Frontline Therapy for CLL: Emerging Agents and Approaches

Anna Schuh, MD, PhD: There’s a need for development of novel agents in CLL [chronic lymphocytic leukemia]. CLL still remains largely an incurable disease. The results from cellular therapy, in particular CAR [chimeric antigen receptor] T cells, have been quite disappointing. CLL leads to T-cell exhaustion, and autologous T cells aren’t an option. Patients with CLL also have a higher risk of infection. They have secondary immune deficiencies, and there are other reasons why cellular therapy might not be the ideal treatment approach.

Is there a need? There is. As I said, CLL remains incurable. A lot of patients with CLL, after coming out of chemoimmunotherapy, go onto ibrutinib and relapse or acalabrutinib, and then they go onto venetoclax or vice versa. These patients who are going through the sequencing pathways aren’t cured, and they’ll eventually relapse and there won’t be any therapy for them unless they find something else. The number of patients where there’s an unmet clinical need is decreasing but still quite significant. [We don’t know] if that number will go down over time as we move the targeted agents into the front line. I suspect it will go down, but it will never go down to 0. There will always be patients, in particular patients with TP53 abnormalities, who will relapse, and they’ll need other therapy.

Apart from cellular therapy, I haven’t forgotten about PI3-kinase inhibitors. They haven’t been studied in the most careful way, unfortunately, because of the adverse-effect profile and the unfavorable adverse-effect profile, the high rate of treatment discontinuations. But this is a class of drugs that we shouldn’t forget about. They’re of course the third-generation BTK [Bruton tyrosine kinase] inhibitors that show promising results in the early phase studies. This needs to be verified in the frontline setting and in randomized studies. If the good results hold up, then these drugs might move into the frontline setting. They won’t be the type of drugs that will help us with multiple-relapsed patients, because they will have already reached resistance at that point. They’d cure because they don’t give you MRD [minimal residual disease] negativity. We’re then on to bispecific antibodies, which might be a promising agent, but they’re also very early on in the development pathways. There’s definitely a need. How many impressive results have we had in the relapsed setting? There’s room for improvement.

John C. Byrd, MD: Outside with the BTK inhibitors, zanubrutinib is the last to arrive of completed phase 3 studies and large phase 2 studies in high-risk patients, such as the 17p group. And the SEQUOIA study with zanubrutinib with 17p disease shows control of disease. I expect that it looks similar to what’s been seen with acalabrutinib and ibrutinib, which is encouraging. But as I look to the future, the most exciting thing I see coming down the pike are 3 classes of drugs. The first, the reversible BTK inhibitors, and with those LOXO-305 and ARQ-537, are the furthest are along, but there are several others trailing. Because those offer the opportunity, BTK has an important target in the CLL patients progressed, those are opportunity to hit that target again. Some people are having durable remissions on these reversible BTK inhibitors. I’m excited about the immune modulating agents that derive from first-generation cereblon degraders, such as lenalidomide, which had problems in CLL, but there are new ones coming. We’re obviously excited about those. I’ve been a long proponent of CDK inhibitors, and there’s a lot of synergy with those as well as venetoclax, and we’ll see where those emerge.

Finally, many of the cellular therapies, particularly some of the CAR T cells that offer the opportunity, may not cure the disease but will kick the can down the street a lon ways for patients who have highly resistant disease.

Paolo Ghia, MD, PhD: At the moment, we have 2 strong pillars of the treatment in CLL. On 1 side, the BTK inhibition; on the other side, BCL2 inhibition. The most promising treatment in the future is a combination of the 2 treatments. These have been explored in the CAPTIVATE study, which is a phase 2 study that includes 2 distinct cohorts, which aren’t randomized. One is, of course, an MRD [minimal residual disease]–treatment cohort, in which patients were treated with 3 cycles of ibrutinib followed by 12 cycles of the combination between ibrutinib and venetoclax. At the end of the treatment, patients were randomized based on the MRD levels. Those with undetectable MRD were randomized to stop the treatments, to the placebo arm, or to continuous ibrutinib. But those with unconfirmed undetectable MRD, so still with disease, were randomized to ibrutinib continuous therapy or a consolidation with ibrutinib plus venetoclax.

On the other side, we had a fixed-duration cohort in which all patients were treated with 3 cycles of ibrutinib and 12 cycles of combination between ibrutinib and venetoclax. Every patient was bound to stop the treatment at the completion of treatment. What we learned from this is that the combination is effective in achieving deep responses and also undetectable MRD in a high proportion of patients, which is typically around 3 of 4 in the briefer blood and 2 of 3 in the bone marrow. In the MRD cohort, we explore the possibility to stop only the patient with undetectable MRD. Indeed, the 1-year disease-free survival confirmed that patients under placebo had a similar or a nonsignificant different disease-free survival at 1 year after completion of the treatment, suggesting that it’s safe in that particular progression to stop the disease.

In the fixed-duration cohort, we learn that all patients, regardless of whether they achieved undetectable MRD, may benefit from completion, from stopping the treatment. Indeed, all patients discontinued at the end of 12 cycles of combination. At 1 year of follow-up, more than 95% of all patients regardless of the level of MRD still responded. This is quite impressive and quite interesting, suggesting that maybe with this protein combination, we’re somehow changing the natural history of the disease and maybe putting a brake on the proliferating capacity of the cells to grow back and relapse. Of course, we need the longer follow-up to be reassured about this. But if the majority of patients remain at least 1 year after therapy, we can also envision the possibility that in case they relapse, we can restart the same combination in mostly all patients.

John C. Byrd, MD: The role for minimal residual disease in CLL depends upon the strategy of therapy. If the strategy of therapy is getting combined therapy to stop treatment, then attaining a minimal residual disease status will for sure be predictive of how long your disease is going to stay in remission. That’s particularly true with venetoclax-containing regimens or venetoclax that you combine with BTK inhibitor or CD20 antibodies. There’s a group of patients who get BTK inhibitors that have been on them for 4 or 5 years. They get down to a small amount of disease that you can detect, but for 1 reason or another, they go off treatment and just stay in remission. When I say they stay in remission, you can still detect the disease, but it doesn’t expand. How we look at this is going to depend upon the therapy. Those patients who stay in remission, and their small amount of disease doesn’t progress, are interesting patients who we can learn from.

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