2020 Patient Seminar
October 25, 2020
Hosted by the Hairy Cell Leukemia Foundation with Dr. Kerry Rogers from The Ohio State University and Dr. Robert Kreitman from the National Institutes of Health (NIH). Moderated by Anna Lambertson from the Hairy Cell Leukemia Foundation.
Presentation Materials
Materials from the presentation and discussion with Dr. Rogers:
View a recording (audio and synced slides) of Dr. Rogers’ presentation. (The file may take a few seconds to load.)
Materials from the presentation and discussion with Dr. Kreitman:
View a recording (audio and synced slides) of Dr. Kreitman’s presentation. (The file may take a few seconds to load.)
Transcript of Presentations and Question & Answer Sessions
The following is a transcript of the 1.)Presentations given by Dr. Rogers and Dr. Kreitman and 2.) Question & Answer sessions with participants.
Presentation by Dr. Kerry Rogers, The Ohio State University
Dr. Kerry Rogers:
Hairy cell leukemia - I like to explain it as a chronic cancer of blood cells. So this is a blood cancer and the blood cells that become leukemia cells or cancer cells are called B lymphocytes. So those are immune system cells and B lymphocytes are a type of white blood cell.
Some people call it a cancer of white blood cells or blood cancers or bone marrow cancers. But really you can think about it as a cancer of B lymphocytes. So it's a cancer of white blood cells that are immune system cells. So hairy cell leukemia is quite rare. It's only 2% of adult leukemias. Most oncologists in general practice, will maybe just see a few people in their entire career that have hairy cell leukemia, or sometimes never see anyone that has this.
And unlike another disease I work in called chronic lymphocytic leukemia, that's the most common adult leukemia, this one's so rare that patients that don't participate in groups like the Hairy Cell Leukemia Foundation has may never meet another person that has this. So, it's actually quite uncommon. The WHO, which is the World Health Organization has a classification that they put out that doctors use to decide what categories different cancers fall in. And it gets revised frequently, but they recognize two types of hairy cell leukemia.
When we talk about hairy cell leukemia, and most of what I'm going to talk about today is really referring to the classic form of hairy cell leukemia. And that's by far the more common forms, it's about 90% of hairy cell leukemia, but there is also a variant of hairy cell leukemia and that's treated slightly differently. So anyone with a variant of hairy cell leukemia has an even more rare type of leukemia.
It's also important to think about who is most likely to get hairy cell leukemia. So the median age that people are diagnosed with it is 55 or around 55, but there's plenty of people in their 30s and 40s that get diagnosed with it. Also, people in their 70s and 80s. So while this is a leukemia that occurs pretty much exclusively in adults and not in children or teens, it does have a spectrum, but around 55 is kind of the median.
Dr. Kerry Rogers:
This is more common in men. So it doesn't mean that women don't get it, but there's about four men for every one woman that gets hairy cell leukemia. So there's more men living with this. And then the last thing I want to mention is just that the expected survival specific to hairy cell leukemia is decades. So for many people living with hairy cell leukemia, this won't shorten their natural life span, meaning they don't necessarily die of hairy cell leukemia and can go on to live for decades.
Someone who had done one of the initial descriptions of hairy cell leukemia was at my institution and that's Dr. Bertha Bouroncle, and there's a picture of her there. Hairy cell leukemia was initially described by two different groups and it was called leukemic reticular endotheliosis and that's based on the pathologic description. We've now come to know this entity as hairy cell leukemia.
So at the time that it was initially described, the survival from hairy cell leukemia was quite short. So people were only expected to live a couple of years with the disease and there weren't effective drug therapies for it.
However, this is a completely different picture today, now that we have highly effective therapies to treat HCL. So just a plug for the science behind this; until you've described something and have a way to study treatments for it, that's how you help people that are living with this live longer and better.
Dr. Kerry Rogers:
So the diagnosis of hairy cell leukemia is really made by finding the leukemia cells in the body. And again, this is a cancer of blood cells, so they like to go where blood cells are. So they're found in the blood, sometimes the bone marrow, you can see them in the lymph nodes and actually in the spleen. So those are really the common areas. Although, you can see hairy cell leukemia cells elsewhere in the body.
Unlike solid tumors, like breast or lung cancer, where if they've spread throughout the body, it's a different prognosis and outcomes, these are blood cancers. So I like to tell people that blood cancers go anywhere that the blood can go, which is everywhere. So just because it's in the blood doesn't mean that it's different. So you cannot think of hairy cell leukemia in the same category as other types of solid tumor cancers you might've heard about.
And then the diagnosis requires doing a biopsy or taking some of these cells and verifying that they're hairy cell leukemia cells. So, that's really how the diagnosis is made. Most commonly, that's a bone marrow biopsy that's done to verify that. And you look at the leukemia cells in the bone marrow.
So the leukemia cells are identified by two different ways. One is really the appearance of them. Hairy cell leukemia has a very specific appearance to the actual leukemia cells. The technical word we use for this as doctors is called morphology, which is the way they look. And I'll show you a couple of pictures of hairy cell leukemia cells in a minute, but they have hair-like projections on them. So it really has a very unusual and specific appearance.
And then the other thing that's commonly used to identify and differentiate between different types of blood cancers and leukemias is which markers they have on their surface. So the things I've listed out after cell markers are the markers that we look for in hairy cell leukemia. And there's two ways that we test for these markers. One is a test called flow cytometry. They paint the cells with these antibodies coated with fluorescent markers and fire them in front of a laser. And then they look to see what markers are present on these white blood cells.
The other way is when you get a biopsy, which is very important in hairy cell leukemia. If you do a core bone marrow biopsy, they take that small piece of bone marrow and use a technique called immune histochemistry to put stains on for the different markers, so you can see where they are in the bone marrow.
So those are the two common tests that you'll see that get done to look for these cell markers, which is really important.
And then lastly, there's a specific mutation that is seen in classic hairy cell leukemia called the BRAFV600E mutation. So when you hear mutation, please understand this is a mutation only in leukemia cells. So it's not like mutations that you pass on to your family and other people get tested. It's just in the leukemia and it's a mutation that helps to make the leukemia cells, leukemia cells. And if this mutation is present, it very much supports the diagnosis of classic hairy cell leukemia, because the vast majority, around 98% of classic hairy cell leukemia will have this specific mutation. So to make the diagnosis, you have to use these techniques to verify the presence of leukemia cells in the body.
Dr. Kerry Rogers:
Here are some pictures of hairy cell leukemia cells. This is taken in the blood. I've put little red arrows for anyone that's not used to looking at blood films. The pinkish stuff in the background is actually red blood cells on the slide when they made these. So you can see those kinds of round purple-ish blue cells. The darker part is the nucleus. And then you can see there's a lighter blue purple part and that's the cytoplasm or kind of the liquid part in the cells.
And then you can see the edges of them look fuzzy. So it almost looks like it's blurry or out of focus or kind of fuzzy like carpet. That's actually the hairs. The hairy projections give it kind of that fuzzy appearance in a ring around the edge of the cell. So these are very classic pictures of what hairy cell leukemia looks like under the microscope.
Dr. Kerry Rogers:
And then here's some pictures of the bone marrow. So the one that has more pink in it on the left side of your screen, that's a picture of a bone marrow core biopsy. The white parts are fat in the bone marrow, and it's supposed to be in the bone marrow. So don't worry about that, but you can see there are quite a bit of cells in there. And then the pink-pink is actually a bone that's in the image. So if we look at this, this is a farther out view. So you can't see the morphology or the appearance of the cells very well.
And then on the right side, there's actually a reticulin state. So hairy cell leukemia can cause the bone marrow to fill up with these fibers that replace some of the bone marrow. And this goes away with treatment and is a feature of hairy cell leukemia. So you can do a special stain and there, you can see the arrow is pointing to something that looks like a cobweb. That's kind of all over the bone marrow there. And that's actually some of the reticulin fibrosis that you can see in people that have active hairy cell leukemia.
Dr. Kerry Rogers:
So, that's what the pathology looks like. So you're all wondering what the clinical features are. And these are just the common ones. Everyone's experience is different. Sometimes people have things that are specific to their hairy cell leukemia that other people don't have, but I've put some common ones up there.
Frequently fatigue too, can be from a low red blood cell count or anemia that happens in hairy cell leukemia. That's not always just from having the cells in the body, but from having low blood counts or low red blood cell count related to that. And then people can get what I call constitutional symptoms. I guess the way to explain it is that since hairy cell leukemia cells are cancerous immune system cells, they can release some of the chemical mediators that immune system cells are supposed to release during infection. So it can make people feel sick and fatigue, weight loss, night sweats, or sometimes just low energy.
So not super common to have severe fatigue, but certainly it can occur.
Blood counts are an extremely common feature of hairy cell leukemia. And the ones that we really think about a lot are neutrophils, which are the white blood cells that fight bacterial infections. Because when those are low, people can get life threatening bacterial infections quite frequently. Red blood cells, which of course, low red blood cells are anemia. Those are the Frisbee looking ones that carry the oxygen and you see on Red Cross posters. And then platelets, which are the cells that help blood clotting. So if the marrow, your bone marrow, which makes all your blood cells gets replaced by leukemia cells or that fibrosis I showed you, your bone marrow can't make the healthy blood cells you need to function. So, that's something that can happen in hairy cell leukemia and people sometimes don't realize they have this and end up with extremely low blood counts.
Dr. Kerry Rogers:
Other things you can see, sometimes you can see leukemia cells in the blood. An enlarged spleen is actually a very common feature for hairy cell leukemia. Sometimes, so large, your spleen is supposed to fit up under your rib cage on the left side, between your diaphragm and kind of the edge of your ribs there, you can see it actually extend down into people's pelvis sometimes because it expands in your abdomen where there's a lot of space. So this can be painful. This can interfere with eating or make you feel full fast.
Sometimes it doesn't cause too many symptoms until it's quite large, but that's real common. And then, especially after people have had it awhile, you can see enlarged lymph nodes and bone lesions have been described. So there's actual hairy cell leukemia clumps in the bone that you can see on x-rays.
And then the last two are directly from the leukemia, but they go along with having it. So people with hairy cell leukemia live at a much higher risk for infections, including opportunistic infections, which are infections you get because your immune system's not working right. And the simple way to think about it is that hairy cell leukemia is a cancer of a type of immune system cells. And it modifies the way your immune system works. So it's less able to protect you from infections.
And then some people get associated autoimmune disorders such as inflammatory arthritis or immune destruction of blood cells. So there are a couple of features like that, that some people get.
Dr. Kerry Rogers:
So a bit about when to consider treating hairy cell leukemia. So as I said, people live with this for decades, so you don't want to do anything that's not going to improve their life or wellbeing. Treatment of hairy cell leukemia is really only needed when there's something you need to improve.
So if this gets diagnosed in someone with no symptoms and relatively normal blood counts, you don't have to treat it just because it exists. And so far we know that early treatment of course exposes people to side effects from treatment earlier. But right now we don't know that it has any long-term benefit or help to them to treat hairy cell just because you have it. So there is about one in 10 people that don't need treatment at the time it's diagnosed and can just be observed, which means regular visits with your doctor to make sure you don't get sick from it and treat it at the right moment.
So you want to take a treatment before you get horribly sick from it, but you don't need to take a treatment when you're doing really well and there's nothing that needs to be improved.
So the standard treatment indications are what doctors use to decide whether or not someone might need treatment. So they're not absolute, they're just things to consider, kind of a guideline.
The most common one usually is low blood counts. So if you see an absolute neutrophil count less than one, which is 1000 per microliter, and usually not just once, but consistently in that range, unless all blood counts are very low, everyone's situation is different, but if blood counts are relatively normal and drop, you want to make sure it's consistently below these marks. Hemoglobin less than 10 or 11, consistently and decreasing. And this has to be from hairy cell leukemia. So if you get iron deficiency and your hemoglobin drops then that's different, you can take iron instead of treat hairy cell. And then a platelet count less than 100, which is a hundred thousand per microliter.
Dr. Kerry Rogers:
If your spleen is in your pelvis and it's causing you problems, very good reason to treat. Usually the spleen won't go back to exactly the size it was before treatment, but certainly it won't remain massive to that degree. And then enlarged lymph nodes or bone lesions, or if you get those constitutional symptoms that are so severe that it's interfering with your daily life or your ability to function. Many people live with mild chronic fatigue, which may not be improved with treatment.
Dr. Kerry Rogers:
So before starting treatment, a couple of things just to keep in mind. One is that a bone marrow biopsy is very helpful. One is you have to make sure if you're being treated for low blood counts, that it is actually from hairy cell and not a second thing that happened to you. if you have iron deficiency, chemotherapy for hairy cell leukemia isn't going to fix that. So you want to make sure you know what's going on in the bone marrow before you start treatment and also where you started out at so that if things do or don't go according to plan later, you can see where you're at by knowing where you started.
For purine analogues, particularly you want to assess kidney function or any other organ function that might be necessary for the treatment you're going to get. Testing for viral hepatitis, particularly hepatitis B, if you're going to take a treatment called rituximab.
And then the last part is very important and that's investigation for any infection. So if anyone has any symptoms or location where they might have an infection, it's really important to figure that out before you start a treatment. Most of our treatments suppress the immune system further. So you don't want to have some sort of infection that's not causing problems, take treatment and then get horribly sick.
And we've all seen this as people that treat hairy cell leukemia as doctors, where someone doesn't have any evidence of infection gets a purine analog treatment ends up with an infection and then when we go back and talk about things, say, “Oh, that probably was something that was controlled by your immune system that you had for a while and now has become apparent after.” And the one I'm thinking of off the top of my head is someone with cryptococcal meningitis. So it's just very important to talk to your doctor about anything that could be a sign of infection. And there are definitely ways to treat hairy cell leukemia in people with an active infection, but requires a lot of special planning. So you have to know about that before you just launch into a treatment.
Dr. Kerry Rogers:
So these are the most commonly used treatments. Cladribine and pentostatin are equally effective, but the dosing scheme between the two is extremely different. So you really want to talk to your doctor about the dosing scheme for either of these before you start them. Their difference is really in how it's given, but the outcomes for people that take them are, as far as we know, the same. Both have extremely high remission rates and almost 80% complete remission depending on which study you look at. And this will result in between two or 10 or more years of remission.
Usually it's around seven or eight years before people need to take treatment again, if it's two years that's really short. So you need to have a talk about whether or not that worked as well as you needed it to and what to do next. I've seen some people that took a single course of Cladribine and are still in remission 20 plus years later. So, there is a spectrum of how well people do and this class of drugs, both cladribine and pentostatin are what have really changed how long people live with hairy cell leukemia from an expectation of two or three years, to an expectation of more than two decades. So this class of drug is what initially moved the mark.
Dr. Kerry Rogers:
What I have listed under other treatments is really things that are continuing to really benefit people with hairy cell leukemia. And these drugs have become kind of under investigation or newer more recently and are in many cases, suited for people that didn't get a benefit that they needed to out of purine analogues, only got two years or three years of remission after a couple of courses. You can get purine analogues repeatedly. And if you take it once every 12 years, well, that's pretty good, but you can't really take it once every two years. That's not a good scheme.
So these other drugs are also suitable for people who have either other health conditions or side effects that means that they shouldn't take purine analogues. So moxetumomab pasudotox; it's an FDA approved antibody drug conjugate that was approved in the last year and a half that's been outstanding. Vemurafenib which is an oral targeted drug approved right now, only for melanoma, but very well studied in hairy cell. It targets that BRAF mutation I mentioned. So you have to have that mutation to use it, but it can be really important for select patients. There's anti-CD20 monoclonal antibodies. There's two, rituximab and obinutuzumab. Rituximab is more commonly used. And these are generally combined with either a purine analog or something like Vemurafenib.
And then a drug that I have put a lot of work into investigating, which is an oral targeted agent called Ibrutinib that targets B-cell receptor signaling, which is a signaling pathway in cells by targeting a protein called Bruton's tyrosine kinase. And I currently lead a phase two study that's sponsored by the NIH investigating ibrutinib in hairy cell. It is FDA approved for four other types of cancer right now, but not hairy cell.
Dr. Kerry Rogers:
I just want to stress that health maintenance is really important. So people living with hairy cell leukemia, again, live decades, but you're at higher risk for infections and other cancers due to immune dysregulation. So make sure you have a good sit down with your primary care physician going over all age and risk appropriate cancer screenings based on family history and that's for, colon cancer, breast cancer and then particularly skin cancer screening is very important. People with hairy cell get a lot of skin cancers. And sometimes it's not even the skin cancers that spread throughout the body, but if you don't get them removed fast, it can be a very bad cosmetic problem when they are finally removed, because it's harder to remove them when they're bigger. And then make sure you get all the vaccinations that are recommended avoiding live vaccines because we don't test live vaccines in immunocompromised individuals.
There can be long-term side effects from treatment. Most importantly, immunosuppression, especially from purine analogs. That lymphocyte immunity can be suppressed for a very long time, years. And then these newer targeted drugs, I mentioned can have long term side effects too, when you take them. So that's important to realize for people's health.
And then the last point is just if people are going to live a long time with this, you can't stop managing your other health conditions. So make sure that you're still not eating bacon every day and exercising. If you have diabetes managing that, take care of your other health, just because you have something with leukemia in the title, doesn't mean that you can ignore everything else going on with your health.
Dr. Kerry Rogers:
This is a slide where these are issues people mention to me all the time about living with hairy cell leukemia that I sometimes don't feel well equipped to help them with, but I know affects the people I take care of hairy cell. So sometimes repeated treatments can be very stressful. Living with a rare chronic disease can be really anxiety provoking, especially if you don't know other people with it. And your doctor tells you, they've never seen anyone with this before. Then there's social stressors so medical bills and also those insurance statements, which even if the financial outcome isn't that bad, you don't have to pay a lot of money for your medical bills, just getting all that paperwork can be tremendously stressful, difficulty getting things like life or disability insurance. People have problems with their work if they need time off for treatments, financial stressors. So all these things are extremely important.
And I have other people on my team that can help people with some of these things. And just finding an experienced medical team can be challenging. Here's some current research questions that I think are pressing, although I'm not going to talk about this too much. And I know Dr. Kreitman is going to talk a lot about treatment, but I think the last one, there is something that's very important, which is we don't know too much about how living with hairy cell leukemia impacts quality of life. As hematologists and oncologists, we focus a lot on how well we're treating the disease and not how much this affects other aspects of our patient's lives. And I think if people are going to live for decades with hairy cell, that's important to think about.
Dr. Kerry Rogers:
And then something I'm sure all of you are thinking about as am I in recent months, which is considerations during the COVID-19 pandemic. So you'll see a lot of headlines about people with cancer and how they do with COVID, but I want you to remember that not all cancers are the same. So understanding how people with breast cancer getting chemotherapy do, if they get COVID may or may not be applicable at all to people who have been in remission with hairy cell leukemia or just received a purine analog. These drugs I'm talking about Cladribine and pentostatin are amazing for treating hairy cell, but do deplete lymphocytes, which are the type of immune system cells that protect us from viral infections like COVID. So just keep in mind if you're seeing data on cancer, that it might not be specific to hairy cell leukemia or treatments for hairy cell leukemia. So there's no high-quality data specific to hairy cell patients yet.
Dr. Kerry Rogers:
I do think that risk for severe infection from SARS-CoV-2, which is the virus that causes COVID-19 is likely to be increased in people with hairy cell. And what we've seen from other types of blood cancers too, is that age and other health conditions don't matter. So I do think that someone who is 32 and in remission from hairy cell having taken treatment three years ago is going to have a better outcome from COVID-19 than someone who is 92 and got treatment last week. So these things still matter a lot. I would love to tell you, I had a better handle on everyone's individual risk and I don't, but talking to your healthcare providers about this and thinking about what's going on in your community matters. I think I already said that the treatments they suppress lymphocytes, which is the immunity needed to fight viruses. So we're still figuring out how the specific treatments for hairy cell might affect people's risk of getting severe COVID-19. If they get the SARS-CoV-2 virus.
Dr. Kerry Rogers:
And then people ask me all the time, Can I get this vaccine? Is it a live vaccine? Am I going to be able to get the vaccine? Are they testing the vaccine in immunocompromised individuals? And what I've told everyone is until I know what vaccine and have seen some of the data with it, I can't help you understand whether or not that vaccine will be right for you or will work for you. But any vaccine that's suppressing the amount of COVID-19 in your community is likely to be helpful as well. So even if all the healthy people, without other conditions get vaccinated, that's going to help you out too by reducing spread.
Question & Answer Session with Dr. Rogers
Anna Lambertson:
So earlier on in your presentation, you talked a bit about the BRAF mutation and you said that this is not the type of mutation that individuals would pass on to their children. So it's not considered to be genetic. We do hear from individuals who, for example, they and their brother both had hairy cell leukemia, which certainly isn't very common or there are multiple members of the family, perhaps two different generations who had HCL, could you speak a bit to that in terms of what we understand to be genetic or not genetic in HCL?
Dr. Kerry Rogers:
The BRAF mutation is a mutation that acquires or occurs in B lymphocytes as part of their process towards becoming cancer cells. So that one is not heritable, but there are many people that have hairy cell, their friends and their family. And actually there's people with cancers of B lymphocytes. Remember I said, the B lymphocyte was kind of the cell that became hairy cell leukemia. There's other cancers of B lymphocytes like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, which I mentioned is common. And you'll see families where, in CLL about 10% of people have multiple family members with it, if they're diagnosed with it and actually just B-cell lymphoma. So you'll see someone with hairy cell, some of them with CLL and someone with a diffuse large B-cell lymphoma, all in the same family.
So we know that these things are inherited and that some families have something where they get this. So we know that that is true, but in medicine and science, there's lots of things that we know are true, but we don't know why they're true. This is not a focus of my research, but there are groups that have looked into why it is that these families get these B-cell cancers. And so far it's been fairly disappointing, but not for lack of effort. So there's people that were willing to allow themselves and people in their family to undergo sequencing tests to try to figure out which genes are involved.
Anna Lambertson:
Why is Vemurafenib not standard for first-line treatment? So that's the first part of the question. And then the second part of the question is related to COVID-19. Can you speak a bit about as a practitioner, the decisions that you're making in administering Vemurafenib rather than purine analogs for a patient here in the midst of COVID-19.
Dr. Kerry Rogers:
So Vemurafenib given by itself, it's approved for melanoma. People with metastatic melanoma don't live as long. So they usually take it until it stops working, which is usually less than two years. People with hairy cell leukemia are expected to live decades and it's not currently given for decades because of side effects. So the treatment duration for Vemurafenib is nice because it's short. So usually it's given for less than six months.
The response rates are nearly a hundred percent, but the amount of time that people remain in remission is short. So less than two years, generally, even for people that have a complete remission where you don't see any detectable hairy cell in the bone marrow at the end. So when you're looking at purine analogues as a first treatment where your remission duration might be two decades and a median would be seven or eight years, you don't want to give something where the median is somewhere around 16 months. You're not going to get as long of a remission or as much benefit from it as a first treatment.
The data I'm talking about with Vemurafenib is in people that have been treated before. So, the reason it's not currently used as an initial treatment is because the remissions aren't expected to be as long. However, there is a very serious effort to study it in combination with either rituximab or obinutuzumab including as a very first treatment for hairy cell leukemia. And I think that in the future, depending on how people do, especially with this combination with anti-CD20 monoclonal antibodies, either rituximab or obinutuzumab, how long they stay in remission, that there's a possibility this could be recommended as an initial treatment based on effectiveness of it.
And it certainly wouldn't be wrong to use it as a first treatment in someone that needed it for another reason. So I've given it as a first treatment multiple times in people presenting with severe infection. So somebody gets diagnosed with hairy cell leukemia and blastomycosis pneumonia, which is a fungal infection. I've given them Vemurafenib, because you should not get this before the pandemic. Should not give people with active infections purine analogues. And it works very fast. Blood counts recover within weeks. So it's an outstanding therapy that can be used in circumstances like that, where you want to get someone better and fix their infections. Then you can go on and give them the pentostatin later or the Cladribine later to get them their multiple years of remission.
It can be used as a first treatment in special circumstances. As we're studying it now as a first treatment, particularly with things like obinutuzumab, it may become an option for first treatment, just as a standard and not just in these cases where it's needed for people with infection and so on. So based on that answer, you're probably guessed what I was going to say about the pandemic. There are two things here. We all believe that these purine analogues that deplete lymphocytes and increase risk for infections, right when you get them increased risk for a bad outcome from COVID. And I mean, I actually haven't talked to anyone that doesn't believe that that's likely to be true, so there's no high-quality scientific evidence yet, but when you see other infections emerge, including viral infections, after giving these drugs, you would expect this to be more risky in a time when people can contract a potentially deadly pandemic virus.
However, again, like I was saying, the outcomes in terms of how long people are being in remission is much longer with purine analogues. So I think this is related to people's risks. So if someone has an extremely low risk lifestyle, lives in a place where there's no COVID like one of our colleagues in Australia said, we don't really have a lot of COVID, I'm going to keep using Cladribine. That makes sense. Or if someone really is in a situation where they can minimize the risk of COVID quite substantially, I think it's very reasonable to give the purine analog and get the long remission duration, because right now it is a more effective treatment for the hairstyle. That being said, there's plenty of people that can't reduce their risk of COVID to low, either they have families like children that need to go to school for their wellbeing or jobs where they might be exposed like people who are healthcare workers.
Although PPE works and healthcare workers are safe. That's more risky than being at home all the time. So for people that are at high risk for COVID are worried about it, or are unable to minimize their potential exposure, I have offered people Vemurafenib as treatment. It is much less suppressive of lymphocyte immunity. I personally do not feel it would be as risky in terms of increased risk of severe COVID-19, if people were to get SARS-Covid-2.
And again, if you're just trying to get through a pandemic, if you get a year or more of remission out of Vemurafenib and then you can go on at a time when the pandemic is controlled to get purine analog therapy. So I've definitely done that, especially for people that couldn't reduce their risk of COVID-19 exposure. And I think that's an extremely important conversation that anyone needs to have with their physician, treating them for hairy cell about what their life is like, what their COVID risk is like and what their hairy cell treatment options are. So I do think that's a really important consideration during this pandemic. And I know a lot of other physicians that treat hairy cell have had this conversation as well with similar conclusions. So there's no right or wrong for any individual, but I do think Vemurafenib can and should be used for people at high risk of getting COVID-19 just because it's less immunosuppressive.
Anna Lambertson:
Could you talk a bit more about chronic fatigue? And also, there is also some curiosity from individuals about osteoporosis and other issues with bones and whether or not there's a correlation between those bone issues and hairy cell leukemia?
Dr. Kerry Rogers:
Fatigue is extremely complex. So there is multiple factors that go into it and hairy cell leukemia is definitely one of those, but also sleep apnea is one of those, work hours and sleep quality is one of those, emotional stress is one of those. So I like to think of fatigue as a pot where multiple factors go into it. And it kind of adds up to what fatigue people are experiencing. I do think chronic fatigue with hairy cell leukemia is real, and this is something that people are really experiencing. So I would not tell someone that it is in their imagination. And then what I like to tell people is that you need to address all the factors that are leading to your fatigue, if you want to feel better.
So you can't say, I'm only going to address my sleep quality, or I'm only going to address my leukemia. You really want to do even things with mental health that are causing fatigue. You really do have to address everything that goes into that. There are many people with hairy cell leukemia that are living with mild chronic fatigue that might impact their daily life in some way. However, the kind of fatigue that usually leads a physician to want to treat someone on that basis is stuff that impacts their ability to work. I had someone, actually it was someone with chronic lymphocytic leukemia, not hairy cell leukemia. So it's another diesel licensee, but this person literally was so tired. He could not get his mail from his front porch. So someone else was so tired. She couldn't go to her full-time job and couldn't even finish making soup without lying on the floor. So these are very striking things that you give treatments and people get better and go back to work.
People that are living with mild chronic fatigue, it's usually not successful to give a cancer treatment to fix that. One, because while the leukemia could be contributing, there are other things that contribute too and two, it's not severe enough that we can fix it. So it is real, it really exists. And for fatigue that's not clearly from disease and clearly severe enough that we can fix it with treatment. It's a frequently very frustrating experience for many patients. And then you just try to do kind of address anything that could be contributing and then sometimes moderate exercise helps, but I'm telling you it's real, but I'm also telling you that unless it's severe, it's not always something that I can fix for people.
I do you not know of any correlation between osteoporosis, which is low bone density and developing bone lesions. So bone lesions occur in about two to three percent of people with hairy cell leukemia. They're kind of tumors within the bone that are hairy cells. And I actually don't know if that being correlated with other markers of bone health, such as low bone density from other reasons. So I'm not sure there's an association there. So I don't know that osteoporosis increases your risk of bone disease from hairy cell. It's interesting, but I don't know that we know that.
Question from webinar participant:
I'm 28 years post-chemo from 2-CdA cladribine that I actually had as an experimental protocol. My platelet count has been chronically low in the range of between 85,000 and 100,000 for several years now. My annual flow cytometry studies have been negative. Bone marrow biopsies have been negative. In addition, CT studies have shown my pancreas to be atrophied. My question to you is, is there any studies or any indication that the long-term effects in the cladribine would cause that problem?
Dr. Kerry Rogers:
I actually don't know of any data that cladribine would cause pancreatic atrophy. I have seen many people that get a purine analog either 2-CdA, which is Cladribine or pentostatin that end up with chronically low platelet counts. I don't know if it just causes bone marrow injury to the extent that the platelet counts are certainly enough platelets that the range you described is, well less than a hundred is usually when people think about treatment. I see a lot of people with platelets that are between 80 and 100 for years, and they're completely fine and that's enough platelets to live your life and not have bleeding. I see some people where platelet counts don't actually recover to what we call normal levels after treatment. And some people that still carries on the bone marrow that have platelet levels and that range for a very long time. So kind of mild low platelet levels can be something that is seen after getting something like Cladribine.
Question from webinar participant:
First of all, I just want to thank you and your colleagues so much for your dedication to this disease. My question is hairy cell the classic and variant is one of a handful of unusual cancers and the mutation almost defines the cancer if you will. I mean, we know BRAF exists in other cancers, but most are much more heterogeneous in their mutation population. What does that mean or is hairy cell and some of these others kind of a unique opportunity for research in better understanding cancer development in general? Is there a significance to these cancers that have such a homogeneous mutation population?
Dr. Kerry Rogers:
So you're asking a fantastic question about cancer biology. I think it's actually a good question for the field in general. So I wish that was something I could answer for you easily. What you're saying I agree is completely correct. So things like colon cancer can be BRAF mutated or even CLL which is another B-cell malignancy and BRAF inhibitors don't work very well there. And it's not a key driver mutation is what we call it of the cancer, like a defining mutation. And you're absolutely correct. The biology of classic hairy cell does seem very dependent upon the BRAF mutation. So some cancers are very genetically diverse. Some are very genetically homogeneous and there's actually one of my colleagues who's not a physician, but a PhD researcher and some other collaborators actually have presented data multiple years in a row at the Hairy Cell Leukemia Foundation scientific meeting, looking at the biology of both classic and the variant of hairy cell leukemia related to many other B cell cancers and to have looked at multiple facets of not only kind of the genetics of it, but also epigenetics, which is the, for anyone who doesn't know, it's kind of the way DNA is regulated and it's extremely interesting to delve into the biology of something that's kind of more homogeneous compared to other cancers. I do think that the field of cancer biology in general seems to learn quite a bit from the study of this
Presentation from Dr. Robert Kreitman, National Institutes of Health (NIH)
Dr. Robert Kreitman:
First, we need to clarify what is the difference between a hairy cell and hairy cell variant. Just briefly, in the hairy cell variant, the spleen size is more severe, these patients can have more in the way of lymph nodes. And while the normal blood counts are less of a problem, they're generally not low they're normal, the leukemic cells in the blood can be much higher. The CD25 is negative, this is the most characteristic difference. The BRAF is unmutated as opposed to classic hairy cell which should have the V600-E mutation. And most importantly, the response to Cladribine or pentostatin, the purine analogous, is poor.
Now I want to mention briefly that this IGHV4-34 variant that was described by my lab in 2009, it makes up a small percentage of patients. These patients can have cells that look like classic hairy cells, because they are positive for CD25 and yet, as you can see here, they resemble the hairy cell variant clinically with severe spleen size, lymph nodes. They can have high leukemic cells in the blood, although they can also have low normal blood counts. And they also generally have unmutated BRAF and most importantly, again, the response to cladribine and pentostatin is poor. Although in patients who are newly diagnosed, these variants are not very common, variant hairy cell tends to be more common among patients with relapsed or refractory hairy cell.
Dr. Robert Kreitman:
So I wanted to also just really quickly review what is a response or remission. It's when you have improved normal blood counts, a smaller spleen and lymph nodes, if they were enlarged before. What does complete remission mean? It simply means that you can't see hairy cell in the standard stains of the bone marrow or blood. These are the right stain of the blood, the H&E, haematoxylin and eosin stain of the bone marrow. This picture of monotonous appearing, hairy cells here being replaced by normal heterogeneous looking bone marrow cells. Patients for complete remission also have to have resolution of their enlarged spleens lymph nodes, the high hairy cell counts, and they have to have normalization of the blood counts to at least ANC of 1.5, hemoglobin 11, platelet count of at least 100. They should compare these numbers to what you need for treatment, which is either an ANC less than one, hemoglobin less than 10 or platelet count less than 100. You need at least one of those in general to be eligible for treatment. You could also be eligible for treatment if you have painful splenomegaly or infections, other more, less common indications for treatment.
So what is minimal residual disease? MRD or traces of hairy cells, which if they're leftover after treatment for hairy cell, these residual hairy cells eventually, if a patient lives long enough can grow back and cause relapse. These could be detected by special stains of the bone marrow biopsy, flow cytometry of the blood or bone marrow, they could be detected by PCR, polymerase chain reaction. The most sensitive standard test of MRD is flow cytometry of the bone marrow aspirate, but this can vary from one institution to another. Generally speaking, CR, complete remission, lasts longer without minimal residual disease. If you get rid of those residual cells, then we find that you have a more deep, complete remission and it'll last longer. So in trying to achieve this for untreated hairy cell, which as you heard, the standard treatment is single agent purine analogue like cladribine. So back in 2010, we started a clinical trial at NIH where we randomized patients between getting cladribine, five daily doses in green with concurrent rituximab in eight weekly doses shown in orange. We call this CDAR. Half the patients randomized to getting cladribine alone and delaying the rituximab until at least six months later, if and when minimal residual disease showed up in the blood. We found at the six month time point before anyone could get delayed rituximab that there was a slight difference in complete remission rate - 100 percent with CDAR versus 88 percent with cladribine alone.
Dr. Robert Kreitman:
So we feel that rituximab can increase the CR rate of cladribine. This was shown previously by Dr. Ravandi at the MD Anderson. MRD free complete remission was hugely different. Here we found that in patients getting CDAR, the concurrent cladribine rituximab, the MRD free CR rate at six months was 33 out of 34 with 97 percent, versus 32 percent after cladribine alone. Not just the rate of MRD free CR but also the durability was different. This shows the percent of patients staying in MRD free CR over time, time is on the X axis here and you can see in yellow that the patient's getting concurrent CDAR, only one of them had a relapse of MRD while seven patients shown in blue had a relapse of MRD after cladribine alone. So of these 11 patients who got MRD free CR with cladribine alone, only four of them remained MRD free when we reported the study.
So this was a huge difference, the chance that this could be due to a random error was a p-value less than .0001. So MRD free CR was both more frequent and more durable with, compared to without rituximab. However, some patients achieved MRD free CR with delayed rituximab. In fact, most of the patients did. We found that 67 percent of 21 patients or 14 out of 21 achieved MRD free CR with a delayed rituximab. We found that these patients in blue, compared to the patients I just showed you in the previous slide that had concurrent cladribine or rituximab, where the rituximab was started out upfront, the patients with delayed rituximab, their MRD free CRs were not quite as durable. As you can see four patients here are relapsing over a period of 100 months of follow up. And this was a significant difference, .0081, in durability. Generally, anything with a p-value, less than .05 is considered significant, but it's not bad. You can see that most of the patients remain in MRD free CR. We gave delayed rituximab, as I said, for blood MRD. So delayed rituximab was effective, but both MRD free CR rate and durability were better with concurrent CDAR. But both of these groups, we think benefited by getting rituximab either up front or delayed compared to the standard, which is to give cladribine and then wait for patients to clinically relapse. We didn't study that in this trial, we didn't think patients would be interested in being treated that way. But we could look at an excellent retrospective study that Monica Elsie reported in 2009, where 90 patients, as you can see here, the arrow is pointing to this curve, got single agent cladribine or pentostatin for low blood counts, either a hemoglobin less than 10 or a platelet count less than a 100. Many of these patients had low neutrophil counts as well. You can see that at six and a half year time point where we are as a median in our study, 28 percent of these patients have already relapsed. They relapsed by blood counts, in other words they needed more treatment at the time that they relapsed.
So relapse before 10 years is not at all uncommon after first line treatment with purine analogues and after Cladribine rituximab together with CDAR or cladribine plus delayed rituximab, only one of our 68 patients has relapsed and that's a huge difference between what we find here. So this leads not only to increased MRD free CR, but either way, an improvement in time to next treatment or prevention of relapse.
Dr. Robert Kreitman:
So what about second line? Second line is after you've already had a prior course of purine analogues and so we are currently testing this at NIH. Again these were randomized patients in these two groups and in historical, 53 patients reported by Dr. Saven at Scripps, 62 percent of these patients would be expected to get a second complete remission with cladribine alone, we found that a 100 percent can get a complete remission with either concurrent or delayed rituximab. And so this is a significant difference between historical control. So rituximab can increase the CR rate of second line cladribine whether concurrent or delayed. Most of these patients achieve MRD free, complete remission and in this case, as opposed to first line, in second line there is no significant difference so far. We're still accruing patients on this trial and we feel it's the best option still for first line hairy cell, because we can get a complete remission rate of a 100 percent.
Dr. Robert Kreitman:
Now, what about multiply relapsed patients getting chemotherapy with rituximab? We have a rituximab trial with either Bendamustine or Pentostatin, this is either pentostatin rituximab or Bendamustine rituximab, we call this a BRPR trial. You can see that in this case, Bendamustine is being used on days one and two, rituximab is being given every other week and with pentostatin both agents pentostatin rituximab are given every other week. This trial so far has a 75 to 85 percent complete remission rate. Most of these are minimal residual disease free, there's no significant difference in the results so far. And while highly effective, this approach may be toxic due to the chemo and these patients have already gotten chemo. So we asked can MRD free complete remission be achieved without chemo and what's the benefit of being MRD free?
So before answering that, I'd like to show some oral agents that are useful, although they may not get rid of minimal residual disease by themselves. So this can be achieved by targeting the BRAF pathway with oral drugs. Most - 80, 90 percent of classic hairy cell patients - have hairy cells which express BRAF V600-E mutation and patients with hairy cell variant and unmutated IGHV4-34 have hairy cells, which do not express this mutation. Up to 50 percent of these patients have a different mutation and these patients are considered to have a disease that that is essentially different from hairy cell. But I'm talking about a hairy cell variant in this talk because many of you do have hairy cell variant and it's important also for anyone with classic hairy cell to rule out a hairy cell variant at least before they start treatment. So in hairy cell as you can see here on the right, BRAF carrying, the V600-E mutation, are shown in red, overstimulates these arrows as you can see are thicker.
They overstimulate that BRAF MEK and ERK pathway, in other words this mutation causes hyperphosphorylation, increased phosphorylation of MEK and then phosphorylated MEK causes increased phosphorylation of ERK. This leads to a cancer phenotype. If it happens in a skin cell, it can cause melanoma, if it happens in a B cell, it can cause a hairy cell leukemia. Then you have normal cells where you have this normal activation going on. So a few years ago, Dr. Tiacci used vemurafenib, which we know from patients with melanoma works to block the BRAF V600-E mutant protein. So in two trials done in Italy and the United States, vemurafenib achieved a complete remission rate of 35 percent in 26 patients and 42 percent in 24 patients. The toxicity most commonly leading to dose reduction included rash, painful or inflamed joints.
Seven patients had skin cancers, which were removed. In the Italian trial all of the complete remissions were MRD positive and half of these patients with MRD positive CR relapsed by 19 months.
Now this shows over here on the right that when you use a BRAF inhibitor, you may block the pathway that leads to cancer, but you also increase the stimulation going down the normal pathway and this can cause toxicity because this pathway is occurring in normal cells like normal T cells. This can cause fever and it can lead to skin problems, joint problems and other inflammatory problems.
So you can target both BRAF and MEK, MEK is the second step here shown in yellow. Dabrafenib inhibits BRAF V600-E, trametinib inhibits MEK. In melanoma compared to vemurafenib alone Dabrafenib and trametinib combination was more effective and less toxic. So why would it be less toxic? This shows why it might be. This shows that as you can see before, the BRAF inhibitor Dabrafenib would block BRAF here, but MEK since it blocks both normal and malignant MEK, it damps down the overstimulation that occurs by the BRAF inhibitor down the normal pathway. So what you see here is a normal level of stimulation coming from ERK and this is due to the combination of dabrafenib and trametinib.
Dr. Robert Kreitman:
So dabrafenib and trametinib combination is also effective in hairy cell, although most patients remain MRD positive. It also has side effects seen with vemurafenib in patients with melanoma and toxicities like fever and chills are more common with dabrafenib and trametinib. There are similar BRAF inhibitors and MEK inhibitors, including Encorafenib inhibiting BRAF and binimetinib inhibiting MEK, which are also approved for melanoma and they're being tested now for hairy cell at the NIH. Also binimetinib alone, which is the MEK inhibitor is being tested at NIH for hairy cell variant and hairy cell patients lacking the BRAF V600-E mutation.
Now, what happens when you add a CD20 antibody to a BRAF inhibitor? So to eliminate MRD, Vemurafenib was combined with rituximab. Rituximab kills cells by binding to CD20. In 27 patients as reported by Tiacci last year, 96 percent achieved complete remission, 65 percent achieved MRD free CR. This was tested not by flow cytometry of the bone marrow aspirate, but by allele-specific PCR Test for BRAF V600-E. To eliminate MRD in the first line, a trial is being led by Memorial Sloan Kettering for untreated hairy cell which combines Vemurafenib and obinutuzumab, which like rituximab binds to CD20.
Dr. Robert Kreitman:
A trial in Italy combines Vemurafenib and obinutuzumab with a MEK inhibitor cobimetinib. Vemurafenib or Obinutuzumab. Rituximab or obinutuzumab causes infusion reactions, notably fever and chills which can often be prevented by steroids and other drugs. Now, rituximab and obinutuzumab which bind and kill CD20 positive cells will decrease the level of normal B cells for at least six months after the last dose. And it will prevent effective vaccination during that time, so if you need to take rituximab or obinutuzumab and it's going to take six months or two months just plan on six months after the last dose before you can get an effective vaccine, whether that vaccine is for the flu or for COVID or anything else.
So if you haven't had your flu shot and you're going to get rituximab or obinutuzumab soon you should get the flu shot first.
So I want to talk about targeting CD22 with moxetumomab pasudotox it's also highly expressed on hairy cell, the recombinant immunotoxin moxe, which we nicknamed moxetumomab pasudotox, is an engineered protein that contains an antibody fragment shown in blue, which binds to CD22, shown in orange here and contains a toxin, the toxin is in yellow and red, that kill cells after it gets to the cytoplasm. Moxe has a complete remission rate of between 41 and 65 percent, most of these complete remissions are MRD free as opposed to the oral agents. No, we do not see chemotherapy type toxicities because this is not chemotherapy. However, we do see capillary leak type toxicities, which included edema, low albumin a patient can gets some headache, a little bit of nausea. This happens because it goes inside the cell and it can kill cells, so it can go inside the cells of line blood vessels and poke holes in the blood vessels. It's actually a good thing because it can get outside the blood vessels. But patients have to keep from getting dehydrated during this time. If they do get dehydrated and they have renal insufficiency, kidney damage, there's a syndrome called hemolytic uremic syndrome that where patients can have an increased creatinine, a decreased platelet count that is seen about 5 percent of patients, but is self-limited, it doesn't require any specific treatment. Really the worst thing about it, it also completely resolves, but the worst thing about it is a patient can't keep getting more treatment with moxe, with these toxicities and efficacious, the FDA approved moxe in 2018, it's called Lumoxiti.
I want to show the importance of MRD free CR from moxe and you can see on the left, that moxe, which is given by 30 minute infusions on days one, three and five repeated every four weeks. In the phase one trial, 11 patients shown in green up at the top here had MRD free CR and only one of these patients relapsed while nine patients who had MRD positive CR shown in blue, eight of these patients relapsed. The patients still in complete remission are the ones shown in the vertical orange bars at a different number of months after getting complete remission, this is up to almost 80 months. We found that seven patients who've got one to four extra cycles. This is after complete remission, did not relapse. This is shown over here in green, on the right. And of 14 patients who did not get extra cycles shown in blue, most of these patients have relapsed. So CR duration is longer if moxe can clear MRD and that seems to require extra cycles. And that makes sense because the hairy cells are hiding out in different tissues in the liver in the lymph nodes in the spleen. It takes lots of cycles for the moxe to go in and get them. So we want to avoid toxicity so we can get these extra cycles. How do you prevent HUS and capillary leak syndrome after a moxe? So due to this capillary leak syndrome where those blood vessels are leaking, they're constantly leaking, that allows the moxe to get out, which is good. But a large volume of fluid if one were to get an IV bolus of fluid, that can cause fluid overload, and that's not what we want. It could cause a edema, even shortness of breath.
And so oral water is rapidly regulated. It'll go out the kidneys as urine, much more quickly than being leaked into different spaces of the body. So drinking an average of one cup per hour prevents dehydration without causing fluid overloaded and also keeping lapses of drinking to less than two to three hours, we find works very well. In other words at night, we have patients get up every two to three hours, drink two or three cups of water and then go back to sleep and in the morning they are not dehydrated like they would be if they slept all night without drinking water. We also find that nausea or headache after moxe which can keep patients from drinking, rapidly responds to a low dose of steroid, dexamethasone, four milligrams orally, allowing patients to continue drinking.
And we found that a grade three HUS rate in the first nine patients was three out of nine patients before we used these precautions and zero out of 17, after we started using these precautions. This is a significant difference, although it was not a randomized comparison and we are certainly using these precautions.
Dr. Robert Kreitman:
Now, what about targeting both CD20 and CD22? So a clinical trial is underway at NIH in which rituximab is given with moxe for two goals. The first goal is to reduce the amount of hairy cell so that moxe can achieve a complete remission more quickly. The second goal is to reduce normal B cells, which prevents the immune system from rejecting moxe by making antibodies. So far, five or 71 percent of the first seven patients who've been restaged on this trial have achieved complete remission. None of these were MRD positive.
Dr. Robert Kreitman:
Now, I want to briefly talk about Ibrutinib. Ibrutinib is another oral agent, it targets Bruton's tyrosine kinase or BTK it's approved for chronic lymphocytic leukemia, CLL, mantle cell lymphoma, Waldenstrom's disease. In relapsed hairy cell variant, Ibrutnib achieved an overall response rate of 50 to 55 percent, complete remission rate of 20 percent. These responses were better in hairy cell than in hairy cell variant and response was much slower with Ibrutinib than with BRAF inhibitor treatment, sometimes taking over a year to obtain a complete remission. Ibrutinib was usually less toxic, though, than BRAF inhibitors. Severe toxicities included low blood counts, infections, and atrial fibrillation. Blood counts often worsen for months before resolving. Ibrutinib usually does not eradicate MRD, so it has to be used chronically. But it should be considered in patients with hairy cell or hairy cell variant who have adequate normal blood counts and prefer an oral chronic therapy.
Dr. Robert Kreitman:
I wanted to highlight the clinical trials that are featured on the Hairy Cell Foundation website. The cladribine rituximab trial in second line after one relapse of purine analog at the NIH. The ibrutinib trial, the bendamustine rituximab versus pentostatin rituximab trial for patients with at least two relapses. Moxetumomab pasudotox and rituximab with at least one to two relapses at the NIH. Encorafenib and binimetinib at the NIH for BRAF V600E hairy cell, and binimetinib for hairy cell variant or BRAF wild Type hairy cell. Vemurafenib and Obinutuzumab for untreated hairy cell at Memorial Sloan Kettering, and then Vemurafenib plus cobimetinib and or Obinutuzumab in Italy.
And this is a complicated algorithm that I put together showing not only standard, but also investigational approaches that are available for different types of stages of hairy cell, where in untreated hairy cell, patients could get cladribine or pentostatin, or the combination of cladribine rituximab, or Vemurafenib/Obinutuzumab clinical trial. Patients with one prior treatment of hairy cell could get these same options, but also ibrutinib or moxe/rituximab. Patients with hairy cell variant with early treatment could get combination purine analog, rituximab, Ibrutinib or moxe/rituximab.
Multiply relapsed hairy cell or hairy cell variant. We like trying moxe first because it's not chemotherapy and it can get rid of minimal residual disease. And then if patients need treatment past that. If the BRAF is mutated to V600E, we try the BRAF inhibitors. If not, then we try these other options. And with that, I'd like to turn it over to questions.
Question & Answer Session with Dr. Kreitman
Anna Lambertson:
We do have a lot of questions about remission. So you said that remission is defined as improved normal blood counts. It seems like there is some confusion among some individuals in terms of how it's defined, and when patients talk about their remission, they sometimes describe it differently. If you could clarify that point.
Dr. Robert Kreitman:
So to get a complete or a partial response, you need to have an improvement in normal blood counts if they're low, prior to treatment. So the need for treatment is defined by a neutrophil count less than one, hemoglobin less than 10, a platelet count less than 100. You have to have at least one of these, and this is need for treatment.
And I mentioned there was some other indications for treatment like painful splenomegaly and things, but you have to have these improved, not only so that these are no longer present, but they have to improve to these levels with a neutrophil count of at least 1.5 and a hemoglobin of at least 11 and a platelet count of at least 100. That is how we define normalization of blood counts.
Now, there are some protocols that allow someone to get a partial response. If you get a 50% improvement in these parameters, but other protocols require that you achieve these levels. You have to achieve these levels by all definitions to achieve a complete remission.
And the only exception is if you also are MRD free, in patients who have had chemotherapy damage to their normal cells, but they're MRD free, they really have no trace of hairy cells left. Then we will consider those patients in complete remission because they really don't have hairy cells and their low blood counts is not due to lack of response. So it's a little confusing, but in general, these are the, when you talk about resolution of normal blood counts, this is what we need. ANC of at least 1.5, hemoglobin of at least 11, and platelet count at least 100.
Anna Lambertson:
So is a bone-marrow biopsy required to determine that a patient is in remission or can it also be done with flow cytometry?
Dr. Robert Kreitman:
So according to the consensus guidelines that were put together in 2017, we still need a bone marrow even to determine whether someone is in partial response. Because part of the definition is having at least a 50% improvement in the hairy-cell infiltration into the bone marrow. For many of our trials, this is not something that we require because patients don't like to get bone marrows just to determine if they're in partial response. But in general, you do need a bone marrow to determine if you're in remission and you certainly need it to determine if you're in complete remission. There, you have to have no hairy cells visible by standard stains of the bone marrow.
Now, people will say, "Oh, I got a complete remission, but I never got a bone marrow after treatment." And what they probably mean is they were in complete hematologic remission, what we call HR, hematologic remission. And that means that you got these counts and maybe you were in complete remission, but you didn't get a bone marrow to prove it.
Anna Lambertson:
I wanted to ask you a two-part question about remission with regards to purine analogs. So the first part of the question is, with Cladribine, how long does remission generally last for patients? So the first part of the question. And then the second part of the question is, are there commonalities among patients who have been treated with purine analogs who have relapsed more quickly than the norm?
Dr. Robert Kreitman:
So, in patients who get purine analog the first time, as you can see on this on curve, patients who have complete remission. What you'll hear is that half of the patients will relapse by 16 years. And there's another report that I often hear. Forty percent of patients will relapse by about 15 years.
But really, in patients who are getting treated because of low blood counts, it really is not quite that rosy for patients getting single-agent purine analog, because as you can see, if you don't need treatment due to the fact that you don't have low blood counts before you get started, you're in this curve up here, which has a much longer time to relapse. But in patients who need treatment due to low blood counts, and these should be the vast majority of patients who are getting treated now, we don't really believe in treating patients who don't have low blood counts and don't really have an indication for treatment.
You can see that already by six and a half years, 28% of the patients have relapsed and more than half of the patients have relapsed by before 16 years. So that's what we can expect from relapse. But this is if you're doing blood counts and the blood counts show when you need re-treatment.
So when these patients relapse, they by definition need more treatment. But if you do bone marrows on patients, particularly young patients less than 40, because these patients are more likely to get bone marrows, you'll find that the complete remission duration median is less than five years, not 15 or 16 years. So, the disease comes back in the bone marrow a lot sooner by about four or five years median, compared to when the blood counts go down to the point where patients need more treatment.
Anna Lambertson:
And there aren't particular characteristics of patients that at least you can see that might cause them to relapse earlier than what might be the norm when it comes to purine analogs?
Dr. Robert Kreitman:
Certainly if patients have hairy cell variant, they should not be treated with a purine analog. And I still see patients being treated with a purine analog for hairy cell variant. That is really ineffective treatment. The complete remission rate is only 8% in historical series. So if you have hairy cell variant and you get a purine analog, you really need rituximab or another antibody combined with it. It's inadequate treatment to get purine analog alone for hairy cell variant. And also many patients miss the diagnosis of the IGHV4-34 variant. That's another factor that can be diagnosed prior to treatment that can signal that a patient will not respond well to purine analog.
Beyond that there are other unusual features of hairy cell. Patients who have really massive spleens, some of these patients, I'm talking about 250 to 300 millimeter spleens, some of these patients will not respond as well to the first course of a cladribine or pentostatin. If they have overwhelmingly large disease, certainly they do much better if they have rituximab added to it.
There are other poor prognostic factors, molecular features that we can diagnose. We like to receive blood samples from patients before they are treated so we can look for these high risk factors. And one of them is large lymph nodes. If patients have lymph nodes prior to treatment, as opposed to just a big spleen, that seems to be a worse prognostic factor. But this is an area that we're still learning more about.
Anna Lambertson:
What is the prognosis as you understand it for patients who have the variant form and what you would consider to be the standard remission for patients once treatment is started?
Dr. Robert Kreitman:
About 45 to 50% of patients would have a partial response with Cladribine alone with hairy cell variant. Hairy cell variant is described to have a median overall survival of only about six years after initial diagnosis. And we feel that this can be largely improved by combining rituximab with purine analog upfront.
We're obviously not going to do that kind of randomized trial. It would not be ethical. But we have patients who are now more than 10 years after cladribine and rituximab for hairy cell variant with no trace of hairy cell variant cells. But other patients can relapse. This is the reason we're doing clinical trials at the NIH with other options for hairy cell variant, including the bendamustine/rituximab pentostatin/rituximab trial for hairy cell variant, even in patients who are newly diagnosed.
Anna Lambertson:
So if a patient was treated one time, relapsed, treated the second time with cladribine, we frequently hear from experts that you would not recommend treating that patient a third time with cladribine. What are the side effects of rituximab when combined with cladribine, and as we are in the midst of COVID-19, are you still adding rituximab to cladribine as you have done?
Dr. Robert Kreitman:
So, rituximab, the toxicities of rituximab are sort of opposite to cladribine in that the rituximab causes its toxicity on the very first dose, with fever, chills, sometimes shaking chills, and therefore, and we can actually prevent some of this by using steroids, so that the chills are maybe very mild if they were seen at all.
But it does not have the severe long-term toxicities that cladribine has, which includes neuropathy, nerve damage in about 15% of patients, and stem-cell damage, which occurs in many patients. So your normal blood counts are not quite as high after treatment with cladribine as they would have been before.
So that's why most experts would not recommend a third course of cladribine. We actually obviously recommend clinical trials, even after one course of cladribine just because usually the remission percentage and the duration of remission will be worse with subsequent doses of cladribine. And yet the toxicity will accumulate. These toxicities add to each other.
Now, in the COVID age, getting cladribine plus rituximab, it is not known to be a problem with respect to a worse outcome with COVID. Rituximab has really not been shown to make COVID worse. Some people even think it might actually prevent some of the immune inflammatory problems that patients die of with COVID, but we certainly don't have any data to prove that.
There is a problem, though, if you want to get a vaccination. So if you want to get vaccinated with COVID as soon as the vaccination is available, then you really don't want to be getting rituximab right now. Some patients tell me that they don't really want the vaccine right away anyways. They'd rather get their immune systems better by getting treated with rituximab now, and then they'll quarantine and continue doing what they've been doing all year until the vaccine has it been used in more people that they're more comfortable getting the vaccine anyways.
So different people have different issues. My feeling is that in patients who really need to be out in the world with other people, and they have a high risk of getting COVID, and they have hairy cell leukemia, and they want to get their blood counts improved, but they want to get cladribine or rituximab. A good way to temporize, to avoid, to delay is to just take a single agent Vemurafenib now. It doesn't harm the immune system. It won't get rid of the minimal residual disease. But it will certainly improve the normal blood counts in most patients. And therefore it's a good way to delay the definitive treatment until patients can have a COVID vaccine. So, as Dr. Rogers mentioned, a lot of people are doing that now, even though there's no clinical trial to really prove that that's a safe and effective method, a lot of people are doing it, and it seems to work well. And I have patients that I'm following where they're being treated that way.
Anna Lambertson:
So someone who has been treated with cladribine is in remission, their blood counts are being monitored. The individual who specifically asked this question this time is actually being monitored at the NIH with flow cytometry every six months. If in the future, hairy cells are found, can a person still be a candidate for delayed rituximab in the future if they didn't receive it during the initial treatment with cladribine?
Dr. Robert Kreitman:
Absolutely. I mean, that's how our trial is being done. As I showed, we're waiting at least six months after cladribine before giving delayed rituximab, but we don't start it until we can see MRD in the blood. But this could be years later. So we have patients even years later that are turning up MRD positive in the blood, and they get delayed rituximab. And we're finding that most of these patients can be rendered MRD free. So we have patients who are getting delayed rituximab at many different points in time. And it's an interesting group of patients in that some people got the delayed rituximab early. Some people got it later. I didn't mention, but this trial actually allows a second course of delayed rituximab for each group. So a patient could get two courses of delayed rituximab, the second one at least six months after starting the first one, if the blood is still MRD positive.
And we find that some patients get MRD free after two courses of delayed rituximab, not just after one course. So, we believe that the advantage of this is that we're not exposing patients to chemotherapy. And also in the delayed setting, there are no significant toxicities of rituximab. In other words, the fever, the chills, the rigors, this is something that we see that's proportional to the amount of tumor, the disease that the patients have, which is high when they first get diagnosed.
But if they have just MRD in the blood, their disease level is very, very low. And we're trying to eliminate their minimal residual disease by targeting when it's only MRD and the cells are spaced out and we're able to pick them off with the rituximab. But then we don't see the toxicity then. So it tends to be very simple to get the drug.
Anna Lambertson:
So if negative minimal residual disease is indicative of longer remission, and combo treatments such as cladribine plus rituximab are resulting in long remission, would the addition of a third or even a fourth concurrent therapy produce even better results?
Dr. Robert Kreitman:
So, it's really hard, I think, to improve on the cladribine and rituximab concurrent regimen, what we call CDAR, in terms of efficacy, where we see that 97% of patients had MRD-free CR, and we really have not seen much in the way of relapse of that after up to 120 months of follow-up.
But in terms of toxicity, we would like to avoid cladribine alone completely because cladribine is chemotherapy, and it has the neuropathy and the stem- cell damage that we talked about. So while we can't really avoid it today in the standard sense, there are trials that are starting, are being developed to try to do this.
And one of them I mentioned was the Vemurafenib/Obinutuzumab trial at Memorial Sloan Kettering. And there is some interest in the combination of moxe and rituximab. And I mentioned the rationale for giving moxe plus rituximab together.
We feel that this trial of cladribine and rituximab is proof of principle that moxe and rituximab can be highly effective. And that's because cladribine has much less ability to eliminate minimal residual disease then moxe. And so if you substitute the cladribine for moxe and use moxe rituximab, we believe we can achieve very good results in first-line not just where we're using it in, in multiply relapsed patients.
Question & Answer Session with Dr. Rogers and Dr. Kreitman
Anna Lambertson:
I want to direct a question to both of you, and this is about vaccines. Dr. Rogers, you specifically spoke about vaccines in your presentation and talked about the importance of them. And we do know that there are some factors that patients and doctors need to take into consideration before having a vaccine of any kind, let alone a brand new vaccine for COVID.
What are the dangers of vaccines, if any for patients? How long do you generally recommend that patients wait after treatments before having a vaccine? For example, for the flu. There are other vaccines, for shingles for example, that I'm sure many patients are also interested in.
Dr. Kerry Rogers:
I get asked this like all the time, is it dangerous to get a flu vaccine while I'm getting rituximab? Is this going to hurt me? And Dr. Kreitman will correct me if there's something he knows that I don't, but I know of absolutely no evidence that rituximab makes vaccines dangerous. So if you get a vaccine while you're getting rituximab, it's not like this vaccine is going to be worse for you in some way. It's just that the vaccines don't work as well.
When you're thinking about an annual or seasonal influenza vaccine, you get those every year. So delaying it six months might put it in a timeframe where you wouldn't use it. So I've recommended people that needed rituximab right away or were already taking it to get seasonal influenza vaccine, knowing that the effectiveness might be very much decreased, but vaccines you don't get don't work at all. The timing of when to take rituximab relative to vaccines is, you have to think about what happens if it doesn't work as well. The tetanus booster, yeah, wait six months, because one, you're probably not going to get tetanus in six months. And then you want that to last a good long time unlike seasonal influenza shots. So you always have to think about what the vaccine is, but I don't know of any risk for taking them with rituximab.
The one thing we worry about is that... I know there's a lot of stuff in the news, especially with the development of vaccines against our SARS-CoV-2, which causes COVID-19, about types of vaccines. But there's some vaccines like MMR, which is measles, mumps, rubella, and then the Zostavax, which is one of two available vaccines against shingles that are live. So they're weakened forms of the virus, but it's actually a living virus that's in that vaccine, just not one that's expected to make people very ill. We don't know in people whose immune systems are normal, if given this live vaccine, it's going to cause an infection, if even a weakened virus is going to make them sick, so we don't give live vaccines to immunocompromised individuals. How dangerous it is, I'm not really sure because we don't do it.
And then when you look at the live shingles vaccine, I don't recommend it, the live one, for people with blood cancers like hairy cell leukemia, or CLL. But I know plenty of people who got it in a timeframe when they had one of these leukemias that hadn't been diagnosed yet, and they're totally fine. If someone accidentally gets a live vaccine, it might work out fine for them, but we don't recommend them. And I don't know if there's a huge amount of studies, and it is, again, specific to the particular vaccine.
For things like shingles, there is now a killed vaccine called Shingrix. So I've recommended people to get that one. There was actually a study in cancer patients, including some with blood cancers, where it looks it's perfectly safe to get the vaccine - side effects that people are getting, or the kind anyone gets with vaccines like muscle aches, or sometimes you can get a low grade fever from the immune reaction that it's supposed to cause. So I get a seasonal influenza vaccine myself every year. I have to for work, but also I want one. And every year when my arm gets sore I just think, "Oh good, it's working." My immune system is responding to this vaccine, and I'll be protected from influenza strains this year.
So that's my two cents on vaccines. And then considering when to get any particular vaccine related to where you're at with your hairy cell leukemia treatment is something that you should discuss with your doctor related to the vaccine.
Dr. Robert Kreitman:
I think that it really is a matter of timing on the flu vaccine. I think it's fine to get it if you have no other option. But in patients who, let's say, six months after rituximab is going to be around February or March, I think that if they can only get the flu vaccine once, I'll advise them to wait until February or March and get it then because it's more likely to work then than if they get it earlier. But the data, and I reviewed this recently, it shows that the response to the vaccine is very poor in the first six months. And it also can be poor in the first nine months. So rituximab does a number on the normal B cells. But that's not to say that it's dangerous to get the vaccine. And I think that if one has no other alternative, it certainly is probably better than not getting one at all.
Anna Lambertson:
Dr. Kreitman, could you quickly summarize which of these treatments are considered to be chemotherapy and why are they chemo while the others are not?
Dr. Robert Kreitman:
So of the things that I talked about; the cladribine, the bendamustine, the pentostatin, these are chemo purine analogues. And those are the only chemo drugs that we're talking about. And these work by interfering with DNA synthesis and replication. Sometimes there are mutated parts of DNA that are damaging the DNA or RNA in cells. And so, this can cause the neuropathy and the stem cell damage that we're talking about. That's what we call chemo.
Sometimes rituximab and obinutuzumab is called chemo, and that's often by the nurses who are giving those drugs because they have to give them like they're giving chemo, they're IV. But they're not really chemo, they're antibodies, and they don't have toxicities like chemotherapy. You can give them many times and they don't have cumulative toxicities.
Then the oral agent inhibitors are also not chemo, and that's the ibrutinib, the encorafenib, and binimetinib, vemurafenib, cobimetinib, and trametinib, and dabrafenib that we've talked about today. And then there was moxe, so moxetumomab pasudotox is also not chemo, but it's highly cytotoxic. In other words, it kills cells directly through a toxin. So it has an efficacy like chemo, but it does not have the toxicities of chemo. And that's one of the reasons it can eliminate minimal residual disease without chemotherapy toxicities. So that's my definition of what's chemo, what isn't chemo.
Anna Lambertson:
And for how long is cladribine toxic? How long does it stay in the system?
Dr. Robert Kreitman:
If you look at low blood counts, we find the platelet counts improving within about three weeks after cladribine and the ANC, the neutrophil counts, improve within about four weeks and can resolve in about five to 10 weeks. There is some variability there. We find that after cladribine plus rituximab CDAR, the resolution at four weeks is better with a combination than with cladribine alone. However, there's a decrease in platelet count that occurs on day two with the combination, but doesn't lead to any clinical bleeding or anything. So that's what we see with cladribine in terms of the blood counts.
However, there are patients who can have very prolonged toxicities from purine analogs with respect to blood counts. They may never get a platelet count above a hundred again, even if they're MRD free. And also, we find that CD4 T cells can be reduced. And this was reported many years ago by Seymour, et al., to take a median of four years to come up to the normal levels. So CD4 count goes down and really takes a beating for a long time because of cladribine, especially in patients who are getting multiple courses of cladribine. This is one of the reasons why we want to avoid patients getting cladribine within four years, because it takes a median of four years for the first course to have resolution of the CD4 cells, and that's going to be worse the faster you retreat with cladribine.
There is a report in 2015 from Memorial Sloan Kettering showing that a CD4 count deficiency can lead to increased incidence of secondary malignancies, not just infections, as part of the immune system. So that secondary malignancies is really important in patients with hairy cell. So that's another reason to really reconsider taking so many courses of chemotherapy purine analog.
Anna Lambertson:
So is there anything to your knowledge that patients can do to strengthen their immune system? We're talking about natural approaches to strengthen their immune system, to raise their blood levels. Because as patients are receiving treatment, they're thinking about what they can do, in addition, at home to be as healthy as possible to perhaps even make their remission last longer.
Then conversely, are there certain things that you would discourage patients from doing that could have a negative impact either on their health or on the remission or their blood counts? One individual specifically asked about alcohol and about its impact on remission or blood counts.
Dr. Kerry Rogers:
This is a phenomenal question, because I get asked this quite a bit. And I want to just be clear that the thing I was talking about was not health factors that impact your leukemia, they are health factors that... What doctors call competing causes of mortality. So if we treat your hairy cell leukemia so effectively that you could live for decades, but you eat cheeseburgers every day and die of a heart attack at three years, that's a competing cause of mortality, meaning something else that would limit your lifespan, not related to leukemia.
I think that the patients want to know is how can these other health factors impact my leukemia outcome. But I want to be clear that what I was really saying is, the leukemia outcome is good, so please don't die of heart disease, diabetes. So I don't think modifying your cardiovascular risk factors is going to make your remission last longer. It's going to make you not die of heart disease while you're in remission from hairy cell leukemia.
I know we had actually an expert in nutrition and cancer outcomes speak at the patient seminar for the Hairy Cell Leukemia Foundation I think three years ago that said what I'm going to say, which is, I know of absolutely nothing you can do in terms of diet or exercise or lifestyle modification that will change your blood counts or remission. It's not green tea, it's not copper powder. It's not exercising 45 minutes a day. These things are not known to improve your leukemia outcome.
I do think that generally paying attention to your health and doing the things that everybody needs to do for their health will make their body healthier so they can live a long time with their hairy cell leukemia, but I don't know that it's going to make your remission last longer or blood counts any better.
I've seen people spend a lot of money, mental anxiety, and effort, and even have really bad side effects of some natural things that they thought would help them and it really hurt them quite a bit. So just be careful when you're thinking of these things, and please remember that natural... If you think it's doing something that it can also have side effects. Non-FDA approved medications aren't regulated, you have no idea what you're paying for, the quality is not guaranteed, and they are not studied in the same way as the treatments that Dr. Kreitman and myself have been discussing. I mostly just don't like seeing my patients get hurt by trying something natural that they're spending money and time and having side effects from that I don't know will help them.
So that being said, you can do things to really hurt your blood counts. So, alcohol use, heavy alcohol use, people that are really drinking to a problematic level can lower your blood counts because it also injures your bone marrow. Cocaine, very bad for blood counts. They cut it with a chemical called levamisole that not only has immunologic side effects, but also causes low neutrophil counts in many cases. So you can do things for your health that will also hurt your blood counts; street drugs and extremely heavy alcohol use, or some of those things.
I actually have not seen any problems from ordinary levels of alcohol use in my patients. So keeping it under the recommended amount of alcoholic drinks for everyone, which for women is seven drinks a week and men is 14, not drinking problematically, like becoming intoxicated on a regular basis, and what we'd all classify as problematic alcohol use. If you're really drinking high amounts of alcohol every day, that can also damage your bone marrow.
Same thing, cigarette smoking. Actually, at ASCO two years ago, I believe it was, they had some data that the chemicals in cigarettes really damage bone marrow and increase risk for acute myeloid leukemia, which is a different type of leukemia. So in terms of what you're putting in your body and what you're doing, you don't want to do things that will further damage your bone marrow. The cladribine and pentostatin can damage the bone marrow, the hairy cell being in the bone marrow isn't good for it. So don't also hurt your bone marrow with some other stuff.
Dr. Robert Kreitman:
It's something we haven't really studied. I have to say. I think that mega vitamins have not really been shown to be very helpful. I can say, though, that bone health, in addition to screening for other cancers, is important. So we try to emphasize checking for skin cancers, to avoid extra sun exposure. Maybe patients with chemo exposure are more sensitive to skin cancers, particularly if they've had a lot of sun damage in the past. And keeping up with mammograms, keeping up with colonoscopies. We try to encourage health maintenance. But not just cancer, also bone health I mentioned.
There are patients who are vitamin D deficient that we've treated with hairy cell, patients who are testosterone deficient, men, and need testosterone replacement to protect bone health. And the consequence of bad bone health can be hip fracture, which can be deadly. Although this disease is mostly in men, we do have some women and it's something that we have to pay attention to. Even men can have hip fractures. I had one myself, so I know that this is something that can be prevented by good bone health, too. So there's a number of different things that do affect diet to some extent that are really important.
Webinar participant:
This is a real top-down question that I've always struggled with. Assuming HCL is caused by some genetic episode that happens in one's biological life. If we would accept that, and then one has HCL, and you become totally negative, no residual trace both by hip examination, flow cytometry, et cetera. And the HCL comes back. Does that mean that our testing abilities in this day and age aren't sensitive enough to find something hiding? Or could it be a repeat of another genetic event that causes it to come back?
Dr. Robert Kreitman:
I would bet on the lack of detection much more than having lightning strike twice. Because in order for you to have the V600E mutation, you have to have a B cell that gets this mutation in exactly the right place, the 600 amino acid codon that produces hairy cell. It's a very rare event, and we know that disease is very rare. I think for that to happen twice would be exceedingly rare. I think it's much more common to miss it in minimal residual disease analysis. We know that the bone marrow aspirate flow cytometry is not 100%.
We have done PCR studies using the immunoglobulin rearrangement. This is something we try to do in all patients who we get samples on before they are treated. And then we can look for the immunoglobulin rearrangement after treatment. And so this is one thing that's a little bit more sensitive than bone marrow aspirate flow. But really, these tests are never 100% sensitive. And it's one of the reasons why you want to use consolidation cycles of something like moxe or moxe and rituximab after someone is already MRD free, because there may be some cells hiding out in some places that you just don't see them. But if you can keep targeting them maybe you can kill those two.
Webinar participant:
I have often wondered whether hairy cell leukemia has any effect on the total cholesterol level in one's body? What happened to me is up until the point that I was diagnosed and received treatment, my total cholesterol level was the high 190s, maybe around 200. Immediately after treatment, once I got my blood work done for my physical, and since then, which has been about five years, my cholesterol level jumped to around the 250 to 260 mark. Luckily, in both cases, the good cholesterol, HDL, has remained high. So I'm just wondering if there's any effect that the presence of hairy cells has on the cholesterol level?
Dr. Robert Kreitman:
This isn't published very often, but the hairy cells do have LDL receptors. And so if you kill them, then your cholesterol level may get worse. And so this is one of the reasons why we tell patients to be careful with their cholesterol. We monitor cholesterol panels in all patients who are coming in for every two year restaging.
Another problem which is not related to the LDL on hairy cells is the fact that when you treat hairy cell, all of a sudden your spleen shrinks, and it's not pressing on your stomach anymore. So you don't have early satiety. So all of a sudden you're hungry and then you eat a lot. And so your cholesterol could go up by that reason. So there's really two reasons that can happen. But you do have to be careful about the cholesterol and one may need to use a statin drug after treatment of hairy cell, whereas they didn't need it before.
Dr. Kerry Rogers:
Are you saying, Dr. Kreitman, that the presence of hairy cells lowers LDL cholesterol because of the presence of this LDL receptor?
Dr. Robert Kreitman:
That's the theory. I haven't seen the actual data that it does that, and haven't seen the before and after. We haven't had time to investigate that and write it up. But I think that it does happen.
Anna Lambertson:
We have reached the end of our time. I want to thank both Dr. Kreitman and Dr. Rogers for presenting today. I want to thank all of you for joining us for today's webinar.
This transcript has been edited for clarity.