Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients
Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients
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DOI：
10.1038/leu.2013.19
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发表时间：
2013-07-01
期刊：
影响因子：
11.4
通讯作者：
Hjorth-Hansen, H.
中科院分区：
文献类型：
--
作者：
Mustjoki, S.;Richter, J.;Hjorth-Hansen, H.
慢性粒细胞白血病（CML）干细胞在体外对酪氨酸激酶抑制剂（TKI）具有耐药性，但其体内影响和药物敏感性尚未得到系统评估。我们前瞻性分析了46例新诊断CML患者在诊断时和伊马替尼或达沙替尼治疗期间费城染色体阳性白血病干细胞（LSC，Ph+ CD 34 + CD 38 =）和祖细胞（LPC，Ph+ CD 34 + CD 38+）的比例（ClinicalTrials.gov NCT 00852566）。在诊断时，LSC的比例在个体患者之间存在显著差异（1-100%），与LPC相比，中位值显著较低（分别为79%和96%，P = 0.0001）。LSC负荷与白细胞计数、脾脏大小、血红蛋白和原始细胞百分比相关。较低的初始LSC百分比与较低的治疗相关血液学毒性和较好的上级细胞遗传学和分子学缓解相关。开始TKI治疗后，两个治疗组的LPC和LSC均迅速降低，但在3个月时间点，达沙替尼组的中位LPC水平显著低于伊马替尼组（0.05% vs 0.68%，P = 0.032）。这些数据首次详细说明了诊断时LSC负荷的预后意义，并表明与体外数据相比，TKI治疗可迅速根除患者中的大多数LSC。
Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38=) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P = 0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P = 0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.