At ASH 2018, I caught up with Dr. Adrian Wiestner with the National Institutes of Health (NIH) who leads all the innovative CLL research happening with our tax dollars in Bethesda, Maryland. We discussed his team’s research on acalabrutinib, a potent but still at the time of this writing, experimental drug for CLL.
We know that ibrutinib and acalabrutinib and the other BTK inhibitors in development work by blocking the B-cell receptor (BCR) by interrupting its ability to signal the cell nucleus to stay alive and proliferate. It does this by blocking BTK (Bruton’s Tyrosine Kinase), an important step in the path from the BCR on the cell’s surface and the cell’s genetic brain, the DNA in the nucleus.
The medicines work by occupying the BTK site, but not activating it. When a signal comes from the upstream BCR on the cell’s surface, it is stopped because the drug is already there occupying the site, irreversibly bound to the pocket of the BTK so there is no way to dislodge it.
The BCR can’t get its message through, and since the purpose of a B cell (especially so with cancerous B cells) is to communicate with other cells through BCR, with no purpose in life, the cell eventually dies off.
This is why these drugs are so potent in controlling our cancer.
The only escape for the CLL cells is to grow more BTK protein which is exactly what it does.
So, knowing how long it takes for the BTK to grow back is critical to understanding how often we need to dose the medication.
Acalalabrutinib is approved for Mantle Cell Lymphoma at a dose of 100 mg twice a day, which is expected to be the dose for chronic lymphocytic leukemia when it is approved.
Here are some of the key lessons I learned in our interview about the research that Dr. Wiestner’s NIH team presented at ASH 2018.
- More than 40 chronic lymphocytic leukemia patients were studied.
- Patients were randomized to receive either 200 mg of acalabrutinib once daily or 100 mg twice daily.
- The percentage of BTK bound by acalabrutinib was measured.
- These brave patients came back nearly every day to have easily accessible lymph nodes biopsied because it is in the nodes and the bone marrow where the CLL cells are active, not in the blood stream. BTK occupancy was measured at 4, 12, 24 and 48 hours after the last dose of acalabrutinib.
- As one would expect, the longer one goes from the last dose, the more BTK builds up in the cells.
- After 48 hours, the CLL cells have produced enough new BTK to reactivate and again start to get the signaling from the BCR to stay alive and proliferate. This is not a good thing and seems to occur when BTK occupancy drops below 90%.
- This reinforces the need to take the meds as prescribed and not skip doses.
- The caveat for this is that if one needs to hold the medicine due to a needed surgery or an adverse event, this is generally safe compared to missing doses here and there every week.
First, we need to thank all the patients who volunteered to have their lymph nodes biopsied on a recurrent basis. That’s commitment.
Second, this is the type of trial that tends to only happen at the NIH because they often ask the difficult questions that might underlie whether treatment will succeed or fail.
Third, this confirms the importance of the BTK pathway in CLL and how blocking it, blocks cell activation.
Finally, the bottom line is that the medicine needs to be taken as prescribed.
Here is my ASH 2018 interview with Dr. Wiestner.