Aplasia medular adquirida, experiencia en un hospital público de referencia / Acquired aplastic anemia: experience in a public hospital

Background: The first line treatment for patients < 40 years old with aplastic anemia (AA) is allogeneic HLA-identical sibling donor transplantation (SCT). Immunosuppressive therapy (IST) with a combination of Thymoglobuline (ATG) and cyclosporine is used for older patients or those without a donor. Five year overall survival (OS) for both therapies is > 70%. Aim: To report the experience with SCT and ATG for AA in a public hospital. Patients and Methods: AA was diagnosed in 42 patients between 1998 and 2016, according to Camitta criteria. Thirty eight (90%) received treatment, 7 (18%) under 40 years old received SCT, and 31 (82%) IST. The rest were not treated. OS was calculated from date of diagnosis until last control, death or loss from follow up. Results: Complete or partial hematologic response, was obtained in 71% and 58% of cases with SCT and IS, respectively. Five year OS was 71% and 55% with SCT and IST, respectively. No difference in response was observed between horse and rabbit ATG. Conclusions: SCT from an HLA-identical sibling donor had a high response rate and survival. IST instead, had a lower response and survival, due to an initial high mortality rate.

Prevalência de doença por citomegalovírus em transplantados renais em unidade de terapia intensiva / Prevalence of cytomegalovirus disease in kidney transplant patients in an intensive care unit

RESUMO Objetivos: Definir frequência de doença por citomegalovírus dentre pacientes transplantados renais na unidade de terapia intensiva nos quais houve a suspeita desta complicação; identificar fatores predisponentes e possível impacto na evolução clínica. Métodos: Estudo retrospectivo observacional, no qual foram incluídos pacientes transplantados renais acima de 18 anos, internados por quaisquer motivos em uma unidade de terapia intensiva, com pelo menos uma coleta de antigenemia ou reação em cadeia da polimerase para citomegalovírus durante internação. Doença por citomegalovírus foi definida por antigenemia positiva ou reação em cadeia da polimerase acima de 500 cópias/mL, na presença de sintomas, no contexto clínico apropriado, conforme julgamento do médico assistente. Resultados: Foram incluídos 99 pacientes (idade: 53,4 ± 12,8 anos, 71,6% homens). A doença por citomegalovírus foi diagnosticada em 39 pacientes (39,4%). Sintomas respiratórios (51%), piora clínica inespecífica (20%) ou sintomas gastrintestinais (14%) foram os principais motivos para coleta de exames. O tempo de transplante foi menor naqueles com doença por citomegalovírus em relação àqueles sem este diagnóstico (6,5 meses e 31,2 meses; p = 0,001), bem como uso de pulsoterapia nos últimos 6 meses (41% e 16,9%; p = 0,008) e uso prévio de timoglobulina no último ano (35,9% e 6,8%; p < 0,001). No modelo de regressão logística, somente o tempo de transplante e o uso de timoglobulina associaram-se à maior frequência de citomegalovírus. Não houve diferença na evolução clínica entre pacientes com ou sem doença por citomegalovírus. Conclusão: Em pacientes transplantados renais com suspeita de doença por citomegalovírus, a prevalência foi alta. O tempo de transplante menor que 6 meses e o uso de timoglobulina no último ano devem aumentar a suspeita do intensivista para esta complicação.

ABSTRACT Objectives: To define the frequency of cytomegalovirus disease among kidney transplant patients in an intensive care unit in which this complication was suspected and to identify predisposing factors and their possible impact on clinical outcome. Methods: Retrospective observational study in which kidney transplant patients over the age of 18 years were hospitalized for any reason in an intensive care unit with at least one collection of samples to test for the presence of antigenemia or cytomegalovirus via polymerase chain reaction during hospitalization. Cytomegalovirus disease was defined as positive antigenemia or polymerase chain reaction above 500 copies/mL in the presence of symptoms and in the appropriate clinical setting, as judged by the attending physician. Results: A total of 99 patients were included (age: 53.4 ± 12.8 years, 71.6% male). Cytomegalovirus disease was diagnosed in 39 patients (39.4%). Respiratory symptoms (51%), non-specific clinical worsening (20%) or gastrointestinal symptoms (14%) were the main reasons for exam collection. Transplant time was lower in those with cytomegalovirus disease than in those without this diagnosis (6.5 months and 31.2 months, p = 0.001), along with pulse therapy in the last 6 months (41% and 16.9%, p = 0.008) and previous use of thymoglobulin in the last year (35.9% and 6.8%, p < 0.001). In the logistic regression model, only the transplant time and the use of thymoglobulin were associated with a higher frequency of cytomegalovirus. There was no difference in clinical evolution between patients with and without cytomegalovirus disease. Conclusion: In kidney transplant patients suspected of cytomegalovirus disease, the prevalence was high. Transplant time less than 6 months, and the use of thymoglobulin in the last year should increase the intensivist's suspicion for this complication.

A retrospective compariso of cyclophosphamide plus antithymocyte globulin with cyclophosphamide plus busulfan as the conditioning regimen for severe aplastic anemia

Allogeneic hematopoietic stem cell transplantation (AHSCT) is the treatment of choice for young patients with severe aplastic anemia (SAA). The association of antithymocyte globulin (ATG) and cyclophosphamide (CY) is the most frequently used conditioning regimen for this disease. We performed this retrospective study in order to compare the outcomes of HLA-matched sibling donor AHSCT in 41 patients with SAA receiving cyclophosphamide plus ATG (ATG-CY, N = 17) or cyclophosphamide plus busulfan (BU-CY, N = 24). The substitution of BU for ATG was motivated by the high cost of ATG. There were no differences in the clinical features between the two groups, including age, gender, cytomegalovirus status, ABO match, interval between diagnosis and transplant, and number of total nucleated cells infused. No differences were observed in the time to neutrophil and platelet engraftment, or in the risk of veno-occlusive disease and hemorrhage. However, there was a higher risk of mucositis in the BU-CY group (71 vs 24 percent, P = 0.004). There were no differences in the incidence of neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, and transplant-related mortality. There was a higher incidence of late rejection in the ATG-CY group (41 vs 4 percent, P = 0.009). Although the ATG-CY group had a longer follow-up (101 months) than the BU-CY group (67 months, P = 0.04), overall survival was similar between the groups (69 vs 58 percent, respectively, P = 0.32). We conclude that the association BU-CY is a feasible option to the conventional ATG-CY regimen in this population.

Agentes imunossupressores, talidomida e ácido valpróico nas síndromes mielodisplásicas / Immunosuppressive agents, thalidomide and valproate acid in myelodysplastic syndromes

Agentes imunossupressores, como a globulina antitimocítica (GAL) ou antilinfocítica (GAL) e a ciclosporina A têm mostrado eficácia nas SMD, particularmente nos subtipos Anemias refratária (AR) e nas SMD com fenótipo HLA-DR15, independente do grau de celularidade medular. Outras drogas disponíveis em nosso meio, de baixo custo, como a talidomida podem ser utilizada em pacientes refratários, e o ácido valpróico está sendo utilizado em ensaios clínicos. A quantificação da resposta a drogas deve utilizar os critérios de resposta do International Working Group (IWG). É proposto um fluxograma para uso de fatores de crescimento, agentes imunossupressores e talidomida em pacientes com SMD, de baixo risco, não candidatos a transplante de medula óssea (TMO).

Patients with refractory anemia subtypes and HLA-DR15 with any degree of marrow cellularity have good responses to immunosuppressive agents, such as antithymocyte globulin, antilymphocyte globulin and cyclosporine A. Other cheaper drugs available in Brazil, including thalidomide may be useful in refractory patients. Valproate acid has started to be used in clinical trials. Response to treatment should be reported using the criteria proposed by the International Working Group. The use of growth factors, immunosuppressive agents and thalidomide in low risk patients with myelodysplastic syndromes who are not candidates for hematopoietic stem cell transplantation is suggested at the end of this publication.

Acquired hemoglobin H disease in a patient with aplastic anemia evolving into acute myeloid leukemia

CONTEXTO: O prognóstico da anemia aplástica grave melhorou com o advento do transplante de medula óssea e do tratamento imunossupressor com globulina antitimocitária. Em contraste com o sucesso destes protocolos, os estudos com seguimento a longo prazo mostraram a ocorrência de doenças clonais, tais como: hemoglobinúria paroxística noturna, síndrome mielodisplásica e leucemia aguda. RELATO DE CASO: Nós relatamos o primeiro caso descrito no Brasil de um paciente com anemia aplástica que evoluiu para síndrome mielodisplásica e leucemia mielóide aguda associada a presença de hemoglobina H e aumento da hemoglobina fetal.

The Treatment of Severe Aplastic Anemia: Outcomes of Bone Marrow Transplantation and Immunosuppressive Therapy in a Single Institution of Korea

The present study represents an analysis of 96 patients with severe aplastic anemia (SAA) treated in Seoul National University Hospital, Seoul, Korea between 1990 and 1999. Twenty-two patients were treated by allogeneic bone marrow transplantation (BMT) from HLA identical sibling donors and 74 by immunosuppressive therapy (IS) with antithymocyte globulin (ATG) or antilymphocyte globulin (ALG). There was no statistical difference between the two treatment groups in age, sex, disease duration, and previous transfusion amount. In the BMT group, grade II-IV acute graft versus host disease (GVHD) develeped in 10% and chronic GVHD occurred in 33% of patient. Only one patient died from complication of transplantation (veno-occlusive disease). Of 74 patients who received IS treatment, 45% achieved a complete or partial response. Twenty patients died among IS treatment group. Major causes of death were hemorrhage (40%) and infection (55%). In the BMT group, the 5-yr overall survival (OS) was 95% after a median follow-up of 42 months. In the IS group, the 5-yr OS was 70% after a median follow-up of 49 months (p=0.04). In conclusion, the long-term survival rates of SAA in Koreans receiving BMT or IS were excellent compared with the Western data. Further evaluation on the prognosis of aplastic anemia in Asians should be done.

Globulina antilinfocítica en el tratamiento de la anemia aplásica severa / Antilymphocyte globulin in the treatment of severe aplastic anemia

Objetivo: Describir la experiencia en nuestro hospital en el tratamiento de anemia aplásica severa con globulina antiinfocítica. Materiales y Métodos: Se estudiaron 58 pacientes con AAS diagnosticados entre 1988-1998 de los cuales 25 recibieron globulina antilinfocítica (GAL), 56 por ciento de ellos eran menores a 20 años de edad, 19 de los pacientes tratados con GAL son del sexo masculino. Resultado: Respondieron favorablemente 68 por ciento (17 pacientes), la mayoría de ellos (64 por ciento) alcanzaron esta respuesta durante los primeros 6 mese. Un paciente evolucionó a hemoglobinuria paroxística nocturna (HPN), efectos adversos fueron leves y de corta duración.

Trasplante renal y rechazo crónico en pediatría / Renal transplant and chronic rejection in pediatrics

The rapid advances in immunobiology, pharmacology and molecular biology have made successful renal transplantation the optimal therapeutic modality for adults and children, reaching a near -90 percent of patient-graft survival among the first years of transplant. But this knowledge also presents clinicians and scientists with difficult challenges, one of the most important remaining is the chronic rejection of the graft. A critical review of the immunobiology, clinical evolution and histopatholgy of chronic rejection is presented. Immunosuppressive agents with emphasis in their mechanism of action is also detailed

Antilymphocyte globulin (ALG) or antithymocyte globulin (ATG) with methylprednisone and oxymethalone in aplastic anaemia.

From 1986 to 1994 we treated 26 patients of aplastic anaemia between 6 to 61 years age group with ATG/ALG, Methylprednisone and Oxymethalone. Five had very severe aplastic anaemia, 16 had severe and 5 nonsevere disease. Disease was associated with hepatitis in 5 patients and with pregnancy and drug use in 2 patients each. In others no cause could be ascertained. A total of 31 courses of treatment were given (range 1-3 courses per patient). Nine patients had complete response (34.62%) and 3 had partial response (11.54%) with an overall response rate of 46.16%. Four patients died within 2 months of starting the treatment. The median follow up was 24 months (range 6-102 months) with an overall survival probality of 45% at 2 yr. At the time of evaluation 12 patients have died, 9 are alive disease-free and 5 are alive with disease. The side effects associated with therapy were tolerable and did not require cessation of therapy in any patient. We conclude that ATG/ALG with Methylprednisone and Oxymethalone is beneficial to significant number of patients with aplastic anaemia.

Globulina antitimocito en el tratamiento de la anemia aplástica adquirida: informe de cinco casos / Anithymocytic globulin in the treatment of aplastic anemia. Five clinic cases

Se informa de la experiencia obtenida en cinco niños con diagnóstico de anemia aplástica adquirida, a quienes se les administró globulina antitimocito. Uno de los niños no había recibido ningún tratamiento previo. Los otros cuatro habían recibido medicación con andrógenos (mesterolona) con pobre respuesta; dos de los cuales tenían menos de un mes de recibir este medicamento. Las reacciones secundarias observadas fueron: eritema máculopapular, prurito, artralgias y fiebre. En ningún caso hubo necesidad de suspender el tratamiento por intolerancia. A todos los niños se les administró mesterolona después de la aplicación de la globulina antitimocito. Se practicó un estudio de médula ósea antes del tratamiento y 12 semanas después de iniciado éste. No se observaron cambios en las diferentes series celulares. Dos de los niños fallecieron meses después por hemorragias e infección. Tres continúan con aplicación de mesterolona. Dos de ellos han tenido menor frecuencia de internamientos para transfusión de sangre y presentan evidente mejoría de la celularidad de médula ósea

Tratamiento de la hemoglobinuria paroxística nocturna con globulina antilinfocitaria / Antilymphocyte globulin therapy for paroxysmal nocturnal hemoglobinuria

Objetivo. Evaluar la utilidad de la globulina antilinfocitos T humanos (GAL) en el tratamiento de la hemoglobinuria paroxística nocturna (HPN). Diseño. Estudio prospectivo, no controlado de casos clínicos. Ubicación. Servicio de Hematología, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, México. Pacientes. Se incluyeron seis pacientes, tres varones y tres mujeres con edad promedio de 37.5 años. El diagnóstico de HPN se estableció por datos clínicos y pruebas de Ham, sucrosa e inulina positivas. Se consideró grave en cuatro enfermos en virtud de su actividad hemolítica continua e intensa, y los requerimientos transfusionales altos (más de dos concentrados de hematíes por mes); cinco de ellos no habían tenido mejoría con esteroides y/o andrógenos; uno no tenía tratamiento previo. Intervención. Se aplicó GAL (Lymphoglobuline Mérieux, Lyon, Francia; lote E 0034) 10 mg/kg/día por cuatro días, en infusión de 20 horas; también recibieron metilprednisolona, 500 mg/día, en infusión de dos horas cambiando, al cabo de siete días, a prednisona de 1 mg/kg y en dosis decrecientes hasta suspenderla en 30 días. Criterios de respuesta. Se valoró por medio del aumento en el nivel de homoglobina, la disminución o ausencia en los requerimientos transfusionales de glóbulos rojos, y la mejoría de la cuenta de plaquetas, granulocitos o ambas, en los tres meses posteriores al tratamiento con GAL. Resultados. En dos enfermos la primera dosis de GAL provocó una reacción anafiláctica y fueron excluidos del estudio. De los cuatro enfermos restantes, sólo dos mostraron respuesta a las 12 semanas post-tratamiento, uno total y otro mínima; ambas respuestas fueron transitorias. En un seguimiento promedio de 12.5 meses, ninguno de los pacientes mostraba mejoría. En los cuatro sujetos hubo necesidad de reiniciar tratamiento en danazol y prednisona. Conclusiones. El paciente con HPN en actividad intensa, la terapéutica con GAL, en las dosis y tiempo dados, no ofreció ningún beneficio. En consecuencia, se deben buscar otras alternativas para tratar a estos enfermos

Anti-lymphocyte globulin therapy in acquired aplastic anaemia.

Thirty five patients with acquired aplastic anaemia (AAA) were treated with anti-lymphocyte globulin (ALG). Fifteen (42.9%) had non-severe aplastic anaemia (NSAA), 14 (40%) severe aplastic anaemia (SAA) and 6 very severe aplastic anaemia (VSAA). There were 17 (48.6%) responders to the first course of ALG while 2 out of 5 (40%) responded to a second course, the overall response rate being 54.3%. Eleven out of 15 (73.3%) with NSAA responded, 8 out of 20 (40%) with SAA responded while none of VSAA responded. All the non-responders have died. Out of the responders, 1 died of non-A non-B hepatitis, and 1 with relapse of AA and sepsis. One has developed paroxysmal nocturnal haemoglobinuria (PNH) and one myelodysplasia. Another 2 needed infrequent red cell transfusion support. Remaining 13 (37.1%) are asymptomatic and without any external support since 18-78 months (35 +/- 21). We conclude that ALG is an effective modality of treatment for patients with AAA.