Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany.
Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Germany.
Haematologica. 2019 Jan;104(1):59-69. doi: 10.3324/haematol.2017.187278. Epub 2018 Aug 31.
Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% (=0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling (=0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1-0.9); =0.03]. decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia.
低甲基化药物治疗骨髓增生异常综合征或急性髓系白血病患者的血液学反应通常会延迟。胎儿血红蛋白是一种有潜力的新型反应生物标志物：最近，我们证明在去甲基化药物治疗前高胎儿血红蛋白水平与更好的结果相关。在这里，我们研究了在去甲基化药物治疗期间早期诱导胎儿血红蛋白是否也具有预后价值，并研究了去甲基化药物诱导红细胞分化和胎儿血红蛋白表达的潜力。在治疗前和每个去甲基化药物疗程后，通过高效液相色谱法测量高危骨髓增生异常综合征（n=16）和急性髓系白血病（n=37）患者的胎儿血红蛋白水平。高于 1.0%被认为是诱导的。作为最佳反应获得完全或部分缓解的患者在两个疗程后获得了 1.9%的中位数胎儿血红蛋白，而未达到完全或部分缓解的患者的中位数值为 0.8%（=0.015）。两个疗程的去甲基化药物治疗后胎儿血红蛋白的诱导与血小板倍增早期相关（=0.006），随后与血液学复发相关。在骨髓增生异常综合征患者中，治疗后第 2 疗程的胎儿血红蛋白诱导与总生存时间延长相关：分别有或没有诱导胎儿血红蛋白的患者的中位总生存时间为 22.9 7.3 个月[风险比=0.2（95%置信区间：0.1-0.9）；=0.03]。去甲基化药物治疗两种双潜能髓系白血病细胞系（K562 和 HEL）导致诱导红细胞（而非巨核细胞）分化程序，并诱导胎儿血红蛋白 mRNA 和蛋白质，与 GATA1 基因去甲基化和上调相关。总之，在骨髓增生异常综合征或急性髓系白血病患者的低甲基化药物治疗期间，胎儿血红蛋白可能提供一种有用的动态生物标志物。
