Idelalisib Speed Bump: Shifting Gears in CLL

Bruce D. Cheson, MD


March 28, 2016

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Hello again. This is Bruce Cheson from Georgetown University Hospital and the Lombardi Comprehensive Cancer Center, speaking to you for Medscape Hematology. Today we have no music, we have no jokes. It is a serious discussion.

Last week, I was in the splendid city of Rome giving a couple of presentations at the Second Postgraduate Lymphoma Conference. I was invited by my good friend Pier Luigi Zinzani, and was asked to give two talks: (1) on Bruton tyrosine kinase (BTK) inhibitors in follicular lymphoma, and (2) on how we're getting to a chemo-free world in patients with follicular lymphoma. That's a particularly favorite topic of mine, because I think that's really the goal of treatment.

Unfortunately, [because of breaking news] I had to make some very last-minute adjustments to both of these presentations. Regarding the chemo-free world, we've had an increasing number of very exciting drugs over the past few years, and I was to talk about these various drugs and how we put them together. Then we get this announcement from Gilead Pharmaceuticals about their PI3 kinase inhibitor idelalisib, a very active drug for chronic lymphocytic leukemia (CLL) and indolent lymphomas.

There are a number of new safety signals with that drug that have halted a number of their clinical trials, particularly those in combination with other agents. There have been cases of serious toxicities and fatalities, particularly pneumocystis and cytomegalovirus (CMV) reactivation.[1,2] These events tend to be more common and more severe when you combine the drug with other agents within the first 6 or so months of treatment, and in patients who are less heavily pretreated. The trials, particularly those looking at upfront therapy, are gone.

This [safety signal] is consistent with some other observations with this drug that the hepatotoxicity and the diarrhea also are more common in the upfront setting.[3] The drug also seems to induce a neutropenia.

So yes, it's a pill, and yes, it's targeted therapy. But yes, there are adverse effects that now require close monitoring, and the company is recommending prophylaxis for pneumocystis and frequent monitoring for CMV[4]—and if either of these events occurs, that's it for the drug for that patient.

The second event related to my talk on BTK inhibitors. There's a great new drug out there, acalabrutinib (ACP-196). Unfortunately, whereas it seems to be fabulous in CLL,[5] [in] the trials from Acerta Pharma, [efforts to pursue indications for acalabrutinib in combination with other drugs] in follicular lymphoma and other indolent lymphomas, such as Waldenström macroglobulinemia, are now terminated, [but Acerta is still conducting single-agent studies in those disease entities because acalabrutinib is showing promising activity with minimal toxicity]. And the company states they want to focus on getting the drug approved in CLL [in personal communications to Dr Bruce Cheson, as reported March 31, 2016]. That's their main objective, and it's a laudable one, but it also suggests that perhaps the drug is not as active as we would like to have it be in follicular lymphoma and the other indolent histologies. Too bad.

Someone in the audience asked me, is that the end for the chemo-free world? I said absolutely not. We have lots of new drugs coming along, venetoclax[6] and others, which still offer this possibility for our patients. It's just a question of being careful, of developing newer and less toxic second- and third-generation drugs, and putting them together in an intelligent and safe fashion. Even though we have a couple of these drugs on the market, they should only be put together in the context of a carefully monitored clinical trial.

Bruce Cheson, signing off for Medscape Hematology, and I look forward to speaking to you again in the near future. Thank you.


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