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The Biology of Follicular Lymphoma

Insights From:Bruce D. Cheson, MD, FACP, FAAAS, Georgetown University Hospital; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine; Richard R. Furman, MD, Weill Cornell Medical College
Published: Monday, Jan 18, 2016



Transcript:

Richard R. Furman, MD:
One of the important things about follicular lymphoma is really trying to predict the clinical behavior that the patient's going to demonstrate at time zero. And certainly understanding the pathology is a very important component of that. With that in mind, the WHO is convening a session in 2016, which will relook at the follicular lymphoma category.

And right now while we, in general, say that follicular lymphomas, 1 and 2, and perhaps even 3a, all share similar biological behaviors and responses to therapies, we're going to start finding individual characteristics at a genetic level that might predict for different aspects. And so the hope is that one day, you will have a pathological diagnosis of follicular lymphoma, but with that you'll get a sub-classification, a, b, or c, which will tell you who are those patients that are going to do extremely well versus those patients who are not.

And when you're dealing with a disease like follicular lymphoma, it really becomes important to identify who, if they're young, you want to do something major like an allogeneic transplant with versus someone who you might be able to treat for years and years and years with much more benign therapies.

Bruce D. Cheson, MD: What we've recognized in recent years is that when the B-cell receptor is stimulated, it activates a number of pathways within the cell that result in proliferation and longevity of the malignant cell. These pathways include SYK, BTK, PI3K, and a number of others. And importantly, we now have the idea that we can target these pathways, resulting in the inhibition of the growth and proliferation of the malignant cells to get a therapeutic benefit.

Shuo Ma, MD, PhD: Follicular lymphoma is a very heterogeneous disease. While most of the patients have a very indolent course, there are a small number of patients who can have a very aggressive course. So, in order to try to understand the heterogeneity of the biology, there have been a lot of studies, including a whole genome gene expression profiling of the lymphoma tissues. Interestingly, when you're looking at the gene expression profiles of the malignant B-cells, there's actually no correlation of that with the prognosis.

But if you're looking at the normal cells in the lymphoma tissue—the lymphoma infiltrating normal immune cells—the gene expression profiling of those immune cells actually correlates with the prognosis of follicular lymphoma.

This is really pointing to the importance of the microenvironment. As we know that tumors are not really living on their own, they really need the support from the environment they're living in. So in the case of follicular lymphoma, it’s the immune cells and the stromal cells, and also the cytokines, that are in the lymph nodes surrounding those malignant cells.

Those microenvironment signals provide the important survival signal and stimulate a tumor proliferation. There are actually a lot of the novel therapies that are targeting the microenvironments. For example, the B-cell receptor pathway inhibitors such as ibrutinib and idelalisib both are targeting the B-cell signaling pathway that is blocking the interaction between the tumor cells and the microenvironment.

And there are also immune therapies, such as immune modulatory agents like lenalidomide, and also the checkpoint inhibitors, such as the PD-1 and PD-L1 inhibitors. All of those therapies are actually targeting the interaction between tumor cells and the surrounding normal immune cells.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Richard R. Furman, MD:
One of the important things about follicular lymphoma is really trying to predict the clinical behavior that the patient's going to demonstrate at time zero. And certainly understanding the pathology is a very important component of that. With that in mind, the WHO is convening a session in 2016, which will relook at the follicular lymphoma category.

And right now while we, in general, say that follicular lymphomas, 1 and 2, and perhaps even 3a, all share similar biological behaviors and responses to therapies, we're going to start finding individual characteristics at a genetic level that might predict for different aspects. And so the hope is that one day, you will have a pathological diagnosis of follicular lymphoma, but with that you'll get a sub-classification, a, b, or c, which will tell you who are those patients that are going to do extremely well versus those patients who are not.

And when you're dealing with a disease like follicular lymphoma, it really becomes important to identify who, if they're young, you want to do something major like an allogeneic transplant with versus someone who you might be able to treat for years and years and years with much more benign therapies.

Bruce D. Cheson, MD: What we've recognized in recent years is that when the B-cell receptor is stimulated, it activates a number of pathways within the cell that result in proliferation and longevity of the malignant cell. These pathways include SYK, BTK, PI3K, and a number of others. And importantly, we now have the idea that we can target these pathways, resulting in the inhibition of the growth and proliferation of the malignant cells to get a therapeutic benefit.

Shuo Ma, MD, PhD: Follicular lymphoma is a very heterogeneous disease. While most of the patients have a very indolent course, there are a small number of patients who can have a very aggressive course. So, in order to try to understand the heterogeneity of the biology, there have been a lot of studies, including a whole genome gene expression profiling of the lymphoma tissues. Interestingly, when you're looking at the gene expression profiles of the malignant B-cells, there's actually no correlation of that with the prognosis.

But if you're looking at the normal cells in the lymphoma tissue—the lymphoma infiltrating normal immune cells—the gene expression profiling of those immune cells actually correlates with the prognosis of follicular lymphoma.

This is really pointing to the importance of the microenvironment. As we know that tumors are not really living on their own, they really need the support from the environment they're living in. So in the case of follicular lymphoma, it’s the immune cells and the stromal cells, and also the cytokines, that are in the lymph nodes surrounding those malignant cells.

Those microenvironment signals provide the important survival signal and stimulate a tumor proliferation. There are actually a lot of the novel therapies that are targeting the microenvironments. For example, the B-cell receptor pathway inhibitors such as ibrutinib and idelalisib both are targeting the B-cell signaling pathway that is blocking the interaction between the tumor cells and the microenvironment.

And there are also immune therapies, such as immune modulatory agents like lenalidomide, and also the checkpoint inhibitors, such as the PD-1 and PD-L1 inhibitors. All of those therapies are actually targeting the interaction between tumor cells and the surrounding normal immune cells.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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