Spring Forward in Initial Therapy for Mantle Cell Lymphoma

I have been heartened by the significant progress that has been made over the last decade in our approach to treating patients with mantle cell lymphoma (MCL). Once associated with an overall survival (OS) of only a few years, a patient diagnosed since 2000 now has an expected OS of more than 10 years.

The most significant advancement in the treatment approach to MCL came with the approval of Bruton’s tyrosine kinase inhibitors (BTKis), the first-in-class covalent BTKi ibrutinib, followed by the second-generation BTKis acalabrutinib and zanubrutinib and, more recently, the first noncovalent BTKi, pirtobrutinib. This class of drugs provides an overall safe and effective oral therapy, with the majority of patients responding to treatment with manageable toxicity. Unfortunately, the cost can be less than desirable, which is an important topic for further discussion.

While almost all patients with MCL respond to treatment with BTKis, their disease will eventually become resistant to this approach. Arguably, the next biggest advancement in treating MCL was the approval of the autologous CD19-directed chimeric antigen receptor (CAR) T-cell product, brexucabtagene autoleucel. While highly active in patients with MCL, including in those with high-risk disease features that are known to be more resistant to standard approaches, this therapy comes with many challenges. The toxicities known to CAR-T therapies, namely cytokine release syndrome and immune effector cell-associated neurologic syndrome, occur with higher frequency in patients with MCL compared with other B-cell malignancies, along with a high rate of cytopenias and infection. Further, MCL is a disease that significantly impacts older adults, making this therapy challenging for the broad population of patients. Thankfully, alternative products with potentially less toxicity are on the horizon.

With all the advances in treating MCL in patients with relapsed or refractory disease, the best treatment approach for patients at the time of diagnosis remains unknown and, one could argue, very controversial. Historically, the approach to patients at diagnosis has been to consider treatment options based on patient age and co-morbidities. The use of autologous hemopoietic stem cell transplant (AHSCT) consolidation in younger patients has long been considered a standard approach in many countries, and yet recent data suggest that a minority of patients treated in the United States who are eligible for this approach receive AHSCT. The role of AHSCT has been questioned in recent trials conducted in both Europe and the United States.

Data from the TRIANGLE study presented at the 64th American Society of Hematology Annual Meeting & Exposition showed the addition of ibrutinib to standard intensive induction therapy and as maintenance improved outcomes over AHSCT alone. They also showed that AHSCT was not superior to ibrutinib without AHSCT, with toxicity favoring the elimination of AHSCT. These interesting results, not yet in publication, have led some practitioners to adopt the approach of BTKi maintenance in lieu of consolidation AHSCT for patients with MCL. Others believe there is still a clear role for AHSCT consolidation, while some await results of the ECOG4151 trial evaluating the role of using minimal residual disease (MRD) to determine which patients may benefit from AHSCT consolidation.

Several trials have evaluated advancing treatment in the older patient population at initial diagnosis. The standard approach for many of these patients has been the bendamustine-rituximab (BR) chemoimmunotherapy regimen, but building upon this backbone has been challenging due to toxicity and potentially the fact that BR can be a very effective therapy in this patient population. The addition of novel targeted therapies, including bortezomib, lenalidomide, and ibrutinib, to the BR regimen has fallen short of changing the standard approach due to either inability to improve efficacy or concerns about toxicity.

The million-dollar question for many is how we incorporate BTKis into the initial treatment approach for all patients with MCL and, taking it a step further, can we do so while eliminating chemotherapy. BTKis are very active in MCL and have already been incorporated into initial therapy in other B-cell malignancies where these agents are highly effective. Why are we not there yet in MCL? In addition to trials evaluating the use of these agents in combination with standard chemoimmunotherapy approaches, several trials have reported outcomes with BTKis in combination with CD20 monoclonal antibodies, CD20 monoclonal antibodies and lenalidomide, and CD20 monoclonal antibodies and BCL2 inhibitors. These combination trials have shown high overall response rates, high complete response rates, and even high rates of achieving undetectable MRD. However, they have been conducted in small patient populations, and we have yet to see randomized data in this setting. That said, there are ongoing studies looking at BTKi combinations versus chemoimmunotherapy that will address these questions.

While there is still no US Food and Drug Administration-approved indication in the United States for BTKis in the initial treatment approach for MCL, I have seen the recommendation to use BTKis in this setting make its way into the treatment guidelines, and many physicians recommend the treatment. It is my hope that the current ongoing trials will help us “spring forward” into a widespread chemotherapy-free approach to treating MCL in the very near future.

Kami Maddocks, MD, is a Professor of Clinical Internal Medicine in the Division of Hematology at the Ohio State University in Columbus.