Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag

Abstract

Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype. The studies were registered at www.clinicaltrials.gov as #NCT00922883 and #NCT01891994.

High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study

“…Fifty percent of the patients achieved a hematologic response, and 18% of the patients developed clonal evolution. Clonal evolution was an early event in 87% of the patients and occurred within six months of eltrombopag initiation, suggesting a direct link between eltrombopag treatment and clonal evolution, and thus close monitoring with bone marrow samples is warranted 185 . Eltrombopag has also been used for untreated patients in combination with hATG/CsA.…”

Detectable mutations precede late myeloid neoplasia in aplastic anemia

“…The presence of unfavorable somatic mutations as a group is associated with a higher risk of clonal evolution and poorer survival [7,8]. Surprisingly, somatic mutations were not frequently detected in clonal evolution to monosomy 7 [9], including in patients treated with eltrombopag (EPAG) [10].…”

Efeito do derivativo de purina SR1 e do derivativo pirimidoindólico UM171 na expansão de células-tronco e progenitoras hematopoéticas na anemia aplástica adquirida

“…2014). Na AAa grave refratária, também foi identificada uma frequência elevada de casos com evolução clonal após o uso de EPAG, em especial com desenvolvimento de monossomia do cromossomo 7 (OLNES et al, 2012;WINKLER et al, 2019). Contudo, a maior evolução para LMA de pacientes com SMD em uso de EPAG não se confirmou em outros dois estudos clínicos (PLATZBECKER et al, 2015;OLIVA et al, 2017), bem como a adição de EPAG à terapia imunossupressora em primeira linha no tratamento da AAa grave não produziu maior incidência de evolução clonal (TOWNSLEY et al, 2017).…”

“…Muito embora a administração de EPAG não claramente modifique a incidência cumulativa de evolução clonal em comparação à história natural da AAa grave, tanto no tratamento de primeira linha, quanto no da doença refratária, o surgimento de anormalidades citogenéticas ocorre mais precocemente, particularmente nos primeiros seis meses de uso da droga, o que sugere que EPAG promova a expansão de clones pré-existentes quiescentes (SCHEINBERG, 2018a;WINKLER et al, 2019). Por tudo isso, essa questão ainda permanece em aberto.…”

“…Além disso, apesar de EPAG aumentar de modo expressivo as taxas de resposta obtidas com a terapia imunossupressora isoladamente na AAa grave, a descontinuição de seu uso leva à recaída em número expressivo de pacientes, níveis semelhantes ou até mesmo maiores que as taxas de recaída de controles históricos utilizando ATG equina e CSA isoladamente (TOWNSLEY et al, 2017), sendo em muitos casos necessário o uso continuado da droga para manutenção da resposta obtida (WINKLER et al, 2019). Assim, a descoberta de drogas com efeito associativo ao EPAG, mais do que aprofundar as taxas iniciais de resposta, poderia diminuir o risco de recaída ainda bastante significativo.…”