CLL Expert Explains Latest Treatment Developments in the Field

Neil E. Kay, MD

Novel agents for patients with chronic lymphocytic leukemia (CLL)—including ibrutinib (Imbruvica), venetoclax (Venclexta), idelalisib (Zydelig), and acalabrutinib (Calquence)—have revolutionized the treatment landscape, according to Neil E. Kay, MD; however, the optimal sequence of these therapies remains unclear.

OncLive: Please discuss the evolution of personalized medicine and sequencing in CLL.

Can you discuss the role of molecular testing for determining the sequence of treatments?

What are some challenges facing these relapsed patients?

In an interview with OncLive, Kay, a professor of medicine at the Mayo Clinic, discussed the available options and sequencing challenges for patients with relapsed/refractory CLL, as well as next steps for advancing outcomes for this patient population.Kay: [There is a lot to discuss with] the sequencing of treatment options for relapsed/refractory CLL. Since there are so many options available for CLL, it is not as straightforward because we still do not have all the data we need to definitively say which agent would go in which order. That is a critical step. For patients with IGVH mutations who have relapsed and do not have a 17p deletion or p53 mutation, they could theoretically be treated with chemoimmunotherapy, such as FCR. The treatment is a reasonable choice for the rare few patients who are relapsed/refractory; however, they need to meet the criteria for not having those adverse prognostic factors. Based on prior clinical trials and prior drugs that were available, once a patient relapses after primary therapy, their responses were short lived. This causes mortality to be much closer [for them].

However, with newer drugs such as ibrutinib, idelalisib, rituximab, and venetoclax, which are all FDA approved for patients with relapsed/refractory CLL, there is much less emphasis on these prognostic factors being criteria that would prevent patients from receiving them. While it is important to know these parameters, it means less to a practitioner if they wanted to use ibrutinib or venetoclax for a patient even if they had an adverse prognostic factor.

However, these parameters still play a role. For example, if a patient relapsed and had 17p deletion as shown via fluorescence in situ hybridization (FISH), they would respond to these novel agents nicely—particularly ibrutinib, idelalisib, or rituximab. However, their responses would be less robust than if they did not have that defect.

Can you discuss emerging combination strategies?

To be specific, I believe the current data for patients receiving ibrutinib with 17p deletion is a progression-free survival (PFS) of around 26 months. Whereas, for the more favorable-risk groups, like 13q deletion or patients with no abnormalities, the PFS has not been reached. While this is an improvement over prior drugs, having that specific genetic defect would suggest that these patients will not respond for as long. There will always be a role for single-agent ibrutinib. The ability to tolerate 1 drug is always better than having to tolerate 2. For the individual who is older, such as in their late 70s or early 80s, being on ibrutinib for 4 or 5 years with a good response would be quite reasonable.

However, ibrutinib alone does not induce a high level of complete responses (CRs). If a patient has a CR, ibrutinib will not give them a minimal residual disease (MRD)-negative status. Therefore, combinations will be necessary if the goal is to get to a CR with MRD-negative status.

What is the role of acalabrutinib in this setting?

There are ongoing trials that are investigating those combinations with preliminary data that look promising. The combinations are encouraging. Acalabrutinib is the cousin of ibrutinib. It works in the same mechanism, but has less off-target effects compared with ibrutinib in terms of enzyme targets. The toxicity profile is likely to be less than it is for ibrutinib. To summarize, ibrutinib’s major issue has not been the response level, since over 90% of patients respond to ibrutinib, but the chronic low-grade toxicity, such as arthralgia, diarrhea, rash, hypertension, and the occurrence of fibrillation. [It will lead to] a significant number of patients to ultimately go off ibrutinib.

Could acalabrutinib ever replace ibrutinib?

What are some of the main takeaways that you would physicians to understand about personalized therapy in CLL?

However, as acalabrutinib continues to be developed, if in fact there is less chronicity of these lower-level toxicities, it will likely become a reasonable option for patients.If it has a toxicity profile that is consistently less than ibrutinib, it might. However, there are a lot of clinical trial data that are needed. There are so many patients who have been treated with ibrutinib either on or off clinical trials; there is a long road to go for acalabrutinib.There is a potential hierarchy for the big salvage therapies for patients with relapsed/refractory CLL. In my opinion, based on clinical trials, these are ibrutinib, venetoclax, idelalisib, rituximab, and also allogeneic bone marrow transplant.

There is no clear way to decide which order to give these to patients, but you can make wise decisions based on age, comorbidities, and what patients’ goals are. Regarding clinical trials, I am hoping that oncologists realize that these are reasonable choices, although bone marrow transplants might be the further down the road due to the morbidity and mortality associated with that approach. The other drugs can be chosen wisely based on the parameters I have reviewed.

It is important to note that in 2 years, the treatment landscape will be very different. There is so much activity ongoing with the novel agents and their combination studies.