Expert Highlights New Era of Treatment for Relapsed MCL

Michael Wang, MD

Michael Wang, MD

Although 15 years ago, the only treatment option for patients with relapsed mantle cell lymphoma (MCL) was chemotherapy, 3 drugs are now approved by the FDA and several other promising agents are making their way down the pike.

Ibrutinib (Imbruvica) was approved by the FDA in 2013 for the treatment of patients with MCL following at least 1 prior therapy. Shortly after the approval of ibrutinib, the FDA approved lenalidomide (Revlimid), followed most recently by acalabrutinib (Calquence) in October 2017. The approvals of lenalidomide and acalabrutinib came based on findings from clinical trials led by Michael Wang, MD, a professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center.

Currently, venetoclax (Venclexta) is being investigated in this patient population as well. This agent is appealing in the treatment landscape because it has so far shown better responses than chemotherapy as an oral pill. A phase III clinical trial is currently evaluating venetoclax in combination with ibrutinib versus placebo. The findings from this trial will support the approval of this agent, Wang said.

CAR T cells are also showing promise for patients with MCL in a multicenter phase II trial in the US with several European sites. The trial is ongoing, and data have not yet been published.

In an interview withTargeted Oncologyduring the 2018 SOHO Annual Meeting,Wang discussed the latest options for patients with relapsed MCL, while also addressing some of the challenges with these agents.

TARGETED ONCOLOGY:Can you give an overview of your presentation on the management of relapsed MCL?

Wang:Managing lymphoma is one of the most exciting areas of clinical research and basic research in the field of oncology. I am a lymphoma doctor, so I may be a little biased, but in my further opinion, I think MCL is one of the most important and most exciting areas in the field of lymphoma. There is no worse challenge than to treat a patient with relapsed MCL, a disease that is rare, but not curable. Although it is rare, it affects thousands of lives in the US, and not only the lives, but the quality of those lives, so it is a very important topic.

I reviewed the FDA approvals for this disease. As you know, 15 years ago when I was a junior faculty fresh out [of] my fellowship, in the clinic for relapsed MCL, there was chemotherapy on the left and chemotherapy on the right. Then, there is suffering, alopecia, blood count, thrombocytopenia, neutropenia, anemia, neutropenic fevers, bleeding, catheter infections, you name it. Not only is the therapy tough and harsh on the patient, but they have many complications, and some of these complications could be fatal.

Now, we are in a new era to treat this disease. For example, in my presentation I listed several exciting therapies approved by the FDA. The first approval was lenalidomide. The second approval, which I think actually brings in the new era of chemotherapy for relapsed MCL, was the small molecule agent ibrutinib. This was approved based on the international study led by myself in November of 2013.

About 4 years later, the second generation acalabrutinib was approved based on another study that I led with my colleagues. It was approved in October 2017. That’s why I’m saying the relapsed setting in MCL is very exciting, because every few years we have new drugs coming up to affect the patient lives and the quality of their lives.

In addition to that, I also listed a new component called venetoclax. It is not FDA approved yet, but it is coming, [as are] so many more therapies. The most exciting therapy I see in the relapse setting of MCL, especially for those who haveP53mutations, or blastoid or pleomorphic disease, the best therapy would be the CAR T-cell therapy. We are moving rapidly along with targeted therapies, but we are ushering in a cell therapy era.

Cell therapy in the direction of CD19 is very effective. I cannot disclose [data from] the trial because it is not finished yet, but I cannot hide my excitement.

TARGETED ONCOLOGY:What results have been seen with venetoclax so far?

Wang:Although it’s not approved, in phase I clinical trials with B-cell lymphomas, including follicular lymphoma, CLL, and marginal zone lymphoma, MCL was the most effectively treated disease by venetoclax. Single-agent efficacy is 75%. You swallow the pill, you get the responses better than chemotherapy combined delivered in the hospital setting. How exciting is that? Venetoclax will be the third medication that is promising. Although it was not for approval, an approval study is coming along. I mentioned the phase III clinical trial with ibrutinib plus venetoclax or placebo, a phase III clinical trial that will deliver the FDA approval data.

TARGETED ONCOLOGY:What advice do you have for oncologists treating patients with relapsed/refractory disease?

Wang:Although the oral, targeted therapies are easy to give with dramatically less side effects, it’s not that you can prescribe a pill for the patient to go home and take. There’s more than that and there are complications. For example, BTK inhibitors including ibrutinib and acalabrutinib have a mild degree of atrial fibrillation, infection, bleeding, rash, and muscle cramps. All those need special skills and knowledge to recognize and manage them.

TARGETED ONCOLOGY:How do you manage the toxicities associated with these agents?

Wang:For example, one of the dreaded side effects would be atrial fibrillation caused by ibrutinib. The heart is the most dynamic organ in our body. It beats 80 times per minute and pumps a lot of blood out so the most dynamic organ in the body may be the most affected by novel therapies. Anything toxic to the heart is very serious because you only need a few seconds of the heart not working well for the person to pass out or go on to die. Anything tied to the heart is very sensitive. Atrial fibrillation is a severe complication related to BTK inhibitors, occurring in anywhere from 4% to 10%, according to clinical trials. We need to know how to manage that.

I manage atrial fibrillation very aggressively. When there is a new occurrence, I stop the drug immediately and send the patient to cardiology. Although cardiology could convert the atrial fibrillation to normal sound by medicine, such as amiodarone, or by cardioversions, I advocate for nodal ablation by a cardiac electrophysiologist. This is a procedure that has a much less recurrence rate if you go on to receive ibrutinib.

Oncology is moving very fast, and this puts a lot of pressure on the other field. For example, cardiology needs to recognize, they need to come out with a more effective way to deal with it in a timely manner. There’s [something] called onco-cardiology. Of course, related to cardio, there is also infectious diseases, complications such as fungal infections, and other potential side effects that need everybody to participate, multidisciplinary, to address this issue quickly.

TARGETED ONCOLOGY:What is the take home message you want oncologists to leave with?

Wang:The take home message is that MD Anderson has a very good MCL program. We have a lot of clinical trials dedicated to MCL, so please consider referring a patient to us to participate in these very exciting trials in both targeted therapies and cell therapies.