ASH 2012: Dr. Tom Kipps Explains why Understanding CLL Biology Helps us Focus Therapies: Bcl-2 and ABT-199; as well as my Reporting on the Suspended Trials
This is not a theoretical construct, but is directly pertain to a powerful drug that is in clinical trials right now: ABT-199. That power is a double edged sword and I discuss the recent news about the trial suspensions later in this post.
It turns out that of the all the B-cell cancer, CLL is guilty of the greatest overproduction of this Bcl-2 which is a strong cellular anti-suicide messenger. Twin that with the contravening fact that CLL cells also overproduce the powerful pro-apoptotic (programmed cell death) compound BIM. But BIM is held in check by the excess Bcl-2. Block Bcl-2 and then the BIM goes bam and the cancer cell suicides.
That is where ABT-199 comes in. But I will let Dr. Kipps explains.
Now all this power to take the safety off the suicide bomber inside every CLL cell comes with a heavy cost. If it is too effective, especially in someone with a high tumor burden (read very high lymphocyte count and huge nodes) and /or there is a significant dose escalation, the cell death toll can exceed the body's ability to cope with all the waste produced by the broken down cells. This is the dreaded tumor lysis syndrome( see this nice explanation by Dr. Sharman), and it can not only kill the patient, it can kill the development of a life saving drug.
I have waited until there was a reliable public source for confirmation before posting this information on my blog and I got it today from Bloomberg news.
The patients died from tumor lysis syndrome, said Tracy Sorrentino, a spokeswoman for North Chicago, Illinois-based AbbVie. The complication stems from the rapid destruction of malignant cells after treatment that can trigger acute kidney failure. It occurs most often with large tumors such as those found in leukemia and lymphoma patients, according to the National Institutes of Health.
After the complication was discovered, AbbVie and its partner, Roche Holding AG, suspended the dose- escalation portion of the studies to determine the amount of drug that is safest and most effective, Sorrentino said. The risk stems from the drug’s potency and can be managed if the dose is carefully controlled, she said.
This is a very powerful oral medication that has a tremendous potential to help even the worst risk patients with CLL. I want to have this option available in the near future to the many of us who might benefit from it, but not at the cost of moving too fast in the clinical trials. I agree that now that we know the danger, we can take appropriate precautions.
Personally, if I wasn't already doing so great on my ibrutinib trial, I would not hesitate to enter an appropriate ABT-199 trial once they have the dose escalation reworked. If anything, they are going to be over cautious from here forward.
Hence my prior post on dotting the I's and crossing the T's that was my loud admonition to take it slow with drug trials.
Nice and easy does it every time.