CDK4/6 Inhibitors-Induced Macrocytosis Is Not Associated with Hemolysis and Does Not Impact Hemoglobin Homeostasis

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.

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.

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.

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.