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Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Professor of Medicine
Weill Cornell Medicine
New York Presbyterian Hospital
New York, New York
John P. Leonard, MD, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb/Celgene, Epizyme, Genentech/Roche, GenMab, Gilead Sciences/Kite, Incyte, Janssen, Karyopharm, MEI Pharma, Regeneron, Sutro, and Miltenyi and funds for research support from Genentech.
Mantle cell lymphoma (MCL) is a challenging disease to manage, with many different treatment options to consider. Below, I share my perspective on how I select therapy for patients with MCL in the frontline setting and beyond.
Current Treatment Approaches
There are numerous options for patients newly diagnosed with MCL, ranging from observation to intensive treatments to novel agents and combinations under clinical investigation. I commonly recommend observation for patients who are asymptomatic with low tumor burden and good laboratory parameters; some patients can go for years without needing therapy.
The options for patients who need treatment fall into a couple of different categories. For older patients, bendamustine/rituximab (BR)—typically with rituximab maintenance—is probably the most commonly used treatment. Recent data from Smith and colleagues from the Eastern Cooperative Oncology Group and Intergroup presented at ASCO 2021 (Abstract 7403) show that the median progression-free survival (PFS) with this regimen is at least 5 years—making this such a reasonable treatment that we sometimes use it even in younger patients.
Many clinicians use more aggressive treatment in younger patients, ranging from induction therapy with R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) variations/sequences, or even BR followed by autologous stem cell transplant (autoSCT). AutoSCT, which is typically followed by rituximab maintenance, can improve PFS. However, because autoSCT after current induction therapies lacks definitive evidence of improved overall survival (OS), I tend to be more conservative about using these intensive approaches.
For patients with TP53 mutations, chemotherapy offers limited efficacy. In practice, many clinicians are moving toward targeted combination approaches for these patients. Emerging data support combining a Bruton tyrosine kinase (BTK) inhibitor with either an anti‑CD20 antibody plus lenalidomide or with venetoclax as approaches that may be of interest. Thus far, data are early and limited.
Selecting Frontline Therapy
When selecting therapy in the frontline setting, I involve the patient in a long discussion because selection is driven by patient preferences along with age, fitness, tumor burden, Mantle Cell International Prognostic Index (MIPI), and TP53 status. I think one issue to consider is how aggressively do you treat patients who are candidates for transplant but perhaps have less aggressive disease? This is a situation where patient preferences play a large role.
Other options in this setting include clinical trials evaluating new agents and combinations. Many are looking at adding chemotherapy (eg, cytarabine) or additional drugs (eg, ibrutinib) to BR as an induction regimen that could potentially be followed by autoSCT. Eastern Cooperative Oncology Group is leading a phase III US NCI Intergroup trial randomizing patients in minimal residual disease (MRD)–negative complete response after induction to rituximab maintenance vs autoSCT followed by rituximab maintenance, with a primary endpoint of OS (NCT03267433). This trial is designed to answer the really important question of whether a more intensive consolidation will lengthen overall survival for a patient achieving the best remission we can detect.
For patients with TP53-mutated MCL in the frontline setting, we think that BTK inhibitor/anti–CD20-based combinations with either lenalidomide or venetoclax are likely to be better than chemoimmunotherapy, but we lack comparative and long-term data to guide us on which combination of novel therapies is the most effective. We also need further information on the toxicity profiles and durability of these combinations. We also await further data on how these combinations compare to chemotherapy for patients without TP53 mutations, along with information vital to patient preferences (which regimens can be given outpatient, long-term outcomes, quality of life, etc.).
Selecting Second‑line Therapy
Most patients with progressive MCL receive a BTK inhibitor in the second-line setting rather than upfront, either alone or in combination with an anti‑CD20 antibody. BTK inhibitors are preferred in the second line because of their high efficacy and good tolerability. The newer BTK inhibitors, acalabrutinib and zanubrutinib, appear to have a better safety profile with similar efficacy to ibrutinib in the second-line setting.
Some data suggest that in the BTK inhibitor–naive population, lenalidomide/rituximab is also an effective second‑line therapy. Studies are underway examining the combination of a BTK inhibitor plus venetoclax, although this combination risks more toxicity and is currently lacking comparative data on OS.
Second-line and Beyond: CAR T‑Cell Therapy
The chimeric antigen receptor (CAR) T‑cell therapy brexucabtagene autoleucel is now FDA approved for treatment of adults with relapsed/refractory MCL. This therapy is more commonly used for patients with progressive disease in the third‑line setting after, typically, frontline chemotherapy with or without stem cell transplant and rituximab maintenance followed by BTK inhibitor monotherapy or combination therapy. Toxicity and logistics can be challenges with CAR T-cell therapy.
If the patient has more indolent disease, they could potentially delay receiving CAR T‑cell therapy or opt for a different approach involving lenalidomide, more chemotherapy, an anti‑CD20 antibody, or other novel agents. However, I anticipate we will see more patients in the future receiving CAR T-cell therapy, particularly those with TP53 mutation in the relapse setting or after a number of prior therapies, because of its high rates of response, particularly complete response. As noted above, the challenges with CAR T-cell therapy are the toxicities, logistics, and expense, all of which can be exacerbated by age.
Future Therapy Options
There are multiple investigational therapies that may enter the clinic in the near future. One is pirtobrutinib (LOXO‑305), a noncovalent BTK inhibitor with early data suggesting activity against disease that is resistant to other BTK inhibitors. Others include bispecific antibodies that engage CD3 on T‑cells and, typically, CD20 on B‑cells; these have very exciting data in other lymphomas, and emerging data suggest promising activity in MCL.
Expert Guidance on Treatment Selection: Interactive Decision Support Tool
Because MCL can be such a challenging disease to manage, it can be very useful to get the perspectives of multiple experts. Clinical Care Options is developing an updated interactive decision support tool for MCL offering treatment recommendations customized to common patient scenarios from a panel of 5 experts, including myself, Stephen Ansell, MD, PhD, Farrukh T. Awan, MD, Christopher R. Flowers, MD, MS, and Julie M. Vose, MD, MBA. Watch for this updated tool to be released in the near future at this link.