Evolving Knowledge of BTK Inhibitors Continues to Shape Treatment Landscape in CLL

Jonathon B. Cohen MD, MS

Although BTK inhibitors have become a staple in the treatment of patients with chronic lymphocytic leukemia (CLL), new data regarding ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) are still emerging, according to Jonathon B. Cohen MD, MS, adding that the first head-to-head prospective trials featuring these BTK inhibitors will continue to shape how they are utilized.

“We’re learning more about BTK inhibitors, which have been around for a long time, their long-term toxicities, and long-term effectiveness. I would encourage colleagues to continue to follow the data because it’s a rapidly evolving field. Within a couple of years, many currently accepted truths will likely be found to be different,” Cohen said in an interview with OncLive® following a State of the Science Summit™ on leukemia and lymphoma.

In the interview, Cohen, who chaired the event, discussed the management of CLL with BTK inhibitors, updates in the treatment of acute myeloid leukemia (AML), and how CAR T-cell therapy could improve patient outcomes in earlier lines of treatment in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Cohen is an associate professor in the Department of Hematology and Medical Oncology; a co-director of the Lymphoma Program; a chair of the Data and Safety Monitoring Committee at Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive®: Please provide an overview of BTK inhibitor management in CLL, and some of the main points that were discussed in your presentation.

Cohen: I presented a review of the current use of BTK inhibitors in CLL. The management of this disease has been revolutionized by the inclusion of these oral agents. In the past, patients received chemotherapy primarily, but now they’re able to be treated with oral therapies that they can take at home and are well tolerated. Now that BTK inhibitors [have been in clinical use for several years], we are getting more data about the best way to utilize them in patients with CLL.

I discussed updated follow-up for some of our initial trials, including the phase 3 RESONATE-2 trial [NCT01722487], which compared ibrutinib [Imbruvica] with chlorambucil. We’ve known for many years now that ibrutinib was a better therapy than chlorambucil. [However,] 8 years into follow-up, most patients still have not progressed. This is a significant improvement in outcomes for patients with CLL, especially this group of patients, where more traditional chemotherapy options were not available.

In addition, I discussed some of the newer BTK inhibitors, acalabrutinib and zanubrutinib. Acalabrutinib is approved for CLL, and we recently saw an update of the phase 3 ELEVATE TN trial [NCT02475681], which continues to show a significant improvement in outcomes for patients who received acalabrutinib as a part of their frontline regimen vs a chlorambucil-based regimen.

We also discussed one of the first trials that compared 2 BTK inhibitors [head-to-head]. The phase 3 ALPINE trial [NCT03734016] compared zanubrutinib with ibrutinib in patients with CLL, and it showed that zanubrutinib appears to be better tolerated. Although [zanubrutinib] has a higher rate of neutropenia, it has a decreased frequency of other common toxicities seen with BTK inhibitors. For the first time, we also saw that there may be an improvement in outcomes in patients who received zanubrutinib vs ibrutinib.

Finally, we are beginning to see emerging data regarding BTK inhibitor–containing combinations. In my mind, the jury is still out regarding whether a combination is better than receiving 2 therapies in sequence. However, the data that are coming out are very encouraging.

Overall, it was an interesting session highlighting some of the newer data. Although BTK inhibitors have been around for a long time, each year we learn more about how effective they are, how well tolerated they are, and how best to utilize them in patients with CLL.

What effects do comorbidities have on survival in patients with CLL?

CLL typically presents in patients in their 60s and 70s. We often are taking care of patients that are middle aged to elderly. As a result, it’s not uncommon for patients to have other comorbidities. Many of my patients have diabetes, heart disease, lung disease, or some other comorbidities that exist prior to them developing CLL. When these patients need therapy, it’s important to consider these comorbidities when making a treatment selection.

In the past, when we had only chemotherapy, this was particularly problematic because many chemotherapy regimens couldn’t be safely given in patients with multiple comorbidities. In the present era, where we have BTK inhibitors and venetoclax [Venclexta], it is often possible to safely administer these oral therapies to patients, including those who have comorbidities. Although they may require additional supportive care or dose adjustments, [treatment with BTK inhibitors] is more feasible. As a result, the prognosis for patients [with comorbidities] is much better.

It’s important that patients communicate with their doctors about what’s going on with their overall health, what other medications they’re taking, or what supplements they may be taking. [These factors] may play into how they tolerate the [BTK inhibitors] and if we need to make any adjustments to the dose.

What adverse effects (AEs) associated with BTK inhibitors are important to consider? How can they be managed?

BTK inhibitors, like any anti-cancer therapy or medication, can have AEs. I always remind my patients that although this isn’t chemotherapy, they still need to be monitored closely and be considerate of AEs that may develop.

With BTK inhibitors, the most significant AEs include a higher incidence of bleeding. This is particularly important for patients that either are on blood thinners already, or those who may need to have an operation or procedure. In addition, there is an increased risk of atrial fibrillation. While this is often not a life-threatening arrhythmia, it can be problematic for patients. This is something that needs to be monitored closely.

Some other less severe, yet potentially problematic, toxicities can include diarrhea, joint aches, headaches, and hypertension. Individual agents may have more specific toxicities. For example, ibrutinib may be associated with an increased risk of neutropenia, whereas acalabrutinib is associated with headaches. It is important that patients recognize that they are susceptible to developing AEs and monitor for that.

Anthony Hunter, MD, of Winship Cancer Institute of Emory University, discussed updates in the treatment of AML. Historically, what has the AML treatment landscape looked like and how has it evolved over time?

AML has been a challenging disease to treat for many years. It presents very aggressively, and patients often have life-threatening complications early on, especially while the diagnosis is being made and during the initiation of therapy.

In the past, once a diagnosis of AML was made, the primary therapy was chemotherapy, usually over [the course] of a week, that was highly toxic and generally effective at inducing a remission. However, the treatment did not typically result in long-term remission, and patients with AML had a high risk of relapse.

As a result, over the past several decades, [autologous] stem cell transplantation [ASCT] has been incorporated into the management of patients with AML that have moderate- to high-risk features. For many patients, the optimal approach is chemotherapy followed by ASCT.

In recent years, we’ve started to identify molecular markers that predict response to therapy and that may predict responses to specific treatments. Dr Hunter spoke to some of the newer therapies that have come along and ways that we’re able to personalize therapies more accurately for patients with AML. It’s been amazing to see the changes in management over even just a couple of years.

Victor M. Orellana-Noia, MD, of Winship Cancer Institute of Emory University, discussed treatment in DLBCL. Could you speak to the role of CAR T-cell therapy in this population?

CAR T-cell therapy is an immunotherapy, whereby we engineer a patient’s own T cells to attack their cancer. This modality is currently approved in [several] indications in hematology, including DLBCL, where we currently have 3 approved products.

At this time, CAR T-cell therapy is only approved in patients [with DLBCL] with relapsed disease. Historically, this [comprised] patients who had progressed after 2 different courses of therapy or who had undergone ASCT, but their disease still came back. However, at the 2021 ASH Annual Meeting and Exposition, several studies suggested that patients with early relapsing DLBCL, who are at the highest risk for continued progression and early mortality, may benefit from moving straight to CAR T-cell therapy as opposed to ASCT. For this reason, those patients are now currently considered for CAR T-cell therapy, even at the time of second-line therapy. This has changed the way that we think about treating patients with DLBCL.

Having said this, it’s important to recognize that CAR T-cell therapy has a long-term benefit in approximately 40% of patients. Although that is a higher percentage than what we have seen [with other treatments] in the past, it still highlights the fact that there is more work to be done to fine tune the use of CAR T-cell therapy in patients with DLBCL.

Jason Romancik, MD, of Winship Cancer Institute of Emory University, dove deeper into CAR T-cell therapy. What may optimal sequencing look like with standard-of-care agents and CAR T-cell therapy in MCL?

MCL is a disease where CAR T-cell therapy has changed the way we think about the management of patients, especially in the relapsed setting. There is research being done and a discussion [is ongoing] within the community about how best to manage patients that have relapsed MCL. In this current era, most patients will receive an aggressive or less intensive chemotherapy-based induction regimen, and most patients will go into remission. Some patients will have consolidation with ASCT, and others may go straight to rituximab [Rituxan] maintenance.

However, most patients with MCL will go into remission and stay in remission for several years. Unfortunately, most folks will ultimately go on to relapse. Historically we have used BTK inhibitors to treat those patients at the time of first relapse, which is typically associated with a remission duration of about 2 years. However, patients who progress after receiving a BTK inhibitor have a shortened overall survival [OS], and their disease is often very difficult to treat.

In the current era, CAR T-cell therapy is approved and is available for patients [with MCL] who have progressed after BTK inhibitors. One of the big concerns focuses on patients who are on BTK inhibitors and if they are likely to have disease progression or aggressive disease. If so, perhaps incorporating CAR T-cell therapy earlier during the treatment may be more beneficial.

This is one of the discussions points that Dr Romancik discussed in his talk on how best to sequence therapy. I still often use the BTK inhibitor first before moving to CAR T-cell therapy, given the fact that most patients will respond, and [BTK inhibitors are] much easier on patients [in terms of AEs]. However, this is still an area of research and remains an area of clinical interest.

Andres Chang, MD, PhD, of Winship Cancer Institute of Emory University, discussed COVID-19 vaccine responses and prevention of severe disease in patients with hematologic malignancies. What has been seen with antibody binding and virus neutralization levels in patients with non-Hodgkin lymphoma (NHL)?

Patients with NHL, especially those that have received rituximab or other monoclonal antibodies targeting CD20, can have an inferior response to the COVID-19 vaccination. Dr Chang and his team have done a number of studies to demonstrate this and to show that those patients who received a CD20-directed monoclonal antibody within the past year are at the highest risk for an inferior response. Because of this, I’ve been recommending that my patients who are receiving rituximab also receive Evusheld [tixagevimab and cilgavimab], which doesn't rely on a vaccine response in order to prevent severe COVID infections.

It still is somewhat unclear what effect the development of antibodies and the detected vaccine response have on a patient's response to an actual COVID infection. What I've told my patients is that although we may not detect a robust antibody response to the vaccine, we still believe that there's likely some protection offered by the vaccine in the setting where a patient is exposed to or contracts COVID. Our sense is this still does provide protection against severe disease.

Those patients with lymphoma, especially those that have been on treatment, are still at an increased risk for complications and increased risk for severe disease. However, I still would strongly recommend that they receive their COVID vaccinations and appropriate boosters. This is even if the antibody levels that are identified are suboptimal, this still provides some protection as opposed to no protection.

Is there any ongoing research at your institution that you would like to highlight?

At the Winship Cancer Institute of Emory University, we are very fortunate to have several ongoing clinical trials for different types of lymphoma and [hematologic malignancies]. For example, we have studies for untreated and low-grade lymphomas, relapsed aggressive lymphomas, and so forth. I would encourage anybody with a [patient with a] lymphoma diagnosis who's interested learning more about clinical trials and some of the newer therapies to seek us out.

In addition, the Winship Cancer Institute has a long track record of involvement nationally with large outcome-based projects. We have 2 large studies, including one for untreated or newly diagnosed patients with lymphoma, and another for patients with relapsed disease, where we are collecting data on an ongoing basis to try to better understand prognostic markers and outcomes for those patients.

Finally, we have colleagues that are developing a translational program where we are using findings from the clinic to inform laboratory research and using some of the laboratory findings to try to improve clinical care. For example, Dr Chang's work in COVID-19 is a perfect example of how this is happening, and his findings are impacting the way I counsel my patients today.