Assessing the Role CAR T-cell Therapy Plays in Mantle Cell Lymphoma Treatment in ZUMA-2 Trial

Kieron Dunleavy, MD

Kieron Dunleavy, MD

In identifying available treatment options for patients with relapsed/refractory mantle cell lymphoma (R/R MCL), physicians first consider whether a patient requires treatment at all. If treatment is required, novel therapies, including chimeric antigen receptor (CAR) T-cell therapies, are emerging for patients and generating excitement among oncologists for their potential activity.

The pending results of the ZUMA-2 (KTE-C19-102) trial are widely discussed amongst physicians, for example. Following the ZUMA-1 trial, which showed that the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) was clinically beneficial and manageable in patients with refractory large B-cell lymphoma,¹ZUMA-2 enrolled 80 patients with R/R MCL into 2 cohorts in which they received 2 different dose levels of axi-cel with conditioning chemotherapy of fludarabine and cyclophosphamide.²Patients were required to have received up to 5 prior therapies, including anthracycline or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and ibrutinib (Imbruvica) or acalabrutinib (Calquence), although allogeneic stem cell transplant was not allowed.

The primary endpoint of the ZUMA-2 trial is objective response rate. The study is also assessing levels of CAR T cells and cytokines in the blood, duration of response, progression-free survival, incidence of adverse events, and overall survival as secondary endpoints.

The trial is ongoing, and results are expected to be presented in the coming months.  

Kieron Dunleavy, MD, professor of medicine, Director of the Lymphoma Program, Co-Director of the Microbial Oncology Program, GW Cancer Center, discussed current approaches to treating patients with MCL, highlighting peer discussions on the subject and information about the ZUMA-2 trial, in an interview withTargeted Oncology.

TARGETED ONCOLOGY: Can you discuss the current approaches for MCL treatment?

Dunleavy:There are many approaches to this disease. One is deferring treatment and a so-called ‘watch-and-wait’ approach. A proportion of newly diagnosed patients have very indolent disease and do not require aggressive approaches upfront. [Whether or not patients do need treatment] depends upon many different clinical and pathologic factors. Historically, more aggressive treatments have been given to patients under the age of 65, whereas less aggressive approaches are given to patients who are 65 and older. Most people who are diagnosed with MCL are in their 60s and 70s and therefore, they are frequently not eligible for very aggressive approaches.

Many experts advocate the use of high-dose therapy and autologous stem cell transplantation in younger patients. For older patients, less intensive approaches are typically used.

I would say that the treatment landscape of MCL is changing very dramatically because of the advent of a number of novel agents that are very effective in the relapsed/refractory setting in MCL, such as BTK inhibitors, BCL-2 inhibitors, and IMiDs (immunomodulatory drugs)—many new agents and approaches are being developed in this space.

TARGETED ONCOLOGY: Are there areas of controversy among physicians treating MCL regarding the role of new agents as well as standard treatment approaches?

Dunleavy:There is broad consensus that many patients with newly diagnosed MCL do not require immediate treatment. There is little consensus on what treatment should be used for patients who do need treatment. Novel agents are exciting in MCL as many classes of drugs have high efficacy in relapsed and refractory disease. An important question is what role these novel agents will have in the treatment of newly diagnosed patients.

There is much interest in a current National Cancer Institute (NCI) Inter-Group study that is looking at the role of autologous stem cell transplantation in patients who receive induction therapy for MCL and then are minimal residual disease (MRD) negative. That study will randomize patients to receive an autologous transplant versus getting maintenance therapy. The results of this study will help address this ongoing controversial question of which patients benefit from autologous transplantation. At the present time, for the treatment of younger patients with MCL, many physicians advocate for autologous translation while others do not.

TARGETED ONCOLOGY: What is the significance of the ongoing ZUMA-2 trial in MCL?

Dunleavy:This trial involved administering anti-CD19 CAR T cells to patients with MCL. The first trial (ZUMA-1) was done in aggressive B-cell lymphoma, principally diffuse large B-cell lymphoma. Now, a number of patients have been accrued to the ZUMA-2 study.

At this point, we don't have long follow-up in patients who have been accrued. [Those results should be] very interesting. Long-term follow-up is needed to assess the effectiveness of this strategy in MCL given the indolent course of the disease.

TARGETED ONCOLOGY: How does the ZUMA-2 trial address the toxicity found in the ZUMA-1 trial?

Dunleavy:In ZUMA-1, 2 of the major toxicities were cytokine release syndrome (CRS) and neurological toxicity. Given the very different biology of MCL, these toxicities may be different in terms of frequency and severity in ZUMA-2 and this will be interesting [to see] when the results of the trial are reported.  

TARGETED ONCOLOGY: What challenges still exist with CAR T-cell therapy in MCL?

​​​​​​​Dunleavy:​​​​​​​One important question is which patients with MCL can significantly benefit from this approach and will results be superior to other approaches in terms of long-term disease control? Second, how problematic will toxicities be in this population? CAR T-cell therapy for MCL has not been widely used, so we need a lot more experience with this approach, assuming the results of the ZUMA-2 and other similar studies are promising.

Much progress has been made in better understanding CAR T-cell efficacy and its toxicities. There now are widely accepted guidelines on how to approach and manage patients with CRS, for example. 

References:

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.N Engl J Med. 2017;377:2531-2544. doi: 10.1056/NEJMoa1707447.
2. Wang M Locke FL, Munoz J, et al. ZUMA-2: Phase 2 multicenter study evaluating efficacy of kte-C19 in patients with relapsed/refractory mantle cell lymphoma.J Clin Oncol. 2018;36(suppl; abstr TPS3102).