Activity and safety of eltrombopag in combination with cyclosporin A as first­line treatment of adults with severe aplastic anaemia (SOAR): a phase 2, single-arm study.

BACKGROUND: Antithymocyte globulin (ATG)-based immunosuppression is standard in front-line treatment for people with severe aplastic anaemia without a histocompatible donor or who are 40 years or older. However, ATG requires in-hospital administration, is associated with infusion-related toxicities and has limited availability worldwide. In this study, we investigated the activity and safety of an ATG-free regimen of eltrombopag with cyclosporin A as a potential treatment for patients with severe aplastic anaemia who might not have access to or cannot tolerate horse-ATG. METHODS: SOAR was a multicentre, single-arm phase 2 trial investigating eltrombopag and cyclosporin in adult (≥18 years) patients with severe aplastic anaemia who were treatment-naive and had an Eastern Cooperative Oncology Group performance status of less than 2. Participants were recruited from 20 hospitals in ten countries. Eltrombopag was initiated at 150 mg (100 mg in patients of Asian ethnicity) and cyclosporin at 10 mg/kg per day (adjusted to a trough of 200-400 µg/L) orally from day 1 to 6 months. The primary outcome was an overall haematological response rate by 6 months in the intention-to-treat population. This is the final report of the primary analysis period. The trial was registered with ClinicalTrials.gov, NCT02998645, and has been completed. FINDINGS: 54 patients were enrolled between May 11, 2017, and March 23, 2020. 34 (63%) patients were male and 20 (37%) were female. 22 (41%) were Asian, 22 (41%) were White, one (2%) was Native American or Alaska Native, one (2%) was Black or African American, and eight (15%) were other race or ethnicity. 35 patients (65%) completed 6 months of treatment with eltrombopag and cyclosporin and six (11%) completed the cyclosporin tapering period up to month 24. Overall haematological response rate by month 6 of treatment was 46% (25 of 54; 95% CI 33-60). The most reported adverse events were increased serum bilirubin (in 22 patients [41%]), nausea (16 [30%]), increased alanine aminotransferase concentration (12 [22%]), and diarrhoea (12 [22%]). Eight patients died on-treatment, but no deaths were considered related to the treatment. INTERPRETATION: Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated. FUNDING: Novartis Pharmaceuticals.

Anemia aplásica / Aplastic anemia

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.