ASH 2015: Dr. John Pagel on Idelalisib as Frontline Therapy in CLL (chronic lymphocytic leukemia)

Many of us with CLL are familiar with the drug approval process: the first FDA approved indication for a new drug may be that it can be used only after other drugs have been tried, and then it is hoped that a frontline indication could be expected from data obtained during subsequent clinical trials. In February 2014, ibrutinib, an oral Tyrosine kinase inhibitor, which inhibits the Bruton Tyrosine Kinase pathway received FDA approval for use in CLL patients who had received at least one prior therapy. On March 4^th, 2016, it was announced that ibrutinib had received approval for frontline use in CLL.

Idelalisib, the only other approved oral TKI for CLL, which inhibits the PI3Kδ pathway was approved in July 2014 in the relapsed refractory setting in combination with rituximab for patients where rituximab would be appropriate. It seems natural that idelalisib might follow the same pathway towards an approval for frontline therapy.

At the 2015 American Society of Hematology (ASH) annual meeting held in December, many researchers were initially surprised by the amount of toxicity discovered when idelalisib was studied in the frontline setting, also known as the treatment-naïve CLL population. This trial was to look at its safety and efficacy in this new setting. 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 that still need to be resolved: 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.

Why then when ibrutinib is relatively benign in the frontline setting, did a somewhat similar drug have such unexpected problems? We know that any drug may have effects on cells that are not their therapeutic target, and result in unwanted side effects. One theory about this higher level of side effects 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.

In my interview with Jennifer Brown out of Dana-Farber Cancer Institute while at the iwCLL meeting in Sydney, Australia, she commented in response to a query about expanded usage:

It’s interesting. The efficacy is better front line, excellent, as we heard in the meeting today, high 90 percent response rates. The toxicities are also greater. So one of my goals with what I am doing with my research is to try to best understand who gets this toxicity and why and see if we can predict ahead of time who will get it and also to potentially design combinations that might mitigate the toxicities. Right now, because of the toxicity pattern, I tend to see it a little bit more in relapsed even though it is more effective upfront, but if we can figure this issue out of how to manage or predict who would get how to prevent the toxicity, then it could more to any line potentially. You can read her entire interview from the first issue of The CLL Tribune here.

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.

I interviewed Dr. John Pagel of Swedish Hospital in Seattle, WA on the importance of these findings. You can view it here:

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.

UPDATE: On Friday, March 11th, the European Medicines Agency announced it would be taking a hard look at the product thanks to an increase in the rate of serious adverse events–including deaths, mostly due to infections–in three clinical trials. Following the EMA announcement on Friday, Gilead said it will terminate Zydelig trials in first-line CLL, according to Bloomberg.

Brian Koffman, MD 3/14/16