Background: CDK 4/6 inhibitors (CDK4/6is) are the first-line treatment for metastatic luminal-like breast cancer (BC). These drugs induce macrocytosis without anemia in most patients. The mechanism for the red blood cell (RBC) changes is unknown. In vitro and animal studies show that RBCs from CDK6-knockout mice have increased membrane fragility, but the clinical impact of CDK4/6is on human RBC lifespan is not known. We sought to determine the impact of CDK4/6is on RBC lifespan and detect changes in the regulation of hemoglobin production. Using the mean corpuscular volume (MCV) measurements at several time points, we can study the evolution of MCV, mean corpuscular hemoglobin concentration (MCHC), and RBC count over time. From this, one can estimate the RBC lifespan under CDK4/6is. Methods: We performed a unicentric retrospective study. Based on published models of RBC population dynamics, we have coded a biologically inspired model which allowed us to extract values for biological parameters, including the RBC lifespan. Results: A total of 122 patients were identified, and 1959 laboratory measurements were analyzed. After the pre-treatment RBCs were replaced, the mean MCV increased by 12.6 femtoliter (fL) (95% Bayesian credible interval [CdI] 13–14), the MCHC increased slightly by 0.69 g/dL (95% CdI 0.42–0.96), and the RBC count decreased by 0.77 × 109/L (95% CdI 0.42 × 109/L–0.96 × 109/L). The net result was a 0.64 g/dL (95% CdI 0.48–0.80) rise in hemoglobin. The mean total RBC lifetime was 118 days (95% CdI 114–122), similar to the value measured in healthy persons. Discussion and Conclusions: These findings suggest that, despite changes in RBC volume, CDK4/6is do not predispose patients to RBC destruction and do not impair regulation of hemoglobin homeostasis. We show that CDK4/6is do not decrease the RBC lifespan in pre-treatment erythrocytes. Unfortunately, this method cannot determine the lifespan of post-treatment RBCs, but further research could help answer this question.
背景：CDK4/6抑制剂是转移性管腔样乳腺癌的一线治疗药物。多数患者使用该药物后会出现大红细胞症但不伴贫血。红细胞发生此种变化的机制尚不明确。体外及动物研究表明，CDK6基因敲除小鼠的红细胞膜脆性增加，但CDK4/6抑制剂对人类红细胞寿命的临床影响尚未可知。本研究旨在探究CDK4/6抑制剂对红细胞寿命的影响，并检测其对血红蛋白生成调控的改变。通过多个时间点的平均红细胞体积测量，我们可以追踪平均红细胞体积、平均红细胞血红蛋白浓度及红细胞计数随时间的变化趋势，从而估算CDK4/6抑制剂作用下红细胞的寿命。 方法：我们开展了一项单中心回顾性研究。基于已发表的红细胞群体动力学模型，我们构建了一个仿生学模型，用以提取包括红细胞寿命在内的生物学参数值。 结果：共纳入122例患者，分析了1959项实验室检测数据。在治疗前红细胞被替换后，平均红细胞体积增加12.6飞升（95%贝叶斯可信区间13-14），平均红细胞血红蛋白浓度轻微上升0.69克/分升（95%可信区间0.42-0.96），红细胞计数下降0.77×10⁹/升（95%可信区间0.42×10⁹/升-0.96×10⁹/升）。最终血红蛋白净增长0.64克/分升（95%可信区间0.48-0.80）。红细胞平均总寿命为118天（95%可信区间114-122），与健康人群测量值相近。 讨论与结论：这些发现表明，尽管CDK4/6抑制剂会改变红细胞体积，但并不会导致红细胞破坏倾向，也不影响血红蛋白稳态的调控。我们证实CDK4/6抑制剂不会缩短治疗前红细胞的寿命。遗憾的是，本方法无法确定治疗后生成的红细胞寿命，后续研究或将有助于解答这一问题。
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