Tag Archive for: BCL-2

Notable New MPN Treatments

Notable New MPN Treatments from Patient Empowerment Network on Vimeo

What’s the latest in myeloproliferative neoplasm (MPN) treatments? Dr. Kristen Pettit from Rogel Cancer Center gives updates about treatment developments for myelofibrosis, polycythemia vera (PV), and essential thrombocythemia (ET) care including JAK inhibitors, BCL-2 inhibitors, BCL-XL inhibitors, BET inhibitors, and others.

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Transcript:

Dr. Kristen Pettit:

There are so many new treatments in MPNs that I’m excited about, so one that is investigational that has been moving through the pipeline is momelotonib, which is a newer JAK inhibitor for patients with myelofibrosis. The mechanism of action is slightly different than the other JAK inhibitors, ruxolitinib (Jakafi), baricitinib (Olumiant), and pacritinib that’s improved as well.

The hope with momelotonib is that it will do some of the good things that the other JAK inhibitors do reduce symptoms and reduce spleen size, but also potentially improve anemia for patients who struggle with anemia, which is such a high proportion of our patients with myelofibrosis. I think that’s one exciting thing, another exciting avenue are new potential up-front treatment strategies that are being studied, so there are a number of different clinical trials going on right now, testing the strategy of either standard ruxolitinib or Jakafi by itself compared head-to-head versus a combination of Jakafi plus another medication.

Those other medications that are being tested in trials include the BET inhibitor called parsaclisib, also BCL-2, BCL-XL inhibitor called navitoclax, and a Pi3 Kinase inhibitor called parsaclisib. These upfront head-to-head treatment strategies are going to be very important to keep an eye out for over the next couple of years. The hope is that these combination strategies could deepen responses and potentially prolong responses when a new drug is combined with the JAK inhibitor as the first treatment option for patients with myelofibrosis. In the later line setting, one thing that’s exciting is Imetelstat, which is a telomerase inhibitor.

This is the first study in my myelofibrosis that is trying to specifically prove whether or not it is linked in survival for patients with myelofibrosis. So, I think that’s very exciting and something to keep an eye out for.

In polycythemia vera, one newer treatment option that’s getting a lot of excitement is the Hepcidin mimetic called rusfertide, this medication will hopefully harness the body’s iron metabolism pathway and act as sort of a chemical phlebotomy as opposed to an actual therapeutic phlebotomy in order to control the hemoglobin and hematocrit for patients with PV as well as improve symptoms.

In ET the newer agents that are being investigated include the BET inhibitor parsaclisib, is also being studied for myelofibrosis as well as an LSD-1 inhibitor called bomedemstat. Both of these look exciting so far, as far as their ability to both control platelet count and improve symptoms for patients with ET.

Understanding Diffuse Large B-cell Lymphoma (DLBCL) and Its Subtypes

Understanding Diffuse Large B-cell Lymphoma (DLBCL) and Its Subtypes from Patient Empowerment Network on Vimeo.

What should patients know about diffuse large B-cell lymphoma (DLBCL) and its subtypes? Expert Dr. Loretta Nastoupil defines DLBCL, discusses the subtypes of DLBCL and reviews the potential impact on treatment options.

Dr. Loretta Nastoupil is Director of the Lymphoma Outcomes Database in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Nastoupil, here.

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Transcript:

Katherine:

So, let’s start with a basic question, what is diffuse large B-cell lymphoma or DLBCL?

Dr. Nastoupil:

That’s a really important question. And I spend a lot of time when I first meet patients explaining to them there are a lot of different terms that are thrown around in lymphoma. Particularly, non-Hodgkin lymphoma is a term many patients will hear and even use. And I remind them that that is sort of an umbrella term that describes essentially every lymphoma that’s not Hodgkin lymphoma.

So, it’s really important to recognize that there are unique types of large cell lymphoma. And almost everything that we care about in terms of what the treatment will look like, whether or not we’re aiming to cure someone, or just maintain adequate disease control is primarily focused on the type of lymphoma someone has.

So, diffuse large B-cell lymphoma is the most common lymphoma subtype. Just in terms of its descriptive name, it is a B-cell cancer. And it is comprised of large cells that are essentially effacing or replacing the architecture of a lymph node.

There are different types, which I’m sure we’ll discuss. But, again, diffuse large B-cell lymphoma is our most frequent lymphoma we encounter.

Katherine:

What is B cell? What does that mean?

Dr. Nastoupil:

Sure. So, stepping back a little bit, I think most people when they know or have known someone with cancer, it is described as the organ it originates in. So, breast cancer’s a great example. That usually is breast tissue that is abnormal. It has malignant potential. And if it spreads beyond its capsule and specifically goes to a lymph node or another organ, generally that’s bad news.

Lymphoma is a cancer of the immune system. And there are various types of immune cells. B cells – they mature on and become plasma cells when they’re behaving normally. And their job is to generate antibodies so that we can develop immunity from exposures or infections we’ve had and we’ve recovered from.

So, if you develop a cancer in the B cell, depending what stage of development – if it’s a stem cell, for instance, that can lead to acute leukemia. If it’s an immature B cell, meaning it has not developed into a plasma cell, that’s, generally, where diffuse large B-cell lymphoma arises. So, these cells tend to live or spend most of their time in lymph nodes because they’re trying to mimic the behavior of a normal B cell where they’re waiting there for that exposure to happen.

So, these are generally not cancers that we try to cut out before they spread. They’re not spreading cancers in terms of how we generally think of those, meaning you’re not going to use surgery to treat it. And, oftentimes, there are malignant B cells kind of dispersed throughout the body because if you think about how your immune system should work, it should be able to fight off an infection anywhere and everywhere.

So, I think those are key things to keep in mind because oftentimes patients will have widespread involvement or lymph node involvement or bone involvement, and that’s just the nature of the disease and not necessarily something that is so far progressed we didn’t catch it early enough.

Katherine:

I see. Are there subtypes of DLBCL?

Dr. Nastoupil:

Yes, absolutely. So, again, stepping back, over the last 20 years, we have tried to understand why we’re able to cure about 60 percent of patients. But for the 40 percent that were not cured with standard treatment, their outcomes were generally poor, meaning most of those patients died as a result of their lymphoma.

And we’ve approached all of them the same. So, that would imply to us that there’s something inherently different about the large cell lymphoma cases that don’t respond to standard treatment. So, an attempt to try and define who those patients are before we initiate treatment, as technology has evolved, we’ve interrogated some of those biopsy samples to try and understand is there an underlying biologic rationale as to why some patients would have very, very disparate outcomes?

So, what we’ve learned is there are genes that are differentiated between different subtypes of large cell lymphoma. And we’ve described those subtypes based off those gene expression patterns. So, there is a germinal center type of large cell lymphoma. There’s a non-germinal center or activated B-cell type.

And then it gets much more complicated meaning there’s probably far more than just two subtypes. Right now, we’re describing at least five different subtypes. I think what’s important for patients to know is that we view this in terms of being able to predict who’s not going to have the typical course. And if we can define who they are, we might pursue something different, including potentially a clinical trial.

So, the subtypes I care the most about right now in terms of defining are the double hit or double expressors, those with other features that might lend itself to targeted therapy.

So, this is an evolving field and will continue I’m sure – that will have more subtypes defined over time. 

What Are the Subtypes of DLBCL?

What Are the Subtypes of DLBCL? from Patient Empowerment Network on Vimeo.

What are the subtypes of diffuse large B-cell lymphoma (DLBCL)? Expert Dr. Robert Dean provides an overview of DLBCL subtypes and how treatments and outcomes can vary by a patient’s individual disease.

Dr. Robert Dean is a hematologist/medical oncologist at Taussig Cancer Institute at the Cleveland Clinic. Learn more about Dr. Dean, here.

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Transcript:

Katherine:

Dr. Dean, welcome. Would you please introduce yourself?

Dr. Dean:

Certainly, and thank you for having me. My name’s Rob Dean, and I’m a hematologist and medical oncologist and a staff physician at the Cleveland Clinic Taussig Cancer Institute.

Katherine:

Excellent. Thank you. Let’s start with looking at understanding and treating DLBCL. What are the subtypes of DLBCL?

Dr. Dean:

The classification of diffuse large B-cell lymphoma has gotten a little more complicated as our understanding of it has gotten deeper. Once upon a time going back maybe 15, 20 years an awful lot of cases were sort of lumped together under the broad label of diffuse large B-cell lymphoma and we always understood in the field that some patients did very well and were cured with the standard treatments of the time and that those treatments didn’t work as well for some patients.

And it’s taken years to get to a somewhat deeper understanding of what the underlying differences are in those cases that help to explain why our treatment outcomes differ for different patients, and I would say that’s feeding forward into trying to identify better treatment options for the patients who are in higher-risk groups. So, one way of understanding the heterogeneity in diffuse large B-cell lymphoma, the differences between cases, is to think about the way in which the normal cells of the immune system that turn into this kind of cancer develop. If you think about the old Time-Life Magazine illustration of the evolution of man where you see the series of figures drawn from left to right going from sort of more primitive, kind of a –

Katherine:

Ape-like.

Dr. Dean:

– ape-like figure to a progressively more modern-looking human standing upright and walking on just their legs. The way that these immune cells, which are the antibody-making B cells of the immune system, develop from a more primitive cell, you can think of it in similar terms. And we understand that cases of diffuse large B-cell lymphoma most commonly arise from a couple of points in that process of maturation that these cells are passing through as they go from the most primitive form that they take to their most mature functional form in the end.

So, one of those subgroups is something called the germinal-centered B-cell. And that involves the part of the maturation process where these immune cells have left the bone marrow, passed into a lymph node, and are interacting with other immune cells as part of their education and development process.

When the cells mutate at that stage of their development and turn into diffuse large B-cell lymphoma, the cure rate for patients with large cell lymphomas coming from that stage of immune cell development tends to be a little higher with standard treatments. When the lymphoma cells arise from an immune cell that has passed beyond that point in the maturation process to what is referred to as an activated B-cell, then the cure rates with standard treatment historically have been a little lower.

And so, you can look at markers on the lymphoma cells, or the activation of different genes in the lymphoma cells, to try to determine whether they came from an immune cell that was in one or the other of those points in its maturation process. And we know that that correlates with outcomes. So, that’s one of the main breakdowns that have become possible in understanding sort of what’s going on under the hood in diffuse large B-cell lymphoma and why do we see different outcomes in different patients.

Katherine:

Right.

Dr. Dean:

The other major change comes from understanding that for cases of large B-cell lymphoma there are common chromosomal changes that result in turning on specific genes. And if some of those genes are present in the right combination, that can create a much more rapidly growing and more chemotherapy-resistant form of large B-cell lymphoma. The two genes that are most commonly involved in that kind of a change are something called BCL-2 which, when it’s turned on abnormally, helps protect the lymphoma cells from being killed or being sort of triggered into dying by chemotherapy medicine.

And another gene that’s called MYC, or M-Y-C is how that’s spelled, and what that gene does is it tends to cause the cells to proliferate more rapidly.

It turns on other pro-survival figures and controls a pretty broad range of different programs that drive the cells to grow more quickly. So, when you’ve got both of those changes at the same time that’s sometimes referred to as a “double-hit lymphoma.” And large cell lymphomas with that double-hit kind of chromosome change have been shown in studies to have a significantly lower cure rate with our most commonly used standard treatment for this form of lymphoma, what we call R-CHOP.

So, being able to recognize those changes in cases of large B-cell lymphoma is important nowadays, both in terms of being able to share prognostic information with patients, to be able to tell them what we think the likelihood of not just getting into remission but eventually being cured will be. And also, for some situations, considering whether a treatment other than the standard R-CHOP regimen might be a better option. 

What Is Diffuse Large B-cell Lymphoma (DLBCL)?

What Is Diffuse Large B-cell Lymphoma (DLBCL)? from Patient Empowerment Network on Vimeo.

What is diffuse large B-cell lymphoma (DLBCL) exactly? Dr. Jean Koff shares information about this specific type of lymphoma and explains why subtypes of DLBCL are important in determining optimal therapy.

Dr. Jean Koff is an Assistant Professor in the Department of Hematology and Oncology at Winship Cancer Institute at Emory University. Learn more about Dr. Koff, here.

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Transcript:

Katherine Banwell:

Hello, I’m Katherine Banwell, your host for today’s program. Joining me is Dr. Jean Koff. Dr. Koff, would you introduce yourself?

Dr. Koff:

Hi, I’m Dr. Jean Koff. I’m a lymphoma specialist and clinical researcher at Winship Cancer Institute of Emory University.

Katherine Banwell:

Great. Thank you for joining us. Well, let’s start with a definition. What is diffuse large B-cell lymphoma?

Dr. Koff:

So, we may want to back up and actually define what lymphoma is, because that may be unfamiliar to patients who are just getting a new diagnosis. So, lymphoma is a pretty general term, but it refers to a cancer that arises from white blood cells called lymphocytes. And normally these lymphocytes are part of your immune system. Normally they help to fight infections and even tumors. But sometimes in some patients often for reasons we don’t fully understand these lymphocytes, these white blood cells, part of your normal immune system can grow out of control to the point that they become a cancer. And when they do that, that’s called a lymphoma.

So, diffuse large B-cell lymphoma or DLBCL, is the most common, aggressive form of lymphoma. And we call it aggressive because it tends to grow quickly, and it tends to cause problems quickly.

Katherine Banwell:

Are there subtypes?

Dr. Koff:

There are and there are several different ways that you can subdivide DLBCL. One of the most common ways that DLBCL researchers and clinicians think about it is breaking it up into ABC and GCB subtypes. And what these subtypes are, are reflections of how the tumor expresses different genes and that makes it potentially susceptible to different types of therapy. Although we’re still trying to figure out the best way to target these different subtypes. You can also divide DLBCL up by other genes that it may express.

Patients may be familiar with the term double hit lymphoma that refers to a large cell lymphoma that has re-arrangements of certain genes, mainly MYC and either BCL-2 or BCL-6.

And then, there are other definitions that we can apply to DLBCL based on where the lymphoma arises. So, as you can see, there are lots of nuances into subdividing, this disease. There are lots of different varieties, and there are lots of subtleties. But one of the main breakdowns is between ABC and GCB.