflicts of interest to declare.

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Diagnostic Whole Exome Sequencing for 166 Patients with Inherited Bone Marrow Failure Syndrome

Blood ◽

10.1182/blood-2020-143241 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-9

Author(s):

Motoharu Hamada ◽

Hideki Muramatsu ◽

Yusuke Okuno ◽

Ayako Yamamori ◽

Taro Yoshida ◽

...

Keyword(s):

United States ◽

Bone Marrow ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Genetic Diagnosis ◽

Primary Immune Deficiency ◽

Whole Exome

BACKGROUND: Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of genetic disorders characterized by bone marrow failure, physical anomalies, and various kinds of organ complications. In addition to classical IBMFSs, such as Fanconi anemia, Diamond-Blackfan anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, and familial platelet disorders, many types of unclassified IBMFSs are reported. Over 100 genes are considered causative genes; however, the precise genetic diagnosis of IBMFSs remains challenging. We developed a capture-based target sequencing method for IBMFSs that covers more than 180 associated genes. Our system achieved genetic diagnosis for 225 (35%) of 738 patients between 2013 and 2018. However, the causative gene remained unknown for 513 (65%) patients, and further genetic analysis of these "target-negative" cases was necessary to achieve a precise diagnosis. METHODS: We performed whole exome sequencing (WES) for patients who were "target-negative" but strongly suspected of having IBMFS based on the following clinical characteristics: physical or organ anomalies (skin, nail, hair, skeletal, growth, cardiac, lung, liver, or genitourinary), family history of hematological disorder, young age (≤2 years), short telomere length (<-2.0 SD), and hyper sensitivity to the chromosome breakage test. A sequencing library was prepared using the SureSelect Human All Exon 50Mb kit (Agilent Technologies, Santa Clara, CA, USA) and it was sequenced using the HiSeq2000 platform (Illumina, San Diego, CA, USA), according to manufacturers' instructions. The candidate germline variants were detected through our Genomon-exome analysis pipeline. With mean coverage of 100×, ≥ 85% of all protein coding bases were covered at 20× or more. RESULTS: Among the 513 "target-negative" cases, 166 patients were evaluated, of whom 17 patients' parents were also analyzed in a trio-based analysis. New pathogenic variants were identified in 18 of the 166 (11%) patients according to the American College of Medical Genetics (ACMG) guidelines, of which 5 variants were revealed to be de novo. Diagnostic variants were identified in FANCF, SRP54, RPL19, RPL5, RTEL1, RUNX1, MECOM, CDC42, GNE, SLNF14 (all n = 1). In addition to IBMFS-associated genes, causative genes for congenital hemolytic anemia (G6PD, PKLR), inborn error of metabolism (SLC46A1), and primary immune deficiency (NFKB2, LRBA) are also identified (all n = 1). Moreover, loss-of-function mutation of ADH5 gene are identified in three patients that seems to be associated to novel IBMFSs. On the other hand, no pathogenic variant in GATA2, ERCC6L2, LIG4, and SAMD9/SAMD9L genes that are reported as unclassified IBMFSs in Europe and United States are identified in our cohort. CONCLUSION: Our findings support the utility of WES (especially trio-based analysis) as a diagnostic tool for IBMFSs. Furthermore, genetic background of IBMFSs in East Asia seems to be different from that of Europe and United States. Disclosures No relevant conflicts of interest to declare.

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Severe Chronic Neutropenia: Primary Immunodeficiency Mutations Are Frequent Causative Agents

Blood ◽

10.1182/blood-2018-99-114462 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2402-2402

Author(s):

Francesca Fioredda ◽

Filomena Pierri ◽

Elena Palmisani ◽

Andrea Finocchi ◽

Gigliola Di Matteo ◽

...

Keyword(s):

Conflicts Of Interest ◽

Genetic Defect ◽

Genetic Diagnosis ◽

Specific Treatment ◽

Pathogenic Mutation ◽

Considerable Proportion ◽

Primary Immune Deficiency ◽

Causative Agents ◽

Pathogenic Gene ◽

Chronic Neutropenia

Abstract Severe Chronic Neutropenia (SChrN) is an heterogeneous group of disorders characterized by persistently low circulating neutrophils (<500/cmm). Within this group, the classical form of Severe Congenital Neutropenia (SCN), once defined Kostman's disease, appears in early infancy, usually shows a marrow block at promyelocyte stage and needs lifetime treatment with G-CSF to prevent severe infections. Mutations in more than 20 genes have been recognized as causative of the disease with a clear prevalence of ELANEgene mutations (70% of cases). However,SChrN may also be an epiphenomena of autoimmune/immune dysregulation disorders (Secondary Neutropenia, SN) which are usually associated to extrahaematological signs and/or positivity of autoimmunity markers, to a normal or "left shifted" bone marrow morphology. In spite of these categorization many cases do not fit either group and share features of both of them. These "Ovelap Neutropenia" (ON) patients represent a challenge for diagnosis and management. AIM OF the study: Investigate the genetic backgroud of a cohort of SChrN subjects screened in two immune-hematology centers in Italy. Material and Methods: Patients SChrN were prospectively seen in participating Centres and diagnosed/followed-up according to published guidelines (3,4). Genetic diagnosis included classical Sanger technique for commonest severe chronic neutropenia genes and an enlarged NGS panel including also genes responsible for PID. Results: From 2008 to 2016, 27 SChrNpatients (52% males)with a median age at last follow of 13y (range 20 mos-53yrs ) entered the study (Table 1). Thirteen/27 subjects (48%) were phenotypically diagnosed as classical SCN. Of them 10 (77%) and 1 (8%) had mutations in ELANEand JAG1 genes respectively and 2 (16%) had no pathogenic gene detectable. Eight/27(30%) patients were phenotypically diagnosed as SN and the remaining 6/27 ( 22%) had the clinical features of ON. A pathogenic mutation in a Primary Immune Deficiency (PID) gene (RAG1, LRBA, CECR1. TACI, CARD11, CD40 and PI3K plus CASP 10) was found in 7/27 patients (26%). Four of them belonged to the group of 8 patients diagnosed with SN (50%) and 3 to that of the 6 ON subjects (50%). In 5/27(19%) patients no pathogenic gene was found. Table 1 shows clinical hematological characteristic of the 3 categories of patients. Conclusions:In our unselected cohort of SChrNa considerable proportion (26%) of subjects bore a genetic defect that qualifies them as PID. These PID genetic defects are located in the SN and ON patients (50% each) that are clinically different from classical ELANE mutated SCN subjects because of the presence of extra-hematological signs, of markers of autoimmunity, of a diverse marrow maturation block and a frequent involvement of more than one hematopoietic lineage. While the use of NGS still leaves a not negligible proportion of SChrN without pathogenic gene, this extensive genetic diagnostic approach enables to identify a relevant portion of subjects with SChrN who indeed carry a PID genetic defect. This has important clinical implications related to specific treatment and monitoring schedules to apply to these patients. The application of the Whole ExomeSequencing technique might fill the gap of the SCHrN patient who are still gene orphan. Disclosures No relevant conflicts of interest to declare.

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Exploring polypharmacy phenomenon in newly diagnosed relapsing–remitting multiple sclerosis: a cohort ambispective single-centre study

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622320983121 ◽

2021 ◽

Vol 12 ◽

pp. 204062232098312

Author(s):

Aurora Zanghì ◽

Emanuele D’Amico ◽

Salvatore Lo Fermo ◽

Francesco Patti

Keyword(s):

Multiple Sclerosis ◽

Age At Onset ◽

Rank Test ◽

Multinomial Regression ◽

Single Centre ◽

Centre Study ◽

Relapsing Remitting ◽

Single Centre Study ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Aims: We aimed to examine the frequency of polypharmacy in a large cohort of patients at the time of diagnosis of relapsing–remitting multiple sclerosis (RRMS) and to explore its effects on discontinuation of first disease-modifying treatment (DMT) using survival analysis. Methods: This was a cohort ambispective single-centre study. We enrolled RRMS patients starting their first DMT between 1st January 2013 and 31st December 2015. According to the number of medicines prescribed (except DMTs), we divided the patients into three groups: no-poly RRMS, minor-poly RRMS (from one to three medications), and major-poly RRMS (more than three medications). Results: A total of 392 RRMS patients were enrolled (mean age 41.1). The minor-poly RRMS group included 61 patients (15.6%) and the major-poly RRMS group included 112 (28.6%). Individuals in these groups were older and had higher median body mass index (BMI) than patients in the no-poly RRMS group ( p < 0.05). Upon multinomial regression analysis, older age at onset was associated with minor and major polypharmacy (OR 1.050, CI 1.010–1.093, p = 0.015 and OR 1.063, CI 1.026–1.101, p = 0.001, respectively) and higher BMI was associated with major polypharmacy (OR 1.186, CI 1.18–1.29, p = 0.001). The rates of discontinuation of first DMT were similar among the three groups (50.7% for no-Poly RRMS, 50.8% for minor-Poly RRMS, and 53.3% for major-Poly RRMS, p = 0.264). At log-Rank test, there were no differences among the three groups ( p = 0.834). Conclusion: Polypharmacy was more common in older RRMS patients with high BMI.

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Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

European Journal of Human Genetics ◽

10.1038/s41431-020-00720-w ◽

2020 ◽

Vol 28 (12) ◽

pp. 1763-1768

Author(s):

Thomas Bourinaris ◽

◽

Damian Smedley ◽

Valentina Cipriani ◽

Isabella Sheikh ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

De Novo ◽

Age At Onset ◽

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Sequencing Data ◽

Juvenile Form ◽

Pathogenic Variants ◽

Degenerative Disorders ◽

Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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Aplastic Anemia in Thailand: Incidence and Treatment Outcome from a Prospective Nationwide Population-Based Study

Blood ◽

10.1182/blood-2020-137047 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Lalita Norasetthada ◽

Somchai Wongkhantee ◽

Jindaratn Chaipokam ◽

Kanyaporn Charoenprasert ◽

Suporn Chuncharunee ◽

...

Keyword(s):

Aplastic Anemia ◽

Anabolic Steroid ◽

Real World ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Population Based ◽

Annual Incidence ◽

Severe Aplastic Anemia ◽

Treatment Modalities ◽

Population Based Study

Background: Incidence of Aplastic Anemia (AA) in Asia tends to be higher than in western countries, but contemporary real-world incidence and outcomes of AA in Asia remain limited. This study aimed to explore the incidence across the country regions and to evaluate the patient outcomes according to age, the severity of disease, and treatment modalities. Method: This is a prospective multicenter nationwide population-based observational study of patients with AA aged over 15 years old, diagnosed between August 1st, 2014 to July 31st, 2016, with a longitudinal follow-up period over 2 years, from 30 medical centers. Patients with suspected hypocellular MDS and congenital bone marrow failure syndrome were excluded. Results: During the study period of 2 years, there were 348 newly diagnosed patients with aplastic anemia, giving the annual incidence of 4.6 per million inhabitants. There was a higher annual incidence of severe (SAA) and very severe aplastic anemia (VSAA) (3.8 per million) than non-severe aplastic anemia (NSAA) (0.8 per million). The incidence was greater among older patients with a peak incidence in patients aged 60-89 years old. (Figure 1) There was a high variation in the geographic incidences across country regions, ranging from 2.6 to 6.6 per million per year. (Figure 2) The 2-year overall survival (OS) for NSAA, SAA, and VSAA were 65.5%, 49.3%, and 20.1%, respectively (P < 0.001). Patients aged older than 60 years had the worst OS (42.6% as compared with 47.7% for the age 41-60 years and 64.5% for the age 15-40 years, P = 0.002). Among patients with SAA and VSAA (n = 280), the overall response rate (ORR) among patients treated with rabbit anti-thymocyte globulin and/or cyclosporin A (rATG±CsA) was significantly superior than those treated with CsA-based therapy and those treated with anabolic steroid (44.4% vs. 36.4% and 31.2%, respectively, P < 0.001). Among evaluable patients, ORR after the 1st treatment with rATG±CsA at 3, 6, 12 and 24 months were 23.9%, 43.8%, 68.4% and 89.2%, respectively. The 2-year OS among SAA/VSAA patients treated with rATG±CsA, CsA-based therapy, and anabolic steroid were 54.8%, 54.5%, and 37.6% (P = 0.037), respectively (Figure 3). From multivariate analysis, age > 60 years (HR 1.63, 95%CI, 1.14-2.33, P = 0.007), VSAA (HR 2.24, 95% CI, 1.45-3.46, P < 0.001) and not receiving immunosuppressive therapy or anabolic steroid (HR 4.96, 95%CI, 2.88-8.54, P <0.001), were independently associated with inferior OS among patients with SAA/VSAA. Conclusion: The incidence rate of AA in Thailand from this contemporary nationwide population-based study is high, especially in the elderly. Patients treated with rATG±CsA had superior survival than those receiving anabolic steroid. The real-world outcome of patients with SAA/VSAA, especially in those aged over 60 years, is substantially poor. Figure 1 Disclosures No relevant conflicts of interest to declare.

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New Bone Marrow Failure Genes: DNAJC21 and ERCC6L2

Blood ◽

10.1182/blood.v130.suppl_1.sci-22.sci-22 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. SCI-22-SCI-22

Author(s):

Inderjeet Dokal

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

Nuclear Export ◽

Conflicts Of Interest ◽

Excision Repair ◽

Bone Marrow Failure ◽

Retinal Dystrophy ◽

Ribosomal Subunit ◽

Genotoxic Stress ◽

Biallelic Mutations

A significant number of cases with bone marrow failure present with one or more extra-hematopoietic abnormality. This suggests a constitutional or genetic basis, and yet many of them remain uncharacterized. Through exome sequencing, we have recently identified two sub groups of these cases, one defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21) and the other in ERCC6L2 (excision repair cross complementing 6 like-2). Patients with DNAJC21 mutations are characterized by global bone marrow failure in early childhood. They can also have a variable number of extra-hematopoietic abnormalities such as short stature and retinal dystrophy. The encoded protein associates with ribosomal RNA (rRNA) and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid patient cells exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced levels of rRNA. Characterisation of mutations has revealed impairment in interactions with cofactors (PA2G4, HSPA8 and ZNF622) involved in 60S maturation. DNAJC21 deficiency results in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles and increased cell death. Collectively these findings demonstrate that biallelic mutations in DNAJC21 cause disease due to defects in early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit. Patients harbouring biallelic ERCC6L 2 mutations are characterized by bone marrow failure (in childhood or early adulthood) and one or more extra-hematopoietic abnormality such as microcephaly. Knockdown of ERCC6L2 in human cells significantly reduces their viability upon exposure to the DNA damaging agent irofulven but not etoposide and camptothecin suggesting a role in nucleotide excision repair. ERCC6L2 knockdown cells and patient cells harbouring biallelic ERCC6L2 mutations also display H2AX phosphorylation that significantly increases upon genotoxic stress, suggesting an early DNA damage response. ERCC6L2 is seen to translocate to mitochondria as well as the nucleus in response to DNA damage and its knockdown induces intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger, N-acetyl-cysteine, attenuates the irofulven-induced cytotoxicity in ERCC6L2 knockdown cells and abolishes its traffic to mitochondria and nucleus in response to this DNA damaging agent. Collectively, these observations suggest that ERCC6L2has a pivotal rolein DNA repair and mitochondrial function. In conclusion, ERCC6L2 and DNAJC21 have an important role in maintaining genomic stability and ribosome biogenesis, respectively. They bring into focus new biological connections/pathways whose constitutional disruption is associated with defective hematopoiesis since patients harbouring germline biallelic mutations in these genes uniformly have bone marrow failure. Disclosures No relevant conflicts of interest to declare.

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