'The Future is Promising' For The Treatment of a Subtype of Non-Hodgkin Lymphoma

Bruton tyrosine kinase (BTK) inhibitors have been a major focus of research for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL), and the recent Food and Drug Administration (FDA) approval of Brukinsa (zanubrutinib) may give patients another option with potentially fewer, more manageable side effects.

BTK, which plays a critical role in the development of B cells, is a clinically validated target in these patients. Previously, the FDA approved the BTK inhibitor Imbruvica (ibrutinib) for this patient population.

“(Imbruvica) has shown very good results; however, the side effect profile of (Imbruvica) results in a fraction of patients who discontinue due to intolerance, especially cardiovascular side effects,” said Dr. Preetesh Jain, an assistant professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center in Houston, in an interview with CURE®. “Atrial fibrillation (irregular heartbeat) is a major concern. Therefore, more selective BTK inhibitors with less chance of side effects are being investigated.”

Dr. Preetesh Jain

Data have shown promise for Brukinsa, especially regarding side effects.

“(Brukinsa) appears to have more benefit for patients with regard to less atrial fibrillation, hypertension (high blood pressure) and other cardiac effects,” Jain said. “(Brukinsa) is easier to take. It has (fewer) side effects, less dose-reduction probability and a good tolerability. The patients can stay on it for a longer time. ...
This means most patients can continue and maintain remission on (Brukinsa) without encountering major safety issues.”

Brukinsa provides patients with MCL a second-generation BTK inhibitor besides Calquence (acalabrutinib).

“(Brukinsa) does not have any (drug-drug interactions) like (Calquence) and, similar to (Calquence), demonstrates an improved safety profile compared to the first-generation medication (Imbruvica),” Dr. Tycel J. Phillips, an assistant professor of medicine at University of Michigan Rogel Cancer Center in Ann Arbor, told CURE®. “(Brukinsa) as well could potentially be given once daily in situations where patient compliance is of concern.”

Data from a phase 1/2 study published in Blood Advances this year demonstrated similar results in 32 patients with relapsed/refractory MCL treated with Brukinsa. After a median follow-up of 18.8 months, patients achieved an overall response rate of 84% and a complete response rate of 25%. The median progression-free survival (time when a patient’s disease does not worsen) was 21.1 months, with a median time to response (length of time it took a patient’s disease to respond to treatment) of 2.8 months.

“(These findings) continue to reenforce that the agent has an improved safety profile and tolerability compared to (Imbruvica),” Phillips said. “Efficacy-wise, the publication supports that (Brukinsa) maintains a high efficacy rate in all populations, given that the original data reported on a Chinese-only cohort of patients.”

In the original study, published in Clinical Cancer Research in 2020, researchers assessed the effects of Brukinsa in 86 Chinese patients with relapsed/refractory MCL. A 160-milligram, twice-daily dose resulted in an objective response rate (patients with tumor size reduction over a period of time) of 84% and a complete response rate (disappearance of all signs of cancer from treatment) of 68.6% after a median follow-up of 18.4 months.

“Given that the treatment of MCL is different in China compared to the U.S., Europe and Australia, this helps to ensure that the efficacy of the drug was not impacted by these differences,” Phillips said about comparing the original data with the newer data.

In the study published this year, the most common side effects of Brukinsa were bruising (37.5%), diarrhea (43.8%), constipation (31.3%) and upper respiratory tract infection (31.3%). At least one side effect considered severe or worse occurred in 59.4% of patients and included pneumonia (9.4%), anemia (12.5%), neutropenia (lower levels of a type of white blood cell, which may indicate infection; 9.4%) and muscle pain (9.4%).

“Patients can also develop other low-grade side effects including fatigue, skin rash (and) headaches,” Jain said. “However, the clinical severity and management of side effects highly depends on many other factors: patient age, comorbidities (the presence of two or more diseases or medical conditions) and organ function.”

Jain added that side effects in most patients can be managed.

Despite the positive data emerging from studies focused on Brukinsa for the treatment of MCL, more research is needed in this area, including for those who may not respond to this therapy or become resistant to it.

“There still remains an unmet need for some patients, as the efficacy of the agent is no different from the others in the class, which means that approximately 15% to 20% of patients will not respond to BTK (inhibitors), and, as such, combinations to improve outcomes are being explored,” Phillips said.

Jain added, “The efficacy and toxicity profile of (Brukinsa) in (the) frontline setting in (patients with mantle cell lymphoma) is being investigated in both (older), transplant-ineligible and frontline young patients in combination with rituximab (Rituxan) and venetoclax (Venclexta). Longer follow-up and randomized studies are needed before confirming the superiority of (Brukinsa) over (Imbruvica).”

As more study results become available demonstrating the possibility of additional treatment options for this patient population, Phillips and other oncologists remain hopeful.

“New treatment options for MCL have continued to expand, which has led to better outcomes for our patients,” Phillips said. “Hopefully, we will be able to cure this cancer, but until that time, if we can continue to have promising agents like (Brukinsa) enter this space, the future is promising.”

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