A multicentre ambispective observational study into the incidence and clinical management of aplastic anaemia in Spain (IMAS study).

Aplastic anemia (AA) is a rare, life-threatening hematological disease, with a poorly defined incidence. As the data available on AA varies substantially worldwide, a multicenter, ambispective, observational study was carried out between 2010 and 2019 to assess the incidence, clinical management and survival of AA at seven Spanish hospitals. The incidence of AA was 2.83 per million inhabitants per year, consistent with that reported previously in Europe, with a median age at diagnosis of 61 years-old (range 12-86), and a similar number of males and females. The initial diagnosis was severe or very severe AA in 55.8% of cases and 93.7% required transfusion. The most frequent first line therapy was anti-thymocyte globulin (ATG) plus cyclosporin A (CsA, 44.2%), followed by other CsA-based regimes (46.3%), with hematopoietic stem cell transplantation an infrequent 1st line therapy. The 6-month response rate was 68.2%, which then increased over a median follow-up of 3.9 years. The 5-year overall survival (5OS) was 73.6%, similar in severe (78.6%) and very severe AA patients (74.6%) but lower in moderate AA (MAA) patients (68.4%). The 5OS was 100% in 0-25 year-old patients but dropping to 58.3% in patients ≥ 60 years-old. At the last contact, 75.8% of the patients were alive. In conclusion, the incidence, characteristics and management of AA in our study are consistent with that reported previously. In terms of survival, although the global long-term OS rate was good, there is room for improvement, particularly in older patients. Finally, what appears to be a worse long-term survival of MAA patients, as reported previously, reinforces the importance of not underestimating this condition when diagnosed as MAA.

Real-World Costs and Cost-Effectiveness Analysis of Rabbit-Antithymocyte Globulin Versus Oxymetholone in Acquired Aplastic Anemia in Thailand.

OBJECTIVES: This study aimed to compare rabbit-antithymocyte globulin and cyclosporine (rATG/CsA) with oxymetholone in terms of direct medical expenditures and economic evaluation in severe acquired aplastic anemia (SAA) and very severe acquired aplastic anemia (vSAA) patients. METHODS: Patients with SAA/vSAA who initiated treatment with rATG/CsA or oxymetholone between 2004 and 2018 were included. Trial-based cost-effectiveness evaluation in healthcare provider perspective was performed. Direct medical costs were retrieved from hospital database, inflated, and converted to 2020 US dollar (30.01 Baht per US dollar). One-way sensitivity analysis and probabilistic sensitivity analysis by nonparametric bootstrap was performed. RESULTS: After 2-year follow-up, the total mean (SD) direct medical expenditures per patient for oxymetholone and rATG/CsA group were $8 514.48 ($12 595.67) and $41 070.88 ($22 084.04), respectively. Nevertheless, oxymetholone had significant lower survival rate than rATG/CsA (P=.001) but higher in second-year blood transfusion need (71.4% vs 18.2%) and hospitalization (14.3% vs 0%). The incremental cost-effectiveness ratio was $45 854.08 per life-year gained when rATG/CsA was used instead of oxymetholone (95% CI $24 244.03-$143 496.67 per life-year gained). The probabilistic sensitivity analysis indicated that rATG/CsA had no chance of being cost-effective for SAA/vSAA when willingness to pay threshold of one to 3 times of national gross domestic product per capita was applied. CONCLUSIONS: Oxymetholone remains a viable alternative in resource-limited country. Despite its high cost, the rATG/CsA is a preferred treatment option because of the significant advantages on reducing mortality, treatment complications, and hospitalization.

Decision analysis of allogeneic bone marrow transplantation versus immunosuppressive therapy for young adult patients with aplastic anemia.

BACKGROUND: Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor is recommended as an initial treatment for young patients. However, immunosuppressive therapy (IST) with cyclosporine and anti-thymocyte globulin may be a viable option even when an HLA-identical sibling donor is available. METHODS: We constructed a Markov model to simulate the 10-year clinical course of patients aged 21-40 years with newly diagnosed severe aplastic anemia. Immediate BMT and IST were compared as an initial treatment assuming the availability of an HLA-identical sibling donor. Transition probabilities after treatment were determined based on a registry data analysis for BMT and a long-term prospective study for IST. RESULTS: Quality-adjusted life years (QALYs) after treatment selection were 6.77 for BMT and 6.74 for IST. One-way sensitivity analysis revealed that the utility for being alive without GVHD after BMT, that for being alive with partial response after IST, and the response rate after initial IST strongly affected the results. CONCLUSIONS: BMT and IST produced similar QALY for young patients with severe aplastic anemia. An estimation of the response rate to the initial IST may enable an individualized comparison between BMT and IST.

Challenges and opportunities in shared care for international patients treated with cellular therapy for nonmalignant disease.

As cellular therapies gradually become the mainstay of treatment for several nonmalignant diseases, there appears to be varied accessibility to these therapies globally. Despite considerable burden of nonmalignant conditions, such as sickle cell disease, thalassemia, and aplastic anemia in populations of low-middle-income countries, the utilization of cellular therapies remain sparse because of lack of resources. Globally, the frequency of hematopoietic stem cell transplant (HSCT) has increased disproportionately in countries with higher gross national income (GNI) per capita, governmental healthcare expenditures, and a high human development index. This leads to a large subset of international patients seeking care in the United States. This review summarizes the unique set of challenges that often arise when offering sophisticated therapies such as HSCT to international patients constituting of cross-cultural, logistical, financial, and medical challenges and the opportunities that are available to bridge the gap.

Quantitative Assessment of Bone Marrow Activity Using 18 F-FLT PET in Aplastic Anemia and Myelodysplastic Syndromes.

PURPOSE: Peripheral cytopenias are typical of blood test abnormalities associated with a variety of conditions, including aplastic anemia (AA) and myelodysplastic syndromes (MDSs). We prospectively investigated the feasibility of quantitative analysis of whole-body bone marrow activity using PET with 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) in AA and MDS. PATIENTS AND METHODS: Sixty-eight patients with cytopenia underwent 18 F-FLT PET/MRI scan, with simultaneous bone marrow aspiration and biopsy for hematopoiesis evaluation. SUVs were measured in the vertebrae (Th3, 6, and 9 and L3), bilateral iliac crests, and extremities. SUV and bone marrow pathology were compared between AA and MDS and analyzed in relation to severity of AA and prognosis of MDS. RESULTS: Of the 68 patients with cytopenia, 12 were diagnosed with AA, 27 with MDS, 12 with bone marrow neoplasia, 2 with myelofibrosis, and 15 with other conditions. Iliac 18 F-FLT SUVs were significantly correlated with bone marrow cell numbers and cell density ( r = 0.47, P < 0.001 and ρ = 0.65, P < 0.001, respectively). There was a significant positive correlation between iliac and vertebral SUVs in AA and MDS ( r = 0.65, P < 0.05 and r = 0.70, P < 0.001, respectively), and the slope of the regression line was significantly steeper in AA than in MDS ( P < 0.05). In AA patients, vertebral 18 F-FLT SUVs significantly decreased with disease progression, and in MDS patients, higher whole-body 18 F-FLT uptake was associated with shorter overall survival (hazards ratio, 3.18; 95% confidence interval, 1.07-9.47; P = 0.037). CONCLUSIONS: Quantitative whole-body bone marrow imaging using 18 F-FLT PET helps distinguish AA from MDS and assess the severity of AA and prognosis of MDS.

Nutritional assessment of patients with aplastic anemia: comparison of four nutritional screening tools.

Introduction: Introduction: nutritional status can affect the treatment of hospitalized patients, and malnutrition can even lead to death. However, the nutritional status of patients with aplastic anemia (AA) is unclear. Objective: to assess the nutritional status of aplastic anemia patients with body mass index (BMI) ≥ 24 kg/m2 (high BMI group) and BMI < 24 kg/m2 (low BMI group), and to compare the consistency between different nutritional screening tools. Methods: patients with aplastic anemia hospitalized from January 2016 to December 2020 were collected. We used the combined index generated by Nutritional Risk Index (NRI), Prognostic Nutritional Index (PNI), Control Nutritional Status (CONUT) and Instant Nutritional Assessment (INA) to assess nutritional status of patients with aplastic anemia. Kappa index was used to measure the consistency between different nutritional screening tools. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of different nutritional screening tools. Results: one hundred and ninety-five patients with aplastic anemia were enrolled. The overall prevalence of malnutrition calculated by the combined index in patients with aplastic anemia was 51.3 %. The malnutrition rates of patients in the low BMI group and high BMI group were 60.9 % and 38.8 %, respectively. The malnutrition rates of very severe aplastic anemia (VSAA) patients, severe aplastic anemia (SAA) patients and ordinary patients were 76 %, 63.8 % and 45.1 %, respectively. Compared with the combined index, NRI had the highest consistency and area under the curve. Conclusions: the nutritional status of patients with aplastic anemia was very poor; the more serious the disease, the worse the nutritional status. Although the malnutrition rate in the low-BMI group was higher than in the high BMI group, the nutritional status of overweight or obese patients can not be ignored. NRI is the best tool for assessing the nutritional status of patients with aplastic anemia.

Introducción: Introducción: el estado nutricional puede afectar el tratamiento de los pacientes hospitalizados y la malnutrición puede incluso causar la muerte. Sin embargo, el estado nutricional de los pacientes con anemia aplásica (AA) no está claro. Objetivo: evaluar el estado nutricional de pacientes con anemia aplásica con índice de masa corporal (IMC) ≥ 24 kg/m2 (grupo de IMC mayor) e IMC < 24 kg/m2 (grupo de IMC inferior), y comparar la consistencia entre diferentes herramientas de cribado nutricional. Métodos: se recogieron datos de pacientes con anemia aplásica hospitalizados entre enero de 2016 y diciembre de 2020. El estado nutricional de los pacientes con anemia aplásica se evaluó utilizando un índice compuesto por el índice de riesgo nutricional (NRI), el índice de pronóstico nutricional (PNI), el índice de estado nutricional controlado (CONUT) y la evaluación nutricional instantánea (INA). El índice Kappa se utilizó para medir la coherencia entre los diferentes instrumentos de detección nutricional. Las curvas de características operativas de los sujetos (ROC) se utilizaron para evaluar el valor diagnóstico de las diferentes herramientas de detección nutricional. Resultados: un total de 195 pacientes con anemia aplásica fueron incluidos en el estudio. La prevalencia global de desnutrición calculada por el índice combinado en pacientes con anemia aplásica fue del 51,3 %. Las tasas de desnutrición de los pacientes en el grupo de bajo IMC y el grupo de alto IMC fueron 60,9 % y 38,8 %, respectivamente. Las tasas de desnutrición en pacientes con anemia aplásica muy grave (VSAA), anemia aplásica grave (SAA) y pacientes comunes fueron del 76 %, 63,8 % y 45,1 %, respectivamente. En comparación con el índice compuesto, NRI tiene la mayor consistencia y área bajo la curva. Conclusiones: el estado nutricional de los pacientes con anemia aplásica es muy deficiente; a mayor gravedad de la enfermedad, peor estado nutricional. Aunque la tasa de malnutrición en el grupo con bajo IMC es mayor que en el grupo con alto IMC, no se puede pasar por alto el estado nutricional de los pacientes con sobrepeso u obesidad. El NRI es la mejor herramienta para evaluar el estado nutricional de los pacientes con anemia aplásica.

Ampliação de uso do eltrombopague para o tratamento adicional a imunossupressor em pacientes adultos com anemia aplástica grave / Expansion of use of eltrombopague for the Additional immunosuppressive treatment in adult patients with severe aplastic anemia

INTRODUÇÃO: A anemia aplástica (AA) é uma doença rara e com risco de vida devido à falha herdada ou adquirida da medula óssea para produzir células sanguíneas, levando à pancitopenia progressiva. O tratamento para AA é determinado por uma série de fatores, incluindo gravidade da pancitopenia, idade do paciente, disponibilidade de doadores de célulastronco hematopoética, fonte de célula-tronco hematopoética, disponibilidade de imunossupressão e acesso a terapias ideais. Eltrombopague, um agonista de trombopoietina (TPO) vem emergindo como uma opção de tratamento para AA grave associado a terapia imunossupressora padrão. INDICAÇÃO: Pacientes adultos com anemia aplástica grave. PERGUNTA: Eltrombopague associado à terapia imunossupressora padrão (imunoglobulina antitimócito [ATG] e ciclosporina) é eficaz, seguro e custo-efetivo no tratamento de pacientes adultos com AA grave, quando comparado à terapia imunossupressora padrão (ATG e ciclosporina) isolada no SUS? EVIDÊNCIAS CLÍNICAS: A partir de uma busca bibliográfica conduzida nas bases PubMed, EMBASE e Cochrane Reviews, um ensaio clínico randomizado (ECR) foi selecionado, fornecendo evidências sobre a eficácia e segurança do eltrombopague adicionado ao tratamento imunossupressor em pacientes adultos com AA grave. Os pacientes apresentaram uma resposta completa em três meses de 10% no Grupo A (controle) e 22% no Grupo B (intervenção) (OR: 3,2; IC 95%, 1,3 a 7,8; P=0,01). Aos seis meses, a taxa de resposta geral foi de 41% no Grupo A e 68% no Grupo B. Os tempos médios para a primeira resposta foram de 8,8 meses (Grupo A) e 3,0 meses (Grupo B). A adição de eltrombopague à terapia imunossupressora padrão não resultou em melhora significativa da sobrevida global. A taxa de sobrevida global em dois anos foi de 85% (IC95%:78 a 92) para o grupo controle e de 90% (IC95%: 82 a 97) para o grupo intervenção. No entanto, o eltrombopague adicionado à terapia imunossupressora padrão aumentou a sobrevida livre de eventos de 34% para 46% em dois anos por meio da redução da refratariedade inicial à imunossupressão. A incidência de eventos adversos graves foi semelhante nos dois grupos. Para os desfechos resposta hematológica, sobrevida global, sobrevida livre de eventos, qualidade de vida e eventos adversos, considerou-se moderada qualidade de evidência pelo GRADE. AVALIAÇÃO ECONÔMICA: Na análise de custo-efetividade, empregando árvore de decisão e considerando-se o desfecho Taxa de Resposta Global, comparou-se o tratamento padrão (TP) versus a adição de eltrombopague ao TP, em um horizonte temporal de um ano. Ao demonstrar menor custo e maior efetividade, eltrombopague + TP se mostrou custo-efetiva no tratamento da AAG em pacientes não elegíveis ao TCTH, considerando-se a RCEI de - R$ 287.140,99. Na análise de sensibilidade, variando-se os custos de ATG e de eltrombopague, os resultados mostraram-se estáveis nos cenários avaliados, continuando a demonstrar que a adição de eltrombopague ao TP é custo-efetiva. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Avaliando-se três cenários diferentes em cinco anos, e considerando uma abordagem epidemiológica e demanda aferida (dispensações de ciclosporina para AA no SUS), a ampliação de uso do eltrombopague pode gerar economia de recursos de até R$ 241,2 milhões, ou seja, 12% menor do que o valor gasto no cenário de referência. Entretanto, nos cenários que se pressupõe menor uso do eltrombopague, a economia de recursos é menor. No cenário 2 o impacto orçamentário incremental é de - R$ 188,59 milhões e no cenário 3 é de - R$ 134 milhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foi detectada uma tecnologia para compor o tratamento adicional a imunossupressor em pacientes adultos com AAG. Trata-se do hetrombopag, um agonista do receptor de trombopoetina, mesmo mecanismo de ação da tecnologia em avaliação neste relatório, encontrando-se em fase 3 de pesquisa clínica, e sem registro para qualquer indicação na Anvisa, FDA ou EMA. CONSIDERAÇÕES FINAIS: A AA é uma doença rara e frequentemente grave ou muito grave e que até o momento, não dispunha de um tratamento clínico com resultados satisfatórios, cenário esse que perdura por mais de 30 anos. No presente relatório, é apresentado um ECR multicêntrico, com moderada qualidade de evidência, recentemente publicado e com um número expressivo de pacientes, considerando-se a raridade da doença e que trouxe resultados significativamente superiores, quando comparado ao tratamento padrão isolado em praticamente todos os desfechos avaliados, além de perfil de seguração comparável ao tratamento atual. Na avaliação econômica, a adição de eltrombopague ao tratamento padrão trouxe vantagens clínicas e econômicas, mostrando ser custo-efetiva. Assim também, na análise de impacto orçamentário, a ampliação de seu uso, considerando-se que a tecnologia já está incorporada no SUS para o tratamento de TPI, trouxe economia de recursos em todos os cenários avaliados. RECOMENDAÇÃO PRELIMINAR DA CONITEC: No dia 09 de março de 2022, em sua 106ª Reunião Ordinária, os membros da Conitec deliberaram que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à ampliação de uso do eltrombopague para o tratamento adicional a imunossupressor em pacientes adultos com anemia aplástica grave. Considerou-se que as evidências apresentadas demonstraram eficácia e segurança acerca do tratamento proposto frente às alternativas terapêuticas já disponíveis no SUS, além de ser custo-efetivo e apresentar economia de recursos para o SUS. CONSULTA PÚBLICA: Foi realizada no período de 04/04/2022 a 25/04/2022. Foram recebidas 51 contribuições, sendo 21 pelo formulário técnico-científico e 30 pelo formulário sobre experiência ou opinião. Todas as contribuições recebidas concordaram com a recomendação preliminar da Conitec, sendo favoráveis à ampliação de uso da tecnologia. Assim, o entendimento da Conitec não foi alterado. RECOMENDAÇÃO FINAL DA CONITEC: Diante do exposto, os membros do Plenário da Conitec, em sua 108ª Reunião Ordinária, no dia 05 de maio de 2022, deliberaram por unanimidade recomendar a ampliação de uso do eltrombopague para o tratamento adicional a imunossupressor em pacientes adultos com anemia aplástica grave. Por fim, foi assinado o Registro de Deliberação nº 728/2022. DECISÃO: Ampliar o uso do eltrombopague para o tratamento adicional a imunossupressor em pacientes adultos com anemia aplástica grave, no âmbito do Sistema Único de Saúde - SUS conforme a Portaria nº 47, publicada no Diário Oficial da União nº 105, seção 1, página 78, em 3 de junho de 2022.

Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Effect of Wuzhi capsules on cyclosporine A concentration in children with aplastic anemia immunotherapy: a single-center observational study.

OBJECTIVE: This research aimed to assess the effect of Wuzhi capsules (WZC) on the blood concentration of cyclosporine A (CsA) in renal aplastic anemia recipients. METHODS: This observational study was carried out at the Hematology Oncology Center, Beijing Children's Hospital between November 2019 and February 2020. A total of 102 Chinese AA recipients receiving CsA (6 mg/kg/d) with or without WZC were included in this study. Baseline data, such as age, therapeutic drug monitoring data, and follow-up information were collected. The promotion concentration of CsA was calculated, and the pharmaceutical economics evaluation with combination of two drugs was also carried out. RESULTS: Dose- and body weight-adjusted trough concentrations (C0/D/W) of CsA in the WZC group were found to be significantly higher than that in the non-WZC group (P < 0.01). The average C0 of CsA increased by (63.27 ± 45.81) ng/mL. The incidence of adverse events was also not statistically significant between the two groups (P > 0.05). CONCLUSION: WZC can increase CsA concentration without increasing adverse drug reactions. Efficient and convenient immunosuppressive effects on AA recipients can be achieved via immunosuppressant therapy in combination with WZC.

Cellular Therapy During COVID-19: Lessons Learned and Preparing for Subsequent Waves.

An evidence-based triage plan for cellular therapy distribution is critical in the face of emerging constraints on healthcare resources. We evaluated the impact of treatment delays related to COVID-19 on patients scheduled to undergo hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy at our center. Data were collected in real time between March 19 and May 11, 2020, for patients who were delayed to cellular therapy. We evaluated the proportion of delayed patients who ultimately received cellular therapy, reasons for not proceeding to cellular therapy, and changes in disease and health status during delay. A total of 85 patients were delayed, including 42 patients planned for autologous HCT, 36 patients planned for allogeneic HCT, and 7 patients planned for CAR-T therapy. Fifty-six of these patients (66%) since received planned therapy. Five patients died during the delay. The most common reason for not proceeding to autologous HCT was good disease control in patients with plasma cell dyscrasias (75%). The most common reason for not proceeding to allogeneic HCT was progression of disease (42%). All patients with acute leukemia who progressed had measurable residual disease (MRD) at the time of delay, whereas no patient without MRD at the time of delay progressed. Six patients (86%) ultimately received CAR-T therapy, including 3 patients who progressed during the delay. For patients with high-risk disease such as acute leukemia, and particularly those with MRD at the time of planned HCT, treatment delay can result in devastating outcomes and should be avoided if at all possible.

Burden of illness among patients with severe aplastic anemia who have had insufficient response to immunosuppressive therapy: a multicenter retrospective chart review study.

This study assessed treatment patterns and healthcare resource utilization (HRU) of patients with severe aplastic anemia (SAA) with insufficient response to immunosuppressive therapy (IST). A retrospective chart review was conducted at Dana-Farber Cancer Institute (DFCI), United States, and Hôpital Saint-Louis (HSL), France. Eligible patients were ≥ 18 years old, diagnosed with acquired SAA between January 1, 2006, and July 31, 2016, had insufficient response to IST, and had ≥ 12 months of follow-up post-diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method. Among the 40 patients, mean age at diagnosis was 44 years and 53% were women. Median follow-up time after SAA diagnosis was 48.3 months. Ninety-five percent of patients received antithymocyte globulin (ATG) as primary therapy prior to hematopoietic stem cell transplant (HSCT). Most common secondary SAA therapies prior to HSCT were eltrombopag (28%) and androgens (15%). Seventy-five percent of patients received HSCT. Prior to HSCT, patients received an average of 2.7 red blood cell (RBC) and 3.3 platelet transfusions per month; patients had 0.9 hospitalizations, 0.4 emergency room visits, and 12.8 office visits per year. Five-year OS was 75%, with infection as the primary cause of death. Additionally, this study provides information on the subgroup of patients receiving eltrombopag which was the most common secondary therapy. This study quantified transfusion and HRU burden associated with SAA and demonstrated high 5-year survival in a recently treated cohort.

Dual-layer detector spectral CT versus magnetic resonance imaging for the assessment of iron overload in myelodysplastic syndromes and aplastic anemia.

BACKGROUND: The purpose of this study is to investigate the performance of dual-layer detector spectral CT for iron deposition compared to magnetic resonance imaging (MRI) T2* imaging. METHODS: Thirty-one patients with a clinical history of myelodysplastic syndromes and aplastic anemia underwent liver and cardiac T2*-weighted unenhanced MRI on a three-tesla MRI scanner, and underwent unenhanced CT scan laterally on a 128-row spectral detector CT. R2* values of the liver, septal muscle, and paraspinal muscle were calculated. Attenuation differences (ΔH) in the liver and myocardium were calculated between the lower (50 keV) and higher (120 keV) energy levels. RESULTS: The liver and cardiac T2* values were 9.54 ± 5.63 ms and 21.41 ± 2.44 ms, respectively. The liver-to-muscle and myocardium-to-muscle T2* value ratios were 0.37 ± 0.23 and 0.79 ± 0.19, respectively. The liver and cardiac ΔH were - 1.13 ± 4.24 HU and 2.22 ± 4.41 HU, respectively. There was a strong linear correlation between the liver R2* and ΔH (r = - 0.832, P < 0.001), but weak correlation existed between the cardiac R2* and ΔH (P = 0.041). CONCLUSIONS: Dual-layer detector spectral unenhanced CT seemed to be equally valuable to MRI T2* imaging for evaluating liver iron overload.

Healthcare resource use and direct costs in severe aplastic anemia (SAA) patients before and after treatment with eltrombopag.

Purpose: This study evaluated healthcare resource utilization (HCRU), and direct costs among severe aplastic anemia (SAA) patients treated with eltrombopag (EPAG) using US claims data.Methods: This retrospective, real-world claims database study identified SAA patients aged ≥2 years treated with EPAG who initiated any SAA treatment between 1 July 2014 and 31 December 2017 (identification period) using the Truven MarketScan databases. A subset of 82 patients treated with EPAG during the identification period were evaluated for all-cause and SAA-related HCRU and direct costs as well as blood transfusion 1 month before EPAG initiation (baseline) and at Month 6 after EPAG initiation (follow-up period).Results: The average patient age was 50.8 (SD = 20.6) years old, predominantly female (n = 43, 52.4%), and had a mean CCI at baseline of 1.1 (SD = 1.7). Hospitalizations, and ER, office, and outpatient visits were significantly lower at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (p < .05 for all four all-cause HCRU and SAA-related hospitalizations). An almost two-fold decrease in reliance on biweekly blood transfusions was observed: 1.0 at weeks 1-2 to 0.5 at Month 6 after EPAG initiation. Although prescription costs (mean [SD]) were significantly higher at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (difference of $11,045 USD [SD = $18,801]), these increases were offset by savings in direct costs. Overall, a mean reduction in total all-cause costs of $29,391 USD [SD = $137,770] was reported at Month 6 after EPAG initiation due to substantial reductions in hospitalization ($40,060 USD [SD = $123,198]) and outpatient visits ($2,043 USD [SD = $25,264]).Conclusion: All-cause and SAA-related HCRU were reduced following EPAG treatment. Prescription costs were higher following treatment; however, these costs were generally offset by reductions in direct costs. These results provide real-world evidence around the role of EPAG in SAA treatment.

Antitimocítica de origen equino en combinación con ciclosporina y corticoide en el tratamiento de pacientes con anemia aplásica severa, sin tratamiento previo, no tributarios a trasplante o postrasplantados no tributarios a segundo trasplante / Antithymocyte of equine origin in combination with cyclosporine and corticosteroid in the treatment of patients with severe aplastic anemia, without prior treatment, not eligible for transplant or post-transplant patients not eligible for a second transplant

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de globulina antitimocítica de origen equino en el tratamiento de pacientes con anemia aplásica severa sin tratamiento previo y no tributarios a trasplante, o postrasplantados no tributarios a segundo trasplante. La anemia aplásica (AA) es un síndrome autoinmune en la mayoría de los casos idiopáticos, caracterizado por pancitopenia periférica y medula ósea hipocelular, con al menos dos de las siguientes características: 1) Hb < 10 gr/L; 2) Recuento plaquetario < 50 x 109 /L; o 3) Recuento de neutrófilos < 1.5 x 109 /L. La severidad de la AA se determina aplicando los criterios de Camitta y Bacigalupo y está basada en el recuento células sanguíneas en sangre periférica y en los hallazgos en médula ósea. En el mundo, la incidencia de AA se encuentra en un rango entre 0.5 y 4 casos por millón de individuos por año. En el Perú, no se cuenta con estudios de prevalencia o incidencia de AA. El tratamiento de primera línea para pacientes con AA severa es el trasplante alogénico de progenitores hematopoyéticos provenientes de parientes HLA1 idénticos, con el cual las tasas de respuesta son de alrededor del 90 %. En aquellos pacientes en quienes el trasplante no es posible, como por ejemplo los casos en los que no se cuenta con un donante o el paciente es mayor de 50 años, la alternativa de primera línea es la terapia inmunosupresora. La terapia inmunosupresora generalmente recomendada por las guías de práctica clínica (GPC) internacionales y locales incluye globulina antitimocítica (GAT) -de equino o de conejo-, ciclosporina y esteroides. En EsSalud se cuenta en la actualidad con GAT de conejo, ciclosporina, micofenolato y danazol como alternativas de terapia inmunosupresora de primera línea en pacientes con anemia aplásica severa no tributarios a trasplante. No obstante, los especialistas manifiestan que la GAT de origen equino podría ser una mejor alternativa como tratamiento de primera línea para dicha población, por lo que han hecho llegar al IETSI una solicitud de evaluación de GAT de origen equino, en comparación a otras terapias inmunosupresoras, en pacientes con AA severa no tributarios a trasplante. METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de globulina antitimocítica de origen equino para el tratamiento de anemia aplásica en las bases de datos de PubMed, TRIP y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); así como organizaciones especializadas en hematología como American Society of Hematology (ASH), International Society of Hematology (ISH), European Hematology Association (EHA). La estrategia de búsqueda en PubMed se encuentra desarrollada en la Tabla 1 del material suplementario. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de globulina antitimocítica de origen equino en el tratamiento de pacientes con anemia aplásica. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA). CONCLUSIONES: El presente dictamen preliminar tiene como objetivo evaluar la eficacia y seguridad del uso de GAT de equino en comparación con GAT de conejo, ambos en combinación con ciclosporina, en el tratamiento de pacientes con anemia aplásica severa que no son tributarios a trasplante. La evidencia central para responder a la pregunta PICO del presente dictamen proviene de un ECA de fase II que compara GAT de equino con GAT de conejo, ambas en combinación con ciclosporina y seis GPC internacionales y locales tanto en la población adulta como en la pediátrica. Las GPC incluidas (n=6) son consistentes en recomendar el uso de GAT como terapia inmunosupresora de primera línea de pacientes con AA severa que no son tributarios a trasplante. De las cuales tres recomiendan GAT de equino o conejo indistintamente y las otras tres recomen dan GAT equina por encima de GAT de conejo, y en terapia combinada con ciclosporina A o terapia triple con cliclosporina A y corticoides. El ensayo por Scheinberg et al. identificado responde directamente a la pregunta PICO del presente dictamen al comparar el uso de GAT de equino con GAT de conejo en el tratamiento inmunosupresor de primera línea de pacientes con AA severa. En este se evidencia que GAT de equino es similar a GAT de conejo en términos de SG y que ambos presentan un perfil de seguridad similar, con una tendencia a un mejor perfil por parte de GAT de equino. En conclusión, se tiene que, la evidencia comparativa disponible a la fecha sobre GAT de equino y GAT de conejo proviene de un ECA fase II de calidad moderada, el cual reporta que no hay diferencias en eficacia en términos de SG, ni en el perfil de seguridad entre los medicamentos evaluados. Si bien la evidencia es de calidad moderada, los resultados de una diferencia en 20 puntos porcentuales en la SG a favor de GAT de equino sugieren que, aún en presencia de limitaciones a la validez interna, es probable que GAT de equino sea al menos tan beneficioso como GAT de conejo en términos de SG. Adicionalmente, ambas alternativas terapéuticas son globulinas antitimocíticas, por lo que comparten el mismo mecanismo de acción. Por lo tanto, no se esperaría que estudios posteriores muestren resultados contrarios. Frente a la ausencia de diferencias en eficacia y seguridad entre los fármacos evaluados, cobra relevancia para la toma de decisión el costo de las tecnologías y la inversión que estas representan para la institución. Así, se tiene que, el tratamiento con globulina de origen equino tiene un costo menor al de globulina de conejo, con lo cual su uso supondría a la institución un ahorro entre S/ 3,300 y S/ 42,660 por paciente entre 8 kg y 90 kg, respectivamente. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), aprueba el uso de globulina antitimocítica de origen equino como terapia inmunosupresora de primera línea en el tratamiento de anemia aplásica severa en pacientes no tributarios a trasplante. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo o al cambio en el mercado peruano de los costos de los productos farmacéuticos comparados.

Healthcare costs and resource utilization in patients with severe aplastic anemia in the US.

Purpose: This study aimed to evaluate the healthcare resource utilization (HCRU) and costs for patients with severe aplastic anemia (SAA) using US claims data. Methods: This retrospective, observational database study analyzed claims data from the Truven MarketScan databases. SAA patients aged ≥2 years identified between 2014 and 2017 who were continuously enrolled for 6 months before their first SAA treatment or blood transfusion, with a ≥6-month follow-up, were included. Baseline demographics and comorbidities were evaluated. Monthly all-cause and SAA-related HCRU and direct costs in the follow-up period were analyzed and differences were presented for all patients and across age groups. Results: With an average follow-up period of 21.5 months, 939 patients were included in the study. Monthly all-cause and SAA-related HCRU [mean (SD)] were 1.65 days (2.61 days) and 0.18 days (0.70 days) for length of stay, 0.18 (0.23) and 0.01 (0.04) for hospital admissions, 0.25 (0.30) and 0.02 (0.07) for ER visits, 2.24 (1.40) and 0.46 (0.99) for office visits, and 2.90 (2.64) and 0.55 (1.31) for outpatient visits, respectively. On average, SAA patients received 0.15 (0.57) blood transfusions per month. Mean monthly all-cause direct costs were $28,280 USD ($36,127) [US dollars, mean (SD)]. Direct costs related to admissions were $11,433 USD (SD $25,040), followed by $624 USD ($1,703) for ER visits, $528 USD ($694) for office visits, $7,615 USD ($13,273) for outpatient visits, and $5,998 USD ($11,461) for pharmacy expenses. Monthly SAA-related direct costs averaged $7,884 USD (SD $16,254); of these costs, $1,608 USD ($7,774) were from admissions, $47 USD ($257) from ER visits, $127 USD ($374) from office visits, $1,462 USD ($4,994) from outpatient visits, and $4,451 USD ($10,552) from pharmacy expenses. Conclusion: SAA is associated with high economic burden, with costs comparable to blood malignancies, implying that US health plans should consider appropriately managing SAA while constraining the total healthcare costs when making formulary decisions.

Patient features and survival of pediatric aplastic anemia in the USA: a large institution experience.

BACKGROUND: We performed the first epidemiologic investigation to examine association of demographics and clinical characteristics at diagnosis, as well as health care expense coverage, with survival of US children with aplastic anemia (AA). METHODS: We obtained electronic medical record data of 1140 children aged 0-19 years diagnosed with AA followed at a pediatric health system between 2004 and 2014. Kaplan-Meier curve and Cox proportional hazards regressions were used. RESULTS: Self-pay patients had a mortality risk five times higher than that of those insured by publicly funded insurance (hazards ratio, 95% CI: 6.0, 3.7-9.8). Other features associated with higher mortality risk include pancytopenia (hazards ratio, referent: 4.2, constitutional AA); underweight (2.0, normal-weight); platelet count <50 × 109/l (1.3, ≥50 × 109/l); male sex (1.3, female); and ages at diagnosis 6-11, 11-16 and 16-19 years (1.6, 1.9, 2.3, 1-3 years), respectively. CONCLUSIONS: Self-pay was the strongest prognostic factor for pediatric AA mortality. Older age, pancytopenia, underweight, male sex and lower platelet count were also associated with increased risk of mortality. These findings may be useful for providers, researchers and policymakers to ensure effective health care delivery to this population and to motivate future etiologic research and establishment of a surveillance registry.

Assessment of genomic instability and proliferation index in cultured lymphocytes of patients with Down syndrome, congenital anomalies and aplastic anaemia.

One hundred and fifteen cases [Down Syndrome (DS) n = 75, Multiple Congenital Anomalies (MCA) n = 15 and Aplastic Anaemia (AA) n = 25], with respect to their nature of predisposition to cancer, were selected for clinical, cytogenetic and cyto-molecular studies to understand the severity of genomic instability according to the nature of the different diseases. Cytogenetic studies included chromosomal aberration (CA) assays and cytokinesis block micronucleus cytome (CBMN-Cyt) assays. In DS, MCA and AA, average frequencies of nuclear anomalies (NA) were 0.015 ±â€¯0.0006, 0.021 ±â€¯0.00123, 0.031 ±â€¯0.00098, respectively and CA were 0.107 ±â€¯0.003, 0.105 ±â€¯0.008, 0.158 ±â€¯0.006, respectively per metaphase. The extent of genomic instability in patients analysed by CBMN-Cyt assays and CA assays was statistically significant in all groups. Comparatively decreased cytokinesis block proliferation index (CBPI) observed in AA patients of 1.59 ±â€¯0.05, support the assumption that decreased levels of CBPI indicate increased genomic damage. Furthermore, we performed peptide nucleic acid fluorescence in situ hybridisation (PNA FISH) analysis to understand the mechanisms behind genomic instability and telomere dysfunction. PNA FISH showed increased frequencies of telomere signal free ends (0.98 ±â€¯0.13) in individuals with higher genomic instability. Therefore, the results demonstrate that increased chromosomal instability along with higher telomere attrition or loss may initiate gross DNA damage and leads to chromosomal instability, which is an important mechanism for triggering genomic instability - an important hallmark of cancer cells.

Globulina antitimocitica para el tratamiento de anemia aplasica severa adquirida / Antithymocyte globulin for the treatment of acquired severe aplastic anemia

INTRODUCCIÓN: Este documento técnico se realiza a solicitud de la Dirección Ejecutiva del Hospital Regional Lambayeque; la cual motivó la realización de la pregunta PICO por parte de médicos y especialistas de la siguiente manera, P: pacientes con diagnóstico de anemia aplásica (AA) severa adquirida; I: terapia inmunosupresora con globulina antitimocítica equina (hATG) o de conejo (rATG); C: terapia de soporte u otras terapias inmunosupresoras; O: tasa de respuesta hematológica. mortalidad, sobrevida global y libre de eventos, recaídas, calidad de vida, eventos adversos y evolución clonal. OBJETIVO: Describir la evidencia científica disponible sobre la eficacia y seguridad de la ATG en el tratamiento de la AA severa adquirida. METODOLOGÍA: Se realizó una búsqueda sistemática en Medline (Pubmed), The Cochrane Library y LILACS. Ésta se complementó con la búsqueda de evidencia en páginas institucionales de agencias gubernamentales y buscadores genéricos. Se priorizó la identificación y selección de revisiones sistemáticas (RS) con o sin meta-analísis (MA), ensayos clínicos aleatorizados (ECA) o cuasi-experimentales, guías de práctica clínica (GPC), evaluaciones de tecnologías sanitarias (ETS) y evaluaciones económicas de América Latina. La calidad de la evidencia identificada se valoró usando las siguientes herramientas: AMSTAR 2 para la valoración de la calidad de revisiones sistemáticas, la herramienta propuesta por la colaboración Cochrane para la valoración del riesgo de sesgo de ensayos clínicos, y el instrumento AGREE II para valorar el rigor metodológico de las GPC. RESULTADOS: Se identificó dos revisiones sistemáticas (RS), siete ensayos clínicos, dos guías de práctica clínica (GPC) y dos evaluaciones de tecnología sanitaria (ETS) que respondieron a la pregunta PICO de interés. CONCLUSIONES: Las ETS incluidas mostraron resultados discordantes sobre la eficacia y seguridad de ATG. Las GPC incluidas recomiendan hATG como terapia de primera línea en ninõs y adultos sin donante HLA compatible, en pacientes de 35 a 50 anõs, y como alternativa en mayores de 60 años. Las RS incluidas presentaron nievl bajo y criticamente bajo. Los ensayos clínicos tuvieron alto riesgo de sesgo en la mayoria de dimensiones evaluadas. Las GPC incluidas mostraron un puntaje entre 76% y 80% en el rigor metodológico.