Allison C. Rosenthal, DO

Allison C. Rosenthal, DO

Expert Perspectives
Allison C. Rosenthal, DO

 

Decisions in the Clinic: Treating Patients With Mantle Cell Lymphoma (MCL)

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Allison C. Rosenthal, DO

Practice Community
Phoenix, AZ
Practice Niche
Hematologic malignancies
Hospital and Institute Affiliations
Mayo Clinic

 

Question

Which individuals are at particular risk for developing mantle cell lymphoma (MCL)? Are there signs and symptoms that distinguish MCL from other non-Hodgkin lymphomas (NHLS)?

Answer

No specific risk factors have been identified with regard to the development of MCL, though the incidence is higher in older adults and in males. Family history may also play a role.

MCL can present with similar signs and symptoms of other NHLs including lymphadenopathy, splenomegaly, bone marrow involvement (cytopenias), and B-type symptoms. Recently we have gained an appreciation that MCL is a clinically heterogeneous disease with a wide range of presentations including: localized disease; splenomegaly/lymphocytosis/minimal nodal involvement; widespread adenopathy; rapidly progressive bulky adenopathy with adverse features such as p53 mutations or blastoid morphology.

There is a high incidence of GI [gastrointestinal] involvement in MCL, which is a somewhat distinguishing factor, though the necessity of screening endoscopies in asymptomatic patients is debatable.

Question

In the era of rituximab and emerging monoclonal antibodies, what role do you foresee cell transplantation playing in the treatment of MCL?

Answer

Autologous stem cell transplant (SCT) is a powerful tool to deepen and prolong first response in young, fit patients with MCL, though it has unclear benefit as a later line of therapy even in the rituximab era. Deep and durable responses following SCT have been more apparent, with the realization that inclusion of cytarabine with induction is critical. Some even suggest that “cure” is possible, with remissions nearing a decade, but caution is advised as late relapses are possible.

The role of autologous SCT consolidation is also highlighted by the paucity of approved therapies for relapsed MCL, though its impact may change with the development of effective novel agents — if they can achieve more sustained disease control.

Unfortunately, without risk adapted management strategies (due to lack of reliable biomarkers and insufficient prognostic tools), it’s difficult to know whether all subgroups of MCL truly benefit from autologous SCT or whether we are over-treating some. I’m afraid the role of SCT will remain in question until we are able to tailor therapy to both clinical and biologic factors associated with MCL. My personal practice is to offer autologous SCT to transplant eligible patients who have had a good response to initial therapy.

Question

Are Bruton’s tyrosine kinase (BTK) inhibitors likely to replace chemotherapy in MCL treatment?

Answer

Not yet, but they are a viable alternative to R [rituximab] with chemotherapy in relapsed or refractory (R/R) patients who don’t want chemotherapy or aren’t eligible from a comorbidity or performance status perspective.

Despite the convenience of oral therapies, there are some significant drawbacks — including the indefinite nature of treatment and the associated cost. Furthermore, up to one-third of patients with MCL don’t respond to ibrutinib, and a substantial proportion of patients discontinue therapy for reasons aside from disease progression.

With the approval of acalabrutinib late last year for R/R MCL, there are now BTK inhibitor options. Currently available data suggest that the side effect profile may be improved and discontinuation rates for AE’s [adverse events] may be slightly lower. Combination strategies using BTK inhibitors in the upfront setting are being studied in clinical trials that may result in additional “chemotherapy-free” treatment strategies.

We know there are subtypes of MCL that are going to do poorly with chemotherapy and need alternative approaches. Which targeted therapies and which combinations might be optimal in this population are questions we are hoping to answer with these ongoing studies.

Question

What are the most important factors when deciding how to best treat relapsed/refractory MCL? Is there a general approach for treating these patients?

Answer

Ideally, we’ll have predictive biomarkers in this space eventually, but for now we rely on clinical factors such as age, performance status, and treatment sequence, as well as response and duration of response to prior therapies.

In those with incomplete response or early relapse following R-chemotherapy, I’m unlikely to use chemotherapy again unless it’s with the addition of a targeted agent (likely on clinical trial). Since the majority of patients respond to ibrutinib (duration of response generally a year or longer), and newly approved acalabrutinib also shows a high incidence of durable responses, a BTK inhibitor is usually the first line of therapy for R/R MCL.

A better understanding of disease biology and resistance mechanisms is needed to better identify patients who are unlikely to benefit from BTK inhibition. When it comes to bortezomib vs lenalidomide (with/without rituximab) for R/R MCL, I largely choose based on patient preference and the presence or absence of significant neuropathy from prior therapy. Both can be effective options, with reasonable timeline of disease control in responding patients.

When possible, patients with R/R MCL should be enrolled in rationally designed clinical trials looking at novel agents in combination such as venetoclax and CDK [cyclin-dependent kinase] inhibitors, which have modest activity as single agents. Particularly, patients with high Ki67 levels, blastoid morphology, and p53 mutations warrant novel treatment strategies and innovative approaches, since responses to currently available therapies are rare and short in duration.

Question

What is your strategy for treating newly diagnosed patients with MCL with a low number of comorbidities?

Answer

For young and fit patients I opt for a cytarabine-containing induction regimen and proceed with consolidative auto SCT in patients with a good response to chemotherapy (though MRD [minimal residual disease] negativity is ideal).

BR [bendamustine plus rituximab] is also an option, and while it was previously the main treatment for older patients with co-morbidities, it is frequently used for induction (with/without cytarabine) prior to auto SCT, given its ease of administration and good side effect profile.

There are now data to suggest that patients induced with BR then consolidated with SCT benefit from 3 years of rituximab maintenance. Older patients with low comorbidities that might still be candidates for transplant likely benefit from this approach.

Question

Do you have a standard strategy for treating relapsed patients more than 80 years old? Do any particular comorbidities affect the strategy you choose?

Answer

No, but I think an overall assessment looking at degree of frailty is an essential first step in determining the options one may have.

A BTK inhibitor would still be my first choice if it were not contraindicated because of existing co-morbidities or drug-drug interactions. BR is also feasible in some elderly patients if they received alternative chemotherapy initially. Low-dose cytarabine with or without bortezomib has also been shown to be tolerable in this population.

R2 [lenalidomide-R] is a simple regimen that can be effective, though cytopenias and fatigue can be a problem in elderly patients. Finally, R-cladribine is also an option with a reasonable side effect profile.

Cardiac comorbidities, pre-existing neuropathy, renal insufficiency, cytopenias, and overall vulnerability to toxicity are all part of my decision-making process. I also consider patient preference, proximity to the center they are being treated at, and availability of clinical trials when choosing a treatment strategy for elderly patients.