Goy Highlights Recent Advancements, Controversies in Mantle Cell Lymphoma

Andre Goy, MD

Andre Goy, MD

Even with many advancements in the treatment of mantle cell lymphoma (MCL), many oncologists still disagree on the optimal induction regimen for patients. Andre Goy, MD, explains that there are about 16 options for induction treatment options included in the National Comprehensive Cancer Network (NCCN) guidelines as frontline treatment for patients with MCL, mostly consisting of chemoimmunotherapy options.

The NCCN divides treatment options based on their aggressiveness. Less aggressive treatment options include preferred regimens such as bendamustine and rituximab (Rituxan; BR), VR-CAP (bortezomib [Velcade], rituximab, cyclophosphamide, doxorubicin, and prednisone), and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Whereas, more aggressive options include R-HyperCVAD (rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) or the NORDIC regimen (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone alternating with rituximab and high-dose cytarabine).

There are many factors to consider when determining if a patient is a candidate for intensive induction chemoimmunotherapy, according to Goy, chief in the Division of Lymphoma, chairman and director at John Theurer (JT) Cancer Center. Such factors include age, fitness, comorbidities, tumor burden, and presentation or subtype of the disease. The option of a watch-and-wait strategy should also be considered, he suggested, for patients with classic MCL and a low disease burden.

Another area of debate in the field is how long to give maintenance therapy for after induction therapy. Should patients stay on maintenance therapy for 1 year or up to 5 years? And will this change with newer treatment options? Goy suggested that maintenance regimens need to be customized to fit each patient and each treatment option.

In an interview withTargeted Oncology,Goy highlighted major controversies being investigated in the field of MCL in terms of patient subgroups and optimal management of each subpopulation. He also discussed changes and ongoing areas of research in the treatment landscape for patients with MCL.

TARGETED ONCOLOGY:Can you discuss some of the recent MCL research at your institution?

Goy:At JT Cancer Center, we have had a strong tradition of working across blood cancers, particularly in lymphoma. In MCL, we have seen well over 500 patients over the last 10 years at JT Cancer Center. Our research has been focused on trying to establish better therapies, both in the frontline setting and the relapsed setting.

In the frontline setting, we were a part of these studies with MD Anderson Cancer Center with bortezomib and hyper-CVAD, which were published several years ago. Particularly in the elderly patients, the results were better than the historical control and were consistent with what has been seen with R-CHOP and bortezomib, or VR-CAP, which became the first regimen approved of a combination of biological therapy with chemotherapy upfront in MCL.

In the relapsed setting, we have also looked at a number of novel therapies. We were part of all the pivotal trials of novel drugs that have been approved in relapsed/refractory MCL. We currently have several combinations in the relapsed/refractory setting, such as R²(lenalidomide [Revlimid] and rituximab) plus ibrutinib (Imbruvica) where the results have been very impressive with an over 70% complete response (CR) rate and an over 80% response rate; this includes some minimal residual disease (MRD)—negative patients including P53-positive patients as well. This is consistent with what has been seen in the European trial, the PHILEMON trial, which has shown the same thing.

We are looking at another combination with the novel agent venetoclax, which is going to be very important in the field of MCL. We have cell therapy, CAR T cells, and we are now building up and are a part of the integration of these novel therapies that have shown such an impact in the relapsed/refractory setting on how we can bring them upfront. We were a part of studies looking particularly at elderly patients where you cannot use dose-intensive therapy, and we are using VR plus or minus ibrutinib or acalabrutinib (Calquence). These trials have been completed, and we are waiting for the results. I believe that this is going to set a new standard.

Finally, as part of our routine management of patients, we have also looked at the impact of MRD and adjust our maintenance based on the MRD result in the patient in the molecular studies. Finally, looking at the bigger picture, what we have done with the outcome data in the real-world in patients with MCL is try to look at the impact of sequence of care and what’s the best way to treat these patients. This research is ongoing, but what is exciting is we can try to see the impact of prognostic factors. We have looked at comorbidities because it definitely impacts the choice of therapy in the frontline setting. We have shown and presented at ASH that patients who have no comorbidities and are at an age of over 60 or 65, can perfectly tolerate an intensive approach and do as well as patients who would be younger with more comorbidities. That sounds logical, but it definitely is something that is important to take into consideration because a cutoff of age 60 or 65 for the approach for the frontline therapy is somewhat arbitrary, so we hope that we are going to continue our research with novel therapy. We believe that there will be, and there are ongoing studies already looking at, biological agents only in the frontline setting with no chemotherapy, particularly in elderly patients who are not candidates for chemotherapy.

TARGETED ONCOLOGY:What are the controversies that exist in the diagnosis and management of MCL?

Goy:Establishing a diagnosis of MCL has now been pretty much been well accepted with being CD20- or CD5-positive, confirming cyclin D1 or t(11;14) translocation. The question beyond this is how you manage those patients. There is no consensus in the recommendation in the frontline setting. There’s actually more than 16 options in the frontline setting from the NCCN guidelines, so how do you pick out of this? There is some proponent of high-dose therapy upfront, consolidation with transplant, versus a much less aggressive approach, so how do we sort it out?

I think that practically, I would sort this situation out in 3 different scenarios. First, are the patients who have truly indolent-behaving MCL, which typically present like a chronic lymphocytic leukemia (CLL), have a high white count, splenomegaly, and no minimal lymphadenopathy typically. When you look at their biology, they have a very different biology by gene expression profile and very different behaviors. To recognize them, they are SOX11-negative and very often when you look at it, they areIGHV-mutated. These patients behave like a CLL and should be just monitored, maybe a little more closely than a CLL because we know that a subset of these patients can evolve overtime with a more complex karyotype and P53 abnormalities, coming to have this more aggressive behavior. That’s about a proportion of 10% to 15% of patients.

On the other hand, you have the blastoid variant of MCL and the high-risk patients, but in the middle, we have this larger number of patients for a rare disease that is MCL with a classic presentation. We refer to this as classic MCL. In these patients, there is always a lot of discussion on how you manage them because only one-third of these patients present with symptoms in MCL, so it becomes difficult since they don’t have any symptoms when you start talking about giving them intensive therapy. The way to look at it is that there is a subset of those patients, maybe 20% to 30%, that present with classic MCL but can be monitored for a while with watch and wait. We look at retrospective studies, and we included an update from the United Kingdom recently at ASH, the first retrospective study, looked at a cutoff of 3 months. The take home message is that about 30% of patients can [undergo a] watch-and-wait approach until 3 months, but really, it’s not a very long time. There was no impact in delaying the therapy, but not surprisingly, the patients that were delayed were the easiest patients who had no high-risk disease. In this series, all patients except a few had non-intensive therapy. It’s not completely clear if delaying therapy had an impact in that setting, but overall, the median time until they started therapy was about 1 year.

The update at ASH was interesting because it showed a bit of an increase in the adoption of the watch-and-wait strategy in the real world. This was demonstrated in the United Kingdom showing the cutoff of 1 year and showing that definitely some of these patients can be watched up until 1 year. The take home message was that the MIPI itself, which is not really the argument when you make a decision, included a low Ki-67, low LDH, and low beta-2-microglobulin that reflected the tumor burden. It’s not surprising that low tumor burden, classic presentation, and no aggressive features can be watched and wait, then depending on their clinical evolution to select the treatment.

TARGETED ONCOLOGY:What about with regards to treatment options for these patients?

Goy:If you decide to treat, that’s when the cutoff of what’s the overall picture of the patient in terms of comorbidities, age, and fitness comes in, [to see if they might] tolerate intensive therapy. If patients are younger and can tolerate an intensive approach, there is no question that cytarabine-containing induction and rituximab followed with or without high-dose therapy consolidation leads to a much longer duration of response, progression-free survival (PFS), and overall survival (OS). What would be really interesting would be to see how much in the real world this has been documented. There are registry data from the SEER database looking at large surveys of patients in the real world outside of clinical trials. When patients received a dose-intensive approach, hyper-CVAD, R-CHOP, and autologous transplant, versus R-CHOP, the PFS was 3-times longer; the survival was also better compared to R-CHOP. Registry data from the United Kingdom also showed that cytarabine induction has an impact, so that’s the frontline setting.

The next question in the frontline setting is, do we need a high-dose transplant? Why the high-dose cytarabine is important in this population is it that it brings a higher, earlier CR rate and molecular CR. Now there is extensive data that an early CR and early molecular CR translates into a much better outcome. That’s become the standard now.

In patients who cannot tolerate dose-intensive therapy, then the default has been to do R-CHOP. In R-CHOP alone, the 2-year PFS rate is less than 25%, so this is really not satisfactory. VR-CAP, which is bortezomib and R-CHOP without the vincristine, has now been accepted and approved by the FDA as the first novel regimen in frontline MCL. The CR rate was way higher than R-CHOP. The duration of CR and the median PFS was doubled with a survival advantage as well, so that could be more of a default.

Bendamustine/rituximab based on the StiL trial was better than R-CHOP in PFS, 20 months with R-CHOP versus 32 months with BR, but still a lot of patients relapsed, provided a backbone to build upon. There have been trials that have been accrued looking at BR plus or minus ibrutinib or plus or minus acalabrutinib, which will likely set up a new standard and the results are pending. Building upon a BR or bortezomib regimen could be the new backbone in the elderly patients.

The data with rituximab and bendamustine plus cytarabine (R-BAC) is interesting because you combine both options if you want both worlds, with the cytarabine at a lower dose because of the age and myelotoxicity, and bendamustine. The R-BAC data, outside of the clinical trial, are very appealing to offer something with a very sustainable PFS, duration of response, and a very high CR rate as well. This is really an overall landscape, and now this is the standard of how to do maintenance in MCL. It’s been shown to be beneficial in duration of response and survival, both in younger and older patients. The question that remains as part of the controversy is how long to give this maintenance. Typically, the trials have been designed for 2 to 3 years with no clear duration with the original elderly patients from the trial where the maintenance had been continued indefinitely and some patients had actually been on maintenance for almost 10 years by now. I would not suggest this in ibrutinib practice because you have more toxicity, infection, etc. I think 1 of the questions that is ongoing now is how long do we need the maintenance and the question we need to ask ourselves in the future is how could we customize the maintenance; can we build upon the maintenance?

Maintenance with ibrutinib is being looked at by the European TRIANGLE study versus transplant or maintenance combined with rituximab and lenalidomide, or rituximab plus ibrutinib in maintenance. All of these studies are ongoing, but I think 1 of the key questions is could we customize this maintenance based on the MRD achievement and could we re-treat patients if they become MRD positive? There are promising data from the NORDIC trial that if you re-treat patients at the time of conversion to PCR-positivity, you still have a very good long-term outcome. That, in a nutshell, is the overview of what the controversies are and where these controversies are clarified for use in practice.

TARGETED ONCOLOGY:Could you also discuss the blastoid variant in MCL?

Goy:The blastoid variant is also a very good question; we reviewed the standards now, but we know that these standards are still not satisfactory in the high-risk patient. Who are the high-risk patients? The high-risk patients have high Ki-67, typically the cutoff is 30% or more; the patient who has a high MIPI do poorly also, patients who are P53-positive, or patients of blastoid variant. The blastoid variant is a morphology that is highly recognizable under the microscope, and it’s very often that these patients are P53-positive. Here we should mention on the P53-positivity, in CLL it’s very often done on cytogenetics where you see deletion 17p, but in MCL, it’s not necessarily done routinely so we’ve done studies and others with next-generation sequencing showing that you can actually find P53 abnormalities in almost 20% to 25% of patients at baseline. We know that this has a huge impact, and we have shown this as well in our institution, even with hyper-CVAD or high-dose therapy, high-dose cytarabine, transplant, the median PFS and OS is clearly superior in P53 up until the point that this is now the recommendation. We now do something different where we start with the combination of novel therapy upfront if the patient is P53-positive and look at consolidation.

TARGETED ONCOLOGY:What are some of the promising agents or combinations being looked at right now with BTK inhibitors?

Goy:The development of BTK inhibitors in MCL has been a huge step. When the response rate is 70% to 80% and the CR rate is 30% to 40%, it’s very impressive and very durable compared to other agents. Overall, this is well tolerated. This really became the standard in the relapsed setting. As a single agent, they don’t cure anyone, and I think this is important to realize, particularly in the relapsed/refractory setting. When patients progress on BTK inhibitors, their progression is very fast and becomes very difficult to treat them at that time.

TARGETED ONCOLOGY:What are the options for these patients after progression on BTK inhibitors?

Goy:If someone progresses on a BTK inhibitor, the CAR T cells can actually be perfect for this population where this is the focus. Patients who have failed our chemoimmunotherapy and BTK inhibitors are eligible for a CAR T cell. A study was just completed called the ZUMA-2 trial, which investigated an anti-CD19 CAR T cell in well over 100 patients. The results are pending, but the preliminary impression is that this is highly promising.

Other agents that are outside of cell therapy is venetoclax, which has activity in patients who have failed BTK inhibitors. This is definitely an area that is a challenge because these patients very often have cognitive failure and don’t even have the time to go for an allogenic transplant. Going back to the question we had before for is that these patients that are at high-risk, it is important to recognize that in the beginning. What I do when I see a patient who has those features, I actually recommend they look for a donor so that we have a backup plan in case the patient fails. Then we can go for a transplant which offers potential long-term cure.

Reference:

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. National Comprehensive Cancer Network. Version 3.2019. Published May 6, 2019.www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed May 6, 2019.