Frederick L. Locke, MD

 Patients with mantle cell lymphoma do have some ongoing unmet needs. We need to better understand those high-risk features. We need to be sure that those high-risk features are looked for at the time of diagnosis, even in community pathologists’ offices, so we can understand very early on the likely trajectory of this patient. Is this a patient who is going to get a good response with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] chemotherapy or other combination chemotherapy, and can then get a consolidative autologous transplant and be in remission for a decade or longer? Or is this a patient who is unlikely to benefit from that additional consolidative autologous transplant, where we need to be thinking about CAR [chimeric antigen receptor] T-cell therapy earlier? We also don’t know the role of novel agents in the up-front setting. There are ongoing multicenter, cooperative group clinical trials testing combination therapies, incorporating BTK inhibitors and other novel agents as part of the frontline regimen so we can understand, even in young and fit and healthy patients, whether they afford better opportunity for ongoing durable remission than the standard chemotherapy, combination chemotherapy, and autologous stem cell transplant consolidation.

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Frederick Locke, MD, addresses the ongoing unmet needs for patients with mantle cell lymphoma such as the role of novel agents in the upfront setting.

Unmet Needs in MCL

CAR [chimeric antigen receptor] T-cell therapy may gain a more significant role in the treatment of mantle cell lymphoma. As we better understand high-risk features in patients, we’ll know who those patients are to give CAR T-cell to early. Well-designed clinical trials need to test that. Novel clinical trials could try things like a lead-in of a BTK inhibitor as frontline therapy and then give CAR T after a number of cycles. That’s 1 way to get CAR T-cell therapy early to very high-risk patients. CAR T-cell therapy offers an opportunity for long-term ongoing durable remissions for patients who are without other options. We know that patients who have been exposed or are refractory to a BTK inhibitor don’t have great options, and CAR T-cell therapy offers the opportunity for remissions in those patients. It is a paradigm-changing treatment option.

CAR T-cell therapy is an innovative new therapy for patients. At this point, it’s not something that is easily administered and can be done in the community oncologist’s office, but that does not take away from the reality that CAR T-cell therapy can lead to ongoing durable remissions for patients with mantle cell lymphoma who are without other treatment options. These patients need to be considered for CAR T-cell therapy as early as possible and have a discussion with the CAR T-cell therapy treatment center that’s nearest or dearest to the community oncologist. Please do not deny patients the opportunity for this therapy. They certainly can benefit from it, and it’s not age dependent. We certainly look at comorbidities and other features. CAR T-cell therapy can lead to impressive and durable responses.

Frederick Locke, MD, considers whether CAR T will gain a more significant role in mantle cell lymphoma and if it will move to the frontline setting.

Future Directions for CAR T in MCL 

Who is the appropriate patient to refer to be considered for CAR T-cell therapy? A patient with mantle cell lymphoma [MCL] who has relapsed following an autologous stem cell transplant should be referred for consideration of CAR [chimeric antigen receptor] T-cell therapy, at least to have that conversation. It is FDA approved for refractory mantle cell lymphoma and could in theory be given in the second line. Many patients can get through CAR T-cell therapy. This is not a treatment that only younger patients can get. We know from data with diffuse large B-cell lymphoma that patients in their 60s, 70s, and even early 80s can fare well with CAR T-cell therapy. They can make it through the acute, short-lived toxicities and come out the other side with long-term ongoing durable remissions. Age should not be a factor to not refer a patient to consider for CAR T-cell therapy. I suggest that any patient who has relapsed mantle cell lymphoma should at least have a conversation and be referred in to have a conversation with a team that could do CAR T-cell therapy. It’s always better to have established that relationship early on and be ready to go with CAR T when it’s necessary.

BTK inhibitors, including ibrutinib, work very well for mantle cell lymphoma. For patients without high-risk features, they can get remissions for many years and remain on BTK inhibitors. CAR T-cell therapy is considered early on as a second line, or sometimes with a BTK inhibitor as a bridge in patients who have those high-risk features or who don’t have a quick and deep remission with a BTK inhibitor. We’re not typically going straight to CAR T in second line. We’re always trying to get that BTK inhibitor in, but we know whom it’s not going to work for based on high-risk features. We don’t necessarily wait for them to progress. We start the ball rolling with getting authorization and getting the patient collected to CAR T-cell therapy when we know that they’re not going to have complete response or a long and ongoing durable remission. When patients relapse on a BTK inhibitor, they have very rapid progression and very high-risk features that make it difficult to get them to CAR T-cell therapy. I’d rather get the patient to CAR T while they’re still on the BTK inhibitor with a partial response or starting to progress than wait for everything to grow rapidly.

With mantle cell lymphoma, certain patients have high-risk disease features that tell us that they’re likely to progress early after frontline therapy or shortly after an autologous hematopoietic stem cell transplant. Those high-risk features include TP53 mutation, high Ki-67 proliferation index, patients with a high MIPI-c [combined MCL International Prognostic Index], and patients with blastoid variant. These are the patients who I’m not comfortable saying are going to remain in remission for years to come following an autologous transplant. In some cases, we may not even do a consolidative autologous transplant because we know that they’re very likely to relapse; in particular, the patient with TP53 mutation. That’s when I want to be thinking about CAR T early on. We always have BTK inhibitors, but even in the era of novel agents like BTK inhibitors, we believe that those patients are not going to have ongoing durable remission, so we have to have CAR T ready to go for those patients.

Frederick Locke, MD, explains when to choose CAR T over BTK inhibitors, patient factors to consider for CAR T cell therapy, and when BTK inhibitors are best utilized. 

Considerations for Treatment Selection in MCL 

 Brexucabtagene autoleucel was recently approved by the FDA for the treatment of refractory mantle cell lymphoma based on the ZUMA-2 clinical trial results. That brings us to the question: What is the role of CAR [chimeric antigen receptor] T-cell therapy in mantle cell lymphoma? On label, it’s patients with refractory mantle cell lymphoma. But in all practical applications, these are patients, at least the younger and fit patients, who still likely should be getting high-dose chemotherapy regimens up front and consolidative autologous transplant if they get into remission. If they relapse following that, the treatment paradigm is generally to try a BTK inhibitor.

In theory, it’s on label to go straight to CAR T-cell therapy in the second line, but it’s been our practice to utilize BTK inhibitors for even the high-risk patients to see what kind of response they can get. A patient who gets into a complete response, a complete remission, and who does not have any high-risk features can probably ride out that remission with a BTK inhibitor for years to come. But a patient with high-risk features or a patient who doesn’t get a complete response after a few cycles, a few months, or 3 or 4 months on a BTK inhibitor is a patient who needs to be considered for CAR T-cell therapy.

What I say to referring physicians is that if you have a patient with mantle cell lymphoma who has gone through autologous transplant, was followed for years in remission, and then they relapse, send them for consideration of CAR T-cell therapy while we start a BTK inhibitor, because we want to have that CAR T-cell therapy ready to go if we need it. That’s generally how we’re utilizing it in the community, in most cases as a third-line agent after high-dose chemotherapy, autologous transplant, and a BTK inhibitor.

Is there a role for an autologous transplant in mantle cell lymphoma? There certainly is, and CAR T-cell therapy hasn’t changed that paradigm. We know that patients who undergo up-front high-dose chemotherapy, get into remission, and are consolidated after first-line treatment with an autologous transplant can maintain remissions for years to come. There are certain subsets of very high-risk patients whose outcomes may not be improved by an autologous transplant, and physicians may choose not to do an autologous transplant, but that’s still 1 of the main treatment paradigms for patients, at least here in the United States.

Older patients with comorbidities may not be fit or eligible for high-dose chemotherapy and autologous transplant, and that’s OK. CAR T-cell therapy has different sets of toxicities than transplant, and a patient who’s not eligible for autologous transplant may actually be eligible for CAR T-cell therapy based on a detailed assessment. Age should not be a factor in deciding whether a patient should be referred for CAR T-cell therapy.

Transplant still remains as something we’ll utilize in mantle cell lymphoma. That being said, there are different companies, cooperative groups, and even single centers that are designing clinical trials that would test out up-front therapy very early on with CAR T for high-risk mantle cell lymphoma patients. If we know a patient has very low chance for prolonged remission with chemotherapy and autologous transplant, can we give them CAR T earlier and improve their long-term outcomes? That’s something we’ll have to answer with clinical trials. For now, I still recommend autologous transplant if a patient is in deep remission, especially with no evidence of minimal residual disease, after frontline lead-in therapy. I would recommend a consolidative autologous transplant.

Frederick Locke, MD, discusses the role of CAR T in patients with mantle cell lymphoma, the impact it has on autologous transplant, and when transplant is recommended. 

Role of CAR-T in MCL

The ZUMA-2 clinical trial is testing CAR [chimeric antigen receptor] T-cell therapy for patients with refractory mantle cell lymphoma. ZUMA-2 tests a CAR T-cell therapy called brexucabtagene autoleucel, which is a CD19-directed CAR T-cell therapy that contains a CD28 costimulatory domain. It is the exact same construct as in axicabtagene ciloleucel, but the manufacturing process is different, where the T-cells are selected out prior to manufacturing.

Brexucabtagene autoleucel was tested in patients with relapsed or refractory mantle cell lymphoma [MCL] who had 1 to 5 prior lines of therapy. Patients had leukapheresis, where their cells were collected and brexucabtagene-autoleucel was manufactured. During that manufacturing period, they could receive bridging therapy with dexamethasone, ibrutinib, or acalabrutinib if necessary. Once the CAR T-cells were manufactured, patients received conditioning chemotherapy with fludarabine and cyclophosphamide for 3 days and then received 2 x 106 brexucabtagene-autoleucels per kg in a single infusion.

Of course, the primary end point was objective response rate. The response rate in these highly refractory mantle cell lymphoma patients is pretty remarkable. The complete response rate was 67% when we looked at the data in the 1-year follow-up; 67% by investigator assessment. A partial response rate of 25% gives us an overall response rate of 92% with a single infusion. These are patients who previously had multiple lines of therapy. These patients had been exposed to a prior BTK inhibitor, and almost all of them were refractory to that BTK inhibitor. This is a highly refractory patient population that we’re talking about.

At a median follow-up of 17.5 months, 29 of 60 evaluable patients, or 48%, remain in an ongoing response, including 70% of those who achieved a complete response. Remarkable and durable remissions were achieved on the ZUMA-2 clinical trial. It’s also important to note that when we looked at ongoing response rate as stratified by high risk or other features generally associated with worse outcomes with mantle cell lymphoma, we did not see any statistical significance of any particular adverse prognostic subgroups. Patients who were over 65 had the same durable response rates. Patients who had blastoid variants had the same durable response rates as other patients. Patients with high Ki-67 proliferation index similarly had the same rates of durable remission. The same held true for patients with intermediate or high-risk MIPI [MCL International Prognostic Index] scores, or patients with a TP53 mutation. Even in high-risk patients, we’re seeing remarkable, durable response rates with brexucabtagene autoleucel CAR T-cell therapy.

Certainly, the therapy is not without some downsides. It can cause toxicity, as we know CAR [chimeric antigen receptor] T-cell therapy can. These are generally self-limited and reversible toxicities, with categories such as cytokine release syndrome [CRS] or neurological events. In fact, these are very similar to the rates of CRS and neurological events seen with axicabtagene ciloleucel for diffuse large B-cell lymphoma, and are generally very manageable and self-limited in these patients.

Frederick Locke, MD, discusses the ZUMA-2 trial, including the study design, results, and practical implications for CAR T in patients with mantle cell lymphoma.

ZUMA-2 Trial and Implications For CAR T in MCL

 Historically, treatment of patients with relapsed or refractory mantle cell lymphoma [MCL] following frontline therapy and consolidative autologous transplant consisted of combinations of chemotherapy, several different regimens, or more novel agents, including BTK inhibitors, such as ibrutinib, zanubrutinib, and acalabrutinib. There has also been some success with proteasome inhibitors like bortezomib and immunomodulators like lenalidomide. All these agents can lead to remissions in patients with relapsed/refractory mantle cell lymphoma. In fact, the BTK inhibitors, like ibrutinib, have been very successful for putting patients into remission.

It is clear that patients with high-risk features have much more opportunity for durable and ongoing remission. Patients with mantle cell lymphoma who have high-risk features, including patients with blastoid variant mantle cell lymphoma, patients with TP53 mutations or deletions, patients with a high MIPI [MCL International Prognostic Index]—zeroing in on patients who have a high MIPI-c [combined MIPI] score that takes a count of over 30% in the Ki-67 index—are the patients who have very high risk. Even BTK inhibitors like ibrutinib don’t do a great job of keeping those patients in remission for a prolonged period of time. Combination chemotherapy regimens have been used. Fludarabine is an agent that has been used in refractory mantle cell lymphoma and some other chemotherapeutic agents. Patients with high-risk features generally fare poorly in the long term, even with these more novel agents.

Frederick Locke, MD, reviews the treatment options historically available to patients with mantle cell lymphoma who had disease recurrence after high-dose therapy and transplant.

Frederick L. Locke, MD | Authors

Articles

Unmet Needs in MCL

Future Directions for CAR T in MCL

Considerations for Treatment Selection in MCL

Role of CAR-T in MCL

ZUMA-2 Trial and Implications For CAR T in MCL

Treatment Options for Mantle Cell Lymphoma (MCL)