Biomarkers in Mantle Cell Lymphoma Pathogenesis

Transcript: Ian Flinn, MD: Tycel, could you talk us through the pathogenesis of mantle cell lymphoma? We just talked about the heterogeneity in how patients present. Is that also reflected in various different forms of mantle cell lymphoma?

Tycel Jovelle Phillips, MD: Sure. When I see a patient with clinical mantle cell lymphoma, ideally the first thing we discuss is diagnostic biomarkers. That can be something that is present in about 90% of patients. We know that’s an early event, but not necessarily a catalyst, that’s been shown in several preclinical studies to develop lymphogenesis. It’s pretty diagnostic in most patients. For those who are negative with cyclin D1, ideally we can also look for SOX11 expression in a diagnostic test.

A key note is that—if we had accurate stains of cyclin D1, D2, D3, cyclin E—there are reports that all of these patients tend to have some sort of cell cyclin dysregulation as part of their progression to developing this lymphoma.

Ian Flinn, MD: Have you seen patients that don’t have the classic t(11;14) translocation and instead have these types of alternative splicing?

Tycel Jovelle Phillips, MD: Yes. At least internally at our site, 11;14 is hit or miss because the breakpoint isn’t uniform in all patients. The probes that we have, specifically, can sometimes miss these patients. I will say our pathologists have become a bit better. Certain characteristics they see morphologically on some of these biopsies will hint them toward suspicion of mantle cell lymphoma, and they will perform some of these extra stains like SOX11 [SRY-box transcription factor 11]. That has been very helpful in diagnosing these cases which, historically, may have been called marginal zones, folliculars, or even CLL [chronic lymphocytic leukemia] in the past.

Ian Flinn, MD: Yes, these are important things. Bijal, do you use SOX11 in testing uniformly? Do you find that there’s variation in expression—for instance, maybe in the indolent version or leukemics? How do you handle that?

Bijal Shah, MD: This has been tough for us. We haven’t found SOX11 to be as helpful because there is certainly a subset of mantle cell lymphoma that won’t carry SOX11. When we do see it, I tend to think of it as a more indolent mantle cell lymphoma. It’s important to keep in mind that there are other features that may drive a more aggressive presentation. If I see a SOX11, but a high proliferative rate, or a sense of nodal disease, I’m going to be less inclined to think it is a more indolent mantle cell lymphoma just by virtue of SOX11 staining.

Ian Flinn, MD: Javier, what about other markers that are important? Do you get antigen Ki-67 on everybody? Does it change the way you treat things? Can you talk a little bit about [tumor protein] p53? We think of that as in CLL, and the many different malignancies as being important, but it’s not always obtained in mantle cell lymphoma. Should we?

Javier Munoz, MD, MS, FACP: I think we should. That’s a great question. In response to your comments regarding Ki-67, I do definitely want to see a Ki-67 in all my patients with mantle cell lymphoma. It’s interesting because in other indolent lymphoma—let’s say follicular lymphoma—you would have a Ki-67 of 30%. Sometimes, you shrug your shoulders and you’re not very impressed by it. When it comes to mantle cell lymphoma, having that Ki-67 higher than 30% has generally been an omen of poor prognosis. That is definitely one of the items or vitals that I like to see and know in my patients.

When it comes to TP53, we know chromosome 17 or mutations of TP53 are going to carry worse prognosis in those situations. That is something that I do want to know, and I factor in when it comes to treatment. Historically, those patients have responded poorly to chemotherapy.

Ian Flinn, MD: I think we’re behind the times, at least in lymphoma, compared to our solid tumor colleagues, in getting next generation sequencing. Here’s a case where, maybe not the broadest panel, but a limited panel, can be really important.

Transcript Edited for Clarity