GATA2 Mutations In Pediatric Myelodysplastic Syndromes and Bone Marrow Failure

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1520-1520 ◽  
Author(s):  
Inga Hofmann ◽  
Daniel Kierstead ◽  
Jennie Krasker ◽  
Dean Campagna ◽  
Klaus Schmitz-Abe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Sanger Sequencing ◽  
Pediatric Patients ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Family Members ◽  
Genetic Alterations ◽  
Cell Transplant ◽  
Monosomy 7

Abstract Introduction Inherited bone marrow failure syndromes (IBMFS), idiopathic aplastic anemia (AA), and myelodysplastic syndromes (MDS) represent a spectrum of bone marrow failure (BMF) conditions for which the underlying genetics and pathophysiology is still poorly understood. Heterozygous germline mutations in GATA2 have recently been described in three distinct conditions that include familial MDS/AML, Emberger syndrome and MonoMac syndrome, each of which exhibits great clinical heterogeneity. The Pediatric MDS and BMF Registry was established in 2010 to carefully characterize clinical and histopathologic phenotypes and investigate the molecular basis for these disorders. To date 158 eligible patients/probands and 28 family members have been enrolled. The goal of this study was to determine the prevalence of GATA2 mutations in pediatric patients with MDS and BMF and characterize their clinical and histopathologic phenotypes. Materials and Methods Sanger sequencing of GATA2 was initially performed on 3 families with a history of familial MDS and 103 patients with sporadic appearing primary MDS, AA or an unclassified BMF enrolled in the Pediatric MDS and BMF Registry. Family members were assessed in patients with pathogenic mutation to determine if the disease was inherited or sporadic. Mutations were confirmed in somatic and germline tissue wherever possible. IBMFS were ruled out by molecular testing. Rigorous phenotype analysis included clinical and laboratory data, and standardized centralized pathology review. Whole exome sequencing (WES) was performed on a subset of patients to evaluate additional cooperating mutations and possible secondary somatic events and clonal evolution. Possible candidate genes were verified by Sanger sequencing. Results We identified pathogenic GATA2 mutations in a total of 16 individuals, including 12 patients (7 familial MDS cases and 5 sporadic MDS/BMF cases) and 4 first-degree relatives from 5 kindreds. Most mutations clustered in zinc finger 2. Previously identified mutations such as N371K and R396Q as well as novel point and frame shift mutations were identified. The median age at diagnosis was 15 years. There was strong male predominance (n=11). The clinico-pathologic diagnoses were RAEB/AML (n=4), refractory cytopenia of childhood (n=6) and MonoMac/other (n=6). Two out of the four families presented with features of Emberger syndrome. Two individuals presented with characteristic features of MonoMac Syndrome, of which one also showed bone marrow failure and pulmonary fibrosis suggestive of telomere disease. Very short telomeres (below the first percentile) were detected in all lymphocyte subsets consistent with dyskeratosis congenita (DC). However, genetic analysis did not reveal any of the known DC associated genes. Other associated pathology included severe gastrointestinal bleeding (n=2), severe polyneuropathy (n=2) and other cancers (n=1). A morphologically distinctive megakaryocytic dysplasia was a characteristic finding on histopathology. Monosomy 7 was the most common acquired cytogenetic abnormalities (n=6). Given this association we identified several additional individuals with MDS and monosomy 7 from our pathology archives and identified 2 additional patients with pathogenic GATA2 mutations. Secondary somatic mutations identified by WES included ASXL1. Thirteen out of the 14 pediatric patients with GATA2 mutations underwent hematopoietic stem cell transplant (HSCT). Ten out of these 13 patients are alive. Conclusion GATA2 mutations occur at a higher frequency than previously anticipated in pediatric MDS, and BMF, often occur sporadically and are associated with monosomy 7. While the clinical presentation is heterogeneous, the histopathologic features are often unique. Somatic genetic alterations likely play a role in clonal evolution. Given its significant implications for treatment decisions and donor selection GATA2 mutation screening should be performed on all patients with MDS, AA, and BMF disorders excluding classical IBMFS, and potential related donors. Disclosures: No relevant conflicts of interest to declare.

Modeling Bone Marrow Failure and MDS in Shwachman Diamond Syndrome Using Induced Pluripotent Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1496-1496 ◽  
Author(s):  
Melisa Ruiz-Gutierrez ◽  
Ozge Vargel Bolukbasi ◽  
Linda Vo ◽  
Ryohichi Sugimura ◽  
Marilyn Sanchez Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Chromosome 7 ◽  
Stem Cell Markers ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Myelodysplastic syndrome (MDS) caused by monosomy 7 or del(7q) is a frequent clonal abnormality that arises in the context of inherited bone marrow failure syndromes, such as Shwachman Diamond Syndrome (SDS). Monosomy 7/del(7q) also develops in a subset of patients with acquired aplastic anemia or de novo MDS in the general population. Monosomy 7/del(7q) is associated with high grade MDS and a high risk of malignant transformation, most frequently to acute myelogenous leukemia (AML). Bone marrow failure and clonal evolution to MDS and AML remain major causes of morbidity and mortality for individuals with SDS. Currently, the only curative therapy for these hematological complications is a hematopoietic stem cell transplant. Prognosis is extremely poor once SDS patients develop leukemia. The basis for this propensity to develop monosomy 7 clones remains unclear. The longterm aim of this study is to understand the molecular mechanisms underlying leukemia predisposition and develop more effective treatments. Whether monosomy 7/del(7q) functions as a driver of MDS, or is merely an associated marker of clonal progression in bone marrow failure remains a critical question. The lack of synteny between murine versus human chromosome 7 has posed a major barrier to the development of mouse models of monosomy 7/del(7q). To study the biological and molecular consequences of monosomy 7/del(7q) in SDS, induced pluripotent stem cells (iPSCs) were generated from bone marrow mononuclear cells of two patients with SDS. Each patient harbored homozygous c.258+2 T>C mutations in the canonical splice donor site of intron 2 in the SBDS gene. The SDS-iPSCs retained the pathogenic homozygous IVS2+2 T>C SBDS mutations, expressed stem cell markers, formed teratomas, and expressed reduced levels of SBDS protein similar to levels noted in the primary patient samples. Proliferation of 4 distinct SDS-iPSC clones derived from two different patients was reduced relative to wild type controls without an increase in cell death. SDS-iPSC formed smaller embryoid bodies with reduced production of CD34+ hematopoietic stem/progenitor cells. Hematopoietic differentiation from CD34+ to CD45+ cells was also impaired. Preliminary data suggest that SDS-iPSCs retain the capacity to give rise to hematopoietic stem/progenitor cells and early myeloid progenitor cells in vitro. These populations were also observed in primary SDS patient-derived bone marrow samples. Because the number of CD34+ cells derived from SDS-iPSCs are limiting, a previously reported 5 transcrition factor re-specification system was used to expand multilineage hematopietic progenitors for further characterization. SDS iPSCs were able to differentiate into an expandable CD34+ population in vitro. Further studies to characterize the hematopoietic impairment in SDS iPSC and primary marrow samples are ongoing. To model del(7q) in SDS iPSCs, a deletion of the MDS-associated long arm of chromosome 7 was genomically engineered using a previously published modified Cre-Lox approach. The deletion of 7q at locus (11.2) was confirmed by karyotyping and by qPCR across chromosome 7. The SDS (del7q) iPSCs retained the SBDS pathogenic mutations, expressed stem cell markers, and formed teratomas. Proliferation of the SDS del(7q) iPSC was markedly impaired compared to isogenic SDS iPSCs. No increase in cell death was observed in the SDS del7q iPSCs. Studies are in progress to determine the effects of del7q on hematopoiesis. Investigation is ongoing to determine the molecular consequences of deleting 7q. These isogenic SDS+/- del(7q) iPS models provide a platform to study the role of 7q loss in clonal evolution from bone marrow failure and to screen for novel therapeutic compounds or pathways to treat bone marrow failure and MDS. Disclosures No relevant conflicts of interest to declare.

Clinically Silent Carriers in Families with Myelodysplastic Syndrome Due to GATA2 Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1264-1264
Author(s):  
Blanche P Alter ◽  
Neelam Giri ◽  
Katherine R Calvo ◽  
Irina Maric ◽  
Diane C Arthur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Family Members ◽  
Lymphoid Cells ◽  
Refractory Anemia ◽  
Cell Transplant ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Variable Expression ◽  
Increased Risk

Abstract Abstract 1264 Patients with familial myelodysplastic syndrome (MDS) associated with mutations in GATA2 are at increased risk of MDS and acute myeloid leukemia (AML). Specific clinical syndromes recently found to be due to mutations in GATA2 include MonoMAC (monocytopenia and mycobacterial infection), Emberger (MDS with severe lymphedema), and DCML (defects in dendritic cells, monocytes, and B and NK lymphoid cells). Features shared by many patients with these GATA2-associated syndromes include monocytopenia, markedly decreased B and NK cells, and clinical immunodeficiency manifested as warts and mycobacteria and fungal infections. MDS and/or AML occur with multilineage dyspoieses, particularly prominent in the megakaryocyte lineage (micromegakaryocytes, small mononuclear megakaryocytes, and large megakaryocytes with multiple separated nuclei). Several reports mention family members who are “asymptomatic,” without further details. We identified mutations in GATA2 in two of three families with familial MDS. In both families, one apparently healthy parent was found to have a GATA2 mutation; only in-depth laboratory examinations uncovered subtle findings consistent with familial GATA2 mutation in these clinically silent carriers. Family 1: The proband presented at age 15 with pancytopenia, and was found to have MDS and monosomy 7; he died from post-BMT complications including aspergillosis. His brother was found to have leukopenia, neutropenia and macrocytosis at age 13 during an infection with H1N1 influenza; the leukopenia and macrocytosis persisted. Six months later, repeat bone marrow showed early refractory anemia; the next year his marrow had myeloid dyspoiesis and dysplastic megakaryocytes; FISH showed −7 in 2.3% of cells, leading to classification as MDS-RCC. In retrospect, both boys had absolute monocytopenia (<100/uL). GATA2 sequencing of samples from the surviving brother and his 51 y.o. mother identified a deleterious mutation (c.1116_1130del15, p.C373del5). The mother had breast cancer at age 50, but otherwise was asymptomatic. Closer clinical examination revealed lower limb lymphedema, while laboratory studies revealed lymphopenia (360/uL), monocytopenia (110/uL), low lymphocyte subsets, especially CD19 (3/uL) and MCV = 100fL. Her marrow did not show overt dyspoiesis in myeloid or erythroid lineages; among mostly normal megakaryocytes there were occasional atypical forms, including some with hypolobulated or separated lobes; G-banded karyotyping and interphase FISH for −7/7q- were normal. She would not have been suspected to have GATA2-related MDS based on her clinical status, and is thus a silent carrier. Family 2: Three children in this family were diagnosed with MDS. The oldest had a history of warts and pancytopenia at age 18; his marrow showed MDS with trisomy 8. His brother was a compatible transplant donor, but he had mild pancytopenia and monocytopenia; his marrow had MDS and trisomy 8. Their sister was diagnosed at age 14 with MDS and trisomy 8; she, too, had monocytopenia. All 3 were transplanted. Subsequently, a mutation - c.1187G>A, p.R396Q - was found in GATA2, in all 3 brothers and their healthy father. He had normal blood counts (monocytes 500/uL) and immunoglobulins, but low B-cells in peripheral blood (CD20 23/uL) and bone marrow. His normocellular marrow had occasional atypical megakaryocytes with separated lobes, hypolobulation, and mononuclear and micromegakaryocytes. He, too, would not have been suspected to have GATA2-related MDS, and is also a clinically silent carrier. These two families indicate that familial GATA2-related MDS is a dominantly-inherited syndrome. In our two families, dominant inheritance was not initially considered, in part because the genetically affected parent was clinically asymptomatic. It is unclear whether GATA2 MDS shows “anticipation,” in which the younger generation is more severely affected than the parental generation. It is important that GATA2 be evaluated in families with apparently inherited childhood MDS, since the variable expression might lead inadvertently to selecting an asymptomatic GATA2 mutation carrier as a stem cell transplant donor. Genetic counseling needs to be provided with regard to risk to other family members. In addition, only long-term follow-up and surveillance of the clinically silent carriers will determine whether they remain unaffected. Disclosures: No relevant conflicts of interest to declare.

Risk Factors For Clonal Evolution Of Acquired Bone Marrow Failure After Immunosuppressive Therapy In Children

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2473-2473
Author(s):  
Asahito Hama ◽  
Hideki Muramatsu ◽  
Masafumi Ito ◽  
Yoshiyuki Kosaka ◽  
Masahiro Tsuchida ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Severe Disease ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Cell Lineages ◽  
A Prospective Study

Abstract Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing clonal evolution after immunosuppressive therapy (IST). We previously reported that the duration of granulocyte colony-stimulating factor (G-CSF) treatment and non-response to IST at 6 months were risk factors for clonal evolution. In 2008, the revised World Health Organization (WHO) classification proposed a new entity, “refractory cytopenia of childhood” (RCC), which is often difficult to differentiate from aplastic anemia (AA). The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) with mild dysplasia to those with normocellular BM with distinct dysplasia meeting the criteria for refractory cytopenia with multilineage dysplasia (RCMD) in adults. Few studies have investigated the correlation between morphological classifications of bone marrow failure (BMF) and clonal evolution. Before introducing the criteria of RCC, we conducted a prospective study with antithymocyte globulin (ATG) and cyclosporine for patients with acquired BMF (AA 97 study), which provided a unique opportunity both to compare the long-term outcome of patients with RCC and AA and to analyze risk factors for clonal evolution. We retrospectively reviewed BM morphology in 186 children (median age, 8 years;range, 1–16 years) who were enrolled in the AA 97 study between July 1999 and November 2008. The median follow-up period was 87 months (range, 1–146 months). Fifty patients had non-severe, 54 had severe, and 82 had very severe disease. RCC criteria were defined as persistent cytopenia with <2% blasts in the peripheral blood (PB) and <5% blasts in the BM. BM aspirate smears showed dysplastic changes in >2 cell lineages or >10% within 1 cell lineage. RCMD criteria were defined as persistent cytopenia with <1% blasts in the PB and <5% blasts in the BM. BM smears showed >10% dysplastic changes in >2 cell lineages. Morphologically, 62 patients (33%) were classified as AA, 94 (49%) as RCC, and 34 (18%) as RCMD. Disease severity differed among the three groups as follows: 76% of the AA patients had very severe disease, while 41% of the RCMD patients had non-severe disease (p<0.001). AA patients received G-CSF more frequently and for a longer duration than other patients (p=0.002). After 6 months, the response rates to IST were not significantly different among the three groups (AA, 52%; RCC, 59%; RCMD, 56%). Predictors of IST response were investigated by multivariate analysis. Morphological classification was not associated with IST response (p=0.519). Acquisition of clonal chromosomal abnormalities was observed in five patients in the AA group (monosomy 7, n=4; monosomy X, n=1), four patients in the RCC group (monosomy 7, n=1; trisomy 8, n=1; other, n=2), and three patients in the RCMD group (trisomy 8, n=3). Although the cumulative incidence (CI) of total clonal evolution at 10 years was not significantly different among the three groups, the CI of monosomy 7 was significantly higher in the AA group than in the other groups (p=0.02). Multivariate analysis revealed that morphology was not related to clonal evolution (p=0.23), and that only duration of G-CSF administration for >40 days was a significant risk factor for the development of monosomy 7 (p=0.016). Death, relapse, development of myelodysplastic syndrome or acute myeloid leukemia (AML), or disease progression requiring clinical intervention was considered to represent treatment failure. A second therapeutic intervention was required in some children. A second IST was therefore performed in 20 children, including five with AA, 11 with RCC, and four with RCMD. Hematopoietic stem cell transplantation was performed in 64 children, including 25 with AA, 29 with RCC, and 10 with RCMD. The rate of failure-free survival at 10 years was not significantly different among the three groups. On the other hand, the rate of overall survival at 10 years was significantly lower in the AA group (85±5.1%) than in the RCC (97±1.9%) and RCMD (100%) groups (p=0.01). Two patients died due to AML, and five patients died due to transplantation-related complications in the AA group. To confirm these results, we are currently conducting a prospective study involving IST in patients with acquired BMF classified according to WHO classification before treatment. Disclosures: No relevant conflicts of interest to declare.

Acute Lymphoblastic Leukemia in a Patient with Monomac Syndrome/GATA2 Haploinsufficiency

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3729-3729
Author(s):  
Ashley Koegel ◽  
Venee N. Tubman ◽  
Inga Hofmann
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Lymphoblastic Leukemia ◽  
Killer Cell ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Definitive Therapy

Abstract Background: Heterozygous germline mutations in GATA2 have been described in three distinct conditions: 1) familial myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML), 2) Emberger syndrome which is characterized by lymphedema, warts and predisposition to MDS/AML, 3) MonoMac syndrome which is comprised of atypical nontuberculous mycobacterial infection, monocyte, and B and natural killer cell lymphoid deficiency. It is now recognized that these conditions represent a spectrum of hematopoietic, lymphatic and immune system disorders due to GATA2 haplosinsufficiency. MDS/AML due to GATA2 mutation shows a unique histopathology with characteristic dysplasia and is often associated with monosomy 7. Although many patients with GATA2 haploinsufficiency are initially asymptomatic the majority of patients will ultimately experience a significant complication such as severe infections due to immunodeficiency, pulmonary alveolar proteinosis (PAP), thrombotic events, bone marrow failure, MDS and progression to AML. Allogenic hematopoietic stem cell transplant (HSCT) is the only curative treatment for patients with GATA2 haploinsufficiency and those who develop MDS/AML. Here we report a unique patient who presented with with acute lymphoblastic leukemia (ALL) and was later found to have classical features of MonoMAC syndrome and GATA2 haploinsufficiency. Case Summary: A previously healthy 11 year-old girl presented with fever, cellulitis, and pancytopenia. Bone marrow biopsy and aspirate were diagnostic for B-precursor acute lymphoblastic leukemia (ALL) with associated monosomy 7 and the following karyotype: 45,XX,-7,del(9)(p13),del(10)(q24). She was treated on Dana Farber Cancer Institute (DFCI) Consortium ALL Protocol 05-001, achieving a morphological and cytogenetic remission. During induction, she developed necrotizing aspergillus pneumonia and molluscum contagiousum. Her planned course of therapy was abbreviated due to the development of restrictive lung disease associated with PAP and disseminated Mycobacterium kansasii infection. Serial off therapy bone marrow studies were obtained given poor count recovery and revealed significant morphologic dysplasia, most prominent in the megakaryocytes. These findings were reminiscent of those characteristically seen in patients with GATA2 haploinsufficiency. Her infectious complications, profound monocytopenia, PAP and bone marrow dysplasia raised concern for MonoMAC Syndrome. Sanger Sequencing of GATA2 revealed a point mutation in the regulatory enhancer region of intron 5 (c.1017+572C>T) confirming the diagnosis. More than 3 years following remission of ALL, she developed a bone marrow relapse with her initial clone. Given her diagnosis of GATA2 haploinsufficiency, HSCT was selected as consolidation therapy in second remission. She succumbed to complications of HSCT 4 months after transplantation. Conclusion: Patients with GATA2 haploinsufficiency show a heterogeneous clinical presentation and are at high risk for MDS/AML often associated with monosomy 7. The development of ALL in association with GATA2 haploinsufficiency has not been described in the literature. Hematologist and oncologists should be aware that ALL may be associated with GATA2 haploinsufficiency and should be attuned to the clinical, laboratory and histopathologic features of the MonoMAC syndrome that would prompt additional testing and potentially alter treatment regimens. As allogenic HSCT is the only definitive therapy for patients with GATA2 mutation, consideration of immediate HSCT following induction of remission should be considered in patients with ALL and GATA2 haploinsufficiency. Further, as patients with GATA2 mutations can be asymptomatic, it is imperative to screen family members for GATA2 mutations and offer genetic counselling prior to consideration as potential bone marrow donors. Disclosures No relevant conflicts of interest to declare.

Paroxysmal Nocturnal Hemoglobinuria (PNH) In Pediatric Patients: Review of a Single Center Series

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2231-2231
Author(s):  
Kevin J. Curran ◽  
Nancy A. Kernan ◽  
Susan E. Prockop ◽  
Andromachi Scaradavou ◽  
Trudy N. Small ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stable Disease ◽  
Pediatric Patients ◽  
Bone Marrow Failure ◽  
Adult Population ◽  
Single Center ◽  
Intravascular Hemolysis ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
5Q Deletion

Abstract Abstract 2231 Background: PNH arises from a genetic mutation of hematopoietic stem cells which leads to the acquired nonmalignant clonal expansion of cells lacking glycosyl phosphatidylinositol-anchored proteins (GPI-APs). Lack of GPI-APs translates into PNH's most significant clinical features: bone marrow failure, intravascular hemolysis and thrombosis. PNH rarely occurs in children and has been reported to have a distinct clinical presentation compared to the adult population. Results: We provide a clinical description of 11 consecutive pediatric patients (pts) aged 11–17 years (median age 13.9 years) diagnosed with PNH since 1993 at a single institution. Bone marrow failure was the presenting clinical finding in 10 pts, including aplastic anemia (AA) (N = 9), hypoplastic myelodysplastic syndrome (MDS) (N = 1), and isolated red cell anemia (N = 1). This rate of bone marrow failure at presentation is higher than the reported rate of 24–33% seen in adult pts. Immunosuppressive therapy was the initial treatment for 8 patients with aplastic anemia and this included: antithymocyte globulin (N = 8), Cyclosporine (N = 8) and prednisone (N = 6). Partial response to immunotherapy was seen in all pts. Five pts had evidence of myelodysplastic features, including one at diagnosis. These included dysplasia with monosomy 7 for 2 pts, 5q deletion for one pt, and dysplasia with normal cytogenetics for 2 pts. The monosomy 7 abnormality was transient and resolved spontaneously for the 2 pts, while the pt with 5q deletion proceeded to transplantation. None of these pts developed excessive blasts or leukemic transformation. Thrombosis occurred in six pts with four of the pts experiencing several sites and episodes of thrombosis. Diagnosis of thrombosis occurred at presentation in one patient. Thrombosis in the remaining five pts first occurred 5–88 months from diagnosis (mean 58.8 months). This rate of thrombosis (55%) is similar to the reported rate of thrombosis in adult pts (40%) but is higher than recent reports of pediatric PNH in the literature. Treatment of thrombosis included anticoagulation and thrombolysis when appropriate. Intermittent episodes of intravascular hemolysis occurred in all 11 pts. Gross hemoglobinuria occurred in only one patient at initial presentation. This rate of gross hemoglobinuria at presentation is similar to other series of pediatric PNH, but much lower than the reported rate of 33–50% in adult pts. Of the 11 pts, 4 underwent hematopoietic stem cell transplant (HSCT) of whom 2 pts are alive and disease free. Eculizumab, a monoclonal antibody directed against the complement protein C5 was initiated in 3 pts of whom 2 pts currently have stable disease; the third non-compliant patient developed progression of thrombotic disease but has since restarted eculizumab therapy. Two pts died following complications related to thrombosis and two patients are transfusion independent with stable disease. Conclusions: This series represents a large single center cohort of pediatric pts diagnosed with PNH. This report highlights the high rate of bone marrow failure in pediatric pts with PNH. This differs from the adult population, and emphasizes the need for PNH testing in all children with AA or MDS, as well as children with unexplained Coombs-negative hemolysis or thrombosis. Both the high prevalence of hemolysis and high risk of thrombosis should warrant early treatment with eculizumab for pediatric pts with PNH. HSCT remains the only curative option for pediatric pts with PNH but its risk must be considered relative to the patient's disease severity, compliance and response to long-term treatment with anticoagulant and/or anticomplement therapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals How I treat myelodysplastic syndromes of childhood

Blood ◽  
2018 ◽  
Vol 131 (13) ◽  
pp. 1406-1414 ◽  
Author(s):  
Franco Locatelli ◽  
Brigitte Strahm
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Germ Line ◽  
Bone Marrow Failure ◽  
Hematologic Malignancies ◽  
Suppressive Therapy ◽  
Severe Neutropenia ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L. Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse.

scholarly journals Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells

Leukemia ◽  
2021 ◽  
Author(s):  
Melvin E. Thomas ◽  
Sherif Abdelhamed ◽  
Ryan Hiltenbrand ◽  
Jason R. Schwartz ◽  
Sadie Miki Sakurada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Transcriptional Profiling ◽  
Hematopoietic Cells ◽  
Protein Translation ◽  
Germline Mutations ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Cellular Environment ◽  
Primary Mouse

AbstractPediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

scholarly journals Nontransplant therapy for bone marrow failure

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Danielle M. Townsley ◽  
Thomas Winkler
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Single Agent ◽  
Telomere Attrition ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

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