Pathogenesis in chronic lymphocytic leukemia (CLL) is strongly linked to the potential for leukemic cells to migrate to and proliferate within lymph-nodes. Previous in vivo studies suggest that all leukemic cells participate in cycles of migration and proliferation. In vitro studies, however, have shown heterogeneous migration patterns.

To investigate tumor subpopulation kinetics, we performed in vivo isotope-labeling studies in ten patients with IgVH-mutated CLL (M-CLL). Using deuterium-labeled glucose, we investigated proliferation in sub-populations defined by CXCR4/CD5 and surface (sIgM) expression. Mathematical modeling was performed to test the likelihood that leukemic cells exist as distinct sub-populations or as a single population with the same proliferative capacity. Further labeling studies in two patients with M-CLL commencing idelalisib investigated the effect of B-cell receptor (BCR) antagonists on sub-population kinetics.

Modeling revealed that data were more consistent with a model comprising distinct sub-populations (p = 0.008) with contrasting, characteristic kinetics. Following idelalisib therapy, similar labeling suppression across all sub-populations suggested that the most proliferative subset is the most sensitive to treatment. As the quiescent sub-population precedes treatment, selection likely explains the persistence of such residual non-proliferating populations during BCR-antagonist therapy. These findings have clinical implications for discontinuation of long-term BCR-antagonist treatment in selected patients.

慢性淋巴细胞白血病 (CLL) 的发病机制与白血病细胞迁移至淋巴结并在淋巴结内增殖的可能性密切相关。先前的体内研究表明，所有白血病细胞都参与迁移和增殖的循环。然而，体外研究显示异质性迁移模式。

为了研究肿瘤亚群动力学，我们对 10 名IgVH突变 CLL (M-CLL)患者进行了体内同位素标记研究。使用氘标记的葡萄糖，我们研究了由 CXCR4/CD5 和表面 (sIgM) 表达定义的亚群的增殖。进行数学建模以测试白血病细胞作为不同亚群或作为具有相同增殖能力的单一群体存在的可能性。对两名 M-CLL 患者开始 idelalisib 的进一步标记研究调查了 B 细胞受体 (BCR) 拮抗剂对亚群动力学的影响。

建模显示数据与包含 具有对比特征动力学的不同亚群 ( p = 0.008) 的模型更加一致。在 idelalisib 治疗后，所有亚群的类似标记抑制表明，增殖最多的亚群对治疗最敏感。由于静止亚群先于治疗，选择可能解释了在 BCR 拮抗剂治疗期间这种残留的非增殖细胞群的持续存在。这些发现对于在选定患者中停止长期 BCR 拮抗剂治疗具有临床意义。