Herman S E M, Niemann C U, Farooqui M, Jones J, Mustafa R Z, Lipsky A, Saba N, Martyr S, Soto S, Valdez J, Gyamfi J A, Maric I, Calvo K R, Pedersen L B, Geisler C H, Liu D, Marti G E, Aue G, Wiestner A
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
1] Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA [2] Medical Research Scholars Program, National Institutes of Health, Bethesda, MD, USA.
Leukemia. 2014 Nov;28(11):2188-96. doi: 10.1038/leu.2014.122. Epub 2014 Apr 4.
Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. Here we report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes (LNs), spleen and bone marrow, assessed phenotypic changes of circulating cells and measured whole-blood viscosity. With just one dose of ibrutinib, the average increase in ALC was 66%, and in>40% of patients the ALC peaked within 24 h of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly, in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in the LN, bone marrow and spleen decreased irrespective of the relative change in ALC. Whole-blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.
依鲁替尼及其他B细胞受体信号通路靶向抑制剂在慢性淋巴细胞白血病（CLL）患者中取得了令人瞩目的临床疗效。治疗诱导的绝对淋巴细胞计数（ALC）升高已成为CLL中激酶抑制剂的类效应，值得进一步研究。在此，我们报告了64例接受依鲁替尼治疗的CLL患者的相关性研究。我们对血液、淋巴结（LN）、脾脏和骨髓中的肿瘤负荷进行了定量分析，评估了循环细胞的表型变化，并测量了全血粘度。仅一剂依鲁替尼，ALC平均升高66%，超过40%的患者在开始治疗后24小时内ALC达到峰值。第2天循环中的CLL细胞显示Ki67和CD38表达增加，表明肿瘤细胞从组织间隙流入血液。治疗诱导的淋巴细胞增多的动力学和程度差异很大；有趣的是，基线ALC高的患者相对升高幅度较小且缓解迅速。两个疗程治疗后，无论ALC的相对变化如何，LN、骨髓和脾脏中的疾病负担均下降。全血粘度取决于ALC和血红蛋白。未发现淋巴细胞增多导致的不良事件。
