MCL Treatment Shifts Away from Chemoimmunotherapy, Enters New Era of Novel Agents and Cellular Therapies

Jia Ruan, MD, PhD

With the shift away from chemoimmunotherapy, and the adoption of novel combinations, as well as cellular therapy, the MCL treatment landscape has entered a new era, according to Jia Ruan, MD, PhD, who added that, looking forward, minimal residual disease (MRD) is bound to play a critical role in terms of guiding treatment selection.

“MCL is a relatively uncommon subtype of B-cell non-Hodgkin lymphoma; this is a unique disease that is frequently seen in older patients with the median age at diagnosis being 65 years,” said Ruan. “Over the past few years, several developments have led to improvements in survival outcomes. Looking forward, we will continue to explore new treatment options that could improve the longevity of patients with this condition.”

In an interview with OncLive, Ruan, a hematologist/oncologist at Weill Cornell Medicine, highlighted her approach to treating patients with MCL, along with the rise of CAR T-cell therapy and novel combinations in the space.

OncLive: What key factors do you consider when making treatment decisions for your patients with MCL?

Ruan: Two important considerations are the biological features of the disease itself and patient-related factors.

Notably, MCL is a heterogeneous disease. The majority of patients have nodal-type MCL, which leads to swelling of the lymph nodes, along with involvement in the bone marrow and blood. Moreover, a significant proportion of patients experience gastrointestinal symptoms. The other subtype is non-nodal disease, which tends to be slow-growing, indolent disease that involves spleen, blood and bone marrow. With these patients, the watch-and-wait approach may be an acceptable way to get a true sense of their condition. When patients are very symptomatic, however, we will consider different treatment options that can alleviate their symptoms and help them achieve remission much more quickly.

In terms of the treatment options that are currently available, there are more intensive options such as chemoimmunotherapy, while low-intensity options include novel agents. Many of these novel drugs come in the form of a pill, which could be taken at home and beneficial to patients with pre-existing medical conditions who may not tolerate chemotherapy. The goal of these agents is to provide effective treatment while preserving their quality of life (QoL).

How do you approach treatment for those with relapsed/refractory disease in your practice?

Patients with MCL frequently relapse because there is no cure for this disease to date. As such, we must develop new treatment options, keeping the challenge of relapse in mind.

When patients present with relapsed/refractory disease, it's critical for us to look at the previous lines of therapy that they received and what their response to that treatment was. This helps us to determine the next best option to get their disease under control and bring them into remission.

High-risk disease features such as TP53 mutations, which tend to be resistant to chemotherapy, along with performance status could help us determine whether patients are candidates for more intensive therapy or whether they are better suited to receive novel agents that can be given in the outpatient setting.

A key development in this setting has been the emergence of CAR T-cell therapy. One product, brexucabtagene autoleucel (Tecartus), recently received regulatory approval from the FDA for use in this patient population. Could you speak to the data that supported this decision? What are your thoughts on this agent?

In the ZUMA-2 trial, investigators evaluated the CAR T-cell therapy brexucabtagene autoleucel in patients with relapsed/refractory MCL; this was an exciting development and addition to the [treatment armamentarium] for these patients.

Notably, the therapeutic outcomes [observed with this product] appear to be very impressive. ZUMA-2 is a phase 2 trial that enrolled about 70 patients with relapsed/refractory disease. All patients previously received BTK inhibitors, such as ibrutinib (Imbruvica). When these patients experience relapse, they tend to have high-risk disease and generally do not respond to chemotherapy or other treatment options in this space.

Results showed that, among those patients, the overall response rate was about 90% and complete remission was around 60%, which was very impressive. Preliminary, the duration of response also appeared to be quite impressive; over 50% of patients remained in remission at 1 year. As such, I am quite excited about this trial and am looking forward to learning more about the durability and adverse effects with this approach, and how this product impacts long-term QoL for these patients.

What role do you believe this modality will have in the future for this disease?

Currently, CAR T-cell therapy is approved for patients with relapsed/refractory disease. The efficacy data are quite impressive; however, a common concern with this therapy is how to apply this modality safely. In the future, we hope to utilize this approach earlier on in the treatment journey, but to do this, we will need more data on the safety and efficacy of this.

We look forward to [seeing more from] ongoing clinical trials using brexucabtagene autoleucel, both as a single-agent, and perhaps in combination to augment its effectiveness and minimize the AEs. We also must determine which patients that will derive the most benefit. Young and fit patients are suitable, but we must see how applicable the therapy is for those who are older or who have other co-existing medical conditions, which happens to account for a large portion of the overall MCL population.

Are any other research efforts being made that you wanted to highlight?

Many exciting areas of research are being explored in the field of MCL, both in the frontline setting, as well as in the relapsed setting.

We are patiently awaiting clinical trial outcomes that are evaluating novel combinations in the frontline setting; this applies to both younger patients and older patients who may not be candidates for intensive chemotherapy options. For example, applying BTK inhibitors to a moderate chemotherapy backbone, such as bendamustine and rituximab [Rituxan], in patients who are not candidates for transplant. Several phase 3 trials are comparing bendamustine/rituximab plus BTK inhibitors versus standard bendamustine/rituximab.

Furthermore, clinical trials are being done in younger patients who are candidates for intensive chemotherapy and novel agents are being compared with a standard chemotherapy induction backbone and consolidation with autologous stem cell transplant.

Could you spotlight the rise of minimal residual disease (MRD) as a biomarker for patients with MCL?

MRD measurement is poised to play an important role in terms of helping us understand the quality of various regimens. [Efforts are being made to] assess whether this particular biomarker could be used as a surrogate to determine treatment intensity, treatment duration, and how to adjust both induction therapy and maintenance consolidation.

One example of using MRD to adjust a treatment strategy is in the Intergroup EA4151 study.

In this phase 3 study, patients complete induction chemoimmunotherapy regimens and are then stratified based on MRD. Consolidation strategies compare autologous stem cell transplant [followed by maintenance rituximab] versus maintenance rituximab alone in the patient population who achieved an MRD-negative status following induction therapy.

Could you speak to the shift away from chemoimmunotherapy regimens?

Treatment strategies have moved away from the use of chemoimmunotherapy, which was believed to be the most common and conventional approach, to the adoption of effective, low-intensity, oral-based, and convenient regimens as in the outpatient setting, especially for those with relapsed disease. This is a great advancement that makes treatment for patients with MCL very accessible, regardless of their age and co-existing medical conditions. This might be the most important development that will impact remission duration and survival outcomes in the years to come.

How has the coronavirus 2019 disease (COVID-19) pandemic impacted treatment of this disease?

The pandemic has been a real challenge that we are facing in practice and in daily life; this will modify the way we practice medicine and how patients access healthcare.

Clinical trials that utilize effective, low-intensity treatment combinations, where immunosuppression can be controlled to a moderate degree, therapies that can be administered safely in the outpatient setting, as well as telemedicine is of critical importance. Potentially, this could be important requirement to provide successful medical care and clinical trial recruitment.

Weill Cornell Medicine has been utilizing these strategies throughout the COVID-19 pandemic and the enthusiasm of our patients, who are seeking high-quality clinical trials, along with our active trial participants, continue to impress us. Ultimately, COVID-19 has certainly been a challenge, but it also has provided us with a roadmap of opportunities for more outpatient treatments in the future.