依鲁替尼治疗慢性淋巴细胞白血病 (CLL) 活性的第一个临床观察结果是淋巴结大小迅速下降。这种现象伴随着短暂或长期的淋巴细胞增多，这与不同的临床反应相关，从而对长期结果产生影响。了解哪些因素决定依鲁替尼治疗后的不同疾病进程仍然是一个科学挑战。从 2016 年到 2021 年，我们对 2 组慢性淋巴细胞白血病 (CLL) 患者进行了一项纵向观察性研究（队列 1，n = 41；队列 2， n = 81）。这些队列反映了 CLL 患者众所周知的临床特征，例如男女性别比为 2/1、诊断时的中位年龄为 70 岁，并且包括接受一线治疗 (27%) 或复发/难治性患者患者（73%）。在依鲁替尼治疗的 2 年期间，对每位患者的血细胞计数进行了跟踪。此外，还对第 1 组患者进行了免疫表型分型和全身磁共振成像 (MRI) 评估。这些数据被整合到一个新建的数学模型中，该模型受到先前 CLL 治疗数学工作的启发，并结合了动力学和统计模型，从而得出识别与两种类型的临床反应相关的生物学机制。这种多学科方法可以确定决定依鲁替尼治疗后淋巴细胞动力学的基线参数。事实上，依鲁替尼诱导的淋巴细胞增多症定义了 2 个 CLL 患者亚组，短暂性淋巴细胞增多症 (tHL) 或长期淋巴细胞增多症 (pHL)，可以在治疗前通过 CD4 T 淋巴细胞 (p = 0.026) 和调节性 CD4 T 细胞的绝对计数进行区分(p = 0.007)、B 白血病细胞上的程序性细胞死亡蛋白 1 PD1 (p = 0.022) 和 CD69 (p = 0.03) 表达、CD19/CD5high/CXCR4low 水平 (p = 0.04) 和淋巴结细胞结构。我们还指出，短暂性淋巴细胞增多症所确定的患者组的反应持续时间较短，临床结果较差。数学方法导致了患者特异性动态的再现和相关患者特异性生物参数的估计，并强调两组之间的差异主要是由于淋巴结区室中白血病 B 细胞的产生，以及T 淋巴细胞和白血病 B 细胞进入血液的程度较小。获取更多数据，特别是纵向 MRI 数据，可以加强有关淋巴结中白血病 B 细胞动力学以及 2 组不同患者的相关性的结论。总之，我们的多学科研究提供了对依鲁替尼反应的更好理解，并强调了新的药效学参数以及依鲁替尼治疗。由于我们的结果强调了短暂性淋巴细胞增多症患者的反应持续时间和结果缩短，因此我们的方法为治疗 3 个月后管理依鲁替尼治疗提供了支持。ClinicalTrials.gov NCT02824159。版权所有：© 2024 Cadot 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

One of the first clinical observations of ibrutinib activity in the treatment of chronic lymphocytic leukemia (CLL) is a rapid decline in lymph nodes size. This phenomenon is accompanied by an hyperlymphocytosis, either transient or prolonged, which is associated with distinct clinical responses and thus has an impact on long-term outcomes. Understanding which factors determine distinct disease courses upon ibrutinib treatment remains a scientific challenge.From 2016 to 2021, we conducted a longitudinal and observational study in 2 cohorts of patients with chronic lymphocytic leukemia (CLL) (cohort 1, n = 41; cohort 2, n = 81). These cohorts reflect the well-known clinical features of CLL patients, such as Male/Female sex ratio of 2/1, a median age of 70 years at diagnosis, and include patients in first-line therapy (27%) or relapsed/refractory patients (73%). Blood cell counts were followed for each patient during 2 years of ibrutinib treatment. In addition, immunophenotyping and whole-body magnetic resonance imaging (MRI) were assessed in patients from cohort 1. These data were integrated in a newly built mathematical model, inspired by previous mathematical works on CLL treatment and combining dynamical and statistical models, leading to the identification of biological mechanisms associated with the 2 types of clinical responses. This multidisciplinary approach allowed to identify baseline parameters that dictated lymphocytes kinetics upon ibrutinib treatment. Indeed, ibrutinib-induced lymphocytosis defined 2 CLL patient subgroups, transient hyperlymphocytosis (tHL) or prolonged hyperlymphocytosis (pHL), that can be discriminated, before the treatment, by absolute counts of CD4+ T lymphocytes (p = 0.026) and regulatory CD4 T cells (p = 0.007), programmed cell death protein 1 PD1 (p = 0.022) and CD69 (p = 0.03) expression on B leukemic cells, CD19/CD5high/CXCR4low level (p = 0.04), and lymph node cellularity. We also pinpointed that the group of patients identified by the transient hyperlymphocytosis has lower duration response and a poor clinical outcome. The mathematical approach led to the reproduction of patient-specific dynamics and the estimation of associated patient-specific biological parameters, and highlighted that the differences between the 2 groups were mainly due to the production of leukemic B cells in lymph node compartments, and to a lesser extent to T lymphocytes and leukemic B cell egress into bloodstream. Access to additional data, especially longitudinal MRI data, could strengthen the conclusions regarding leukemic B cell dynamics in lymph nodes and the relevance of 2 distinct groups of patients.Altogether, our multidisciplinary study provides a better understanding of ibrutinib response and highlights new pharmacodynamic parameters before and along ibrutinib treatment. Since our results highlight a reduced duration response and outcome in patients with transient hyperlymphocytosis, our approach provides support for managing ibrutinib therapy after 3 months of treatment.ClinicalTrials.gov NCT02824159.Copyright: © 2024 Cadot et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.