Targeted Therapy in CLL May Impact Blood Cell Behavior

Targeted therapies used to treat chronic lymphocytic leukemia (CLL) may influence blood flow properties by affecting red blood cell (RBC) aggregation, a factor linked to cardiovascular complications, according to new research.1 Published in Micromachines, the study examined how 2 common CLL treatments, ibrutinib and combination obinutuzumab/venetoclax, affect RBC behavior.

The findings indicate that ibrutinib restores RBC aggregation levels to those seen in individuals without CLL, while obinutuzumab/venetoclax does not significantly alter the increased RBC aggregation seen in untreated patients with CLL. These insights highlight potential off-target effects of CLL therapies on blood viscosity, which may contribute to thrombotic risks in some patients, according to the authors.

CLL and Red Blood Cell Aggregation

Monitoring RBC aggregation could help predict which patients with CLL may be at higher risk for thrombotic events. | Image credit: wanchalerm – stock.adobe.com

CLL is characterized by the accumulation of malignant B cells in the blood, bone marrow, and lymphatic system. Although targeted therapies have dramatically improved survival, the study authors said how they affect blood flow dynamics have been largely overlooked.

Using a microfluidic system designed to mimic blood vessels, researchers measured RBC aggregation in patients with CLL. They found that untreated patients with CLL had significantly higher RBC aggregation than healthy controls, forming complex 3D clusters. This altered blood viscosity could contribute to cardiovascular risks, as high RBC aggregation is associated with increased hydrodynamic resistance and potential thrombotic complications.

“It should be noted that the aggregates from P4 were found in only half of the samples of the control group, highlighting the variability in the structural complexity of RBC aggregates in healthy individuals,” the authors noted regarding one of the 5 population groups in the study.

How Ibrutinib and Obinutuzumab/Venetoclax Differ

The study looked at a pair of widely used CLL therapies to see whether they influenced RBC aggregation. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, reduced RBC aggregation to levels seen in controls without CLL, suggesting it may help mitigate blood flow complications in CLL. The researchers hypothesized that the drug’s effect might stem from its ability to reduce inflammation and cytokine activity, both of which can alter RBC behavior.

Meanwhile, the combination of anti–CD20 antibody obinutuzumab with BCL-2 inhibitor venetoclax did not significantly alter RBC aggregation compared with untreated patients.

“This finding suggests that the mechanisms that drive RBC aggregation in CLL may remain unaffected by this therapy and that it does not directly alter the mechanisms that lead to increased RBC aggregation in CLL,” the authors said about the combination treatment.

Additionally, 40% of the patients on this combination therapy had anemia, which can increase oxidative stress in RBC and contribute to continued RBC alterations.

“However, it is difficult to distinguish the impact of the disease itself through the effect of anemia on RBC morphology and aggregation because both conditions can induce overlapping changes in RBC behavior,” they noted. “Therefore, further research is needed to fully elucidate the mechanisms of action of this combination therapy on RBCs in CLL.”

Clinical Implications

The study also raised important clinical considerations regarding the impact of CLL therapies on cardiovascular health. Since thrombotic events are a known risk in CLL, these findings suggest that monitoring RBC aggregation could help predict which patients may be at higher risk for complications.2,1 On the other hand, patients treated with obinutuzumab/venetoclax may require additional monitoring for blood viscosity-related complications, especially those with pre-existing anemia.

“Understanding the changes in RBC aggregation in CLL patients and the impact of the targeted therapies is critical for predicting potential complications, including thromboembolic events and cardiovascular risk,” the authors concluded. “The quantification of RBC aggregation may therefore be a useful tool for monitoring CLL disease progression, improving the process of clinicians’ decision-making.”

References

1. Alexandrova-Watanabe A, Abadjieva E, Gartcheva L, et al. The impact of targeted therapies on red blood cell aggregation in patients with chronic lymphocytic leukemia evaluated using software image flow analysis. Micromachines (Basel). 2025;16(1):95. doi:10.3390/mi16010095

2. Gade IL, Riddersholm SJ, Christiansen I, et al. Venous thromboembolism in chronic lymphocytic leukemia: a Danish nationwide cohort study. Blood Adv. 2018;2(21):3025-3034. doi:10.1182/bloodadvances.2018023895