Webinar: Understanding Hairy Cell Leukemia
October 26, 2019
Hosted by the Hairy Cell Leukemia Foundation with guest speakers Dr. Michael Grever from The Ohio State University Comprehensive Cancer Center-The James and Dr. Robert Kreitman from the National Cancer Institute, NIH.
Materials
You may view the powerpoint slides and synced audio recordings by accessing the links below.
View synced audio recording and slides of Dr. Michael Grever’s presentation. >>
View Dr. Grever’s slides only. >>
View synced audio recording and slides of Dr. Robert Kreitman’s presentation. >>
View Dr. Kreitman’s slides only. >>
Transcript
The following is a transcript of the Presentations given by Drs. Grever and Kreitman, followed by a Question and Answer session with the audience.
Presentation by Dr. Michael Grever
Dr. Michael Grever:
Welcome to this webinar on hairy cell leukemia. I want to first thank Anna for helping us organize this. And also I would like to thank the Hairy Cell Leukemia Foundation for supporting this opportunity to speak with you about this disease. Dr. Kreitman who is my colleague is with us and he will be following me with a lot of information about some of the new advances. I would just like to begin to provide just a basic understanding for our discussion of hairy cell leukemia.
I’d like to inform you that I have served as a consultant for some of the pharmaceutical companies, but we're not going to be bringing information necessarily to bear with the exception of some of the drugs that might be new. If they are not approved for use in hairy cell leukemia, we'll let you know that when we're presenting the information.
Hairy cell leukemia is a rare form of chronic leukemia and it represents about 2% of all leukemia in the adults. The World Health Organization recognizes two distinct entities, classic hairy cell leukemia, and then a variant hairy cell leukemia. The classic hairy cell leukemia is much more common than the variant. While a classic hairy cell leukemia is also rare, the hairy cell leukemia variant represents about 10% of all the patients with hairy cell leukemia and is therefore even more rare.
The leukemic cells in this disease are found in the bone marrow, in the blood and the spleen, but they can also be present in the lymph nodes, particularly in patients who have a variant of hairy cell leukemia. There are clinical differences between both of these clinical entities. The presence of the leukemic cells in the bone marrow compromises the production of normal blood elements and therefore patients can become anemic or have a low white blood cell count or a low platelet count. Furthermore, because the spleen tends to be enlarged in many of the patients with hairy cell leukemia, that can actually sequester some of the blood cells that are made in the bone marrow and can contribute to the pancytopenia, which is a medical term indicating that the patient has lower than normal blood cellular elements.
The first descriptions of this disease were back in the 1950s. Both Dr. Kreitman and I had the honor and the opportunity to work with Dr. Bertha Bouroncle at the Ohio State University and she was responsible for publishing one of the most comprehensive reviews of this entity. The name initially was called leukemic reticular endotheliosis, but as more information became available on the type of cell that was involved in the leukemia, it was called hairy cell leukemia. This is a picture of Dr. Bouroncle and she was one of the best clinicians and investigators and teachers that we had at Ohio State University. Was very dedicated to her patients.
Dr. Michael Grever:
Some of the clinical features of this disease are on this slide. There is a remarkable male predominance. For every woman, there's about four men who have this disease. The median age at the time of diagnosis, is around 55 years. However, there's a big spread and we see that there are patients as young as in their 20s or even up into their eighties. But approximately a third of the patients might be less than 50 and a third of the patients might be more than 65. But the median ages is 55 years old.
The symptoms that bring the patient to the doctor often will be described as a gradual onset of fatigue and increased frequency of infections. On physical examination, it's very frequent that the spleen is enlarged. Back in the 1950s when Dr. Bouroncle described this disease, over 80 to 90% of the patients had a very enlarged spleen. We're currently seeing enlarged spleens, which is typical for this disease, but because the diagnosis is now made earlier, some of the patients are presenting with a much smaller size of the spleen. Sometimes this disease is discovered when people go for a routine medical checkup and they're found to have a low blood count. The medical term that is used to describe this is cytopenias.
The patients are then told that they need to have a bone marrow biopsy to confirm the diagnosis and also the physician will look at the peripheral blood smear because these cells do circulate and they have a very characteristic appearance which I'll show you. One of the most important critical tests for making and establishing the diagnosis is flow cytometry and this can be done on the blood or the bone marrow. On the hairy cells, there are very specific characteristic markers and you may have heard the doctors talking about CD11, CD25, CD103 and CD123. In some of the patients with the variant to hairy cell leukemia, they can be deficient in CD25 and they are usually deficient in CD123. This helps to distinguish between the classic form of the disease and the variant.
Dr. Michael Grever:
The patients often, as I indicated, will complain of fatigue and this is most often a symptom of a lower blood count or anemia. They may find that it's easier to bruise or that they will bleed more vigorously if they cut themselves. Infections can be almost anywhere but early on, before patients are treated because their white blood cells are low, they do have an increased frequency of infections. For example, pneumonia or a sinus infection or cellulitis or a skin infection. And this is sometimes one of the reasons why they come to the doctor.
One of the things that we are very concerned about is that patients with hairy cell leukemia are susceptible to herpes zoster infections or shingles, and this can sometimes or most often, probably results from a previous episode of chicken pox. And whenever the immune system goes down with the onset of this disease, there's a resurgence of that virus and it can produce as a painful skin rash. And it's very important if this happens, that you get seen by the physician because it's important to get on medicine to keep this from becoming more serious.
Dr. Michael Grever:
Some of the patients with this disease will have paradoxically an autoimmunity. In addition to having an impaired immune system or infection, they can sometimes have an increased immune reaction to either their own blood cells or inflammation in the blood vessels called vasculitis. And it's not infrequent that patients can present with an arthritis like picture. In about 10% or less, probably less than 10% patients, can actually have some bone lesions that look very discretely like a small hole in the bone. And this can be detected by x-ray studies and other radiographs.
On this slide you can see why this disease is called hairy cell leukemia. The nucleus of these white blood cells, which are the two white blood cells that face us, the two leukemic cells, the nucleus is very characteristic and it's usually round and the chromatin material in the nucleus is usually finely distributed. Probably the most characteristic finding, if you look along the edges of the cells, you'll see this hairy fragmented looking appearance and this is why the disease has been called hairy cell leukemia. The orange looking cells in the background are red blood cells for comparison.
Dr. Michael Grever:
This just shows another slide of another patient where there is an increased number of hairy cells and you can see that same characteristic hair-like border to the cell cytoplasm.
This is a picture of a bone marrow in somebody with hairy cell leukemia. Typically in a normal bone marrow, you'll have approximately 50% of the cells, 50% of the bone marrow space will have cells, and the other 50% will be fat. And sometimes there's a little variation where you could be 40% cells, but some patients with hairy cell leukemia can even present with a very low, empty looking bone marrow. But in this typical picture, you can see that there are a lot of cells present in the bone marrow biopsy that have almost like a halo appearance around the nucleus. And this is because the cytoplasm is very distinctly keeping the cells from being overlying each other. And this is often referred to as a fried egg appearance. But this is the characteristic bone marrow picture.
Dr. Michael Grever:
Now you can imagine with this infiltrate of these leukemic cells in the bone marrow, there's a decreased production of the normal elements that should be in the bone marrow. And that's why the patients end up having a decreased production of red blood cells, a decreased production of the infection fighting white blood cells and a decreased production of platelets. This is what the bone marrow looks like and this is a stain that the pathologists use and this stain is positive for a marker on this cell called CD20. And so when you look at this, you can tell that almost all of the cells in this field of the bone marrow express that CD20. That's because they're hairy cell leukemia cells.
This shows another feature of stained leukemic cells, but there's also a pattern here of increased fibrosis along the middle portion. And this is characteristic of classic hairy cell leukemia. When you're doing a bone marrow you can get the biopsy to come out pretty efficiently, but it's really very difficult to get the liquid portion to come out. This is referred to as a dry tap and we believe that 75% of patients who have classic hairy cell leukemia will have this extensive fibrosis in the bone marrow. That's one of the reasons why it's very difficult to get the bone marrow aspirate to come out easily. As patients get treated effectively for their hairy cell leukemia, this fibrosis often will regress. And so when the person is having a bone marrow after they're in remission, the liquid portion is a little bit easier to secure. This just shows a special stain that points out those fibers of fibrosis and so you can see how diffuse this is and that's one of the reasons why the bone marrow is difficult to aspirate.
Dr. Michael Grever:
After you made the right diagnosis, and that's what's really important is to confirm the right diagnosis and it's important to know whether you're dealing with a patient who has classic hairy cell leukemia or a variant of the disease. Approximately 10% of patients with hairy cell leukemia do not require immediate treatment. This is often concerning to patients because they hear that they have leukemia and the doctor says, "Well, we don't need to treat you right away, we're just going to follow you." But we have criteria that we use where we follow the patients closely and if we see that their white blood cells or the red cells or their platelets are their declining below some guideline values, then we want to start treatment before those numbers go too low. Patients can sometimes present with an active infection and we think it's probably somewhere around 17% of the patients who are newly diagnosed or have a complication of an active infection. And this requires some special planning because the treatments that we use to bring people into remission can further temporarily reduce the blood counts and this could make the infection harder to control.
Dr. Michael Grever:
It's also another reason why if we see the granulocyte count, which is responsible for protecting the patient from infection is going too low, we'd like to get started before that happens to avoid having the complications of infection being there where we need to treat the patient. Because some of these drugs are cleared from the body through the kidney, it's important to assess the kidney function and also if patients are going to be treated with these immunosuppressive drugs, particularly if rituxan is going to be used, it's important to understand whether or not the patient's had a previous history of hepatitis.
The bone marrow biopsy is clearly needed to establish the diagnosis and while there's some difference of opinion here, I believe that there's some value to completing or doing a bone marrow at the completion of therapy to see where we are with the amount of leukemia still present.
Dr. Michael Grever:
When we look at the patients, what do we use to decide when to treat them? The majority of patients are probably going to need to be treated at the time that they present because they're already having some symptoms. First of all, we want to confirm the diagnosis to make sure we're absolutely certain on what disease we are treating. As we see the absolute neutrophil count go less than a 1,000 and progressively less than a 1,000, then that would be an indication to consider starting treatment before it goes too low. If the platelet counts are under 100,000 and declining, then we also consider starting therapy. And if the patients are anemic to the level where their hemoglobin is less than 11, it's probably a good idea to get started on therapy. If you're having symptoms though, from an enlarged spleen or having problems with bone marrow failure and symptoms associated with infections and low counts, then we make the decision to try and start therapy.
Dr. Michael Grever:
We were very fortunate to have the advice of a large group of experienced hairy cell leukemia doctors sit down with us and over the course of about a year we came up with guidelines for the diagnosis and management of classic hairy cell leukemia. The publication in 2017 may be updated as a result of some of our meetings that we've held with the help of the Hairy Cell Leukemia Foundation. But basically these are the principles that we use when we're following patients.
Dr. Michael Grever:
After therapy, some of the infections that you encounter before treatment are replaced by some of the consequences of therapy. The drugs that we use to treat this disease do have the capability of suppressing the immune system. And this can bring concern, some opportunistic infections and viral infections. And so some of us will follow the CD4 count to give us an idea of when we can let the patient understand that they are at more risk or less risk. This is only a rough guideline however. And many patients will be put onto some medicines prophylactically to prevent the development of shingles or to prevent the development of other infections. This is an area where the physicians use their own judgment in terms of what programs they recommend.
One of the most common long-term infections though is shingles or herpes zoster. And one of the things I always advise my patients is that if you have a painful rash, don't sit at home on that because you need to get onto medicine to try and control that before it becomes progressive and painful. Shingles can become disseminated if you don't get treated. And so if that happens, it's a much more serious complication. It's always important if there's a concern about shingles, they get seen by the physician.
Dr. Michael Grever:
There is extensive investigation of the results of a lot of the studies as to whether or not patients who have been treated are at risk for secondary malignancies as a result of the immunosuppression, either resulting from the disease itself or from the treatment. In general, there's some question about this and some controversy. There may be an increased risk for second malignancies, but we believe that that risk may be slight or increased in the risk for having another lymphoid malignancy, but it's more important to understand that the treatment itself for the hairy cell leukemia has to be initiated consistent with the guidelines because if you don't treat the hairy cell leukemia, there's many more serious complications that may come about.
Bone marrow toxicity can result from excessive therapy and so it's always important when considering second and third cycles of therapy, to understand where you are with the bone marrow cellularity. Some of the drugs that are most important for treating this disease can have an effect on the bone marrow stem cells and so we don't want to provide excessive therapy. We're just trying to optimize management of the patient.
Dr. Michael Grever:
There's some recent advances. Doctors Tiacci and Falini who were at our meeting yesterday, really have contributed substantially to understanding the disease and how it may come about. They found that this expression of a mutation in a gene called BRAF is associated with 90% of the patients who have classic hairy cell leukemia. When they published this in 2011, this was a very big help in differentiating whether or not somebody has the classic form of the disease where they would express this, compared to those patients with a variant of the disease where they essentially do not express this mutation.
And so the other important part of this is that this presence of this mutation can actually be useful in therapy. Vemurafenib, which is an inhibitor of this target, can improve the blood counts and help in patients with relapsed or resistant disease. This is however, as I've indicated on the slide, it's an approved FDA drug for the treatment of melanoma, not for the treatment of hairy cell leukemia. Its use in hairy cell leukemia has been called off label, which means that hasn't been officially approved by the FDA to treat this disease. However, we have found it very useful in treating patients with some forms of relapsed or resistant disease. We've also found it helpful in patients who have a serious life threatening infection because you can get a rapid improvement in their blood count. And then after patients are improved and the infection is cleared, then there's a good reason to consider maybe consolidating the patients with more therapy after they're over their infection.
Dr. Kreitman, who's an expert in this disease, is going to be discussing some of the extensive work that he's done in developing novel therapies for this disease. I'm not going to go over this slide except to just point out that there's a lot of remaining unanswered questions. Somebody sometimes asks, "Is there anything left to do with this disease?" because we've been very fortunate over the last 30 years or so to come up with very effective therapy for the disease, but it's important to understand that 40% of the patients, roughly 40% will relapse and require retreatment. There's a lot of still unanswered questions about this disease and that's why research here is so important.
Dr. Michael Grever:
Living with hairy cell leukemia, I think can be challenging unless one is well informed and understand that when you're told you have this disease but you don't require immediate treatment, you can get another opinion, but you need to have some confidence that close follow up is very important here. And you may be able to go for some time depending on what your blood counts are, without getting exposed to the immunosuppressive aspects of the treatment. Most patients, however, will require treatment and about 40% of these patients will relapse and will require a retreatment.
Living with a rare chronic disease can produce anxiety and depression until you have a chance to learn more about it, learn about the outcome and the improvements that we've been able to see. Also it's important to meet other patients with the disease. And so you can share your experiences. It can also present challenges with medical insurance, life insurance and employment. However, the most important advice I would give is to find a medical team where you can rely on their expertise and identify individuals who can help you deal with these anxieties. Sometimes not finding the right medical team can produce anxiety and so the Hairy Cell Leukemia Foundation may be able to give you some recommendations in that regard.
Question and Answer
Dr. Michael Grever:
So the first question we've received is that a person has been treated twice and is interested in knowing whether or not nutrition can have an impact on the duration of remission and whether or not nutrition can help in the management of the disease. We've had several nutrition experts come and talk to the patients in some of our sessions. And this has been an area where I have to just be honest with you, I'm not an expert in nutrition. I personally believe that it's important to get exercise and eat well and to ask some of the more detailed questions to your provider.
One of the things that you need to be aware of is though that some of these medicines that people are taking to treat the disease may have an interaction with some of the natural products that you'll encounter. These products, which come in nutrition stores, often are not carefully reviewed by the FDA. So my advice would be if you're concerned about some of the products that you're taking and whether or not they're going to interfere with the medicines that you're on, it would be wise to ask one of the pharmacists, particularly in working in conjunction with your physician, whether or not that's going to have any impact on the medicines that you're on. In general, I don't know of any specific advice that I can give you about what nutritional supplements would be helpful in managing the disease.
Webinar participant:
Are we any closer to knowing what actually is the cause of hairy cell leukemia as opposed to what the symptoms are, and therefore, any possibility of an actual cure as opposed to remission?
Dr. Michael Grever:
Well, that's an important question. Dr. Tiacci and his team plus a number of other basic scientists at [Memorial Sloan Kettering] in New York have identified the presence of this mutation in the bone marrow cells. And so, when the BRAF mutation is present, it triggers a pathway at the send signals within cells within the bone marrow to increase their ability to proliferate, to grow and to survive. And so, some of these pathways that we are learning about will be important in letting us understand at the molecular level, why these cells are so apt to have an advantage to grow in the bone marrow and to crowd out the normal cells. There's still a lot of things that we need to define in my opinion. For example, 10% of patients with hairy cell leukemia can present with a very empty looking bone marrow. Sometimes the bone marrows looks almost as empty as in aplastic anemia.
So there is a concern that there may be some auto immune contribution to suppressing the normal cells growing that results from the hairy cells. So in terms of understanding why the disease occurs in the first place, it would be understanding the acquisition of this mutation and what kinds of things lead to that. The other interesting thing that we've been thinking about is, I was contacted recently by a hematologist and she has a family of patients with hairy cell leukemia and this has been reported before. And I have a family that I was following that has hairy cell leukemia. This however is a very, very rare entity. And so we don't really understand the mechanism whereby this would arise in a family, because most of the time that doesn't happen. So to answer your question whether we're closer, I think we are, because we're starting to focus in on some of the pathways to lead these cells to grow and to have a growth advantage in the bone marrow and the spleen over the normal cells.
And also we're learning some of the electrical signaling pathways that occur within these cells that could furthermore not only help explain the disease but also give us an idea about how we can target the disease promoters and then have a better chance of getting control. For example, if you have an over vigorous signal coming from an abnormal gene and if it's causing the production of signals to keep the cell alive, the more we understand that circuitry we'll be able to develop targeted therapy to add to a more effective control of the disease.
And many patients that are diagnosed with this need to be told that with all of the therapy we have currently in our hands and hopefully will develop in the future, we're getting more and more effective at getting a complete remission. And if you take a look at the long-term outcome, in this day and age, most patients with hairy cell leukemia can live a long time. Back in the 1980s, Dr. Bouroncle projected the survival was only about four years, and we're now telling patients that they may live as long as they would have, even if they didn't develop the hairy cell leukemia.
However, they may go through multiple relapses and need to be retreated. So it's important to try and do what you suggest and that is to come up with a more effective combination of drugs that will keep the remission lasting longer so that there's fewer of these relapses.
Webinar participant:
I am 72; I had never had HCL. My blood counts were low and then I got pneumonia. So that's how they found it. And I'm in a clinical trial at Yale (with MSK) with Vemurafenib and Obinutuzumab. I'm on week nine-and-a-half of the treatment and my numbers have skyrocketed. My doctor really feels that this treatment, this particular combination, will definitely put it in remission and it could be a cure for it. So have you heard about this? I'm sure you have.
Dr. Michael Grever:
I think this combination is very promising. Dr. Tiacci in Europe as well as the doctors from Memorial; see this Vemurafenib is a drug that goes after that target called the BRAF.
What we've seen with that is it can raise the blood count very efficiently. And so that's good for getting patients out of danger. The Obinutuzumab is a very interesting and effective monoclonal antibody that directly attacks markers on the leukemic cells. And so this combination has been very effective in getting patients into a complete remission. I mean, it's not guaranteed; you have to wait until the treatment is done, but there's a very high probability of getting a very good remission with this combination. And the standard therapy has been using either Cladribine or Pentostatin as the initial therapy. However, if you had pneumonia, one of the problems if you have an active infection, getting Cladribine as the frontline therapy is risky. If you go back to the original papers with Cladribine back in 1990-91, they actually excluded patients from getting Cladribine if they had an active infection.
So a lot of the original exciting work with Cladribine was done in patients who did not have an active infection. So if you had pneumonia or around the time of pneumonia, whenever they decided to treat you, then starting with Vemurafenib would be, in my opinion, a very reasonable approach and using Vemurafenib just by itself has been done. But we're finding that combining it with one of these molecules that go after CD-20 provides a stronger and more durable remission. I'd love to say we're on the verge of getting cures, but this is early on, it's very exciting. And I could understand why they chose that for you.
Well, the question I'm going to try and relay here is: This patient who asked us now had two treatments for hairy cell leukemia and apparently is now facing a relapse. And the question relates to how low can the counts go and be watched while it's still safe. So what I would say there would be, if a remission lasts about five years, it's often said that you could go back and use that same agent. What we see in practice is that if patients relapse and they are needing to have a second treatment, if there's no contraindications, then in addition to the Cladribine, they may also be given Rituxan to get a more solid remission.
So the treatment decisions for the third cycle of therapy in terms of what they would use will depend on whether or not they plan to add something like Rituxan to a subsequent use of purine nucleoside analog. In contrast, there's other drugs that can be used and Dr. Kreitman will be able to give you some information about this new agent that's been approved called Moxetumomab, which can be used for patients who have relapsed. To answer your question more specifically, we have used the guideline, if the absolute neutrophil count is less than 1,000 in showing that it's validated to be less than 1,000 and showing that it's going in the wrong direction, then it's wise to consider re-treatment before somebody becomes actively infected. Now, to get specifically to a number. What I tell people is if the absolute neutrophil count is 990, you don't have to full panic and start treating until you're sure that the patient doesn't have an active infection and that they're in good physical shape, otherwise to take the therapy.
But if you see that the count's going from less than 1,000 to 800 and then they start to go down, there's no sense waiting until they're down in the five and 600 range where you're more likely to get an infection. I've had patients who were followed and the doctor very carefully documented this decline and then they did get an infection, and what we often tell them is well that's wise that you were following them, but you might've started the therapy a little bit sooner. But so there's some clinical judgment that goes into this and also the rest of the patient's health has to be factored into the equation at the time. But in general, if I were following a patient and I saw that the neutrophil count was consistently and well documented going down, at below 1,000, goes down to the 700 range and dropping, then I wouldn't wait until it was a lot lower.
But, that's where the clinical judgment comes in. I had a patient not too long ago who had an absolute neutrophil count of zero. I've never seen anybody that's had a persistent count that low with this disease and he came in with a fungal pneumonia and a dental infection, so we hadn't seen him ever before. He didn't get identified until he already had these infections. So I don't know if that answers your question, but I would follow the count. I usually follow the patients pretty carefully because you can't always predict how long it's going to take for the counts to get lower. So if somebody had a count that was falling, I would probably be repeating it at least monthly until I knew what direction things were going in and I wouldn't wait until it was in the 500 range. I would treat it before then and clinical judgment would have to be incorporated into that decision.
Dr. Michael Grever:
The next question is frequently asked about the shingles vaccine [whether it’s safe to take]. Shingrix, which has a been on the market recently, has been identified as being effective in patients who are immunocompetent. If you have a normal immune system and your elderly or you're even younger, if you have a normal immune system, I think there's a general consensus that the Shingrix vaccination is safe and effective. What is not very well defined, in my opinion, is that patients who have a compromised immune system, whether or not they're going to get a valid response to the Shingrix vaccine. This is something that comes up in a lot of the conferences we have and so some people will say, "Well, what's the danger of taking it?" I don't think that the Shingrix itself is necessarily so dangerous, but if we don't know whether or not you're going to be able to respond, then some people have a false sense of security.
If they have had Shingrix and some of these people who need to be on prevention drugs like Valtrex or Valacyclovir may stop their medicines because they think that they're protected. One of the things that we know is that the immune cells in patients with hairy cell leukemia are very compromised. And after you get treated with Cladribine or Pentostatin or Rituxan, you will have a decline in your healthy lymphocytes as well as the bad cells. And when the lymphocytes go low, you may not respond very well to attempts to vaccinate. So before the treatment your immune system is going to be compromised and we don't know whether you're getting a valid response to the vaccination. This has not been adequately studied to my knowledge. But, Dr. Kreitman has done some studies.
And then the other concern is, and a lot of people don't appreciate this, but the lymphocytes stay down for a long, long time after Cladribine or after Pentostatin, and when Rituxan is added to it, it's certainly going to contribute to the lymphocyte count going down and staying down. I've looked and I cannot find the bodies that usually make recommendations about vaccinations. I have not found anywhere where they have yet recommended the Shingrix vaccination for somebody who is immunocompromised.
In patients with this disease, you may see your granulocytes coming back to the normal range, hopefully whenever you're treated. But the lymphocyte counts usually go down and they stay down for well over a year or longer. And the other thing that we don't know is when the lymphocyte count gradually makes its way back to normal, we still don't know that they're working right. You can see them circulating in the blood but you don't know that they're functional. So what we've been doing in our clinic is telling patients that we don't know about the effectiveness of the Shingrix vaccine. And I know that statement has made some patients mad at me, but that's just the honest statement that I can make.
I don't vaccinate with shingles. You may find a doctor that will vaccinate you with ... the question is, what do you do? Well, I educate the patients. If they see anything that looks like shingles, they have to get to the doctor right away. And if their counts are really low, we put people on prophylactic medicines that are pretty well tolerated to try and protect them. That hasn't been studied all that well either. So you're at risk for developing shingles and if you get shingles you have to get onto a therapeutic dose. The Valtrex or Valacyclovir. So I'd like that risk to go away, but we can't fix the immune system that quickly.
Webinar participant:
So, after your white blood cells have returned to normal, can you have vaccines then?
Dr. Michael Grever:
The question is after your white blood cells have returned to normal, can you have the vaccine then? The cells that people normally talk about coming back to normal are the Granulocytes, they're the cells that fight off bacterial infection. The cells that are responsible usually for getting an immune system is a different set of white cells and they often fall within the lymphocyte count. And if people are very tuned and appropriately tuned to look at the Granulocytes, and we're very glad when they come back to normal because that decreases your risk for bacterial infections.
However, your lymphocytes usually go down and they stay down for a very long time, much longer than most people realize. And so during that time your immune system is compromised. So just because the Granulocytes come back to normal doesn't mean that you're no longer immune suppressed.
Back in 1972 I published a paper in the Journal of Immunology on the effect of these drugs on lymphocytes. And you can really knock out the functional aspects of the lymphocyte, even though you haven't killed the lymphocyte, they're sitting there, they don't always work normally after you've been exposed to these drugs. So this is an important, in my opinion, an important research question. I'd like to have an answer, but I don't have an answer.
Dr. Michael Grever:
This is my friend and colleague Dr. Kreitman.
Presentation by Dr. Robert Kreitman
Dr. Robert Kreitman:
I'm Dr. Robert Kreitman. I want to thank Dr. Grever for an excellent presentation and introduction to what I'm going to talk about, which is what's new with treatments for hairy cell leukemia. I don't have a slide on my disclosures, but I'm a co-inventor on the NIH, National Institutes of Health, patent for Moxetumomab pasudotox that we'll be talking about and I also received research funds at the NIH from several drug companies including Novartis for the BRAF and Ibrutinib.
Also Teva, which makes bendamustine, also Genentech that makes rituximab and also Astrazeneca, which makes Moxetumomab pasudotox, which is now being covered by a company called Innate.
So this introduction was really excellently covered by Dr. Grever. I want to add that there is a variant which is more rare than the hairy cell variant that we talked about today. That's called the IGHV IGHV4-34 variant, which can look like hairy cell classic. It's about two to 5% of the patients that we see that are newly diagnosed and we tend to see it more often in patients who are multiply relapsed, that have very resistant disease, and yet seem that they have classic hairy cell because their CD-25 is positive. CD-25, as we've discussed already, is one of the markers for classic hairy cell leukemia.
But, if they have a molecular marker called IGHV IGHV4-34, they can have this aggressive variant that seems like the hairy cell variant and they have a poor response to Cladribine or Pentostatin even with primary treatment when they're first diagnosed. So this is important to think of if patients aren't responding well to initial Cladribine and Pentostatin. This is the guidelines, this is called the NCCN guidelines for hairy cell leukemia, which really resulted from Dr. Grever's leadership effort in the hairy cell experts coming up with a consensus guidelines for how to treat hairy cell leukemia.
I've circled the guidelines, the treatments in red. So you can see on the left, the purine analogs Cladribine and Pentostatin are recommended for first line initial treatment. And as we move to the right in patients who relapsed, their recommendations include retreating with the initial purine analog, that would be Cladribine or Pentostatin, versus the alternative purine analog, or with and without rituximab or rituximab alone.
Dr. Robert Kreitman:
There are options for patients to be treated with interferon. And in patients who progress, Vemurafenib, which Dr. Grever talked about, with or without rituximab are options and also Ibrutinib. Ibrutinib is a very interesting drug that is currently being tested in clinical trials. And it's on the guidelines as well. It's approved for chronic lymphocytic leukemia and mantle cell lymphoma.
First I want to clarify what do we mean by complete remission? So complete remission just simply means that there's no hairy cells visible by the standard stains. We call this a H&E (Hematoxylin and Eosin) or right stains of the bone marrow and blood. And you also have to have resolution of enlarged spleen and lymph nodes. You have to have a resolution of normal blood counts and high hairy cell counts in the blood. So, in addition to meeting the criteria for complete remission, you can have minimal residual disease, either present or absent.
And minimal residual disease is traces of hairy cells that can be detected by special stains of the bone marrow biopsy, by flow cytometry of the blood or bone marrow aspirate, by molecular studies including PCR (polymerase chain reaction). In many diseases, complete remission, CR, can last longer if MRD is negative. In other words, if MRD is undetectable.
So we'll be talking about the evidence at least in one situation where CR does last longer in hairy cell if the minimal residual disease is negative. So the new developments, which come after this 2011 and 2017 guidelines, that I want to mention include the FDA approval of moxetumomab pasudotox. That was in September of 2018. The American Society of Hematology meeting presentation of Dabrafenib and Trametinib, a large multicenter trial that was presented in December of 2018, and then just recently the American Society of Clinical Oncology (ASCO) presentation of combination of Cladribine and rituximab, which was a randomized trial. And that was in this just past June.
Dr. Robert Kreitman:
So, I want to start by just reviewing the Cladribine and rituximab for first-line treatment of hairy cell and this is actually not the ASCO presentation. This is earlier data from MD Anderson by Dr. Ravandi's Group, showing that rituximab, which follows Cladribine by one month. So patients are treated with Cladribine for initial treatment of hairy cell. And then one month later they start rituximab. This is associated with 100% CR rate in 59 patients. And at the three month time point, there were bone marrow biopsies done where high sensitivity tests were run for MRD, for minimal residual disease. And it was negative in 76% of the patients. At subsequent time points, patients were tested in blood. And so a number of those patients were negative in the blood as well. But up to three months, they were tested in the bone marrow. In hairy cell variant, several patients had complete remissions as well. And so these results were published in 2011 and 2016.
What we did at the NIH was a randomized trial, and our patients were treated both at the NIH and by their local doctors, really all over the country. We randomized patients against getting Cladribine alone, as you can see on the bottom, where the green bar represents five daily doses of Cladribine versus getting Cladribine with eight weekly doses of rituximab shown in orange. And that starts immediately after the first dose of Cladribine given on day one. For the delayed group, the delayed group could receive delayed rituximab, started at least six months after Cladribine.
Dr. Robert Kreitman:
So we found that Cladribine alone at the six months time point achieves the complete remission rate of 88%. This is very similar to what other experts have found, including Dr. Saven at the Scripps Clinic, and other investigators around the world. Cladribine is highly effective for inducing complete remission.
And like Dr. Ravandi's studies, the Cladribine plus rituximab started immediately gives a complete remission rate of 100%. So we know that rituximab can increase the CR rate of Cladribine, the question is what about the minimal residual disease?
Dr. Robert Kreitman:
So I want to just briefly mention that the reason we're interested in minimal residual disease is that it's possible that the minimal residual disease may improve the outcome for hairy cell patients in terms of whether the complete remission will last longer, or whether patients will enjoy a longer period of time until their next treatment.
In the early treatment for hairy cell though, we don't know until further follow up if this is going to occur. But the first step is to see, can we even decrease the rate of MRD in complete remission after Cladribine with rituximab? And so this shows that the MRD free complete remission rate was 97% after combined concurrent Cladribine and rituximab versus 32%. In other words, 11 out of 34 patients after Cladribine alone.
Dr. Robert Kreitman:
And if you take those 11 patients that achieved MRD negative complete remission, and that's in blue, you can see in the blue curve in terms of the percent of patients that are still MRD negative over a certain number of months on the X axis, on the horizontal axis, you can see that the curve falls down.
In other words, patients are becoming MRD positive over time. Most of the patients, whereas only one patient became MRD positive so far in the concurrent Cladribine rituximab arm. And so far we have follow up up until 120 months. That's 10 years.
Dr. Robert Kreitman:
So we know that the MRD free CR was both more frequent and more durable with than without rituximab, and that some patients achieved MRD free CR without the rituximab. And then with delayed rituximab, as we can see on this curve, the delayed rituximab was also effective.
So in comparison to the group in yellow that I just showed, that were treated with concurrent Cladribine and rituximab, we had 14 out of 21 patients, or 67%, two thirds, that achieved MRD negative complete remission with delayed rituximab. As you can see in those 14 patients, some of those patients became MRD positive over time, more so than the patients who had the concurrent Cladribine rituximab.
Dr. Robert Kreitman:
And there was a statistically significant difference favoring the group that got the concurrent Cladribine and rituximab. However, as you can see, most of the patients who became MRD free with delayed rituximab have remained MRD free.
So we conclude that delayed rituximab was effective, but both MRD free complete remission rate and durability were better with concurrent Cladribine rituximab. And I want to mention that we gave the delayed rituximab when we found the evidence of MRD in the blood.
Dr. Robert Kreitman:
So I want to briefly mention that we also gave the same regimen, Cladribine with immediate rituximab for hairy cell variants. In historical analyses, historical trials that have been done in the past, we know that the Cladribine alone for a hairy cell variant has a low complete remission rate, about 9% out of about 39 patients, that we could find in the literature. And our complete remission rate with Cladribine plus rituximab was 95%.
So a single agent, Cladribine or pentostatin, should really not be used for hairy cell variant at this point. One should use a more active regimen like Cladribine plus rituximab, or Cladribine plus another approach.
Dr. Robert Kreitman:
So in patients who are multiply relapsed, in addition to using Cladribine and rituximab, we are also using Bendamustine and rituximab, shown in the green and the orange, and also pentostatin in the blue, and rituximab.
And these can give complete remission rates of 75 to 85%. These are in patients who have relapsed several times. So their expected complete remission rate to a single agent treatment is quite low. And most of these complete remissions are free of minimal residual disease.
Dr. Robert Kreitman:
But while highly effective, this approach may be toxic, because these patients have already had chemotherapy, and the toxicities from chemotherapy, which include nerve damage as well as damage to bone marrow stem cells, and leading to infections and other problems. This could be cumulative.
And so the question is, can MRD free complete remission be achieved without chemotherapy? And really what is the benefit of being MRD free? Is it really worth it to get rid of MRD, and why worry about it?
So I want to introduce a couple molecules. We've talked about rituximab. By itself, single agent, the complete remission rate was reported at 13% by Dr. Saven a couple of decades ago now, and this is in patients with relapsed hairy cell who needed to be treated.
Dr. Robert Kreitman:
So on the right is a model of moxetumomab pasudotox, which is what we call a recombinant immunotoxin. It's an engineered protein which has an antibody fragment that binds to CD22, and it's connected to a toxin that kills a cell after it gets inside. There's a complicated process where it goes inside the cell, it unfolds as you can see, there is a break that occurs in the yellow part, and it goes to the endoplasmic reticulum, which is abbreviated by ER, and then it gets into the cytoplasm of the cell, where it's very powerful at catalytically killing the cell by apoptosis.
And this has a complete remission rate of 50 to 65%. Most of the complete remissions are MRD free. It was approved by the FDA about a year ago for relapsed hairy cell. And this shows what the effect of being MRD free is on complete remission duration. And so the moxe, we call the moxetumomab pasudotox moxe, because it's just easier to pronounce. It's given by 30 minute infusion on days one, three and five, and that's repeated every four weeks.
In the phase one trial of moxe, there were 11 patients that had MRD free CR, and this is in the curve on the left, in the green on top, and only one of these patients relapsed. You can see the downward deflection around a little before 40 weeks. Versus nine patients that remained MRD positive. And most of these patients, eight of them, relapsed.
Dr. Robert Kreitman:
Now the curve on the right is looking at patients who had either one to four extra cycles. We call these consolidation cycles of moxe. This is the number of cycles that they got after complete remission was documented. And in blue are patients that had no consolidation cycles.
And you can see that the seven patients who got one to four extra cycles after complete remission did not relapse. And of the 14 patients who did not get extra cycles, most of these patients relapsed. And so CR duration is longer if moxe can clear minimal residual disease, and this requires extra cycles.
Dr. Robert Kreitman:
Now, further follow up is being done on these patients to determine if it's not just the complete remission duration, but if also the time to next required treatment is also better in the patients who have MRD negativity achieved. And this is an end point which is really more useful for the average hairy cell patient, because just having relapsed from complete remission doesn't necessarily mean that your life is altered. Complete relapse from complete remission may mean that your bone marrow is positive now, but it doesn't mean necessarily that your blood counts are low, or that you need to worry about getting more treatments.
So the one question that people ask is, why can't a higher percent of patients get complete remission from moxe? Four to 9% of patients on these trials got a toxicity called hemolytic uremic syndrome. We call this HUS, where platelets decrease and the creatinine increases. The HUS is temporary, it lasts for about one to two weeks, but patients cannot be re-treated after this. And this limits the number of extra cycles which can achieve complete remission without MRD.
Because the toxin in moxe comes from a bacteria, it actually comes from pseudomonas bacteria, the immune system can recognize the toxin and reject it. That doesn't happen severely in most patients, but it does happen a little bit in a lot of patients, and it can happen in a fraction of patients from the very beginning. So the more cycles a patient needs for complete remission, the more chance that the immune system has to interfere with moxe, and prevent extra cycles from working. If there is a lot of hairy cells, especially big lymph nodes, it takes longer for the moxe to work. And this gives the immune system more time to reject the moxe.
Dr. Robert Kreitman:
In the phase three trial, a maximum of six cycles were allowed, so it would be best to achieve complete remission by two cycles, and have four extra cycles to get rid of MRD. So to accomplish this better than using moxe alone is to combine rituximab plus moxe. And you can see that in this slide. And a clinical trial is currently underway at NIH to look at this. The first goal is to reduce the amount of hairy cell so that the moxe can achieve CR more quickly. And a second goal is to reduce normal B cells. We've already heard that rituximab reduces normal B cells, and that may prevent the immune system from rejecting the moxe.
Dr. Robert Kreitman:
I want to mention about some of the precautions that we're using with moxe. This is really important, because this drug is approved now, and many people are getting this out in the community. And the package insert doesn't mention some of these hints and recommendations for preventing toxicities. And these are based on the fact that when moxe is given, it gets out of the blood vessels by going through the living cells that line the blood vessels. And this kills some of those cells. And it causes leaking.
We actually don't mind that happening. That's actually a good thing, because it gets the moxe out of the blood vessels, and gets to the hairy cells, which may partially be outside blood vessels. But it can cause leaking. And because of that, patients have to drink plenty of water to keep from being dehydrated.
And a large volume of liquid. An IV infusion of liquid, however, will cause overflow. I liken this to a bucket and I have the bucket on the right. You can see the bucket leaking. And we don't want to overflow the bucket, because this leads to problems clinically, like edema and fluid around the lungs. It can make patients short of breath. So we want to just keep the bucket full, but not to overflow. And oral water, water that you drink, is very rapidly regulated by the body, much more so than IV fluid.
And so we want to prevent a delay of drinking. We want to keep lapses in drinking to less than two to three hours. And so what we recommend is that patients drink about a cup of water an hour, and when they're sleeping at night to not go more than two to three hours without waking up to drink a cup or two of water, and then go back to sleep. And this will prevent patients from waking up in the morning and feeling dizzy and dehydrated.
Dr. Robert Kreitman:
Also we find that patients can have some nausea or headache after moxe. This can be rather mild, however, it's a problem if it keeps patients from drinking water. And we find that this responds very quickly to a low dose of steroid dexamethasone, four milligrams orally. And that allows patients to continue drinking with a normal appetite.
So at NIH, where we use these precautions, we had a 69% complete remission rate on the phase one trial, 73% complete remission rate on the phase three trial. And this is a little bit higher than the international average, before these precautions were known. Before we had these precautions, the first nine patients on our phase three trial had grade three. This is severe hemolytic uremic syndrome, whereas after these precautions were followed, only one out of 17 patients got a mild version of hemolytic uremic syndrome.
So we think that these precautions are important. And really the most serious long-term consequence of having HUS is not permanent kidney damage, we haven't seen that in our patients, but it's really the inability to continue moxe to achieve MRD free CR.
Dr. Robert Kreitman:
Now I want to shift to talk about the BRAF drugs. We've already heard about Vemurafenib, and this takes advantage of the fact that as reported in 2011 by the Tiacci and Fellini Group in Italy, BRAF carrying the V600 mutation overstimulates the BRAF/MEK/ERK pathway. You can see on the right in red, this mutated BRAF, which overstimulates MEK, and that overstimulates ERK, and that leads to cancer. It can lead to melanoma if it's a skin cell, it can lead to hairy cell if it's a B cell. And Vemurafenib inhibits this, and results in this 35 to 45% complete remission rate in hairy cell.
Now these complete remissions were reported to be MRD positive. Dabrafenib is a different drug that inhibits BRAF V600E. Trametinib also inhibits this system, but it inhibits the MEK. So if you use both together, the dabrafenib and trametinib were found to be more effective and less toxic in melanoma.
And these two drugs are also reported, at least at the ASH meeting, to be effective in hairy cell. However, they do not completely get rid of MRD. And to eliminate MRD, a trial is being led by Memorial Sloan Kettering for untreated hairy cell, that combines vemurafenib and obinutuzumab. This is a combination that one of our callers has already mentioned. And obinutuzumab, like rituximab, binds to CD20. A trial in Italy combines vemurafenib and obinutuzimab with a MEK inhibitor called cobimetinib. And that's also underway. And these agents can have side effects, including skin rashes and cancer for vemurafenib, and fever and chills for the vemurafenib and trametinib. So one has to be aware of these problems.
Dr. Robert Kreitman:
So in conclusion, there are many new options for hairy cell leukemia that we call targeted therapies. And ibrutinib is also on this slide. It can be effective as a chronic treatment for hairy cell. It's felt to be generally less toxic than the BRAF inhibitors. The moxetumomab pasudotox can achieve minimal residual disease-free complete remission without chemotherapy. The ibrutinib and the BRAF inhibitors are oral treatments, so they have that convenience. The rituximab and moxetumomab pasudotox, moxe, are both IV treatments.
Dr. Robert Kreitman:
Current efforts are to optimize efficacy in hairy cell by a combination of several of these options with rituximab. And these are the clinical trials that are featured on the Hairy Cell Foundation website. The Cladribine and rituximab and rituximab, bendamustine, pentostatin that we've talked about already.
We've already talked about moxetumomab pasudotox and rituximab. The ibrutinib trial is currently still enrolling. And that's being led by Ohio State. And the vemurafenib obinutuzimab, and the vemurafenib cobimetinib and/or obinutuzumab trial that we briefly mentioned.
Dr. Robert Kreitman:
And this sort of sums up what we've talked about today. For standard and also investigational approaches, just putting it all together. For untreated hairy cell, patients are getting either Cladribine or pentostatin. This is abbreviated PCF. Cladribine is abbreviated CBA. Or Cladribine rituximab combination, or vemurafenib obinutuzumab, patients with one prior treatment are getting these same options, but also ibrutinib or moxe and rituximab. Patients with hairy cell variant, with one or no prior treatments, are getting Cladribine and rituximab, or bendamustine and rituximab, or pentostatin and rituximab. This is DCFR, pentostatin rituximab. Or ibrutinib or moxetumomab pasudotox and rituximab.
And then this is agent being used for multiply relapsed hairy cell. In patients who are BRAF V600E positive, they can get these BRAF inhibitors. And then there are other options for patients who are not eligible for everything above this line.
So these drugs that are being used for patients with multiple relapses, even MEK inhibitors like cobimetinib or trametinib alone, are being used in patients, particularly with hairy cell variant. There are palliative options like splenectomy, rituximab alone, or just pairing analogs, just to try to keep patients going with improvements in their normal cells.
Question and Answer
Anna Lambertson (relaying question from webinar participant):
Are there ranges that you would consider acceptable or unacceptable with regards to MRD?
Dr. Robert Kreitman:
Okay. So the question is what is the range of MRD positivity that one would consider acceptable? And so first of all, I want to restate that the goal of eliminating MRD is to try to improve outcome, but we don't know for sure if there is a real benefit to elimination of MRD.
What we know so far is that, at least in the moxe treatment, there is an improvement in the complete remission duration. The complete remission lasts longer if the patients are MRD negative. So we would like to eliminate MRD in all patients 100% if possible. That's not always possible. But further follow up will determine whether an improvement in complete remission duration leads to more tangible benefits.
For example, an increased time to the next treatment will be called the time to progression where you need more treatment. And many patients want to know, "Will this improve my overall survival?" And that's something that will take decades to determine. So that's not a question that we can answer very soon.
Anna Lambertson (relaying question from webinar participant):
Another question is, how delayed can treatment with rituximab be in order to still achieve favorable results?
Dr. Robert Kreitman:
Yeah, so the question is, how delayed can the rituximab be and still be effective in eliminating minimal residual disease? So what we found is that we gave delayed rituximab only if and when we saw the blood MRD detectable in the blood. And this sometimes in some patients would take years. And so even after many years, three, four years, we would give patients delayed rituximab, and we saw that that was still effective in eliminating MRD.
However, if you wait until you actually relapse, in other words, the blood MRD is positive, but also several years later when you actually relapse, when you have hairy cell in the blood, and then the spleen is large, and then all the other signs of hairy cell come back and you need treatment, the rituximab is much less effective in getting rid of MRD, and also achieving complete remission.
Webinar participant:
I am BRAF negative, but I was diagnosed at the institution like classic hairy cell leukemia. But my BRAF 600 was negative and I was tested for the mutation IGHV IGHV4-34, it was also negative. Immediate rituxan and Cladribine are effective. Do they have the same prognosis as classic, BRAF positive hairy cell leukemia? Why is BRAF 600 negative, and at the same time it shows classic markers for classic hairy cell leukemia with bright CD25 positive.
Dr. Robert Kreitman:
This is a complicated question. I want to make sure that other patients on the line understand it. What we're talking about now is that there are several issues that you're bringing up.
One issue is the IGHV IGHV4-34 variant that I mentioned in the very beginning is associated with a more aggressive form of hairy cell. I didn't mention, but it was on the slide, that those patients are wild-type, in other words, negative for the BRAF mutation in general. And that's a sign that their disease is a little bit more aggressive. It's pretty rare, but one of the patients on the Cladribine and rituximab trial had that problem and got the Cladribine and rituximab together and never relapsed from being MRD-negative in complete remission. We know at least that it's possible to have a good outcome with Cladribine and rituximab together even if you have that problem.
But the other part of your question is what if you don't have the IGHV IGHV4-34, if you just are a wild-type or a negative for the BRAF mutation, but you have a classic hairy cell. In other words, the CD25 is bright positive.
There's a number of reasons why the BRAF might not be detectable. One of the reasons that's very clearly known is that there may be another mutation near the BRAF which has no impact on the disease whatsoever, but it prevents the assay from working for BRAF. So it may be kind of a false negative test. And this can be most easily determined by next-generation sequencing or by more detailed sequencing, there's other names for it. These are studies that we're doing. They're a lot more slow to come back and get results from then the BRAF test.
My guess is that most patients who are BRAF wild-type or negative for mutation and have other features of classic hairy cell will actually be okay and not have this aggressive variant. These patients, in general, don't have the clinical features either of the IGHV4-34 variant. In other words, they don't appear to have a very highly aggressive disease; very high white counts, et cetera. So I think I answered that completely.
Anna Lambertson:
We have a question about long-term side effects for the standard treatments for hairy cell leukemia - purine analogs, Cladribine, pentostatin as well as for rituximab and Lumoxiti. What are the more serious side effects are for those drugs? Is there a likelihood to develop other types of blood cancers or other types of cancers after using these treatments for hairy cell leukemia?
Dr. Robert Kreitman:
The chemotherapy drugs, the purine analogs, pentostatin and Cladribine and also bendamustine - it's actually an old purine analog but it's more newly used for hairy cell and other diseases - these can cause STEM cell damage, long-term decreases in CD4 counts, a type of T-Cell that's really important for immunity and we know that long-term decreases in CD4 count can be associated with increased secondary malignancies. These are other cancers. It can be associated with opportunistic infections. These are infections that are unusual infections but they can be associated with a poor immune system. We know this from other diseases but it hasn't been definitively proven in hairy cell just because there haven't been studies that have had so many patients to be able to definitively show that these drugs cause secondary malignancies. It's still an open question in hairy cell leukemia. However, there is a suspicion among many that there is at least a low rate of secondary malignancies as well as infections that can occur late in patients.
The other problem long term with these drugs is that they can cause neurotoxicity. It was shown that one course of purine analog can cause neuropathy or nerve damage in about 15% of patients. And that can be cumulative if you get more than one cycle. This was shown by Dr. Bruce Chabner several decades ago. So this is another issue because the nerve damage is often not reversible and it can actually worsen with time. The other drugs include Ibrutinib. Ibrutinib is targeted therapy. It doesn't tend to cause the problems that we talked about. It can cause atrial fibrillation which is a heart abnormality. Sometimes it goes away when you stop the drug. Sometimes it doesn't. But otherwise, that drug is very well tolerated.
The BRAF inhibitor is, as I mentioned, I mentioned those toxicities already. They're generally reversible when you stop the drugs. The moxetumomab pasudotox and rituximab. They are not known to have long-term toxicities that accumulate with time. If the patient were to have a very severe form of HUS though the kidney function could theoretically not reverse. And so that's why it's very important to follow the precautions that we've mentioned.
Webinar participant:
My question's about the BRAF mutation. I'm hairy cell classic, I believe. Post-Cladribine only. But I had asked for the testing to find out the BRAF mutation and my doctor didn't see the need for it. What's the importance of determining that at the beginning of your treatment versus waiting to see if you respond well or not?
Dr. Robert Kreitman:
One reason to know the BRAF mutation at the very beginning is if you were interested in being in a clinical trial, that required knowledge of that. For example, if you wanted to get into a Vemurafenib obinutuzumab trial I'm sure they would want to know if you have the target for Vemurafenib, which is the BRAF mutation. Another reason to know is to be able to classify because if you're positive for the mutation, it's very good evidence that you have classic hairy cell leukemia. That's why it's being run now almost routinely for patients who are newly diagnosed. I want to mention that in patients who have already been treated it's very difficult sometimes to detect the mutation because the purine analog is so good, fortunately, at getting rid of the hairy cells. So even if you have MRD, the level may be too low to even detect the BRAF mutation. A BRAF test may be false negative and so your doctor may not want to do the test because if it's negative it might raise concerns that you don't have hairy cell but it probably would be a false negative test.
Webinar participant:
We've met a few years ago. I've finished three rounds of moxe and I was just curious to know when I may see a difference in my blood work.
Dr. Robert Kreitman:
If all goes well, we see a reversal of the blood counts. So we see the platelet count coming up by the third week of the first cycle. Then we see in the middle of the second cycle, about five weeks after starting moxe, we see that the neutrophil count comes up. So by the end of the second cycle in other words, right before the third cycle, we should see fairly normal blood counts.
If you don't have normal blood counts by then, there are several reasons for that. One reason might be that you have antibodies against the moxe. This is something that you're not tested for beforehand but if you do have antibodies, you're not going to get a good response. You're likely not going to get any toxicity either. A good sign for that though is if you had flow cytometry done of your blood and they found that the numbers of hairy cells were not going down with each cycle and in fact, might be going up a little bit or staying the same. That would be good evidence that you're not getting benefit from the moxe. In patients that we've treated, we've gone ahead and stopped the moxe because we don't want to continue it if it's not going to work.
But the other reason that your counts may not have resolved yet is that you may have had a lot of tumor to begin. You may have had a very large spleen or a lot of hairy cells in the blood and it may just take longer for the moxe to work because, in order to work, the moxe has to bind to every single hairy cell. Go inside and kill the cell. And if you start out with a lot of hairy cells, it's going to take a lot of moxe to do that. So it really depends on what your situation was before treatment.
Anna Lambertson:
We have a question from a group of patients about a lot of pain that they experience since being treated for hairy cell leukemia. So a lot of pain in the back, pelvis, joints. It hasn't been determined by their doctor that this is autoimmune arthritis. They have low energy levels and they really want to know are these symptoms, these pains, this discomfort is it something that they have to get used to? Does it ever get better?
Dr. Robert Kreitman:
What was the treatment in this case?
Anna Lambertson:
That's not exactly indicated but some of these patients, it seems they've received a purine analog so most likely Cladribine or pentostatin.
Dr. Robert Kreitman:
Fatigue and these kind of nonspecific symptoms, joint pains, back pain that occurs after chemotherapy. Some of this may be related to neuropathy or nerve damage that might be actually present a little bit before the chemotherapy. It's for example in patients with diabetes that can have a little bit of neuropathy. They get a purine nucleoside analog and that can make it worse. It may be a problem that's not related to the chemotherapy. But we often see this in patients getting chemotherapy for other diseases as well, that there can be certain problems including chronic fatigue. Then it can occur after chemotherapy. And it's good to have a doctor take a personalized approach to this. Look for things that are reversible. We have found low thyroid levels in some patients that haven't had that checked and they feel better after getting that problem corrected. So sometimes it takes a good internist and oncologist to try to figure out those things. I don't know if Dr. Grever wants to add anything to that question.
Dr. Michael Grever:
We have observed that there's, and I'm not sure what the percentage is, there's a arthritis and joint pain that can sometimes antedate the diagnosis of hairy cell leukemia too. It can be migratory. It's called palindromic arthritis and when it comes on it can come on rather quickly and be pretty severe. There's inflammation associated with the joints. It could be in the elbow or the hip and sometimes this is hard to pin down exactly what's causing but it's migratory and it's not performing like rheumatoid arthritis. It's just an inflammatory process. It comes on quickly. This is sometimes a clue that there's an underlying lymphoid malignancy. And you treat the disease and sometimes it goes away and sometimes it doesn't, unfortunately. Sometimes if the pain is too severe and you can't control it with nonsteroidal anti-inflammatory agents, then maybe a short course of low-dose of prednisone can sometimes help. But you have to be careful because prednisone increases the risk for infection.
Anna Lambertson:
I'm going to continue working through these questions and maybe each of you can jump in and answer as they come. We've actually had two questions about whether or not hairy cell leukemia is hereditary. So if a woman has hairy cell leukemia and is pregnant, can her child have it? The BRAF mutation - Is it something that is passed on to children? They're concerned about whether or not their children can end up having hairy cell.
Dr. Michael Grever:
Claire Dearden is very familiar with trying to address some of these questions because we have often passed on some of these questions to her about pregnancy and hairy cell leukemia. I don't have numbers on this, but we've seen a number of very normal births and very healthy children. You have to be careful, though, if treatment occurs during pregnancy. That can have an impact. And so that has to be carefully discussed with the hematologist. I'm talking about in general just having hairy cell leukemia. I think it's a pretty low likelihood that the child is going to have it.
Hereditary hairy cell leukemia probably exists. There was one report where they total up the number of cases of families. Maybe about 25 or something like that cases of hereditary. But they're really, really rare and there's not much known about that. I think that based on the normal deliveries that I've seen I would reassure the person, the fact that she has hairy cell leukemia, it's not likely that she's going to pass this on at all. The only thing is if she's pregnant and has to be treated, that has to be handled carefully because these medicines have to be carefully considered depending on what trimester you're in. That's something to be in consultation with your doctor and your obstetrician.
Dr. Robert Kreitman:
I would agree with that. There are two issues I think a pregnant woman would be worried about. One is whether they would have a problem with any kind of genetic problem in the baby and would hairy cell specifically be passed on. I think the chance that hairy cell specifically would be passed on would be extremely rare and probably not be a consideration to worry about.
The consideration of whether there would be any genetic damage to the fetus though, all the evidence we have is that it does not alter fertility and it doesn't cause fetal malformations. There's not a lot of studies that have been done but all the studies that I've looked at have been negative for that. So I think that would be a little bit reassuring.
And then a third issue is how you treat a patient who's pregnant and has hairy cell. And in general, we try to avoid giving chemotherapy in patients with hairy cell leukemia. I've seen many cases where a splenectomy could be safely done in patients who are pregnant and that avoids having to worry about chemotherapy until perhaps after the delivery.
Webinar participant:
I have a question on the rituximab. It can be delayed for years, it sounds like, post-Cladribine. What blood tests should be done or could be done that would detect the HCL in the blood? The routine blood tests that I have done I don't think are looking for that. They're just watching what my blood counts are doing. So is there a count that should be done?
Dr. Robert Kreitman:
Basically, the flow cytometry of the blood is a fairly routine test nowadays. It's not done usually when patients get blood counts. But if a doctor wants to know is there hairy cell in the blood, he can run a blood flow cytometry. That's pretty good for detecting hairy cell in the blood. And in our clinical trial that I mentioned, we are giving delayed rituximab in patients who got Cladribine alone, if we see that MRD being positive. But again, this is part of the clinical trial. It doesn't necessarily mean that all patients should get delayed rituximab if they have their blood MRD positive. But when we're talking about MRD in the blood, we're talking about flow cytometry in the blood. Which is a pretty standard test nowadays.
Webinar participant:
Do you see the FDA approving any new drugs for hairy cell leukemia soon, for example, Cladribine plus rituximab? Anything that really will be approved by the FDA in the near future?
Dr. Michael Grever:
Cladribine and ritiximab are both approved by the FDA already. The drugs right now that I think should be considered or looked at, one would be the Vemurafenib. This is an FDA approved drug for the treatment of malignant melanoma. However, I think that we already know a lot about the drug experience in patients with melanoma. We're learning a lot about the drug experience in patients with hairy cell leukemia. It appears to be effective in bringing up blood counts fairly quickly and it doesn't appear to have very much myelosuppression which is a benefit. It doesn't tend to lower the infection fighting cells and the platelet count recovers fairly quickly. And so patients who have an active infection often have benefited. We've seen patients who were on a ventilator with a serious infection be able to survive and get off the ventilator. I would hope that we would be able to pool the data together and get some consideration for the FDA to at least look at that data because it would make it easier for patients to have access to the medicine if they need it.
Ibrutinib is already approved by the FDA for the treatment of CLL, and we're getting ready to submit the paper which I think is important because I think the people who are prescribing Ibrutinib should see the written paper that we have so that they'll know what to expect. One of the things we were encouraged about that was it had stabilization and prolongation of the stable disease for a long period of time. Even though the numbers overall are small, some of the patients have achieved a very substantial remission that's been stable and so I think it would be good to first publish that and then hope that the FDA can take a look at that. Or maybe do we do extended studies because as [Dr. Kreitman] had pointed out, some of these drugs might be more effective if used in combination.
One combination that we would like them to consider looking at would be the Ibrutinib plus a BRAF inhibitor in patients with resistant disease. So we're trying to get this data published and then get it presented to the FDA. But the one drug right now hoping that somebody will take a look at because it's already approved for other patients with malignancy and we know a lot about it is the Vemurafenib. The one thing we don't know about the Vemurafenib, which is interesting, is the optimal dose. The original doses that were used for Vemurafenib were that 960 milligram dose twice a day. And that's the dose that was used and approved for melanoma. And we think that it would be important to try and optimize the dose for patients with hairy cell leukemia which we anticipate is going to be lower.
Dr. Robert Kreitman:
I think it's important for hairy cell patients to know that just because a combination or a drug is not approved specifically for hairy cell, doesn't necessarily mean that it's not effective in hairy cell and it's not safe in hairy cell.
Dr. Robert Kreitman:
The moxetumomab pasudotox drug is approved. That's a new one for hairy cell that's specifically approved for hairy cell. There are other options as well that are also good. But the drug companies need to ask the FDA to get their drug approved for hairy cell and some of the drug companies are not really concerned about hairy cell because it's not a very big market. That shouldn't come to an offense to hairy cell patients. And because there is a compendium which recognizes these treatments as being valid and so many insurance companies are covering drugs including rituximab, which is also not approved specifically for hairy cell, but it's used very widely for hairy cell and it's easy to get reimbursed for.
Other drug combinations like the dabrafenib and trametinib, like Vemurafenib and Ibrutinib are already being approved by insurance companies for hairy cell because they've demonstrated efficacy. The clinical trials are also very important to try to get into because there you're really being treated by experts and really contributing to the knowledge base that allows these treatments to be used.
Anna Lambertson:
During these webinars we've always received more questions than we can get to. But I want to thank both of you, Dr. Kreitman and Dr. Grever, for generously contributing your time and bringing your expertise to this discussion. And thank you to everyone who joined us today via phone and computer. We will have other webinars and meetings in the future and we'll make sure to email that information. Enjoy the rest of your day or evening wherever you are in the world. Thank you.
This transcript has been edited for clarity.