This was a long-term follow-up—up to 10 years—and it showed a significant advantage both in PFS and OS. Clearly, we have shown across the board that maintenance rituximab impacts outcomes. The question that remains is, “Should everyone get maintenance, or should we identify the patients who need rituximab?” This is in the context of cost and toxicity. The future will be based on minimal residual disease (MRD) studies to potentially decide who needs maintenance therapy, particularly rituximab.
With all of these new data, what do you predict for the future of MCL?
It’s interesting; we presented a registry study on many patients with MCL in the real world, and large academic institutions, as well, and looked at the impact of how therapy consolidating influences CR. Therefore, there are these registries that show that we must use intensive therapy, and simultaneously, we are developing these novel regimens that are potentially chemotherapy free. The option will be in the middle—combining novel therapy with some of the chemotherapy agents. There are several trials that have been completed that we are awaiting, such as R-CHOP with bortezomib (Velcade) and also bendamustine and rituximab with or without acalabrutinib. Those studies will likely build upon the backbone of chemotherapy.
The other question would be, “When do we stop treatment?” As I said before with maintenance, the MRD studies will be very critical in terms of achieving early and deep responses in patients with MCL. This is where the field is going to go.
In the relapse setting, we also have venetoclax, which has shown great activity in MCL. There are some ongoing studies combining BTK inhibitors with venetoclax showing impressive results in the relapsed/refractory setting.
Also, we are hearing about chimeric antigen receptor (CAR) T-cell therapies. There are ongoing studies, such as ZUMA-2, focusing on a MCL population, with very promising results at this point.
What is a significant challenge that the field is still facing?
One of the big challenges of MCL is that it is truly a disease that has a spectrum. There are about 10% to 15% of indolent MCL, and these patients present with splenomegaly, no lymphadenopathy, high white blood cell counts, and the cytogenetics are not usually complex, making this a much more genetically stable disease. These patients can probably be monitored for quite a while. A very small fraction of those patients will evolve over time and develop 17p deletion and can become more aggressive, but that is kind of a rare event.
We are trying to take advantage of the data published about gene expression profiles looking at the proliferation signature in MCL. We are using Ki-67 as a surrogate marker, and if you have less than 30% versus 30% or more [of Ki-67] that clearly impacts the outcome. The Mantle Cell Lymphoma International Prognostic Index (MIPI) combined with Ki-67 is a factor, but it is not a factor that helps predict the outcome of MCL and customize our treatment. As we dive deeper, patients with p53 mutations or deletions, regardless of the therapy and transplant, their outcomes are worse. These patients should probably receive a different lymphoma therapy. Clearly, chemotherapy is not enough for those patients.
As we further dissect and understand the different subtypes of MCL, we will be able to develop biomarkers. We do not have this yet, because there has been an increased awareness of the biological complexity of MCL. The separation has been a bit difficult. p53 will definitely be a factor, as well as ATM, 11q, and Ki-67 proliferation. This has not yet helped stratify patients.
Is there anything else from the meeting that you would like to touch on?
Data were presented from the LyMA trial where, instead of cisplatin, researchers used oxaliplatin, which has not been tested much in MCL before but had been used in relapsed large cell lymphoma. Replacing the cisplatin with oxaliplatin seems very promising, so the group behind LyMA is moving in the direction of using this as a backbone for induction therapy in MCL.
This is not something that we are really using in the United States; we are still using a combination of alternating anthracyclines and cytarabine with or without high-dose therapy and transplant. The paradigm in MCL is building up on novel therapy in the relapse setting, and then combining novel therapy with chemotherapy to try to get deeper responses in the frontline setting, as well as customizing maintenance based on MRD. That is where we are heading.
A lot of the 2017 ASH Annual Meeting has centered around immunotherapy. There are a lot of presentations trying to understand biomarkers to predict response to CAR T cells. This is from the microenvironment, the general inflammation status of the patient, the bulk of the disease. We have an update of the ZUMA-1 trial which showed impressive data. There are definitely some patients who initially relapse, but we also had some partial responses that converted into CRs 1 year later. Once a patient receives a CR over 3 months, very few relapse.