MCL Paradigm Moves Toward More Nuanced Risk Stratification, Novel Treatments

Jia Ruan, MD, PhD

Clinical and pathological features have to be taken into account to appropriately risk-stratify patients with mantle cell lymphoma (MCL) and determine whether they are in need of conventional chemoimmunotherapy up front or novel agents in the relapsed/refractory setting, explained Jia Ruan, MD, PhD.

“When we evaluate patients with MCL, we have to apply the most up-to-date precision medicine approach by looking at pathology, risk features, cytogenetics, fluorescence in situ hybridization, and immunohistochemical markers such as Ki-67,” said Ruan. “We have to have a very comprehensive discussion with patients regarding treatment options, from conventional chemoimmunotherapy to experimental treatments.”

In an interview with OncLive, Ruan, a hematologist/oncologist at Weill Cornell Medicine, discussed the current risk-stratification parameters and the evolution of treatment from high-intensity chemoimmunotherapy to novel therapy in MCL.

OncLive: Could you shed light on some of the features that are characteristic of MCL? How do you risk-stratify patients?

Ruan: MCL is a unique subtype of non-Hodgkin lymphoma (NHL) that affects a relatively small population. MCL comprises about 5% to 8% of all B-cell NHL. MCL has very unique clinical and pathological features. Specifically, t(11;14) and cyclin D1 expression.

Patients present with various risk features. We use a range of clinical and pathological features to determine how to risk-stratify patients. We use a number of risk stratification tools, such as the MCL International Prognostic Index (MIPI) that consists of clinical parameters, such as age, performance status, lactate dehydrogenase, and white blood cell count. We usually combine a patient’s MIPI score with their Ki-67 [index], which reflects the proliferation potential of the disease.

[We use] the combined MIPI score and Ki-67index to give us the MIPI-c score which helps us refine those groups, particularly the patients with very high-risk disease, including elderly and younger patients.

A patient’s genetic mutation profile is also quite important; p53 is an important genetic aberration, either as a mutation or deletion that we pay a lot of attention to. Generally speaking, we group them together as aberrations, but mutations [have a bigger impact on] outcomes.

We have learned from previous prospective studies using chemoimmunotherapy that the survival data for patients with TP53 aberrations are much less favorable compared with patients who do not harbor this mutation. We’re talking about overall survival of less than 2 years compared with what could be more than a decade. That doesn't mean we won't offer chemoimmunotherapy to these patients, but rather that we have to think about backup options at the get-go should they not respond to chemoimmunotherapy, or have an early relapse. [For example,] should we be thinking about more [precise] medicine with targeted therapy that could be incorporated in the initial therapy of those patients?

We also have more old-fashioned morphology-based parameters [we use to risk-stratify patients]. Patients may have blastoid or pleomorphic MCL. Now, we can correlate those morphologies with MIPI scores, for example, or Ki-67 proliferation, which are usually tightly related. If we know from the pathology report that a patient has those features that potentially define a more aggressive clinical course and less favorable outcome, we can devise a [carefully thought out] treatment strategy from the get-go.

Could you discuss the evolution of treatment from high-intensity chemoimmunotherapy to novel therapy?

Over the last 2 decades, we have seen an explosion of options in MCL. [Treatment advances] come in waves based on the availability of treatment options, our understanding of disease biology, and the risk factors that help us develop more personalized approaches.

Initial treatment is really anchored by conventional chemoimmunotherapy. We saw the introduction of rituximab (Rituxan) in B-cell NHL and exploration of chemotherapy partners that would deliver the best outcome. Initially, this was focused on intensity. We wanted to define the most active ingredient, such as high-dose cytarabine. That, in conjunction with consolidation of autologous stem cell transplant (ASCT), really pushed the bar in terms of response rate, complete remission, and prolonged progression-free survival.

However, we realized that [these approaches] were limited to a very small pool of patients. The median age of diagnosis is 65 years, so the majority of patients may not fully benefit from this type of approach [due to toxicity].

Along the way, we have discovered other combination chemotherapies, such as bendamustine/ rituximab, which are used extensively as a backbone in the clinical setting. [The combination] is quite convenient in the outpatient setting and is generally well tolerated by patients who have a reasonably good performance status.

We’ve also seen chemoimmunotherapy [emerge as a] maintenance strategy. Rituximab seems to lead to better survival if it is given after R-CHOP—based chemotherapy induction for patients who are more elderly and also after ASCT, so following high-intensity treatment. That was really the first breakthrough, where we utilize chemoimmunotherapy followed by consolidation and maintenance.

Over the [past] decade, we have come up with so many good options with targeted agents that provide a selection based on efficacy and adverse effects (AEs). This was spearheaded by agents such as proteasome inhibitors, such as bortezomib (Velcade) and immunomodulatory compounds, such as lenalidomide (Revlimid).

The agents that have made a real impact are the BTK inhibitors. Three BTK inhibitors—–ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa)––are approved and are available for treatment in relapsed/refractory MCL. Each of their associated AEs vary.

With these agents, we have more options for patients. It is remarkable that a single-agent oral medication can provide an overall response rate in the range of 60% to 80%. Complete remission can be achieved anywhere from 20% to 50% of patients. We don’t have head-to-head comparisons, but it is quite remarkable to achieve that [level of response. BTK inhibitors] have become very active agents that are being incorporated into combinations with chemotherapy or with other biological agents in the frontline and relapsed/refractory settings.

Finally, [CAR T-cell therapy], which is just emerging, [has the potential] to unleash some major therapeutic power if it's applied properly. CAR T-cell therapy is an application of immunotherapy. There are multiple CAR T-cell products out there. The furthest product in development is KTE-X19. Most recently, the phase 2 ZUMA-2 trial in over 70 patients showed that just a single infusion of KTE-X19 can lead to major response rates in about 80% to 90% of patients and complete remission rates of up to 60%. These are durable [responses] of over 1 year in more than 50% of patients.

Longer [follow-up] and larger studies are needed to understand what the durability [of response] and the short-term and long-term AEs are. Are we looking at a potentially curable option if it can be used in the relapsed setting, as well as in the frontline setting, in tandem or in sequence with novel agents or chemoimmunotherapy? It’s very exciting to see all of these options.

What are some of the factors that influence treatment selection?

We have to factor in the features of the disease, reflected by the clinical parameters, mutational profile, and morphologic features that inform us whether it's a conventional form of MCL, versus an aggressive and resistant form of MCL that has a very short duration of response to high-intensity chemotherapy.

We also think about the patient preferences. [Should they receive] a short-defined duration of chemoimmunotherapy, which we can dial up the intensity to with high-dose cytarabine, ASCT and maintenance treatment, outpatient chemoimmunotherapy with maintenance, or oral pills that can be taken at home with less frequent acute medical care?

The decisions would be easier if we had data comparing the efficacy and AEs of these drugs. Or, could we introduce novel agents to chemotherapy [improve patient outcomes]? What are the biomarkers that can help us make those determinations? Could this be something [we could assess with] minimal residual disease (MRD)? Could our treatment choice regarding intensity or duration be based on the response assessment? Not only on conventional imaging studies and clinical parameters, but also novel biomarkers that can detect a good response earlier, or a potential relapse also much earlier.

What planned or ongoing research in MCL would you like to spotlight?

Participation in clinical trials are instrumental in pushing the envelope forward. I would like to spotlight 2 options that are being evaluated in the frontline setting. There is a study, which is looking at how we can apply novel biomarkers to determine if patients need high-intensity treatments, such as ASCT versus maintenance rituximab.

An ongoing study is measuring MRD at the end of induction chemoimmunotherapy. Patients who have MRD negativity will be randomized to rituximab maintenance or ASCT, consolidation and then rituximab maintenance. If patients can achieve very MRD-negative CRs, do they need high-intensity consolidation? It’s a very important study that's open to physically fit patients who can tolerate chemoimmunotherapy and ASCT.

I would also like to bring attention to the importance of exploring chemotherapy-free biological combinations as initial therapy. There is an emerging body of literature that provides good efficacy data for novel combinations for patients with relapsed/refractory disease, especially those with high-risk features, such as TP53 mutations. There are a number of trials in the initial treatment setting that are employing combinations with a BTK inhibitor as a backbone, and incorporating other agents, such as BCL-2 inhibitors or immunomodulatory compounds, such as lenalidomide in conjunction with anti-CD20 agents. Those trials are ongoing and will help us understand the type of efficacy we can achieve and how fast we can achieve it.

How long is needed for a chronic approach with novel combinations, and is there a way for us to know, based on biomarkers, when to deescalate treatment and when some patients might be safe to observe without long-term chronic novel agents? Those are relatively new questions that will put us on track toward comparing novel agents versus chemoimmunotherapy.