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Classifying Mantle Cell Lymphoma

Panelists: Alexey V. Danilov, MD, PhD, Oregon Health & Science University; Andre Goy, MD, Hackensack University Medical Center; John P. Leonard, MD, New York-Presbyterian/Weill Cornell Medical Center; John M. Pagel, MD, PhD, DSc, Swedish Medical Center Seattle and Issaquah>; Stephen J. Schuster, MD, The University of Pennsylvania
Published: Friday, Dec 22, 2017



Transcript: 

John P. Leonard, MD: Thank you for joining this OncLive® Peer Exchange® on mantle cell lymphoma.

Mantle cell lymphoma is a clinically heterogeneous disease that develops in a diverse patient population, highlighting the need for more personalized treatment approaches. In this OncLive® Peer Exchange®, I’m joined by a panel of experts in lymphoma research. During this discussion, my colleagues and I will explore the benefits and risks of intensive and deintensified treatment approaches, the success of novel agents in the relapsed and refractory setting, and their potential use in frontline combinations. In addition, we will highlight studies from the 2017 ASH Annual Meeting, and explain how the new data will impact your clinical practice.

I am Dr. John Leonard, The Richard T. Silver distinguished professor of hematology and medical oncology, and professor of medicine at New York Presbyterian Hospital, in Weill Cornell Medicine. Joining me for this discussion is Dr. Alexey Danilov, associate professor of medicine at the Knight Cancer Institute of Oregon Health and Science University, in Portland, Oregon; Dr. Andre Goy, chairman and executive director at the John Theurer Cancer Center, and the Lydia Pfumb Chair for Lymphoma at Hackensack University Medical Center in New Jersey; Dr. John Pagel, chief of hematologic malignancies and director of stem cell transplantation for the Center of Blood Disorders and Stem Cell Transplantation at Swedish Medical Center, in Seattle, Washington; and finally, Dr. Stephen Schuster, professor of medicine, director of the lymphoma program, and director of lymphoma translational research at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Thank you all for joining us today. Let’s go ahead and begin.

First, I think we want to give the audience a little bit of a background on mantle cell lymphoma. I think we would all agree that mantle cell lymphoma is a very heterogenous disease, and it is a disease that can be quite aggressive. It’s a disease that can be indolent with a lot of in-between. Andre, how do you approach, or what is your take on, first of all, the classification of mantle cell lymphoma? What does the audience need to know about it as they see patients? What is the genetic variance, or the clinical variance that we see? And what kind of subtyping, that at least perhaps relates to a prognosis and perhaps also therapy, do we see? Your thoughts?

Andre Goy, MD: That’s an important question. As you say, we have a growing awareness of the biologic complexity and heterogeneity of mantle cell lymphoma and how it translates into the clinic. By definition, mantle cell lymphoma has an overexpression of cyclin D1, due to a rearrangement of the 11;14 translocation that is critical for the diagnosis of mantle cell lymphoma. Some may be cyclin D1-negative, which is really rare. But we’re showing the importance of the cell cycle disruption. They actually overexpress cyclin D2 or cyclin D3, and actually have rearrangement typically with the light chain.

How can we go beyond that? When you do cytogenetics on a patient with mantle cell lymphoma, you see some patients who have complex karyotype because it’s inherent to genetic instability, particularly for any patients who have 11q deletion, and it can present at presentation, or get worse over time with more complex abnormalities.

In practice, what matters is the proliferation signature surrogate marker that we use, called Ki-67. So, by gene expression profile in lymphoma, we find a different subtype of lymphoma. In mantle cell lymphoma, what we find is proliferation signatures from the slow proliferation to the higher proliferation. We tried to duplicate this using a cutoff of 30%, of Ki-67, and by immunohistochemistry. Some of the more recently noticed is SOX11. SOX11 is typically expressed in mantle cell lymphoma and in the more aggressive subtype. Some subtypes are SOX11-negative, and have a more indolent course.

Some of these patients, with this more indolent course, present with chronic lymphocytic leukemia features, in a way, with a high white count to splenomegaly. And a few, or any, with lymphadenopathy. These patients are somatically mutated. They don’t have the complex target type. They have a much more indolent course, and probably should be managed very differently.

And then, finally, I think one important aspect of molecular subtype is p53. Deletion 17p, at baseline, is not very common. It can happen. When you look at it by immunohistochemistry, or by mutation profile, there were several presentations at the 2017 ASH Annual Meeting confirming this.

Up to 23%, 25% of patients that present at baseline demonstrate p53 abnormalities. And these patients, obviously, even with the high-dose therapy, do poorly. I think this heterogeneity at the molecular level is reflected by what we already know from mantle cell lymphoma. When we describe the morphology of mantle cell lymphoma, we talk of pleomorphic variant, blastoid variant, and the nodular and diffuse patterns. In reality, all of this represents a sort of spectrum of disease. So, again, the indolent subtype, and then the rest of it that have a proliferation signature varies among patients and clearly affects their prognosis.

Transcript Edited for Clarity 

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Transcript: 

John P. Leonard, MD: Thank you for joining this OncLive® Peer Exchange® on mantle cell lymphoma.

Mantle cell lymphoma is a clinically heterogeneous disease that develops in a diverse patient population, highlighting the need for more personalized treatment approaches. In this OncLive® Peer Exchange®, I’m joined by a panel of experts in lymphoma research. During this discussion, my colleagues and I will explore the benefits and risks of intensive and deintensified treatment approaches, the success of novel agents in the relapsed and refractory setting, and their potential use in frontline combinations. In addition, we will highlight studies from the 2017 ASH Annual Meeting, and explain how the new data will impact your clinical practice.

I am Dr. John Leonard, The Richard T. Silver distinguished professor of hematology and medical oncology, and professor of medicine at New York Presbyterian Hospital, in Weill Cornell Medicine. Joining me for this discussion is Dr. Alexey Danilov, associate professor of medicine at the Knight Cancer Institute of Oregon Health and Science University, in Portland, Oregon; Dr. Andre Goy, chairman and executive director at the John Theurer Cancer Center, and the Lydia Pfumb Chair for Lymphoma at Hackensack University Medical Center in New Jersey; Dr. John Pagel, chief of hematologic malignancies and director of stem cell transplantation for the Center of Blood Disorders and Stem Cell Transplantation at Swedish Medical Center, in Seattle, Washington; and finally, Dr. Stephen Schuster, professor of medicine, director of the lymphoma program, and director of lymphoma translational research at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. Thank you all for joining us today. Let’s go ahead and begin.

First, I think we want to give the audience a little bit of a background on mantle cell lymphoma. I think we would all agree that mantle cell lymphoma is a very heterogenous disease, and it is a disease that can be quite aggressive. It’s a disease that can be indolent with a lot of in-between. Andre, how do you approach, or what is your take on, first of all, the classification of mantle cell lymphoma? What does the audience need to know about it as they see patients? What is the genetic variance, or the clinical variance that we see? And what kind of subtyping, that at least perhaps relates to a prognosis and perhaps also therapy, do we see? Your thoughts?

Andre Goy, MD: That’s an important question. As you say, we have a growing awareness of the biologic complexity and heterogeneity of mantle cell lymphoma and how it translates into the clinic. By definition, mantle cell lymphoma has an overexpression of cyclin D1, due to a rearrangement of the 11;14 translocation that is critical for the diagnosis of mantle cell lymphoma. Some may be cyclin D1-negative, which is really rare. But we’re showing the importance of the cell cycle disruption. They actually overexpress cyclin D2 or cyclin D3, and actually have rearrangement typically with the light chain.

How can we go beyond that? When you do cytogenetics on a patient with mantle cell lymphoma, you see some patients who have complex karyotype because it’s inherent to genetic instability, particularly for any patients who have 11q deletion, and it can present at presentation, or get worse over time with more complex abnormalities.

In practice, what matters is the proliferation signature surrogate marker that we use, called Ki-67. So, by gene expression profile in lymphoma, we find a different subtype of lymphoma. In mantle cell lymphoma, what we find is proliferation signatures from the slow proliferation to the higher proliferation. We tried to duplicate this using a cutoff of 30%, of Ki-67, and by immunohistochemistry. Some of the more recently noticed is SOX11. SOX11 is typically expressed in mantle cell lymphoma and in the more aggressive subtype. Some subtypes are SOX11-negative, and have a more indolent course.

Some of these patients, with this more indolent course, present with chronic lymphocytic leukemia features, in a way, with a high white count to splenomegaly. And a few, or any, with lymphadenopathy. These patients are somatically mutated. They don’t have the complex target type. They have a much more indolent course, and probably should be managed very differently.

And then, finally, I think one important aspect of molecular subtype is p53. Deletion 17p, at baseline, is not very common. It can happen. When you look at it by immunohistochemistry, or by mutation profile, there were several presentations at the 2017 ASH Annual Meeting confirming this.

Up to 23%, 25% of patients that present at baseline demonstrate p53 abnormalities. And these patients, obviously, even with the high-dose therapy, do poorly. I think this heterogeneity at the molecular level is reflected by what we already know from mantle cell lymphoma. When we describe the morphology of mantle cell lymphoma, we talk of pleomorphic variant, blastoid variant, and the nodular and diffuse patterns. In reality, all of this represents a sort of spectrum of disease. So, again, the indolent subtype, and then the rest of it that have a proliferation signature varies among patients and clearly affects their prognosis.

Transcript Edited for Clarity 
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