Kahl Looks Toward the Future in MCL

Brad S. Kahl, MD

The treatment landscape of mantle cell lymphoma (MCL) has seen several advances in the last few years, but curative strategies are still an unmet need in this uncommon malignancy, said Brad Kahl, MD.

Trials with ibrutinib (Imbruvica), venetoclax (Venclexta), and axicabtagene ciloleucel (axi-cel; Yescarta), for example, could provide solutions for this challenge.

The SHINE trial (NCT01776840) is a phase III trial of ibrutinib in combination with bendamustine and rituximab (Rituxan; BR) in older patients with newly diagnosed MCL. This ongoing study aims to evaluate the safety and efficacy of this combination regimen in patients over the age of 65 with MCL.

Those enrolled in the experimental arm will receive ibrutinib at 560 mg once daily until disease progression or unacceptable toxicity, 90 mg/m2 of IV bendamustine on days 1 and 2 of cycles 1 through 6, and 375 mg/m2 of IV rituximab on day 1 of cycles 1 through 6. The primary endpoint of the SHINE trial is progression-free survival (PFS), while secondary endpoints include overall survival, overall response rate (ORR), and duration of response (DoR).

Venetoclax showed promising activity in combination with ibrutinib in a phase II study published in the New England Journal of Medicine. Treatment with ibrutinib/venetoclax induced a 16-week complete response rate (CR) of 42% in patients with untreated or relapsed/refractory MCL per CT imaging compared with a 9% CR at 16 weeks in a historical cohort of patients who were previously treated with ibrutinib monotherapy (P <.001). At week 16, CR rate measured by PET imaging was 62%, investigators reported. This study demonstrated that ibrutinib plus venetoclax has the potential to improve outcomes in a population of patients with few options.

ZUMA-2 (NCT02601313) is a phase II multicenter trial of the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory MCL. This study is addressing one of the biggest clinical challenges in the treatment of patients with MCL, which is resistance to BTK inhibitors. Patients are given a conditioning chemotherapy regimen of fludarabine and cyclophosphamide, and then will be given a single infusion of axi-cel. The primary outcome of this study is ORR, with secondary endpoints of DoR, best objective response, and PFS. ZUMA-2 is currently enrolling.

OncLive: What is the biggest unmet need in the treatment of patients with MCL?

Could you discuss the work being done with ibrutinib in MCL?

What about the potential for chimeric antigen receptor (CAR) T-cell therapy in MCL?

In an interview with OncLive, Kahl, a professor in the Department of Medicine, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discussed the exciting new advancements on the horizon for the treatment of patients with MCL.Kahl: The biggest unmet need for MCL is that we don't cure it. We need curative strategies for MCL so we do not have this relentless disease with this continuation of relapse and needing subsequent salvage therapy. We would really like to improve outcomes in the frontline setting. There are a lot of novel targeted agents that are showing good activity in MCL, such as ibrutinib, acalabrutinib (Calquence), and venetoclax. A lot of us who do research in MCL are very interested in combining these promising targeted agents with our standard therapies to see if we can improve outcomes through that strategy. In MCL, ibrutinib is currently approved for relapsed disease, and it gets a lot of use in the relapsed setting. It is being tested now in the frontline setting. There is a large trial called the SHINE trial, in which older patients with MCL who are ineligible for stem cell transplant were randomized to receive either BR or BR and ibrutinib. Ibrutinib was given throughout the 6 months of induction therapy, but then it was also continued as a postremission therapy. The SHINE trial is fully enrolled, but we do not have any readout yet from that trial. If it is a strongly positive trial, it has the potential to change the standard of care in frontline MCL, at least for older patients.CAR T cells have a lot of potential in MCL. As I mentioned, MCL is not curable right now, so eventually, all patients relapse and need therapy in the second-, third-, and fourth-line settings. Ibrutinib and acalabrutinib are very effective, but their benefit is finite. They do not work forever. We really need more options for relapsed MCL, so I am hopeful that CAR T-cell therapy will be another good option for patients with MCL. We do not know yet, because there is just not enough data, but it is a very promising strategy. In 1 or 2 years from now, we will likely know a lot more about CAR T-cell therapy in MCL.

Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018; 378:1211-1223. doi: 10.1056/NEJMoa1715519.