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Ibrutinib-Resistant Patients a Core Challenge in MCL

Gina Columbus @ginacolumbusonc
Published: Thursday, Jun 15, 2017

Bijal D. Shah, MD

Bijal D. Shah, MD

Therapeutic approaches, including chimeric antigen receptor (CAR) T-cell therapy, are being explored in patients with mantle cell lymphoma (MCL) who have demonstrated resistance to the BTK inhibitor ibrutinib (Imbruvica)—a patient population that is worrisome to practitioners, explains Bijal D. Shah, MD.

“The spectra of ibrutinib resistance is the main thing,” said Shah. “If I had 1 thing to say about MCL, ibrutinib resistance is bad for the majority of the patients we see, and it has to be acknowledged. It works wonderfully for some individuals. We see that 20% are going to see these prolonged remissions with ibrutinib and I would never say anything bad about the drug, but the take-home message is when resistance emerges in MCL, it’s really bad.” 

Shah, who specializes in medical oncology at Moffit Cancer Center, discussed the current treatment paradigm of MCL, what therapies are moving through the pipeline at a rapid rate, the potential benefit with CAR T-cell therapy, and pivotal biomarker studies currently being conducted, during an interview at the 2017 OncLive® State of the Science Summit on Hematologic Malignancies. 

OncLive®: What is generating excitement in the field of MCL?

Shah: When I think about MCL, the most complicated patient I see now is the ibrutinib-resistant patient, particularly those who develop ibrutinib resistance early. These individuals tend to have extraordinarily aggressive lymphoma, and these lymphomas tend to be very chemotherapy resistant. I’m going to cite data from Moffitt Cancer Center. For our patients, the median survival when someone progresses on ibrutinib is only about 2 months. About three-fourths of the group who die within 2 months, die within the first 2 or 3 weeks, just to give some insight of what we’re running up against. 

We have been profiling patients with MCL to try to understand what drugs work and what do not. We have a sophisticated assay, in which we are finding that almost no drug works, which is frightening. It is what we see clinically, as well. How are we going to succeed in this space? It is no question—when ibrutinib works, it can work wonders. But when it stops working, we have a real problem. 

This is where CAR T-cell therapy has a very important role to play. We have treated a number of patients, and the inclusion criteria for patients on the Kite Pharma trial is that they must be ibrutinib-intolerant or resistant. What we are seeing is incredible. I don’t know when Kite Pharma is going to present the data, but I will simply say that we are seeing some truly incredible results and outcomes. Therefore, I am very excited about CAR T cells as they enter the MCL space.

What about other novel therapies on the horizon? I think it’s a done deal: we are going to see venetoclax in MCL. A 75% overall response rate on a phase I trial is unheard of. These are the kind of response rates on ibrutinib that got us excited about ibrutinib. This is not something that can be ignored. 

It should be stated that none of the patients were ibrutinib-resistant on that trial. However, to see that magnitude of response tells you, very clearly, that there is a signal here. We are already in the process of generating more data in the space. 

Ibrutinib plus venetoclax in MCL [is] something I would pay attention to. Yes, we are going to see more myeloid toxicity with that regimen, but we are significantly prolonging that event-free survival. It tells you the answer: that we have moved on to something important. That is another important agent. 

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