Stratification Schemes Guide Treatment Decisions in MCL

Partner | Cancer Centers | <b>John Theurer Cancer Center</b>

Andre Goy, MD, MS, shares insight on the stratification of patients with mantle cell lymphoma and other molecular markers that are being applied towards optimal treatment decisions in this disease.

Andre Goy, MD

Deciding which therapy to pursue for a patient with mantle cell lymphoma (MCL) is dependent on 3 criteria, explained Andre Goy, MD, MS. Specifically, whether a patient’s disease is indolent or symptomatic, their age and fitness, and the presence of certain high-grade molecular markers.

“Typically, MCL is treated by subset,” said Goy. “It’s important that we do a full pathology of [the patient’s lymphoma], that we have Ki-67 status, at least, and [check for] p53.”

With a pathology report, physicians can account for important markers such as p53, mutated IGHV gene, and Ki-67 status—–all of which carry clinical weight, explained Goy. In addition to molecular markers, physicians have to consider the age and fitness of the patient, as it will determine whether they are eligible to receive a dose-intensive, and often chemotherapy-based regimen, such as cytarabine and rituximab (Rituxan).

OncLive: Could you discuss the treatment options for patients with MCL?

In an interview with OncLive, Goy, chief, Division of Lymphoma, chairman and director, John Theurer Cancer Center, shared further insight on the stratification of patients with MCL and other molecular markers that are being applied towards optimal treatment decisions in this disease.Goy: Approximately 5% to 15% of patients have indolent disease. These are asymptomatic patients who have a high white count, splenomegaly, and minimal lymphadenopathy, if any. These patients can be monitored over time. Sometimes, these patients can acquire a p53 abnormality, [in which the disease] can transform aggressively. It's rare, but it can happen. These patients can be monitored and not treated early on.

There are also patients who present with symptomatic disease who need treatment for classic MCL. Here, one of the most important factors is the age and fitness of the patient. Ki-67 status helps you identify how to treat these patients. In a patient who is fit for dose-intensive therapy, they can receive the combination of cytarabine and rituximab as induction followed with or without high-dose therapy and transplant. Typically, these patients do really well. Maintenance is also of benefit in younger patients.

In older patients, bendamustine and rituximab (BR) has become the backbone. [We may add] ibrutinib (Imbruvica) or acalabrutinib (Calquence), dose depending. We alluded to VR-CAP [frontline bortezomib (Velcade), rituximab, cyclophosphamide, doxorubicin, and prednisone] where the data are replacing bortezomib in the R-CHOP backbone. The results are very impressive in terms of the complete response rate, durability, and even survival advantage, so it is an option for older patients.

Beyond these classifications and Ki-67 status, we have to identify the molecular high-grade features, particularly p53 and 17p deletion. Though, p53 is not found very frequently in MCL, contrary to chronic lymphocytic leukemia. We look at IGHV and p53 and do a sequencing panel if need be. We have shown that up to 23% to 25% of patients [with IGHV] can be found at baseline. Those patients should not receive frontline chemotherapy. We use ibrutinib and rituximab as a window of opportunity followed by chemotherapy consolidation.

Finally, in frail patients who are not eligible for chemotherapy, we're moving toward doublet and triplet regimens. In clinical trials, we’re looking at the combination of ibrutinib and venetoclax (Venclexta), for example, in the relapsed setting. The activity was so impressive we'll definitely add that combination to an anti-CD20 agent in an ongoing trial.

What remain the biggest challenges in the field?

The last aspect that's important in MCL is achieving minimal residual disease (MRD) negativity, as it really translates into better outcomes. It might be able to guide maintenance therapy in the future. This is a really exciting time in MCL. There's a shift towards identifying the subset of high-risk patients who should receive frontline biological therapy and then chemotherapy, the patients who are frail and can’t get chemotherapy, and the rest who can receive different treatment based on their stratification.There are still a number of challenges that we face, one of which is that the median age at diagnosis is the mid- to late-60s. That makes intensive chemotherapy difficult. We still don't know if high-dose therapy and autologous transplant is beneficial after induction therapy, particularly in patients who are MRD negative. Achieving a deep complete remission and MRD early in MCL matters.

What are some other promising agents?

This is being looked at in the TRIANGLE study. We are looking at the same induction they have had in the past, with or without transplant, and replacing the transplant with maintenance by ibrutinib. Those are things we’re looking at to see whether we need to do high-dose therapy. The third challenge is the subset of patients who present with p53, blastoid variant, high-proliferative disease, and have a complex karyotype. These patients can do very poorly. That's where the chimeric antigen receptor T cells that are being examined in the ongoing ZUMA-2 trial seem to show promise.The BTK inhibitors with rituximab are very impressive in the salvage setting. The combination of venetoclax and ibrutinib is going to move towards the frontline setting. R-BAC [rituximab, bendamustine, and cytarabine] outside of a clinical trial is very impressive in patients, even in the relapsed setting. It also [looks impressive] in the frontline setting. If we adjust the dose of cytarabine, it also becomes feasible in elderly patients. The field is changing. It is important to refer patients to clinical trials to give them access to the best options. It is important to recognize that the field is going to move toward MRD as well.