BTK Inhibitors in the Management of CLL

Nitin Jain, MD: Hello, and thank you for joining this OncLive® Events program titled “Updates in CLL: What’s on the Horizon in CLL?” I’m Nitin Jain. I’m an associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas. Tonight, I’m joined by Dr Richard Furman from Weill Cornell Medicine. Dr Furman, do you want to introduce yourself?

Richard R. Furman, MD: I’m Richard Furman from Weill Cornell Medicine in New York City.

Nitin Jain, MD: The treatment of CLL [chronic lymphocytic leukemia] has evolved and continues to evolve as we’re incorporating new agents in the therapy of CLL. Through our discussion, we hope to review the head-to-head data of BTK inhibitors in the treatment of patients with CLL, discuss new and novel therapies on the horizon, and take an in-depth look at where new therapies and regimens will fit into the already evolving treatment paradigm for patients. Please submit questions for our Q&A portion of the program, and we’ll take as many as possible toward the end of the session. This program will be led by myself and Dr Furman. Let’s get started.

In the first segment, we’ll talk about the role of BTK management in the context of CLL. We have at least 2 BTK inhibitors approved for CLL in the frontline and relapsed settings. These include ibrutinib, which was the original BTK inhibitor approved in 2014 for patients with CLL based on the RESONATE study, which was in relapsed/refractory CLL. Subsequently, we have RESONATE-2 data, which led to the approval of ibrutinib in the frontline setting. Then we have acalabrutinib, a second-generation BTK inhibitor that was approved a couple of years ago. It has fewer off-target effects than ibrutinib.

Several phase 3 studies have been reported with this agent. The first, in the relapsed/refractory setting, was the ASCEND trial, which was acalabrutinib vs BR [bendamustine, rituximab] or idelalisib. In the frontline setting was the ELEVATE-TN trial, which was focused on acalabrutinib vs acalabrutinib plus obinutuzumab vs chlorambucil-obinutuzumab. More recently was the ELEVATE-RR trial, which compared 2 BTK inhibitors head-to-head. The therapy options for CLL with these agents have evolved, and both agents are approved in the frontline and relapsed settings for CLL. The other agent I didn’t mention is venetoclax, a BCL2 inhibitor that’s approved in combination with obinutuzumab in the frontline setting for CLL and in combination with rituximab for relapsed/refractory CLL.

In terms of the strategy recommended by the NCCN [National Comprehensive Cancer Network] Guidelines, the role for chemotherapy is very limited in the context of CLL. An argument could be made for a certain subgroup of patients who are young and fit and have IGHV mutations, where chemotherapy such as FCR [fludarabine, cyclophosphamide, rituximab] could be used. But I’d argue that with the data we’re seeing and will see at the upcoming ASH [American Society of Hematology Annual Meeting], the use of FCR [fludarabine, cyclophosphamide, rituximab] has gone away, and the role of chemotherapy has declined for these patients. In the frontline setting, we have 3 FDA-approved agents: the 2 BTK inhibitors I already mentioned, which are to be given continuously indefinitely, and a time-limited approach of venetoclax plus obinutuzumab for patients with CLL, which is to be given for 1 year.

There are pros and cons for these approaches. I’ll let Dr Furman share his thought process for when he’s thinking about these frontline FDA-approved approaches for patients with CLL. Richard?

Richard R. Furman, MD: Thank you, Nitin. I appreciate the opportunity. This is an amazing time in CLL treatment because for the first time, we have the ability to treat our patients with very effective agents that don’t appear to have significant long-term toxicities. The most worrisome toxicity, as you alluded to, is the chemoimmunotherapy affecting not just the immune system function but also bone marrow survival. Patients who have mutated immunoglobulin genes and achieve a long-term remission with FCR [fludarabine, cyclophosphamide, rituximab] chemotherapy have to worry about secondary MDS [myelodysplastic syndromes and AML [acute myeloid leukemia], as well as infections. With COVID-19, it should be ever-present. We have the opportunity to control the disease with therapies that are extremely well tolerated, and taking advantage of them is in the best interest of our patients.

Nitin Jain, MD: One of the questions that comes up is how to select between the 3 FDA-approved therapies. There’s the BTK inhibitor vs the combination of BCL2 plus obinutuzumab. There are pros and cons to these approaches. In terms of the data, we have the longest track record with ibrutinib. It has the longest follow-up data available. But patients on ibrutinib have risk of atrial fibrillation, ventricular arrhythmias, and other adverse effects, which can be quite problematic, including arthralgias and hypertension.

With acalabrutinib, all the same adverse effects could occur but at a lower frequency, and it has the adverse effect of headaches, which can occur during the first month of therapy. Then we have venetoclax-obinutuzumab, which has the advantage of being a time-limited therapy. There’s no risk of atrial fibrillation, but it requires the logistics of TLS [tumor lysis syndrome] monitoring. Patients have to come to the clinic quite often. Obviously obinutuzumab is given IV [intravenously], so that requires chair time in the infusion unit. There’s also neutropenia. Almost 50% of patients will develop grade 3 or 4 neutropenia. You have to watch them closely and give them G-CSF [granulocyte colony-stimulating factor] support. Many times, there are dose reductions for these patients. For the usual patients, these are the options I discuss in the clinic with them to come up with the right plan of what they want to do.

Transcript Edited for Clarity