RESUMO
The treatment of aplastic anemia (AA) has significantly advanced in the last 50 years, evolving from a fatal condition to one where survival rates now exceed 80-85%. Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have become the primary treatments, with the latter widely adopted due to factors like the scarcity of compatible donors, patient age, comorbidities, and limited HSCT access. A therapy breakthrough was the introduction of antithymocyte globulin (ATG), with its effectiveness further boosted by cyclosporine. However, it took years to achieve another major milestone in management. Initially, treatments aimed to intensify immunosuppression following the success of the ATG-cyclosporine combination, but these methods fell short of expectations. A major turning point was combining immunosuppression with stem cell stimulation, surpassing the efficacy of IST alone. Earlier, growth factors had shown limited success in AA treatment, but thrombopoietin receptor agonists represented a significant advancement. Initially applied alone as salvage, these were later combined with IST, forming the most effective current regimen for medically managing SAA. Horse ATG is the preferred formulation combined with cyclosporine and eltrombopag. This progress in AA treatment offers improved outcomes for patients afflicted with this once-lethal disease.
Assuntos
Anemia Aplástica , Imunossupressores , Humanos , Imunossupressores/uso terapêutico , Anemia Aplástica/tratamento farmacológico , Ciclosporina/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Terapia de Imunossupressão , Resultado do TratamentoRESUMO
The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.
Assuntos
Anemia Aplástica/patologia , Anemia Aplástica/terapia , Anemia Aplástica/diagnóstico , Anemia Aplástica/imunologia , Animais , Benzoatos/uso terapêutico , Gerenciamento Clínico , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hidrazinas/uso terapêutico , Terapia de Imunossupressão/métodos , Pirazóis/uso terapêutico , Índice de Gravidade de DoençaRESUMO
ABSTRACT Background: Secondary immune thrombocytopenia (ITP) is a heterogeneous and unpredictable disease associated with various underlying conditions. Objective: The objective of the study was to investigate clinical evolution and chronicity predictors in secondary ITP. Methods: Patients treated at an academic medical center during 2008-2019 were stratified by age as children <16 years and adults >16 years. Responses to steroids, intravenous immunoglobulin G (IVIG), rituximab, and eltrombopag were classified as response (R) and complete response (CR). Risk factors for chronic ITP were determined by multiple regression with uni- and multi-variate analysis. Results: Eighty-three patients were included, 37 children and 46 adults. The most frequent associated conditions were infections 53%, systemic lupus erythematosus (SLE) 24%, thyroid disease 9.6%, and Evans syndrome 3.6%. Response to first-line treatment in the whole cohort was 94%; CR 45.7%; and R 50.6%. Initial response to steroids alone was 91.3% (n = 21/23), rituximab plus high-dose dexamethasone (HDD) 93.3% (n = 14/15); children receiving IVIG alone 100% (n=12/12); and eltrombopag in adults 100% (n = 3/3). Relapse was documented in 19.4% of children and 34% of adults, at a median time of 15 and 2 months, respectively; 30.4% of adults (15.2% from the miscellaneous group, 10.9% SLE-associated, and 4.3% infection-associated) and 18.9% of children followed a chronic course; age ≥10 years and platelets ≥20 × 109/L were risk factors for chronic ITP in children. Conclusion: Evolution was heterogeneous: a better and more sustained response was documented in the infections group compared to SLE or the miscellaneous group. (REV INVEST CLIN. 2021;73(1):31-8)
Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Encaminhamento e Consulta , Doença Crônica , Estudos Retrospectivos , Resultado do Tratamento , HematologiaRESUMO
Eltrombopag has been added to first-line treatment of immune aplastic anaemia (AA), resulting in higher responses. We analysed marrow samples of AA patients who responded to immunosuppressive therapy (IST) alone or in combination with eltrombopag for the composition of the haematopoietic stem and progenitor cell (HSPC) compartment. The number of CD34+ cells and multipotent progenitors was higher in patients treated with eltrombopag (P < 0·005; P < 0·05; respectively), but not the number of stem cells. No aberrant phenotype was observed. These results indicate that eltrombopag augments CD34+ cells in vivo and preferentially expands multipotent progenitors, but not stem cells.
Assuntos
Anemia Aplástica/tratamento farmacológico , Benzoatos/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Hidrazinas/farmacologia , Células-Tronco Multipotentes/efeitos dos fármacos , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Adolescente , Adulto , Antígenos CD34/efeitos dos fármacos , Benzoatos/administração & dosagem , Biópsia por Agulha/métodos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Brasil/epidemiologia , Feminino , Citometria de Fluxo/métodos , Células-Tronco Hematopoéticas/citologia , Humanos , Hidrazinas/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/citologia , Pirazóis/administração & dosagemRESUMO
Resumen La pandemia de enfermedad por coronavirus 2019 (COVID-19) ha cambiado la perspectiva médica para el tratamiento de no solo de enfermedades hematológicas, sino en general de la medicina. Respecto a la anemia aplásica (AA), principalmente la muy severa, en la que el paciente se presenta con menos de 200 neutrófilos absolutos, el riesgo de infección potencialmente mortal es alta y el inicio de terapia inmunosupresora también representa un riesgo, al menos temporal, para COVID-19. Se ha recomendado incluso aplazar el trasplante de células progenitoras hematopoyéticas en muchos pacientes para evitar un contagio. Una inmunosupresión moderada preferentemente ambulatoria que incluya agentes trombomiméticos es la opción terapéutica en tiempos de la pandemia actual. En esta revisión se enlistan las recomendaciones internacionales y nacionales respecto al tratamiento y seguimiento de pacientes con AA con base en experiencias de países que ya han pasado por esta emergencia sanitaria.
Abstract Medical practice in general has changed due to coronavirus disease 2019 (COVID-19) pandemic. Some hematologic diseases require immunosuppresive therapy placing patients at high risk of infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Aplastic anemia (AA) especially the very severe type in which the count of absolute neutrophils is less than 200/ml is a life-threatening condition. Although bone marrow transplant is a potential curative treatment, it should be delayed temporally in order to prevent a contagion. Hospitalization may expose patients to infection, thus an ambulatory immunosuppression with oral cyclosporine and thrombopoietin agonist should be an adequate option. This work reviews international and national treatment recommendations and follow-up of patients with AA based on experiences from countries that have already faced this health emergency.
RESUMO
Primary immune thrombocytopenia (ITP) is an intriguing autoimmune disease characterized by autoantibodies against platelets and megakaryocytes. Clinical outcomes, response to treatment, and chronicity predictors were investigated. Patients with newly diagnosed primary ITP treated at a hematology referral center from 2008 to 2018 with complete medical and recent medication history were stratified by age as children < 16 years and adults > 16 years. Responses to treatment including steroids, splenectomy, rituximab, and eltrombopag were classified as response (R) and complete (CR). Factors for developing chronic ITP were determined by multiple regression with uni- and multivariate analysis. p < 0.05 was considered significant. A total of 175 patients were included, 52 children and 123 adults; women predominated with 57.7%. Response to first-line treatment in the whole cohort was 86.18%, CR 43.42% and R 42.76%. The initial response to steroids alone was 83.9% (n = 52/62), rituximab plus high-dose dexamethasone (HDD) 87.2% (n = 34/39), eltrombopag plus HDD 90.9% (n = 10/11), and children receiving IVIG alone 100% (n = 8/8); 9 children were under clinical observation and achieved spontaneous response; loss of response was documented in 15.21% children and 28.3% adults with a median time of 15.95 and 4.07 months respectively; 37.39% of adults and 30.76% of children progressed to a chronic course. Platelets ≥ 20 × 109/L and age ≥ 6 years were risk factors for chronic ITP in the univariate analysis in the adult and children groups, respectively. Clinical course and treatment outcomes for ITP are considerably heterogeneous. Higher platelet counts at diagnosis in adults and age ≥ 6 years in children were associated with an increased risk of chronicity.
Assuntos
Benzoatos/administração & dosagem , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Púrpura Trombocitopênica Idiopática/terapia , Pirazóis/administração & dosagem , Rituximab , Esplenectomia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Estudos RetrospectivosAssuntos
Benzoatos/administração & dosagem , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/administração & dosagem , Rituximab/administração & dosagem , Adolescente , Adulto , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/diagnósticoRESUMO
Immune thrombocytopenia (ITP) is a bleeding disorder caused by a decrease in platelet count resulting from increased destruction and insufficient production of platelets. Although impaired regulatory T-lymphocyte activity plays a critical role in platelet destruction, many other immunologic abnormalities are also likely to be involved. Importantly, patients with ITP appear to have defects in a thrombopoietin-mediated physiological mechanism that compensates for a decrease in platelet count by increasing platelet production. Thus, simultaneous treatment of multiple pathogenic pathways involved in ITP could potentially result in synergistic efficacy. While conventional treatments for ITP suppress or modulate the immune system to reduce platelet destruction, a unique class of ITP therapy, namely thrombopoietin receptor agonists (TPO-RAs), improves platelet production by activating the thrombopoietin pathway. As hypothesized, preliminary studies show that combinations of eltrombopag, an oral TPO-RA, with conventional treatments improve outcomes in both newly diagnosed and refractory patients. In this review, the clinical experience with eltrombopag-based combinations in patients with ITP is summarized and the implications of the available data are discussed.