William G. Wierda, MD, PhD
Although ibrutinib (Imbruvica) remains the go-to drug for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), new drugs and novel combinations are showing potential. With this progress, questions regarding sequencing continue to pose a challenge.
The BCL-2 inhibitor venetoclax (Venclexta) as monotherapy has demonstrated a high rate of objective response and is well tolerated in patients with 17p deletion, but is also showing promise outside of that indication, says William G. Wierda, MD, PhD.
Another novel combination in this space is ibrutinib, cyclophosphamide, fludarabine, and obinutuzumab (Gazyva)—referred to as IFCG—that is undergoing investigation as a frontline treatment for young fit patients who have been determined to do well on fludarabine, cyclophosphamide, and rituximab (FCR)-based treatment.
During an interview with OncLive
at the National Comprehensive Cancer Network (NCCN) 12th Annual Congress on Hematologic Malignancies, Wierda, executive medical director of the Leukemia Center at The University of Texas MD Anderson Cancer Center, discussed the continued importance of ibrutinib, the promise for novel combinations, and the impact this progress has had on sequencing for CLL.
OncLive: What has led to the need for this discussion on sequencing in CLL?
It is because we have so many agents now, and most of the agents approved as monotherapy. Ibrutinib was approved as monotherapy, venetoclax was approved as monotherapy—so the early trials were looking at the activity of those single agents and patients have been treated based on what was available. For example, ibrutinib was the first drug that was available, so most of the patients who were treated in the community initially had gone on ibrutinib. Now, we have venetoclax, so that is another option.
There is a lot of work and research devoted to identifying good combinations. Perhaps [the next successes will be] combinations of the agents that I have mentioned, or combinations of these agents with a CD20 antibody or other drugs to get better remission. And then there are also considerations about what is the right sequence to give them in, and do you expect to have a response to one thing if patients have developed resistance to another. For example, responses in ibrutinib-refractory patients with venetoclax.
Speaking of combinations, are there any that are looking particularly promising?
We have a couple trials with new novel combinations in the frontline setting with previously untreated patients. We have a trial of a combination based on an FCR regimen that Dr Michael Keating developed at MD Anderson. So, it is the next generation of treatment combination with IFCG—4 drugs for patients that we know do the best with FCR-based treatment. These are patients who are young and have a mutated immunoglobulin heavy chain variable gene (VG), and we know that these patients, over 50% of them, can get a good remission that lasts more than 10 years with FCR.
This 4-drug combination trial is now intended to achieve the same thing or better but, what we are doing is a little bit different. In addition to modifying some of the drugs, we are just giving 3 cycles of the chemotherapy part. So, not only are we working on making a more potent regimen and combination to treat patients, but we are trying to reduce or pull back on the amount of chemotherapy that they are exposed to in order to reduce their risk for other malignancies in the bone marrow, as well as Richter's Transformation. We are excited and interested in that new combination for young, fit patients with a mutated VG.
Another combination that we are excited about, which is generating some data, is ibrutinib plus venetoclax. In this trial, patients receive 3 months of ibrutinib by itself, and then up to 2 years of the combination. There are 2 patient cohorts for that trial, an untreated patient population and a previously-treated patient population. We are generating some data in that trial, which, along with the IFCG data will be presented at American Society of Hematology (ASH) this year. We are seeing good, deep, minimal residual disease (MRD)-negative remission already in that trial.
With all of these newer agents, what importance do older agents such as ibrutinib hold in CLL?
Ibrutinib is an extremely effective drug. It is effective in the frontline setting—so we see the patients who initially receive it have very long periods of disease control. The more common reason for frontline patients to come off of treatment is because of tolerability and toxicities.