Determining Fitness Is Key in Mantle Cell Lymphoma Treatment Selection

It is critical to assess the fitness of a patient with mantle cell lymphoma (MCL) from the get-go as part of the treatment decision-making process, according to Shalin Kothari, MD.

As part of a visit to Yale Cancer Center in New Haven, Connecticut, CancerNetwork^® spoke with Kothari about the current treatment paradigm for MCL as well as key characteristics to consider when sequencing different therapeutic options. Patients who are younger and have more fitness, for example, are eligible to undergo treatment with BTK inhibitor-based regimens such as those employed in the phase 3 TRIANGLE study (NCT02858258).¹ On the other hand, combinations that include bendamustine (Treanda) and rituximab (Rituxan) may be suitable for use among those who are older and have frailty.

Kothari is an assistant professor of Medicine (Hematology) at Yale University.

Transcript:

The current treatment options for MCL depend on the [patient’s] own fitness. The fitness is [quite] important to determine from the get-go. For patients who are young and otherwise fit, the standard of care has recently changed among most lymphoma doctors. That is based off the TRIANGLE study, which [evaluated] a combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] with rituximab plus dexamethasone, cytarabine, and cisplatin or oxaliplatin [R-DHAP] alternating with R-DHAP in combination with a BTK inhibitor. The TRIANGLE study used ibrutinib [Imbruvica], which is the first-generation BTK inhibitor, but at this time, that’s off the market, so we typically would end up using a second- or third-generation [BTK inhibitor] such as acalabrutinib [Calquence] or zanubrutinib [Brukinsa].

If patients are [older], frail, or less fit or do not meet [inclusion] criteria for the TRIANGLE study, then we typically go for rituximab [Rituxan] and bendamustine [Treanda]-based therapy in combination with or without BTK inhibitors. The addition of BTK inhibitors in [patients who are older and] frail is something that is still in research. I would not say that that is a settled question, but there are 2 important trials in that arena called SHINE [NCT01776840] and ECHO [NCT02972840].^2,3 The ECHO study and the SHINE study showed that if you add ibrutinib to a [rituximab/bendamustine] backbone in [patients who are older and] frail, the [progression-free survival] is improved. But it has not yet led to an overall survival benefit. [Meanwhile], in the ECHO study, which combined acalabrutinib with rituximab and bendamustine, overall, we have seen more favorable outcomes, most likely due to acalabrutinib being less toxic than ibrutinib and being more selective. That’s basically the current paradigm.

The third bucket, I would say, of patients who are very frail—where they cannot tolerate any chemotherapy whatsoever—I would consider BTK inhibitors with rituximab as a standard combination, although we have clinical trials ongoing here, so we would put patients on that. In addition, the biology is important, especially for TP53-mutated disease. We [usually] would want to avoid chemotherapy because those patients are typically chemotherapy-refractory.

References

1. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi: 10.1016/S0140-6736(24)00184-3.
2. Wang ML, Jurczak W, Jerkeman M, et al. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med. 2022;386(26):2482-2494. doi: 10.1056/NEJMoa2201817.
3. Wang M, Salek D, Belada D, et al. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol. 2025;43(20):2276-2284. doi: 10.1200/JCO-25-00690.