Understanding Recent Developments in Mantle Cell Lymphoma

Jia Ruan, MD, PhD

Advances have been made in mantle cell lymphoma (MCL) space due to the development and availability of many effective biological agents, including ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and Bruton tyrosine kinase (BTK) inhibitors.

At the Tenth Annual Meeting of the Society of Hematologic Oncology (SOHO), Jia Ruan, MD, PhD, highlighted the current MCL landscape and the value of chemotherapy-free regimens.

Ruan, associate professor of Clinical Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine also discussed various phase 2 and 3 clinical trials evaluating regimens of ibrutinib in combination with rituximab (Rituxan), or zanubrutinib in combination with rituximab for patients with MCL.

Further studies will continue evaluating novel therapies and combinations for patients with MCL who have mutations, such as a tp53 mutation. More research regarding novel biomarkers, the potential role of bispecific antibodies will continue to shape the treatment landscape for MCL.

In an interview with Targeted Oncology^TM, Ruan, discussed the updates in the MCL space, including understanding molecular pathogenesis and risk stratification for this patient population.

Targeted Oncology: Can you give an overview of the available treatment options for mantle cell lymphoma? How have options evolved over the past few years?

Ruan: In the past several years, significant advances have been made in mantle cell lymphoma, primarily because of the availability of many effective biological agents. They were initially investigated in the relapse setting, but now, we're trying to move them into the frontline initial therapy setting. The most important class of those agents are Bruton's tyrosine kinase inhibitors or BTK inhibitors.

It started with the first generation ibrutinib, and that was approved almost 10 years ago in 2013. Subsequently, we now have second generation BTK inhibitors, and they are represented by acalabrutinib and zanubrutinib. We have maybe 3-5 years of experience of using those BTK inhibitors. The BTK inhibitors are by far the most effective single agent treatment for mantle cell lymphoma. In the relapse setting, we expect overall response rates in the range of 60%-80%. Complete remission rate is also achievable, especially for the second generation BTK inhibitors. With acalabrutinib and zanubrutinib, we're looking at 30%-40% CR rates, so that is quite remarkable. Those are agents that are effective and easy to administer. They come in oral form and patients can take them at ease and convenience at home. They're very suitable for chronic use and their adverse event profiles are quite tolerable.

When we do start prescribing BTK inhibitors to patients, we do discuss adverse event profiles, specifically, those that are specific for this class of agents such as their effect on blood pressures, their effect on cardiac rhythm, atrial fibrillation, their effect on gastrointestinal, and their effect on platelets, bruising, and bleeding. It has transformed the care of mantle cell lymphoma.

What has been discovered recently to help better understand molecular pathogenesis?

In several different levels, our understanding of molecular biology has really helped in terms of designing rational approaches. One of them is to understand that not all mantle cell lymphomas are the same as they have different subtypes. For example, there's this classic mantle cell lymphoma, which is predominant about 70%. They present with no disease, they have a proliferation signature, and they have a lot of genomic characteristics such as instabilities. We also know there's a non-nodal form of mantle cell lymphoma which represents about 30% of mantle cell lymphomas. They tend to be more indolent, they have more peripheral blood and splenic involvement, but not as much as nodal involvement. We do know that they tend to have a lower proliferation index and they also have less of those genomic instability. They have more simple karyotypes when we do pathology evaluation on those cases. That's 1 aspect which are different forms of mantle cell lymphoma. They have a slightly different pace of growth, and we can watch and wait a little bit for a non-nodal form of mantle cell lymphoma as opposed to coming up with a treatment plan more urgently for a more aggressive form of mantle cell lymphoma.

The other aspect of knowing biology is there are recurrent genetic mutations called driver mutations that essentially have risk that determine the aggressiveness or risk category. We know that mutations such as tp53 tend to have a more aggressive clinical course and tend to be associated with blastoid mantle cell lymphoma, and more resistance to chemoimmunotherapy. Knowing those biological determinants of mantle cell lymphoma allows us to devise treatment strategies. For example, for patients with high risk tp53 mutations, we want to talk to them about if chemoimmunotherapy is optimized for them, can we consider a more novel treatment which may be more effective and with less adverse events, and perhaps we can improve the duration of response. We encourage those patients to participate in clinical trials with novel treatment combinations which may be more sensitive and overcome resistance coming from tp53 mutations

What updates can you give on risk stratification in this space?

Risk stratification is very important, and that's the evaluation that we do when we start initial management for patients with mantle cell lymphoma. Based on the risk stratification, we would come up with a plan on whether those patients can be easily watched and waited vs those patients who require treatment. Within those patients who may be requiring treatment, we try to figure out if they are a good candidate for conventional chemoimmunotherapy vs if they may benefit from addition of novel agents. With those risk stratifications or prognostic factors, we look at the mantle cell international prognostic index [MIPI]. It has 4 clinical parameters, including age, performance status, LDH, and white blood cell counts. It gives us a general assessment of the pace of this condition, in a particular patient. MIPI score is important.

For risk stratification, we also look at Ki-67, which is the proliferation index. We also look at their genetic mutation profiles, and collectively for those patients with high MIPI scores or high Ki-67, and particularly with high-risk mutation profiles, we would consider a treatment plan for those that would overcome treatment resistance.

What options excite you most for the future of this space?

There's a lot of the excitement that's going on, especially in the frontline setting, trying to figure out if chemoimmunotherapy is the most optimal option vs whether we introduce novel agents into the frontline setting. Within that, we would like to find out if the combination of chemoimmunotherapy plus novel agents would improve response rates and survival outcomes vs chemotherapy-free, novel agent combinations. Can they be as good or even better in terms of efficacy and less side effects profile? All of those are being looked at in a number of ongoing randomized clinical trials. Some are comparing chemoimmunotherapy plus novel agents vs the standard chemoimmunotherapy examples of that, including the triangle studies, the ECOG 4181 studies [NCT04115631].

We know that the SHINE study [NCT01776840] has recently been reported as a similar study that's conducted by the combination of ibrutinib plus bendamustine and rituximab and is maturing. The other category would be a direct comparison of chemoimmunotherapy vs a novel agent combination. I think that would be very exciting to see in certain selected patients that we can do away with chemotherapy therapy altogether. There are 2 very important randomized trials ongoing to address this question. One of them is called the ENRICH study [NCT01880567] to compare the ibrutinib plus rituximab combination vs chemotherapy. The second study is looking at zanubrutinib plus rituximab, the next generation BTK inhibitor, and comparing that with bendamustine plus rituximab, which is a form of chemoimmunotherapy. I'm looking forward to knowing more about the study outcomes of those clinical trials.

What should oncologists know about the current MCL space and the current unmet needs?

We're getting more comprehensive reviews of clinical biomarkers and prognostic indexes. We know more about the biology of mantle cell lymphoma and secondly, we are getting a more in-depth analysis of ongoing and also mature data from frontline clinical studies, as well as relapsed/refractory settings. I think there are more options out there and I think this will be informative to recommend for patients to consider participation in clinical trials. Also, it's a more in-depth analysis of published clinical trials and how we can apply the results from those reports in order to serve our patients in a more optimized fashion.

The unmet needs of the mantle cell lymphoma continue to be, how can we move new agents in a rational, designed fashion to the frontline settings, especially for those high-risk patients who have tp53 mutations and are resistant to chemotherapy. What are the best combinations out there? I think those would require more clinical trials, combinations with chimeric antigen receptor T cells with bispecific antibodies, and maybe in combination with small molecule inhibitors.