An Interview from the International Workshop on CLL with Jennifer Brown from the Dana Farber Cancer Institute
Dr. Brian Koffman: Dr. Brown, you’ve done some of the original and follow-up research on idelalisib. I’m wondering if you could explain a little bit about what idelalisib is, how it works and maybe a little bit about what the findings have been?
Dr. Jennifer Brown: Idelalisib is an inhibitor of the PI3 kinase enzyme specific to the Delta isoform. There are 4 different isoforms, but the Delta type is the one that is expressed in the hematopoietic, or blood forming cells and specifically in CLL cells. We know from studies in knockout mice that this is the most important form in B cells. We know from studies of CLL cells that if we inhibit that isoform, you’ll pretty much knock out all PI3 kinase activity in CLL. Idelalisib is the first in class inhibitor in that category and was approved by the FDA in combination with rituximab for relapsed patients with CLL who are appropriate for rituximab. I was involved in the initial phase I study and the results were really quite striking in very heavily pretreated CLL patients. We’ve had some very durable remissions including a couple of patients over 5 years…one of them ongoing who I will present at this meeting actually. In the phase I study, we established that the recommended dose would be 150 mg which is one pill twice per day. There are no strict criteria regarding taking with or without food.
These responses have been independent of the usual prognostic factors. That has been most evident in the registration trials or the randomized trials. We’ve seen that the progression free survival benefit as well as the response rate in the idelalisib arm, in the one case idelalisib with rituximab and in another case the idelalisib with ofatumumab was independent of the more adverse unmutated IgVH and independent of the 17P deletion. In fact in the idelalisib/rituximab study, the curves are overlapping with and without 17P deletion, so that is a fairly remarkable benefit of the drug compared to what was seen in the past.
BK: You said that the responses have been pretty remarkable. Can you give us some numbers?
JB: We are seeing in the phase I trial for relapsed refractory patients, median progression-free survival (PFS) in patients treated at the recommended Phase 2 dose or higher was 29 months. In the randomized trial which treated older CLL relapsed/refractory patients with severe comorbidities with rituximab and idelalisib, and of which 50% had 17P deletion, the median PFS was 19 months.
Idelalisib has a very classic pattern of somewhat predictable toxicities as long as you’re looking out for them. The most important consists of the elevation of liver enzymes, diarrhea with colitis and potential drug related pneumonia, or pneumonitis
Elevated Liver Enzymes or Transaminitis
This is handled in a pretty straightforward way: It usually takes place after being on the drug for 4-8 weeks. Usually we just hold the drug and it goes away on its own. We can restart, often at the same dose, sometimes at a lower dose. If you restart at the same dose and it happens again, you can just hold the drug again and next time restart at a lower dose. Most patients are able to continue on the drug despite having this as an early event.
There can be some early, mild diarrhea which typically responds to anti-diarrheal agents like Imodium. It’s usually self-limiting and is not a major issue, but what we do see is a delayed diarrhea which often is associated with colitis which can be a fairly severe diarrhea with colonic inflammation if someone had a colonoscopy. The average time when that occurs is actually late, almost 7 months into therapy. By that point people aren’t thinking anymore that this is a drug-related toxicity, but you really have to have a low threshold to thinking that it is because it may well be. It’s important to withhold the drug early. We usually treat it with oral budesonide, which is a non-absorbable steroid which will calm down.
BK: It goes down the gut and stays in the intestine and works there without having a systemic effect.
JB: Exactly. If people are really sick then we can use oral prednisone or even IV prednisone, but I usually try to catch it early and use the budesonide then hold the idelalisib until the colitis resolves, potentially start tapering the budesonide and start reintroducing idelalisib at a lower dose. With a slow tapering of the budesonide, that seems to optimize the control of the problem and allow the continuation of the drug.
Pneumonia and Pneumonitis
BK: We think of pneumonia as infectious and pneumonitis as inflammatory or autoimmune. Can you explain that for us?
JB: That’s right. It’s a little complicated to tease out from the data we have so far. We know that any study involving relapsed CLL patients will typically have relatively high rates of pneumonia, most of which are infectious. With idelalisib, we’ve been able to tease out a 2% or3% rate of what is probably a drug related inflammation of the lungs, we call pneumonitis in the absence of infection. That usually responds to steroids. Again, if you have a high threshold for suspecting it, you can usually catch it early and treat it with steroids. I’ve been able to restart all my patients back on the drug who had that without recurrence.
BK: These are very different toxicities than those we see with chemo-immunotherapy. Do you see any of the low blood counts, or low neutrophils which increase your risk for infection, or anemia which you can get from the bone marrow suppression, the high infection rates and things like that? Do you see any of that?
JB: It’s much, much less. If you look at the phase I data or even some of the randomized trials, you will see it reported because in relapsed patients, these are events that you do often see, but in the upfront data, it’s pretty limited. In my experience, a lot of it is a result of the disease or prior therapy and much less related to the drug. The toxicity pattern of the hepatitis, pneumonitis and colitis, I suspect may be related to direct inhibition of the delta isoform of the PI3 kinase in a subset of T cells that normally suppress the immune system. We have some data from mice that have been reported that suggest that that could be the case. I’m currently working on that with samples from people.
BK: So it sounds like this drug would be an excellent drug for a patient who could not tolerate chemo-immunotherapy or had some other significant comorbidities. Where do you see it fitting in your practice now and where do you see it going in the future?
JB: Right now I used it for relapsed patients. My personal belief is that its efficacy is fairly similar to ibrutinib. The data don’t look as good but I think that has to do with the patient populations studied and some of the toxicity management that’s limited the dosing. The toxicity profile is generally a little bit harder with idelalisib than ibrutinib, so all other things being equal, I tend to go to ibrutinib first. But for patients who are on anticoagulation, I definitely go to idelalisib first. I’m very cautious about combining anticoagulation with ibrutinib. Similarly for patients who have significant underlying heart disease, I worry about those patients on ibrutinib as well. That would shift me towards idelalisib before ibrutinib.
BK: Especially atrial fibrillation I would think.
JB: Yes and No. I also worry about patients who just have a low ejection fraction as a promotor of risk for any type of arrhythmia, but also people who have atrial fibrillation.
BK: Where do you see it going in the future? Do you see it being used as a single agent? Right now it’s approved in combination with rituximab. Do you see it moving forward to front-line? The data is probably better frontline as you were saying.
JB: 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.
BK: And that might be some combination with something that mitigates what might be a T cell effect and we certainly have pharmacologic agents that can help in that area. Any final thoughts that you want to share about idelalisib that would be helpful for patients to understand?
JB: It’s a very effective oral agent that is one of two very effective oral agents, so it’s great to have options. Together those 2 agents have really transformed our CLL universe. I think going forward will continue to transform it as we develop combinations and define duration therapy and learn more about how to manage the toxicities.
Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the unpaid medical director of the CLL Society Inc.
Jennifer Brown, MD, PhD is the Director of the Chronic Lymphocytic Leukemia Center at the Dana Farber Cancer Institute and is an Associate Professor of Medicine at Harvard Medical School.
Originally published in The CLL Tribune Q3 2015.