Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy
Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy
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DOI：
10.1182/blood-2013-09-527853
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发表时间：
2014-03-20
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Woyach, Jennifer A.;Smucker, Kelly;Byrd, John C.
布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼在慢性淋巴细胞白血病患者中具有突出的活性。大多数患者出现淋巴细胞增多症，代表淋巴细胞从淋巴结隔室流出。大多数患者在8个月内消退，但一个亚组的淋巴细胞增多持续>12个月。在这里，我们报告了伊克替尼治疗期间持续性淋巴细胞增多患者的详细特征。信号传导评价显示，虽然BTK被抑制，但B细胞受体（BCR）信号传导的下游介质在持续淋巴细胞中被激活。这些细胞不能通过BCR刺激，也没有显示出靶基因激活的证据。这些患者的κ和λ表达、IGHV测序、Zap-70甲基化和靶基因测序的流式细胞术在基线和随后的时间点是相同的，表明持续存在的淋巴细胞不代表克隆进化。在体外治疗与靶向激酶抑制剂表明，他们不沉迷于一个单一的生存途径。最后，长期淋巴细胞增多患者的无进展生存期并不比传统缓解患者差。因此，持续的淋巴细胞增多在伊鲁替尼治疗后很常见，可能代表静止克隆的持续存在，并且不能预测可能早期复发的患者亚组。
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for kappa and lambda expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.