RESUMO
Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here, we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in thromboxane A synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin H2 (PGH2), a cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function mutations in TBXAS result in an increase in PGH2 availability for other PG synthases. The current treatment for Ghosal hematodiaphyseal dysplasia syndrome consists of corticosteroids. We hypothesize that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated 2 patients with Ghosal hematodiaphyseal dysplasia syndrome, an adult and a child, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvements concerning hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenia, and should be considered for first-line treatment for Ghosal hematodiaphyseal dysplasia syndrome.
Assuntos
Anemia Refratária , Anemia , Pancitopenia , Adulto , Criança , Humanos , Anemia Refratária/tratamento farmacológico , Anemia Refratária/genética , Anti-Inflamatórios não Esteroides/uso terapêutico , Anemia/tratamento farmacológico , Prostaglandina H2 , Síndrome , Transtornos da Insuficiência da Medula ÓsseaRESUMO
Germline mutations in tubulin beta class I (TUBB), which encodes one of the ß-tubulin isoforms, were previously associated with neurological and cutaneous abnormalities. Here, we describe the first case of inherited bone marrow (BM) failure, including marked thrombocytopenia, morphological abnormalities, and cortical dysplasia, associated with a de novo p.D249V variant in TUBB. Mutant TUBB had abnormal cellular localisation in transfected cells. Following interferon/ribavirin therapy administered for transfusion-acquired hepatitis C, severe pancytopenia and BM aplasia ensued, which was unresponsive to immunosuppression. Acquired chromosome arm 6p loss of heterozygosity was identified, leading to somatic loss of the mutant TUBB allele.
Assuntos
Pancitopenia , Trombocitopenia , Humanos , Tubulina (Proteína)/genética , Pancitopenia/genética , Deleção Cromossômica , Trombocitopenia/genética , Transtornos da Insuficiência da Medula Óssea/genética , Células GerminativasRESUMO
Inherited biallelic pathogenic variants (PVs) in BRCA2 cause Fanconi Anemia complementation group D1 (FA-D1), a severe pediatric bone marrow failure and high-risk cancer syndrome. We identified biallelic BRCA2 PVs in a young adult with multiple basal cell carcinomas, adult-onset colorectal cancer and small cell neuroendocrine carcinoma, without bone marrow failure. No PVs were identified in any other known cancer susceptibility gene, and there was no evidence of reversion mosaicism. The proband's deceased sister had a classic FA-D1 presentation and was shown to carry the same biallelic BRCA2 PVs. A lymphoblastoid cell line derived from the proband demonstrated hypersensitivity to DNA damaging agents, and bone marrow showed aberrant RAD51 staining. Family expansion demonstrated the presence of BRCA2 related cancers in heterozygous family members. Our data highlight the striking phenotypic differences which can be observed within FA-D1 families and expands the clinical spectrum of FA-D1 to include adult presentation with a constellation of solid tumors not previously thought of as characteristic of Fanconi Anemia. Early recognition of this syndrome in a family could prevent further morbidity and mortality by implementation of hereditary breast and ovarian cancer screening and treatment strategies for heterozygous family members.
Assuntos
Anemia de Fanconi , Neoplasias , Humanos , Proteína BRCA2/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Irmãos , Adulto JovemRESUMO
Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60-75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40-0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53-0.94). A sub-group of patients with equipoise, likelihood at least 30%-70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75-1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.
Assuntos
Citarabina , Leucemia Mieloide Aguda , Humanos , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
INTRODUCTION: Busulfan is a common component of allogeneic hematopoietic cell transplant (alloHCT) conditioning, however interpatient pharmacokinetic variability can result in enhanced toxicity or increased relapse risk. Therapeutic drug monitoring (TDM) can minimize variability, yet the optimal frequency of TDM is unknown. We compared outcomes for patients with one versus two sets of busulfan TDM during myeloablative conditioning (MAC) prior to alloHCT. METHODS: We analyzed the impact of busulfan TDM frequency and dose adjustments, with the primary outcome being relapse-free survival (RFS). Other outcomes included the incidence of acute and chronic graft versus host disease (GVHD), oral mucositis, pulmonary toxicity, sinusoidal obstruction syndrome (SOS), the cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: Twenty-two patients underwent one set of sampling while 53 patients underwent two sets. Similar baseline characteristics were observed between the groups. There were no significant differences observed in RFS by day +180 (77.3% vs. 79.2%, p = 1.0), CIR by day +180 (18.2% vs. 17.8%, p = 0.74), or OS (p = 0.73). The incidences of acute GVHD, chronic GVHD, SOS, and severe mucositis were also similar. In each group, 63% received busulfan dose adjustments after one set, with 52.8% receiving further dose adjustments following the second set. CONCLUSION: We observed no significant difference in alloHCT outcomes between patients who underwent one versus two sets of busulfan TDM sampling, suggesting that a single-time TDM and dose adjustment may be adequate to maximize outcomes after MAC alloHCT.
RESUMO
Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related nonmalignant bone marrow failure disorders linked to T-cell-mediated autoimmunity; they are associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15% to 20% of AA patients and 2% to 6% of PNH patients go on to develop secondary MDS/AML by 10 years of follow-up. Factors determining an individual patient's risk of malignant transformation remain poorly defined. Recent studies identified nearly ubiquitous clonal hematopoiesis (CH) in AA patients. Similarly, CH with additional, non-PIGA, somatic alterations occurs in the majority of patients with PNH. Factors associated with progression to secondary MDS/AML include longer duration of disease, increased telomere attrition, presence of adverse prognostic mutations, and multiple mutations, particularly when occurring early in the disease course and at a high allelic burden. Here, we will review the prevalence and characteristics of somatic alterations in AA and PNH and will explore their prognostic significance and mechanisms of clonal selection. We will then discuss the available data on post-AA and post-PNH progression to secondary MDS/AML and provide practical guidance for approaching patients with PNH and AA who have CH.
Assuntos
Anemia Aplástica/patologia , Hemoglobinúria Paroxística/patologia , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/etiologia , Idade de Início , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Medula Óssea/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 7/genética , Evolução Clonal/efeitos dos fármacos , Células Clonais/efeitos dos fármacos , Células Clonais/patologia , Progressão da Doença , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/genética , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Modelos Biológicos , Monossomia , Mutação , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Seleção Genética , Encurtamento do TelômeroRESUMO
INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. METHODS: We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017-2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. RESULTS: Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19-32) with day + 4 initiation vs. 24 days (21-30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. CONCLUSION: Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Mucosite , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Metotrexato/uso terapêutico , Mucosite/tratamento farmacológico , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodosRESUMO
BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.
Assuntos
Antibioticoprofilaxia , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/etiologia , Infecções por Clostridium/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipersensibilidade/complicações , Transplantados , Vancomicina/administração & dosagem , Administração Oral , Adulto , Idoso , Antibioticoprofilaxia/métodos , Clostridioides difficile/imunologia , Infecções por Clostridium/mortalidade , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tempo para o Tratamento , Transplante Homólogo/efeitos adversos , Adulto JovemAssuntos
Anemia Aplástica , Humanos , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/induzido quimicamente , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Segunda Neoplasia Primária/etiologia , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Idoso de 80 Anos ou mais , Síndromes Mielodisplásicas/tratamento farmacológicoRESUMO
PNH is the most common clonal hematopoietic disorder arising in patients with aAA. PNH is caused by mutations in PIGA, a gene that encodes the catalytic subunit of an enzyme involved in the biosynthesis of GPI anchors, transmembrane glycolipids required for cell surface expression of many proteins. PNH clones likely arise as immune escape mechanisms in aAA by preventing CD1D-restricted T-cell recognition of GPI anchors and GPI-linked autoantigens. Though many patients with aAA treated with IST will develop subclinical PNH clones, only a subset will develop PNH disease, characterized by increased thrombosis, intravascular hemolysis, and potential for severe organ dysfunction. In contrast to IST, allogeneic HSCT for patients with aAA is thought to cure bone marrow aplasia and prevent hematopoietic clonal evolution to PNH. Herein, we present a phenomenon of host-derived PNH disease arising in a patient with aAA many years following MSD-BMT, highlighting the importance of monitoring for this clonal disease in aAA patients with stable mixed donor/recipient chimerism after HSCT. We also provide a literature review for similar occurrences of PNH arising after HSCT.
Assuntos
Anemia Aplástica/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemoglobinúria Paroxística/etiologia , Adolescente , Anemia Aplástica/genética , Células da Medula Óssea/metabolismo , Quimerismo , Ciclosporina/administração & dosagem , Diabetes Mellitus Tipo 1/complicações , Sobrevivência de Enxerto , Hemoglobinúria Paroxística/genética , Hemólise , Humanos , Imunossupressores/administração & dosagem , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Neutrófilos/metabolismo , Recidiva , Trombocitopenia/terapia , Trombose/etiologia , Resultado do TratamentoRESUMO
The JAK2 V617F mutation is characteristic of most Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and occurs rarely in de novo acute myeloid leukaemia (AML). We sought to characterize AMLs that harbour this mutation and distinguish those that arise de novo (AML-DN) from those that reflect transformation of an underlying MPN (AML-MPN). Forty-five patients with JAK2 V617F-mutated AML were identified; 15 were AML-DN and 30 were AML-MPN. AML-MPN cases were more likely to have splenomegaly (P = 0·02), MPN-like megakaryocytes and higher mean JAK2 V617F VAF at diagnosis (P = 0·04). Mutations involving TET2 were exclusively identified in AML-DN patients. Mutations of genes affecting DNA methylation were more common in AML-DN (P < 0·01). A complex karyotype was more frequent in AML-MPN cases than in AML-DN (P < 0·01), with AML-DN more likely to display a normal karyotype (P = 0·02). Bone marrow histology after recovery from induction chemotherapy in AML-DN cases revealed no morphological evidence of any previously occult MPNs, while this was evident in most of the AML-MPN specimens (P < 0·01). These findings in this largest study of JAK2 V617F-mutated AMLs indicate that AML-DN is distinct from AML-MPN.
Assuntos
Transformação Celular Neoplásica/genética , Janus Quinase 2/genética , Leucemia Mieloide Aguda/genética , Mutação , Transtornos Mieloproliferativos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Transformação Celular Neoplásica/patologia , Metilação de DNA/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Leucemia Mieloide Aguda/patologia , Masculino , Megacariócitos/patologia , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Estudos RetrospectivosRESUMO
Myeloproliferative neoplasms arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of myeloproliferative neoplasms is based on hematologic, histopathologic and molecular characteristics including the presence of the BCR-ABL1 and JAK2 V617F. Although thought to be mutually exclusive, a number of cases with co-occurring BCR-ABL1 and JAK2 V617F have been identified. To characterize the clinicopathologic features of myeloproliferative neoplasms with concomitant BCR-ABL1 and JAK2 V617F, and define the frequency of co-occurrence, we conducted a retrospective multi-institutional study. Cases were identified using a search of electronic databases over a decade at six major institutions. Of 1570 patients who were tested for both BCR-ABL1 and JAK2 V617F, six were positive for both. An additional five patients were identified via clinical records providing a total of 11 cases for detailed evaluation. For each case, clinical variables, hematologic and genetic data, and bone marrow histomorphologic features were analyzed. The sequence of identification of the genetic abnormalities varied: five patients were initially diagnosed with a JAK2 V617F+ myeloproliferative neoplasm, one patient initially had BCR-ABL1+ chronic myeloid leukemia, while both alterations were identified simultaneously in five patients. Classification of the BCR-ABL1-negative myeloproliferative neoplasms varied, and in some cases, features only became apparent following tyrosine kinase inhibitor therapy. Seven of the 11 patients showed myelofibrosis, in some cases before identification of the second genetic alteration. Our data, reflecting the largest reported study comprehensively detailing clinicopathologic features and response to therapy, show that the co-occurrence of BCR-ABL1 and JAK2 V617F is rare, with an estimated frequency of 0.4%, and most often reflects two distinct ('composite') myeloproliferative neoplasms. Although uncommon, it is important to be aware of this potentially confounding genetic combination, lest these features be misinterpreted to reflect resistance to therapy or disease progression, considerations that could lead to inappropriate management.
Assuntos
Neoplasias da Medula Óssea/genética , Medula Óssea/patologia , Proteínas de Fusão bcr-abl/genética , Janus Quinase 2/genética , Sistemas Multi-Institucionais , Transtornos Mieloproliferativos/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Medula Óssea/sangue , Neoplasias da Medula Óssea/tratamento farmacológico , Neoplasias da Medula Óssea/patologia , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/sangue , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Mielofibrose Primária/sangue , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Estudos RetrospectivosRESUMO
Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A. Here, we present the current knowledge of clonal haematopoiesis in AA as it relates to aging, inherited bone marrow failure, and the grey-zone overlap of AA and myelodysplastic syndrome (MDS). We conclude by discussing the significance of clonal haematopoiesis both for improved diagnosis of AA, as well as for a more precise, personalized approach to prognostication of outcomes and therapy choices.
Assuntos
Anemia Aplástica/genética , Hematopoese/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Doenças da Medula Óssea/genética , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Células Clonais/fisiologia , Diagnóstico Diferencial , Feminino , Marcadores Genéticos , Hemoglobinúria Paroxística/genética , Humanos , Evasão da Resposta Imune/genética , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Prognóstico , Recidiva , Adulto JovemRESUMO
BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders defined by proliferation of one or more myeloid lineages, and carry an increased risk of vascular events and progression to myelofibrosis and leukemia. Portal hypertension (pHTN) occurs in 7-18% of MPN patients via both thrombotic and nonthrombotic mechanisms and portends a poor prognosis. Transjugular intrahepatic portosystemic shunt (TIPS) has been used in the management of MPN-associated pHTN; however, data on long-term outcomes of TIPS in this setting is limited and the optimal management of medically refractory MPN-associated pHTN is not known. In order to assess the efficacy and long-term outcomes of TIPS in MPN-associated pHTN, we performed a retrospective analysis of 29 MPN patients who underwent TIPS at three academic medical centers between 1997 and 2016. The majority of patients experienced complete clinical resolution of pHTN and its clinical sequelae following TIPS. One, two, three, and four-year overall survival post-TIPS was 96.4%, 92.3%, 84.6%, and 71.4%, respectively. However, despite therapeutic anticoagulation, in-stent thrombosis occurred in 31.0% of patients after TIPS, necessitating additional interventions. In conclusion, TIPS can be an effective intervention for MPN-associated pHTN regardless of etiology. However, TIPS thrombosis is a frequent complication in the MPN population and indefinite anticoagulation post-TIPS should be considered.
Assuntos
Proteínas de Fusão bcr-abl , Hipertensão Portal , Transtornos Mieloproliferativos , Derivação Portossistêmica Transjugular Intra-Hepática , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/mortalidade , Hipertensão Portal/cirurgia , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoRESUMO
OPINION STATEMENT: Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells. Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice of frontline therapy is determined by a number of factors including AA severity, age of the patient, donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia, bone marrow transplant should be pursued in all pediatric patients and in younger adult patients when a matched sibling donor is available. Frontline therapy in older adult patients and in all patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include encouraging results with closely matched unrelated donor transplants in younger patients and the emerging benefits of eltrombopag combined with initial IST, with randomized studies underway. In the refractory setting, several therapeutic options exist, with improving outcomes of matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations in AA. Future longitudinal studies of large numbers of patients are needed to determine the prognostic significance of somatic mutations and to guide optimal surveillance and treatment approaches to prevent long-term clonal complications.
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Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/terapia , Anemia Aplástica/patologia , Doenças da Medula Óssea/patologia , Transplante de Medula Óssea , Ciclosporina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Terapia de Imunossupressão/métodos , Irmãos , Doadores de TecidosAssuntos
Proteínas Ligadas por GPI/genética , Animais , Evolução Molecular , Genômica , Humanos , CamundongosRESUMO
Dyskeratosis congenita (DC) is a rare inherited telomeropathy most frequently caused by mutations in a number of genes all thought to be involved in telomere maintenance. The main causes of mortality in DC are bone marrow failure as well as malignancies including leukemias and solid tumors. The clinical picture including the degree of bone marrow failure is highly variable and factors that contribute to this variability are poorly understood. Based on the recent finding of frequent clonal hematopoiesis in related bone marrow failure syndromes, we hypothesized that somatic mutations may also occur in DC and may contribute at least in part to the variability in blood production. To evaluate for the presence of clonal hematopoiesis in DC, we used a combination of X-inactivation, comparative whole exome sequencing (WES) and single nucleotide polymorphism array (SNP-A) analyses. We found that clonal hematopoiesis in DC is common, as suggested by skewed X-inactivation in 8 out of 9 female patients compared to 3 out of 10 controls, and by the finding of acquired copy neutral loss-of-heterozygosity on SNP-A analysis. In addition, 3 out of 6 independent DC patients were found to have acquired somatic changes in their bone marrow by WES, including a somatic reversion in DKC1, as well as missense mutations in other protein coding genes. Our results indicate that clonal hematopoiesis is a common feature of DC, and suggest that such somatic changes, though commonly expected to indicate malignancy, may lead to improved blood cell production or stem cell survival. Am. J. Hematol. 91:1227-1233, 2016. © 2016 Wiley Periodicals, Inc.