Richard R. Furman, MD, discusses the continued evolution of the field of chronic lymphocytic leukemia and how physicians decide on the optimal treatment sequence for their patients.
Richard R. Furman, MD
The FDA approval of agents such as ibrutinib (Imbruvica), venetoclax (Venclexta), and obinutuzumab (Gazyva), offers flexibility in choosing the best therapy for a patient with chronic lymphocytic leukemia (CLL), according to Richard R. Furman, MD.
“I typically use ibrutinib as my frontline therapy, since it has excellent tolerability and efficacy. When patients progress on ibrutinib, I then utilize venetoclax and obinutuzumab,” said Furman.
Combination regimens and emerging agents, including BGB-3111, acalabrutinib, and SNS-062, offer further opportunities to advance the field, noted Furman.
Furman, director of the CLL Research Center at Weill Cornell Medicine, lectured on CLL at the 2017 OncLive® State of the Science Summit on Hematologic Malignancies. In an interview, Furman discussed the continued evolution of the field of CLL and how physicians decide on the optimal treatment sequence for their patients.Furman: I took what I believe to be a slightly unique approach and discussed how we should be using risk assessment in the era of novel agents. The goal is that our prognostic markers are no longer prognostic. In a way, that’s good because everyone seems to respond to novel therapies. The question then becomes how long will they see a response for.
The hope is that we can identify those patients who might need more than just a BTK inhibitor or a BCR antagonist. Those patients may have an increased risk of developing Richter’s transformation, and [so we could] possibly come up with the means for intervening [with] them differently, which might enable them to enjoy long-term positive outcomes. The 3 most exciting and important agents that we have for the care of our patients include ibrutinib, venetoclax, and obinutuzumab. These 3 agents afford a great deal of flexibility in choosing the best therapy for a patient and inducing dramatic responses. Although ibrutinib is well tolerated most of time, there are a few patients who have contraindications to it, mainly patients who have bleeding risks or atrial fibrillation. For those patients, venetoclax and obinutuzumab offer great alternatives.
In patients who don’t want to have an IV infusion or worry about the tumor lysis risk, venetoclax or obinutuzumab can certainly be used, respectively.
There is a great deal of flexibility with those 3 agents. Importantly, the agents are able to induce long-term and deep remissions in patients. Although ibrutinib is able to have good outcomes at 5 years, it takes a long time to induce a deep response. In those patients who have some potential indication of either Richter’s transformation or developing a resistance to ibrutinib—those are the patients who have 11q deletion, 17p deletion, NOTCH1 mutation, or 1 of the certain V genes that seem to be stereotypical. Due to their risk of transforming, those patients might be better served by a more rapid depletion of their CLL clones. In those patients, the use of obinutuzumab or venetoclax offers certain advantages.
What’s also very intriguing is the move toward combining ibrutinib and venetoclax together. This is important because it combines our 2 best agents and takes advantage of the fact that they are synergistic in the laboratory, since ibrutinib’s ability to remove the adhesion of the CLL cells to the microenvironment deprives them of an important resistance mechanism to venetoclax. Hopefully, the 2 together will be effective and rapid in inducing responses. With what might be a lifelong therapy with ibrutinib or venetoclax, there is the potential change to what could be a defined treatment course that stops once a patient achieves MRD negativity.BGB-3111 and acalabrutinib are what I consider to be second-generation BTK inhibitors. There are some interesting differences between the 2 of them. BGB-3111 out of all the BTK inhibitors, sees sustained serum levels far more than we see with acalabrutinib.
Acalabrutinib is the other extreme with ibrutinib being right in the middle. With acalabrutinib, it has a very short half-life, mainly about 30 minutes, and it is only due to the covalent bond that it is able to have 24-hour coverage that sees any benefit.
Interestingly, we are not sure whether or not both drugs have certain advantages over the other. Both have less EGFR inhibition than ibrutinib does, which I believe affords a benefit in terms of diminished risk of diarrhea, rash, and some other adverse events.
With regard to efficacy, I do wonder if there might be differences between acalabrutinib, ibrutinib, and BGB-3111 depending upon the tumor types. There’s some preliminary evidence for BGB-3111 in Waldenstrom macroglobulinemia that looks quite impressive. It would be interesting to see if these data are continued out by subsequent clinical trials. It’s important to keep in mind that the algorithm always needs to be tailored to the one that will show the highest efficacy and tolerability for the patient. Ibrutinib is my first-line choice for most patients who need therapy for CLL. As I mentioned, some patients have reasons that ibrutinib might be less optimal for them, so then those are people who I look to either obinutuzumab or venetoclax for treatment.
Otherwise, I typically use ibrutinib as my frontline therapy since it has excellent tolerability and efficacy. When patients progress on ibrutinib, I then utilize venetoclax and obinutuzumab. SNS-062 I consider to be a third generation BTK inhibitor. SNS-062 is an interesting BTK inhibitor because unlike the others, it’s reversible, which means it no longer requires cysteine 481 that BGB-3111, acalabrutinib, and ibrutinib all require. As a result, since most of the CLL progression that occurs on ibrutinib is related to a mutation, ibrutinib is no longer able to bind. In essence, it makes ibrutinib a reversible inhibitor. The enzyme action only has inhibition for about 4 to 6 hours.
By having a reversible inhibitor that doesn’t require that amino acid residue, we would be able to use BTK inhibition, which I do believe is our most effective means for controlling CLL, even after they develop resistance to ibrutinib.What I think is important is trying to identify those patients who are not going to be able to enjoy long-term remissions and treat them differently.
The question becomes, if we intervene a bit earlier, could we change the outcome of their disease course? If we were to use combination therapy or other therapies, like SNS-062, we might be able to have those patients enjoy long-term disease remissions.