Personalized Selection of Upfront Therapy in CLL - Episode 15
John Fox, MD, MHA: Already we’ve seen the publication of a number of trials that combine anti-CD20 therapy, such as Rituxan, with these newer agents—the BTK inhibitors, the PI3K, the BCL, to pathway agents such as venetoclax. What will be very interesting, then, is the combination studies with these B-cell receptor pathway agents. The combination of ibrutinib and venetoclax, for example, is very interesting, because venetoclax acts more in the marrow component of CLL, whereas the ibrutinib acts more on the sequestered cells in a lymph node. So, those will be very interesting. Ibrutinib produces a lower CR than venetoclax, so what happens when you put those together? Time will tell. There are new PI3K inhibitors, such as duvelisib, that are going to be very interesting if their toxicities can be overcome, and there is a host of new mechanisms of action. Again, targeting that B-cell receptor pathway, that is going to be very important to understand.
The 1 thing that I’m certain of is that these combinations of therapies will be extraordinarily expensive. The combination of venetoclax and ibrutinib could be $250,000 a year. So, understanding not only what the response is but also when we can shut off or stop therapy and give a treatment-free interval and reduce both the drug toxicity and the financial toxicity is going to be critical. Many of these patients have Medicare, and even once they walk through the doughnut hole, they still have a 5% cost sharing—and, well, let’s see, 5% of $250,000 is about $7500 a year. So, it’s going to be critical that we understand in these combinations not only what the optimal combination is but also when we can shut it off.
To further add to the complexity, there are studies going on that look at the combination of anti-CD20 therapies with the BTK and BCL-2 treatment pathway inhibitors. And so, now we have the potential for a 3-drug regimen, which increases the cost and increases the toxicity. We’ll just have to wait to see if that produces even higher rates, minimal residual disease, and complete response that could ultimately lead to discontinuation of therapy and giving patients a treatment-free interval.