Personalized prediction of drug dose

Sigrid S. Skånland
Sigrid S. Skånland

Precision medicine is required to manage the heterogeneous drug responses observed in patients with leukemia.

In a recent study published in the journal Leukemia, Sigrid S. Skånland and co-workers at Oslo University Hospital developed a method for dose prediction, which may be implemented in clinical practice.

Recent advances in the management of patients with chronic lymphocytic leukemia (CLL), the most common form of adult leukemia in the western world, include small molecule drugs. Although these therapies have improved patient outcome, several patients do not tolerate the treatment or develop resistance. In order to delay resistance and optimize drug response, patients are commonly treated with combinations of drugs. However, biomarkers that can predict patient response is lacking.

Now, Skånland and co-workers have used high-throughput flow cytometry to map the doses of the small molecule drugs ibrutinib (Btk inhibitor) and venetoclax (Bcl-2 antagonist) that induce drug synergy (see Figure). Combination treatment with ibrutinib+venetoclax has shown promising results in clinical trials on CLL. However, the drugs are administered at the highest tolerated dose although reports show that drug dose can be reduced without loss of effect. Lowering the drug dose may reduce side effects, as well as drug costs.

The researchers at Oslo University Hospital show that both ibrutinib and venetoclax can be reduced 10-100 fold and still induce synergy (Figure, red area). Based on these findings, the authors of the publication are currently planning a clinical pilot study to test their method for dose prediction in patients with CLL.

Figure: CLL cells were treated with ibrutinib (y-axis) and venetoclax (x-axis) alone or in combination. The red area shows drug synergy on a marker for cell death. Standard drug doses given to patients are indicated with the two black lines. As shown, the dose of both drugs can be lowered without loss of synergy.


An in vitro assay for biomarker discovery and dose prediction applied to ibrutinib plus venetoclax treatment of CLL.
Skånland SS, Cremaschi A, Bendiksen H, Hermansen JU, Govinda Raj DBT, Munthe LA, Tjønnfjord GE, Taskén K.
Leukemia. 2019 Aug 30. doi: 10.1038/s41375-019-0569-7
PMID: 31471562

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