The Role of Combination Venetoclax and BTKi Therapy for Firstline Treatment of CLL
Ricardo Parrondo, MD, discusses the potential of combining BTK and BCL2 inhibitors in chronic lymphocytic leukemia treatment, emphasizing their synergistic effect and cautioning against use in frail patients or those with cardiovascular comorbidities, while Pooja Advani, MBBS, MD, stresses the importance of medical history and risk stratification, especially regarding cardiovascular adverse effects.
Asher A. Chanan-Khan, MD, MBBS: Dr Parrondo, initially in your summary of the therapeutic approaches, you very nicely mentioned the second big beast we have in terms of fighting the disease is the BCL2 inhibitor. What are your thoughts on combining 2 big guns in terms of BTK [Bruton tyrosine kinase] and BCL inhibitors, and what data exists that directs that thought process for you? Could you highlight some of that?
Ricardo Parrondo, MD: Yes, absolutely. There is a rationale to combine a BCL2 inhibitor and a BTK inhibitor [BTKi]. They work synergistically to eradicate the CLL [chronic lymphocytic leukemia] cells by eliminating [both] dividing and resting CLL cells. The BTKi inhibits tumor cell proliferation, and they also mobilize leukemic cells from protective lymphoid niches to enhance killing with BCL2 inhibitors. We have laboratory data that BTKi increases the sensitivity of CLL cells to BCL2 inhibition. Given that, naturally you would want to combine these 2 therapies to eradicate as many CLL cells as possible to achieve deep responses. In terms of when I would consider using a BTKi plus a BCL2 inhibitor in the frontline setting, it would have to be a young, fit patient without extensive cardiovascular disease and who desires a time-limited all-oral therapy and does not have p53 mutation or deletion 17p. We have data from the phase 3 GLOW study [NCT03462719], which included frail patients with a CRIS [Cochin Risk Index Score] of 6 or greater and a creatinine clearance of less than 70. They were treated with 3 cycles of ibrutinib, followed by venetoclax plus ibrutinib for 12 cycles. However, there were about 7% treatment-emergent deaths in the ibrutinib/venetoclax arm, including 4 cardiac or sudden cardiac deaths that occurred in the ibrutinib and venetoclax arm. All of those patients were very frail with a CRIS score of 10 or greater and an ECOG performance status of 2. They all had a history of hypertension, cardiovascular disease, and diabetes. So I don’t think this doublet with ibrutinib at least plus venetoclax is the right choice for patients who are very frail or have extensive cardiovascular comorbidities. But there is emerging data combining venetoclax with a second-generation BTKi. I'm looking forward to seeing that data and the toxicity profile, and if it will be better. We also have data from the phase 2 CAPTIVATE trial [NCT02910583], which was a fixed duration of ibrutinib plus venetoclax and frontline CLL. The reason why I wouldn't use this doublet in patients with p53 mutated CLL is because the outcomes were inferior in that patient population. From the CAPTIVATE trial, the 4-year PFS [progression-free survival] was 79%, but in the TP53 mutated patients it was 63%. So we’ll see the upcoming data from the MAJIC trial [NCT00002615] of acalabrutinib plus venetoclax. What I’m most looking forward to seeing is the data from the arm of the SEQUOIA trial [NCT03336333], which was zanubrutinib plus venetoclax in patients with deletion 17p. From the SEQUOIA trial, we will have a direct head-to-head comparison of a single-agent BTKi, single-agent zanubrutinib, which is arm C of SEQUOIA, and continuous zanubrutinib in patients with deletion 17p vs the time-limited doublet of the zanubrutinib plus venetoclax in arm D.
Asher A. Chanan-Khan, MD, MBBS: Absolutely. I enjoyed looking at the schema and design of the trial because you’re right, this is one particular trial where they tried to address very nicely the single agent as you said, indefinitely. I have a question, somebody coming in with a high-risk disease with 17p, what do you do? Should you give a single agent because there is a ton of data on BTKi as a single agent being ineffective, or should you give them a combination for a small period of time and then leave them alone? And the reason I say, I think, leave them alone is important…because with a continuous exposure to BTKi, we have learned in the past [that] a resistance induction to BTK happens. And when that happens, I have had patients who are BTKi resistant, and I just could not take care of them in terms of putting them back into remission. And that was a major concern. Do you have any comments that you would like to make, Pooja [Advani], on Dr Parrondo’s comments? When the votes were given, there was, at least in 1 trial, a higher cardiotoxicity. Is that a concern on your end? Would you recommend, in your expertise, doing BCL2 plus BTKi? In that initial model that you suggested to the community when we are doing these 2 big guns together, should we be paying attention to that model system more so that an inadvertent effect does not happen? We are trying to enhance response, but in the CAPTIVE trial, as Dr Parrondo mentioned, it showed an interesting twist.
Pooja Advani, MD, MBBS: Absolutely. I think that it would be even more important to gather the medical history and think about risk stratification for these patients. I think in the data that Dr Parrondo mentioned, it appears that the vast majority of these events, particularly sudden cardiac death, etc, were more attributable to the first-generation BTKi, ibrutinib. And I think that the upcoming data will be able to help tease out who contributed to this effect. When you look at venetoclax, it can cause edema. But when we look at the risk of myocardial infarction and hypertension, it is much less compared to a single-agent BTKi. So I think all of these factors are important. But, thinking from a clinical trial perspective, I would be really excited to see the second-generation BTK inhibitors and BCL2 data, not only from an efficacy perspective but also from a cardiovascular adverse effect profile perspective.
