ASH 2015: Dr. John M Pagel on Idelalisib as Frontline Therapy in CLL (chronic lymphocytic leukemia)
This step forward in CLL therapy only comes after years of research and is due in no small part to the brave patients who volunteered for these trials including the pivotal RESONATE-2 trial.
As a reminder, ibrutinib is a small molecule taken orally, a tyrosine kinase inhibitor or TKI, that inhibits the BTK pathway that is so important for B cell communication. By doing so, it blocks a critical pro-survival signal in our CLL cells and helps control our disease.
I will comment more on the significance of this frontline approval in a coming post, but to give some perspective, I want to reflect on the only other approved oral TKI for CLL, namely idelalisib that inhibits the PI3Kδ pathway. This pathway is also important for B-cell signaling in our CLL cells and blocking it also blocks the same strong survival signal. That is a big part of the reason why both these drugs work as well as they do.
Researchers want to discover which CLL patient will get the most benefits with the least risks from these new therapies.
At ASH 2015 in December, many researcher were initially surprised by the amount of toxicity discovered when idelalisib was studied frontline or in the treatment-naive CLL population.
Keep in mind that it is currently only approved for use in combination with rituximab in the relapsed and refractory CLL population, not frontline. This trial was to look at its safety and efficacy in this new setting.
I interviewed Dr. John Pagel of Swedish Hospital in Seattle, WA on the importance of this negative findings.
It is a truism in science that we often learn as much or more from the trials that don't go as planned as from those that do.
Though most of the research on idelalisib presented at the ASH meeting was positive, the title of this abstract tells us there were significant issues: Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities.
Three quarters of the patients had grade 3 toxicities or severe problems. For 56% of them this was liver toxicities where the blood tests that measure liver inflammation were 5 to 10 times the upper limit of normal. These are much higher levels than generally seen when idelalisib is used in patients who have had prior treatments.
The good news is that with immune suppressive therapies including steroids, all the patients recovered.
The details of the trial are here.
Why then when ibrutinib is relatively benign in the frontline setting, did a somewhat similar drug have such unexpected problems.
Any drug may have effects on cells that are not their therapeutic target, resulting in unwanted side effects. One theory is that idelalisib lowered the balancing activity of the regulatory T cells or Tregs that are important in preventing auto-immunity. The PI3Kδ pathway is critical to the function not just of CLL cells but of the Tregs too.
This is why we need to do research. This is why we need to laud the brave subjects who jump into these trials. Without them, we make no progress.
Here is my interview with Dr. Pagel on this subject from ASH 2015.
As Dr. Pagel emphasizes, idelasilib is a powerful drug that helps many patients with CLL. How and when to best use it is a matter of ongoing research.