RESUMO
A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).
Assuntos
Hematínicos , Síndromes Mielodisplásicas , Humanos , Lenalidomida/farmacologia , Hematínicos/farmacologia , Eritropoese , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Fator Estimulador de Colônias de Granulócitos/farmacologia , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Resultado do TratamentoAssuntos
Inflamação/genética , Síndromes Mielodisplásicas/genética , Transcriptoma , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mesoderma/fisiopatologia , Síndromes Mielodisplásicas/fisiopatologia , Análise de Sequência de RNARESUMO
ATP-binding-cassette (ABC) transporters are evolutionary extremely well-conserved transmembrane proteins that are highly expressed in hematopoietic stem cells (HSCs). The physiological function in human stem cells is believed to be protection against genetic damage caused by both environmental and naturally occurring xenobiotics. Additionally, ABC transporters have been implicated in the maintenance of quiescence and cell fate decisions of stem cells. These physiological roles suggest a potential role in the pathogenesis and biology of stem cell-derived hematological malignancies such as acute and chronic myeloid leukemia. This paper reviews the (patho)physiological role of ABC transporters in human normal and malignant HSCs and discusses its implications for their utility as therapeutical targets to eradicate leukemic stem cells in these diseases.
