Two studies called IOSI-EMA001 and IOSI-EMA003 looked at 102 patients with chronic lymphocytic leukemia (CLL) who were treated with Ibrutinib. We collected 702 samples from these patients over time. These studies were designed to detect patterns in the data. Out of these patients, 33 had a high risk of CLL, with some getting their first treatment and others who had relapsed. We kept track of these patients continuously until their disease got worse or they had to stop taking Ibrutinib because they couldn't tolerate it.
The genetic and clinical features of these 33 patients suggested they were at high risk for the disease. We examined their blood and used machine learning to find biological patterns. Before treatment and while the patients were in a state where there was still a bit of CLL left in their blood (but it wasn't causing problems), they couldn't find any genetic changes related to Ibrutinib resistance.
So, we looked at how Ibrutinib affected the cells in the body. We found that certain genes related to cell growth and energy production decreased after starting Ibrutinib. This suggested that the CLL cells were becoming less active. We also found that the cells that were still in the blood got smaller and less active over time. It was like the cells were trying to avoid the effects of Ibrutinib.
We also saw changes in certain genes related to a pathway called MAPK, which helps cells communicate. These genes became more active in the remaining CLL cells under Ibrutinib. To confirm this, we looked at a protein called Ki-67, which is related to cell growth, and found it decreased in these cells.
Next, we checked if these changes were due to genetic mutations. We tracked the mutations in the CLL cells and found that only a third of the patients had significant genetic changes. So, the majority of patients seemed to adapt to Ibrutinib without major genetic changes.
We also looked at how Ibrutinib affected the way genes are switched on and off, and we found some genes that were more active despite unchanged genetic features. These changes pointed to a pathway called ERK as a way the cells were avoiding the effects of Ibrutinib.
To test these findings, we used a cell line in the lab and found that blocking the ERK pathway along with Ibrutinib worked better than Ibrutinib alone. We then tested this in mice and saw that the combination of drugs helped control the cancer better and improved the mice's survival.
In summary, the research suggests that CLL cells survive Ibrutinib treatment by making non-genetic changes that allow them to use a pathway called ERK to stay alive.
