Mantle Cell Lymphoma: Identifying Patients With Indolent Disease

Nancy A. Melville

September 10, 2020

Dr Eduardo Sotomayor

Mantle cell lymphoma (MCL) can run the gamut from an indolent to aggressive disease, and identifying biomarkers is key in determining which patients should follow a watch-and-wait strategy and which should receive aggressive treatment strategy, Eduardo M. Sotomayor, MD, inaugural director of the George Washington University Cancer Center in Washington, DC, told an audience at a "How I Treat" session during the recent American Society of Hematology's (ASH) Meeting on Hematological Malignancies. The meeting was held virtually because of the coronavirus pandemic.

Such a strategy could indeed save lives, he added.

"What I tell my patients is that all of us are going to die one day. But my job as a lymphoma doctor is to make sure that you do not die because of your mantle cell lymphoma," said Sotomayor.

"I strongly believe we are making MCL a chronic disease. We have the knowledge and the tools, and even more tools and therapeutic approaches are coming at a rapid pace," he said.

Among new developments, he explained, are the drugs that act as Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma-2 (BCL-2) inhibitors, and novel immune therapies such as CAR T-cell therapy.

Some Cases Can Be Indolent

MCL has long been believed to be a very aggressive disease with poor outcomes, but more recent research has shown great variation in outcomes.

"In fact, some cases can be indolent," he noted.  

Specifically, approximately 10% to 20% of patients with MCL will have a clinically indolent lymphoma, and the biomarkers that indicate those cases include low or absent expression of transcription marker SOX11, in addition to a more recently identified 16-gene signature called L-MCL16.

"Patients with clinically indolent forms of disease can have long-term survival even in the absence of treatment," Sotomayor said. "It is important to identify this group of indolent MCL patients because their treatment can be delayed while patients can maintain an excellent quality of life," he said.

Patients with indolent MCL can have a 5-year overall survival of as much as 100%, compared with 49% for classical MCL, he pointed out.

The majority of patients with MCL, about 60% to 70%, have "classical," lymphoma and the remaining 20% of presentations are aggressive forms, which are associated with P53 abnormalities (deletion or mutations) and/or KMT2D mutations.

In addition, TP53 overexpression — or absence — on immunohistochemistry assays has been also recently linked to worse outcomes in younger patients.

"It is important to remember that these biomarkers can identify a population with a biologically different high-risk disease that does not seem to benefit from the standard high-dose chemoimmunotherapy we currently use," Sotomayor said.

"As such, this high-risk patient population should be treated differently as part of clinical trials with targeted therapies and/or immunotherapies," he cautioned.

In addition to the conventional tools for risk stratification, including the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the simplified (s)-MIPI, minimal residual disease (MRD) is a key measure.

"MRD negatively correlates with outcomes, both pre-autologous stem cell transplantation (ASCT) and post-ASCT," Sotomayor said.

"In addition, in elderly patients, MRD represents an independent predictor of clinical outcomes after combined immunochemotherapy."

"Watch and Wait" for Indolent Cases

Patients with indolent forms of MCL typically have a leukemic, non-nodal presentation with lymphocytosis, splenomegaly, but no or minimal lymphadenopathy, Sotomayor explained.

For those patients, Sotomayor says he takes the watchful waiting approach — with a close follow-up.

"I follow those patients every 2 months for one year and then every 3 to 4 months. If there is no clinical progression then the frequency of visits can decrease further" he said.  

"I have patients that I have followed for several years and now I follow them once a year," he said. "Patients are instructed that if they notice any new lumps or bumps or masses or fatigue or new symptoms, that they should call us to be seen immediately."

Some research has suggested that, for patients presenting with leukemic, non-nodal MCL with symptomatic splenomegaly, a splenectomy as initial treatment may be beneficial.

Sotomayor noted research indicating that the failure of disease to progress within a year of diagnosis should give some reasonable assurance that the MCL is a clinically indolent disease.

However, once there is progression, treatment should be according to the type of progression (ie, whether it is "classical" or aggressive progression).

"These days, the diagnosis of MCL is relatively straightforward in the large majority of patients," Sotomayor said.

"The challenge is to identify those patients that are in need of treatment vs those in which you can safely pursue a watchful waiting approach."

Frontline Treatment for Classical MCL

For patients who present with classical MCL, there are multiple factors that influence treatment decisions, Sotomayor said.

"It is important to balance the aggressiveness and tumor load, ie the tumor characteristics, with the intensity of the therapy, age of patient, patient tolerance, comorbid conditions, and unique disease features," he said.

For younger patients with aggressive, bulky disease, high intensity therapy should be considered, whereas elderly patients with aggressive, bulky disease may require therapy with moderate intensity.

Younger or older patients with non-aggressive, non-bulky disease can be treated with low-intensity therapies.

For aggressive MCL with P53 abnormalities, Sotomayor notes that younger patients present a therapeutic challenge. With no benefit from standard or high-dose chemoimmunotherapy, he recommends referral of those patients to a lymphoma center with MCL expertise.

"For our colleagues in the community, early referral of your patient to a center with experience and high volumes of MCL patients will help to determine to which clinical group the patient belongs (indolent, classical, or high-risk) and as such, provide the most appropriate therapeutic approach at the right time," Sotomayor told Medscape Medical News.

And importantly, these patients should be enrolled in clinical trials with targeted therapy and/or immunotherapy because of the known lack of benefit from chemoimmunotherapy.

"We should always look for clinical trials for these patients," he said.

Current ongoing clinical trials include:
  • Investigation of a combination of BTK inhibitors with BCL-2 inhibitor and monoclonal antibodies (mAbs)

  • Integration of a BTK inhibitor into a first-line, high-dose chemoimmunotherapy in younger patients

  • The Italian "V-RBAC" phase II trial, involving consolidation with venetoclax after 4 cycles of R-BAC in elderly patients with either TP53 disruption or Ki-67 score >30% or blastoid variant

  • Front-line consolidation with reduced-intensity conditioning (RIC) allogeneic transplantation for younger and fit patients is also being considered

  • Future studies are looking at the role of CD19 CAR T cells for high-risk patients with MCL and P53 abnormalities


Emerging evidence regarding CAR T cells in mantle cell lymphoma are particularly encouraging, Sotomayor said.

"The recent data with anti-CD19 CAR T cells in patients with relapsed/refractory MCL, including patients with aggressive features, provide additional hope that we will be able to have a positive impact in the clinical outcomes of patients with high-risk disease," he said.

Sotomayor was referring to data on brexucabtagene autoleucel (Tecartus) from the ZUMA-2 phase 2 multicenter trial that was published this past April in the New England Journal of Medicine.

This study was conducted in 74 patients with refractory/relapsed MCL who had previously received up to five lines of therapy. The results showed that a single infusion of the product elicited responses in 85% of patients, and that 59% of patients achieved a complete response (CR). These data formed the basis of the Food and Drug Administration granting an accelerated approval for Tecartus in July.

Sotomayor's disclosures include relationships with Seattle Genetics, Pharmacyclics, Gilead/Kite, Janssen, and AstraZeneca.

American Society of Hematology's (ASH) Meeting on Hematological Malignancies: Presented August 27, 2020. 

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