Panel: Frequently Asked Questions About Hairy Cell Leukemia
December 1, 2022
Hosted by the Hairy Cell Leukemia Foundation with speakers Dr. Michael Grever from The Ohio State University, Dr. Leslie Andritsos from the University of New Mexico Comprehensive Cancer Center, and Dr. Robert Kreitman from the National Cancer Institute, NIH. Anna Lambertson from the Hairy Cell Leukemia Foundation assisted with the panel moderation.
Transcript of Panel Discussion
Anna Lambertson:
My name is Anna Lambertson. I'm the executive director of the Hairy Cell Leukemia Foundation. I am delighted to see many familiar names on today's webinar. And if you're new to the Foundation, welcome. This year, we have held over a dozen different programs for patients and families, including webinars and coffee chats. And for the first time since 2019, we've also resumed regional meetings, which are an opportunity to meet others in your region. We hope that through these programs, you find the information you need to feel empowered and make good decisions about your healthcare, and to meet others who are affected by hairy cell leukemia, by this rare disease. So welcome to everybody, whether you're new to the Foundation or not, we're delighted that you're here today. Please keep your eyes open for programs in 2023. Today is the last program of 2022, but we'll be sharing many more programs on our website and in our email listserv over the next year.
We partner with about 29 institutions around the world where some of the most important research in hairy cell leukemia is being conducted and where we know individuals have significant experience and expertise in HCL. All three of our speakers are from a Hairy Cell Leukemia Center of Excellence, and you can learn more about these centers on our website.
Today we have three speakers, Dr. Michael Grever from the Ohio State University, Dr. Leslie Andritsos from the University of New Mexico Comprehensive Cancer Center, and Dr. Robert Kreitman from the National Cancer Institute of the NIH. We do encourage you to read their bios as presented in the webinar registration. So without further ado, Dr. Grever, I'm going to turn it over to you and we can get started with the panel.
Dr. Michael Grever:
Thank you Anna. Thanks to the Hairy Cell Leukemia Foundation for providing this direct access to patients and to try and address some of their questions. I'm very honored to be working today with Dr. Leslie Andritsos and Dr. Bob Kreitman. Both of these individuals are internationally known as experts in hairy cell leukemia, and they are outstanding clinicians and investigators. So thank you for making this possible. I believe we're going to hop right into some of the questions. Do you want to identify which questions you would like us to approach?
Anna Lambertson:
I think what we wanted to start with is a discussion among you about how you go about diagnosing hairy cell leukemia and also how you follow your patients as they go through treatment and beyond.
Dr. Michael Grever:
Well, would either of you, Leslie or Bob like to begin on how you diagnose patients and then follow them after treatment?
Dr. Leslie Andritsos:
I would point out that Dr. Grever actually wrote the guidelines for diagnosis of hairy cell leukemia. I would be happy to give sort of a big overview, especially for patients who are new to their diagnosis. And then maybe Dr. Kreitman and Dr. Grever could fill in some more detailed information. So most of the time when we suspect hairy cell leukemia, it's because somebody has abnormal blood counts or maybe they come in with a really big spleen or some other physical manifestation. And occasionally we do find abnormal hairy cells in the bloodstream, but most of the time we do not. And so usually the diagnosis does require a bone marrow biopsy to try to determine why the blood counts are low. The abnormal blood cells should be in the bone marrow and visible to the pathologist who will perform a series of tests on the bone marrow, including stains.
They will run the bone marrow through machines that can sort of calculate the percentages of types of blood cells and the actual types of blood cells and determine what types of proteins are on the outside of the hairy cells. The typical hairy cell leukemia cell will have a very, very specific pattern of protein expression on the outside of the cell, which can for most patients be diagnostic.
I think the caveat is sometimes patients have a very small number of cells in the bone marrow, which can make it challenging because sometimes there's a type of scar tissue in the bone marrow. So sometimes that first bone marrow biopsy is actually not diagnostic, but over time usually we can arrive at a diagnosis pretty quickly, and it's very important to do that because most people are diagnosed because their blood counts are low and may need some type of intervention. I'm going to turn it over to Dr. Grever and Dr. Kreitman to talk in a little bit more detail about how we arrive at that diagnosis.
Dr. Robert Kreitman:
Flow cytometry is really one of the mainstays. Flow cytometry now has become very, very accurate and sensitive specific in diagnosing hairy cell leukemia. It's done through a computer laser and doesn't require a lot of blood, but it can often be done on blood as well as bone marrow aspirate. This liquid is analyzed and you can tell what type of markers the hairy cell is making. And so you can not only diagnose hairy cell leukemia, but you can tell if all the markers are the normal ones that are expected or if there's anything unusual.
And so flow cytometry is one of the mainstays in getting a good diagnosis, and that can be done on blood or bone marrow. Bone marrow is often important not just for flow cytometry but in looking for other problems that might be in the bone marrow, not just hairy cell but other things. And so that's often why bone marrow is also done prior to treatment. Some patients get an imaging study to look at the spleen size because the spleen is often abnormally enlarged before treatment. It doesn't necessarily have to be a CAT scan, it could be an ultrasound. Most patients don't have big lymph nodes, and if lymph nodes are suspected, a CAT scan is useful to pick up those. An ultrasound usually misses lymph nodes in the abdomen and other places.
But lymph nodes are not very common, and so ultrasounds are sometimes done without a CAT scan. And one of the important things that is done nowadays since the really important discovery of the BRAF mutation in hairy cell leukemia is to do PCR on either the bone marrow aspirate or the blood to look for the BRAF mutation. And most classic hairy cell patients should have the BRAF mutation. And so that can be very, very useful.
(BRAF is) a mutation that is also seen in melanoma, in colon cancer, in lung cancer in a certain percentage of patients, but in hairy cell leukemia seen in very high percentage of classic hairy cell patients. So if you have the BRAF mutation, you know that you have classic hairy cell leukemia. And so those are the main tests that are done. Blood counts are absolutely important. I like to see blood counts not just the recent one, but the ones going back several years to get an idea of how long this has lasted. And you'll find often that blood counts were abnormal five years ago. It gives you an idea that this is a very indolent disease, one that moves very slowly, and so I think those things are important too.
Dr. Michael Grever:
Thank you. These are really excellent features of what we normally do to work up patients. There are other diseases that can look like hairy cell leukemia, and one of the conditions is called hairy cell leukemia variant. And those cells underneath the microscope will have a lot of projections. Those patients (with HCL variant) are far less common than patients with classic hairy cell leukemia. Patients who have the hairy cell leukemia variant often will have a higher white blood cell count than the patients who present with classic hairy cell leukemia. And those markers that Bob and Leslie mentioned that are determined by the flow cytometer are very important in trying to differentiate between the more common classic hairy cell leukemia and the less frequently encountered variant hairy cell leukemia. It turns out though most doctors who take care of classic hairy cell leukemia also end up taking care of the variant hairy cell leukemia.
And so we want to make that broad distinction between the two. And this BRAF analysis, the mutation in that gene, is found in the classic hairy cell leukemia, and it's not found in patients with the typical variant. The other thing that Bob mentioned is that looking back over blood counts, this disease is more indolent in its presentation as opposed to some other forms of adult leukemia like acute leukemia, which is usually very explosive when it presents. When we look back and we see that there is a history of a low white blood cell count, sometimes these are picked up by your primary care doctor and pursued, and the diagnosis is made early. In the old days when Dr. Bertha A. Bouroncle and her colleagues were describing hairy cell leukemia, it was estimated that about 90% of the patients would have an enlarged spleen. But because the diagnosis is now made early because your family doctor or your primary care doctor has picked up on these low counts, there are many fewer patients now who have an enlarged spleen compared to how it was originally described.
The other kind of information that can be useful on patients who have a bone marrow biopsy, there's a small group of individuals who present with a very empty looking bone marrow, and it was estimated that maybe somewhere around 10% of patients with hairy cell leukemia have a very unpopulated bone marrow. We don't completely understand everything about that. But the presence of hairy cells can be confirmed by doing a flow cytometry on those marrows. And sometimes people have had a mistaken diagnosis of aplastic anemia, but they really have hairy cell leukemia, and the treatment is very different. So it's important to get the bone marrow done and look for those parameters that Leslie and Bob have outlined, and then that will help you determine how you're going to treat the patient and when you treat the patient. We sometimes have followed patients without treatment because they have low counts, but they're not so dangerously low that they need to be treated.
And we've come up with some recommendations that if certain features are present showing that the infection fighting cells or the neutrophils are consistently less than a thousand or if the platelet count is consistently less than a hundred thousand or if the patient is anemic or has symptoms from an enlarged spleen, these are the indications that we often use to decide when to treat somebody. I've followed some patients for five to 10 years where they have hairy cell leukemia, but their counts weren't low enough to really warrant immediate treatment, but we follow them closely. I usually follow those patients with blood counts every three or four months. And if they start to fall down to those dangerously low levels, it's important to consider treating them before they get very dangerously low. There's nothing to be gained by waiting until the counts are so dangerously low that the treatment becomes more dangerous.
So that's how we make the diagnosis, and we follow patients after treatment. And I think one of the other parts of Anna's question was, how do you follow patients?
Dr. Leslie Andritsos:
I'm in a different kind of practice than Dr. Kreitman because I think a lot of his patients travel to see him, but I have a lot of patients that live in my own state, so it's probably a little bit more flexible for me. But if I have someone who's diagnosed with hairy cell leukemia, and their blood counts have been pretty stable, I usually see them every three months to make sure that nothing is changing and also that there haven't been any new medical problems that could potentially be connected to the hairy cell leukemia or they don't have any new symptoms of perhaps a spleen enlarging or something else happening. I think that every three to four months is probably often enough. If people have been really, really stable, sometimes we can push that out, especially after they've already received treatment. If they're in a good remission, I may see people every six months or so. I'd be curious to see how often Dr. Kreitman is able to see his patients because he has people coming from all over the country and all over the world probably.
Dr. Robert Kreitman:
Yeah, I think that is similar. I think we try to see patients every three to six months. The difference is that at the NIH we have patients who can travel from all over the country that come here, but a lot of the patients we can follow through FedEx, which basically means that we have them send blood and their CBC results, and we can learn a lot from looking at their CBCs. Are those stable? Are they changing? And then we can look at their blood by flow cytometry to determine the number of hairy cells in the blood. We can get the number of cells in terms of cells per cubic millimeter of blood, and we can follow that and see if those are changing.
The one thing though that's really important to understand for patients and also doctors, is that you can have fluctuations that go up and down, and it doesn't mean the end of the world if you see a low blood count. You might find that a week or two later it's back to where it was last time. And it doesn't necessarily mean that the patient is getting worse and needs to be treated immediately. Again, hairy cell leukemia is an indolent disease, but you do see when you follow patients for a long time, these kind of ups and downs in different parameters like the platelet count and the neutrophil count.
Some patients who are being followed before they get treated with hairy cell, if they have a low neutrophil count, it's slightly low and they want to put off treatment for some reason, which is reasonable, let's say, they need surgery or they need their tooth extracted and their neutrophil count is low, some patients occasionally will get Neupogen, which is a drug that will artificially or at least temporarily elevate the neutrophil count. And so that sometimes is done. When patients need that often though it kind of tells you that it's time to treat because treating should correct that neutrophil count, and then the patient has less chance of infections in the future.
Dr. Leslie Andritsos:
I'm so glad you made that point Dr. Kreitman about the fluctuations in blood counts because I think that's really anxiety provoking, but I would say very normal in our patients.
Dr. Michael Grever:
Yeah, I agree with both of you. When we wrote the guidelines, and actually the title (of the article) is Consensus Guidelines, so everybody really had an opportunity to comment on it. Most of our colleagues agree with Bob and Leslie. We put these numbers in there just to have a reference point. But one of the things that we wrote in the guidelines is to try and show that the change that's prompting you to treat the person is replicated, that it's persistent or it's confirmed. As Bob pointed out, sometimes you'll see a white blood cell count go down or a platelet count go down temporarily, and then below those numbers a thousand neutrophils or less than a hundred thousand platelets. By trying to make the point that if somebody has an absolute neutrophil count of 990, that's below a thousand, but you have to use judgment, and you have to not only use judgment, but you have to repeat the values.
I'm following one patient right now who's elderly, and we're trying to figure out when to treat his relapse. His neutrophils were down to 700, but he was feeling fine, and we repeated his count in one week and they were up to 1200. So you have to put some clinical judgment in following the guidelines and not follow it just as a pattern that you follow without using common sense.
Anna Lambertson:
On that note, Dr. Grever, we've had some questions come in that I think are really relevant to the points that you're making. We do hear from individuals from time to time who say, "Look, I know I have hairy cell leukemia, why not just treat me now? Why wait?” So could you address that in greater detail for everyone listening? Why wait?
Dr. Michael Grever:
Well, briefly what I would say is we have very effective treatments for hairy cell leukemia. Over the last 30 to 40 years we've taken this from a disease that had an average survival of probably about four to four and a half years, and now patients can live almost as long as they were going to live if they didn't have hairy cell leukemia. Despite this tremendous progress, and many of my colleagues here on the phone had a lot to do with that, but despite this tremendous progress, still somewhere between 40-50% of the patients are going to relapse. Current therapies that we have are not curative, but they put people into very sustained remissions.
So treating somebody earlier before they absolutely need to be treated doesn't guarantee that they're going to live longer than they would've until they met the criteria for treatment. And the treatments that we use, despite the fact that they're very effective, they carry with them some very serious potential consequences. Most of these agents can suppress the immune system, and so if you treat somebody before they absolutely need to be treated, you're putting them at risk as well. So maybe Bob and Leslie could add to that.
Dr. Robert Kreitman:
One thing that I would add is oftentimes you're in this waiting period after they've had one course of treatment, whether it's cladribine or pentostatin, and you know you need to get treated again, but you're just waiting. And oftentimes then the question comes up, why don't we just treat right away? And there, there's an additional issue where you'd like to not have to treat so close to the previous treatment because you have immunosuppression from the first treatment and then you're going to have immunosuppression from the next course of chemotherapy. So it's nice to be able to have some time between that. And so if you can buy yourself some time, you may have less toxicity overall, and so waiting sometimes is helpful.
Dr. Leslie Andritsos:
I totally agree with that. And all of the treatments have potential side effects, so if there's not a really great reason to treat, then you're getting potential side effects and toxicities without necessarily the benefit. This is a disease that will very likely need to be treated again. And so some of the treatments have very long term toxicities. For example, the cladribine and pentostatin may suppress the immune system for six to 12 months. And so it is a big decision when to start, and I always feel like I want to have a very good reason to do that.
Anna Lambertson:
Some other questions have come through on the topic of how you follow up with your patients. Dr. Kreitman, you talked quite a bit about flow cytometry and PCR and that those methods can be used to analyze a bone marrow biopsy or to analyze a blood sample. Some of the questions from participants today are on that topic. If you can use these tests on a bone marrow biopsy or a blood sample, is the bone marrow biopsy necessary? When is it necessary or when do you all feel it's really most important to do a bone marrow biopsy as opposed to analyzing the blood sample? And then are there tests in hairy cell leukemia, diagnostic or therapeutic regimens, that can only be used with a bone marrow biopsy?
Dr. Robert Kreitman:
One of the benefits of a bone marrow is quantitative. In other words, the hairy cells are sometimes very few in the blood, but they're much more concentrated in the bone marrow aspirate, the liquid part of the bone marrow. So if you're going to do flow cytometry and the blood has a very low amount, sometimes you can get a much better test with the bone marrow aspirate. That's becoming less of an issue nowadays when flow cytometry is so good that you can detect 0.01% of the lymphocytes being hairy cell, and so you can often get a lot of information from the blood. Bone marrow generally we do before patients are treated to look for other processes.
There's a problem that occurs in patients, particularly older patients called myelodysplastic syndrome, where the normal blood cells are not quite normal. They have some chromosome mutations which cause them to look a little abnormal. Part of the low blood count may be due to that, and you really want a bone marrow to be able to rule that out before you start to get an idea of what's going on with the normal cells. The other thing is that some patients with hairy cell leukemia have other malignancies, and they don't even know it. They may have not only chronic lymphocytic leukemia, which you can detect in the blood, but they may have a little bit of what's called MGUS, monoclonal gammopathy of uncertain significance, which is an early form of multiple myeloma. Multiple myeloma often can be in the marrow but not in the blood, and the marrow is the only place you can see this evidence.
We have quite a few patients that have that, and it doesn't necessarily become a problem but it's very important to know about, and that can often only be detected with a bone marrow. For that reason a bone marrow is important.
The other thing about a bone marrow is that to determine if you're in complete remission or really according to the hairy cell leukemia guidelines, even a partial remission, you really need a bone marrow. We recommend that patients get a bone marrow after treatment four months after or six months after. We don't recommend it too soon. I think one month afterwards is too soon. We try to do it for six months after treatment. That bone marrow can allow us to say if the patient's in a partial response or complete remission. Not everyone has that, but those bone marrows are very helpful. So those are some of the reasons that bone marrows are done. When we're following patients, we try to minimize doing bone marrow because we know the patients don't particularly enjoy them.
Anna Lambertson:
We understand that the bone marrow biopsy is extremely important in part for the BRAF mutation test and also to ensure an accurate diagnosis. We have individuals today on the webinar who are still trying to figure out whether they have Hairy Cell Leukemia variant or something else like splenic marginal zone lymphoma. I'm sure a biopsy could be extremely important in that regard. What if, for the BRAF mutation, the doctor or the clinic refuses to do the bone marrow biopsy or refuses to do the BRAF test, are there other mechanisms for a patient to have that BRAF test other than a bone marrow biopsy from the clinic?
Dr. Robert Kreitman:
We certainly will do that test on samples that are sent into us. We have the luxury of being able to not charge patients because we're federal government and we pay for FedEx and everything. So patients often do that. They have their blood sent to us. We can check that test and can help them confirm the diagnosis and confirm the best treatment that their local doctor often is already doing. But I think that there is also hairy cell leukemia Centers of Excellence where patients can go to get that test, and it often can be done on blood in addition to bone marrow.
Anna Lambertson:
Thank you. And on the topic of remission, Dr. Grever, we are receiving a lot of questions about remission. So how long does remission generally last? I'm sure you get that question as well from a lot of your patients. What length of remission can they expect? And patients also have a lot of questions about how they can extend their remission, steps they can take during or after treatment to extend the length of their remission.
Dr. Michael Grever:
There are some hematologists that would maybe disagree with the importance of the bone marrow after treatment. I agree completely with Dr. Kreitman on that. We try to encourage all of our patients to get the bone marrow done not immediately after treatment, and we watch the recovery of the blood counts until they get back to what we consider the optimum level. You see them improving usually after therapy's given. And then sometimes this improvement takes, as Bob pointed out, a couple months, so once the blood counts are stable and it looks as though the white counts have recovered to levels that we've outlined in our guidelines. Even a platelet count of a hundred thousand is not normal. The normal platelet count is around 150,000. So before we would even consider maybe calling it a remission, we would like to see that the platelet count is sustained and gets over a hundred thousand and not just 101,000 but over a hundred thousand, looks steady, and that the hemoglobin gradually returns to normal.
And then we do the bone marrow biopsy to see how much residual disease is left. And there was one small study that was done in the past where they found that just by looking at the marrow, if there were 5% residual hairy cells, you could predict that that person was going to have a much shorter remission than somebody who had less than 1%. That was just by looking underneath the microscope. And there are now much more sophisticated techniques for looking at residual disease after treatment. The fewer remaining hairy cells, the longer the remission is likely to last. There's variable results, but if the remission only lasts less than maybe two years or two to three years, then the recommendation is to consider when the person gets re-treated to take a different therapeutic approach. If somebody would relapse within one year, for example, after treatment, they would probably not get a very prolonged remission by just simply repeating the same therapy.
So as a result of that, there are other monoclonal antibodies that do help improve the residual hairy cell leukemia. Bob has done a lot of work on this. We've all used Rituxan and there's another anti-CD20 directed monoclonal antibody called obinituzumab, which also is very efficient in decreasing the amount of residual disease. So certainly if they relapse, you want to take into consideration how long were they in this remission? Did they actually get a remission confirmed by a bone marrow biopsy and then decide about the next treatment. If you look across the board, I think many hematologists believe that if they've relapsed, if they get retreated with a purine analog either pentostatin or cladribine and they get Rituxan added to that second treatment, they're more likely to get a deeper remission. Now, Bob has done a lot of work on whether or not we should just include these monoclonal antibodies in upfront therapy. He can tell you more about that, but some people still consider treating patients with either cladribine or pentostatin as a single agent for first therapy.
But certainly after patients relapse, we want to give them more effective therapy to try and get a longer remission duration. And the amount of residual disease appears to have an impact on how long that remission is going to last. But it's impossible to sit down, I think, for most patients and say, "Well, your remission is going to last six years, and so you've got five years to just be carefree." I mean, you need to follow patients because as Leslie pointed out, there are a lot of things that can happen to patients who are immunocompromised that they need to follow up, but the duration of remission is variable. Some people go 15 years without a relapse, and then they have a relapse. So it's hard to predict. There's other tests that we do. We look for other mutations as well. And so when we send the sample of bone marrow or blood off to the lab, I usually get FISH cytogenetics to look for abnormalities in chromosome 17 or mutations in P53, which is another important gene.
And if there are mutations in P53 or if there are abnormalities in the chromosome 17, that form of hairy cell leukemia usually is a little bit more aggressive. And so you could predict that those patients may have a shorter remission duration than somebody who does not have those abnormalities. So, again, you have to put clinical judgment with some additional testing. I feel personally very strongly that the patient should have a post-treatment bone marrow biopsy so that you can make the best plan for how they're going to be followed and then how they subsequently will be treated.
Anna Lambertson:
Dr. Grever, you spoke about how you can't predict how long a patient's remission will be. I'm sure all three of you frequently receive that question from people: “How long will I be in remission?” You can point them to the research, the evidence that we have about average or median remission for patients who maybe have been treated with cladribine alone or have had cladribine plus rituximab. We have some data around that. I have seen this question three different times already in the Q&A, written in different ways, “Why can't we predict, really predict, the length of a patient's remission?”
This is a really important question about how accurately we can predict or understand a patient's response or potential response to treatment. Could you all speak to that a bit?
Dr. Michael Grever:
Well, I'd like to hear what the others have to say, but you can certainly tell when somebody is likely to have a shorter than anticipated remission. But it's hard sometimes to predict exactly how long the remissions are going to last. But a lot of it may relate to how much residual disease is detectable after you're done with the treatment. That's one of the reasons why some people are in favor of the approach that Bob has explored, and he can talk about that, where they combine more than one drug or one agent to treat patients in an effort to prolong the remission. But the other thing you have to weigh against that is that some patients with hairy cell leukemia, particularly those people who have an active infection may be at more risk if you use intensive therapy upfront.
So there's a lot of factors that you have to consider here. And despite people wanting to have an accurate prediction, sometimes we just can't do that. You can give a ballpark figure, but you can't tell somebody you're going to be in remission for four and a half years. I can't. Maybe somebody else can. Bob, do you have a way of predicting this?
Dr. Robert Kreitman:
No, I can't tell someone exactly when they're going to relapse. But we do have statistics, and we can give people what the averages are, what the medians are, the median is sort of the middle point, the average is the mean or the average. But generally what we find in patients getting cladribine alone, and same thing with pentostatin alone is, these are from very long term follow-up studies, it depends on how you're following the patient. If you're following the patients through blood counts, in other words you wait for their blood counts to go down to the point where they need re-treatment and then you do a bone marrow and see if the patients are relapsing and often at that point they are, you find out that the median is about 15, 16 years, which is very long after the first treatment of pentostatin or cladribine. So that shows you how good these treatments are. But if you check at the six and a half year time point, you find out the 28% of the patients are already relapsed and need more treatment.
Even though the median is very long at six years, six and a half years, we checked, and about 28% of the patients will need more treatment at that point. If you follow patients by bone marrow, Dr. Saven’s group has done this, and you look at younger patients, you find out that after four and a half years patients have already relapsed in the bone marrow, but their blood counts are generally fine. So you'll get shorter durations of remission, so to speak if you do bone marrows to follow patients regularly rather than just doing blood counts. I can tell you about combining rituximab with cladribine, but first maybe if Leslie has some comments about that first.
Dr. Leslie Andritsos:
I think my first comment is we know that none of our treatments are curative, so they're highly, highly effective, but we always make the assumption that the hairy cell is still present, whether it's present enough to detect on a bone marrow test or by some type of peripheral blood testing or whether it's present in large enough numbers to lower the blood counts is pretty variable across patients. But I think with modern therapies and Dr. Kreitman is going to talk about his practice changing study, which was to combine Rituxan with cladribine in the upfront setting, I think that we have made a lot of strides. It's very, very difficult to predict the biological activity of any individual's hairy cell leukemia. So we're often surprised. Very occasionally we will have patients that don't achieve a good remission, not even a partial remission, even with combination of correct therapy.
And these are the people who really should see a Center of Excellence to look at clinical trials or other types of therapies or potentially more deeper investigations such as next generation sequencing to see if they have an unusual mutation in their bone marrow such as MAP2K1 mutation, which is in the map kinase pathway. Those patients tend to have more aggressive disease. I think very often people tend to do very well. Occasionally we have outliers who don't have good remissions and need more attention. But for the most part, even in relapse, people don't always need treatment right away. And so even though the watch and wait period in relapse is stressful, it's still better to wait for re-treatment until there's a good reason to do it for the reasons that we talked about before. And so I'll let Dr. Kreitman talk a little bit about his study, which was very important.
Dr. Robert Kreitman:
There's about three different ways to combine rituximab, which is an anti-CD20 antibody that have used quite a few patients, many dozens of patients, followed them for many years. There's three ways that has been done.
The first way was actually not by our group but by Dr. Ravandi's group at MD Anderson. He started about 10 years before we did and published the results around 2011. And then an update to that was published in 2016 where cladribine was used first. The cladribine was five daily doses, and the rituximab in eight weekly doses was started four weeks after the cladribine. This was a very user friendly way to do it because by the time the rituximab was started, the number of hairy cells were very few. Most of the patients still had detectable hairy cells in the bone marrow, and many of them had hairy cells in the blood too.
But because of the lower number of hairy cells, they didn't have much side effects with rituximab. Because of the side effects of rituximab, the chills, fevers, sometimes shaking chills, they are proportional to the amount of hairy cells that are there. And so when you start the rituximab a month later or four weeks later after the cladribine, it's generally very easy to do. They found a hundred percent of patients had a complete remission. In our experience, we did a randomized trial where we treated patients with cladribine alone or we treated with simultaneous cladribine and rituximab where we started those eight weekly doses on the very first day of the cladribine. What we found also is that we had a hundred percent complete remission rate in the group that got the simultaneous rituximab and about 88% complete remissions in the patients who got cladribine alone.
Now, the patients who got cladribine alone, they could get delayed rituximab later after six months at a time that their blood showed hairy cells by flow, they could get delayed rituximab, but it was the same course. It was eight weekly doses. So we had the benefit of comparing the patients in a randomized way, the patients who got immediate rituximab and the patients who got no rituximab up front. And what we found, we found actually that the platelet count and the neutrophil count at four weeks was actually better in the patients who had rituximab than the patients who didn't have rituximab. But we did find a very rapid drop in platelets in patients who got the early rituximab on the second day. In other words, since we were giving cladribine every day and we got blood counts every day, 24 hours after the first dose of rituximab, we could see the platelet count drop about 50 points.
And so the patients who started out with a platelet count of about 70 or 80, we could see that drop about 50 points. They did not need platelet transfusion. Patients who started out with a platelet count of 40 or 30, their platelet counts might go down to five or six. We didn't see any serious bleeding in these patients, but many of the patients got platelet transfusions because, of course, their platelet count was very low, so we didn't want to leave them with a low platelet count. If we didn't do anything, the platelet counts would come up on their own anyways. So that was a difference in what we found as far as toxicity. But in terms of the efficacy, besides this hundred percent complete remission, we had a 97% MRD free.
Now, MRD is minimal residual disease, and minimal residual disease is leftover hairy cells, which you can detect by flow cytometry, you can detect by bone marrow, immunohistochemistry, special stains, and you can show that over time in different types of treatments that are used for hairy cell, you can show that there is a difference in relapse rate in patients who have MRD versus patients who don't have MRD, but it's not a huge difference in classic hairy cell.
For example, I mentioned that 28% of patients getting cladribine alone at the six and a half year time point will relapse. And in patients who are getting immediate rituximab, that number is about 3%. So there's a very significant difference in the relapse rate, not just the minimal residual disease rate. So we think there's a benefit in using rituximab, but honestly whether it's 78% of patients who are MRD free or 97% that are MRD free, not sure that that is going to have a very long term effect. And we are following patients to determine if that's the case. So that's mainly what we've seen. And one of the ways that we explain the difference is that in the laboratory we find that the way that these two drugs, the cladribine and rituximab work together, they synergize with each other, is that the rituximab makes the cells more sensitive to the cladribine.
And so if you wait for four weeks, the cladribine's going to be gone because the cladribine has a very short half life. It gets out of the body very quickly. The rituximab stays for a long time, up to six months after the last dose. So when you start that rituximab and there's no cladribine a month later or after the cladribine is used, there's not going to be synergy. But still it's very effective, and it's probably because the rituximab can get to all the individualized hairy cells. There's only a few left after the cladribine and can often eliminate the minimal residual disease.
What does this mean long term? Well, we follow patients now up to 12 years. Median followup now is longer than the six and a half year time point that we reported, and we still are seeing about 94% of patients after immediate cladribine and rituximab still MRD free, not just in complete remission. So we're pretty happy about those results, but again, this is something that is a work in progress and we still need longer time to follow patients.
Anna Lambertson:
Thank you.
Dr. Grever, we have a lot of questions from patients about mitigating the risks of COVID as they continue to work through their treatment and their followup. And there are also a lot of questions about how to stay healthy, what changes to make to potentially strengthen the body's response to treatment. I know that that's one of the topic areas that we wanted to discuss today. But before we move on to that, could I really quickly ask you all to provide some really succinct nuts and bolts about two topic areas that we're receiving a lot of questions about. How do you define remission, and how do you define relapse just in a real succinct nuts and bolts way so that individuals in the webinar today can have some clarity?
Dr. Michael Grever:
Well, when we wrote the guidelines, we decided that the blood counts would have to be markedly improved. We said that the neutrophils had to be above 1500 and the platelets above a hundred thousand and the hemoglobin above 11 and that the bone marrow would show no evidence of hairy cell by looking underneath the microscope. Now, we know subsequently, and we knew at that time, that there were more sophisticated ways of saying whether or not there was any residual disease by using either flow cytometry or the markers, the immunohistochemistry markers that Bob referred to. But our definition of a complete remission when we wrote that paper was that you had to have a bone marrow (biopsy) and you couldn't see any morphology that was consistent with hairy cell leukemia. And then somebody would be in a complete remission, but they would have residual disease.
And so this has led to some confusion because you'll hear people say, well, the patient's in complete remission, but they still have minimal residual disease. So if they're in complete remission but they have minimal residual disease, if it were defined by some of these more sophisticated tests that there were no hairy cells that they could see, that's a minimalist definition of complete remission that you can't see any hairy cells and that the blood counts return to that improved range and that the spleen is no longer palpable by physical examination because we had a lot of discussion about did you have to get a CAT scan and did you have to do more sophisticated detection of minimal residual disease to see that there was no hairy cells. And we agreed that the definition of a complete remission would be based on the morphology and the recovery of the counts and improvement on examining of the spleen on physical examination.
And then subsequently, we all wrote a paper together on minimal residual disease and how you detect it and what the importance of it is, probably as therapies get more effective, the definition of complete remission may change to include a more sophisticated look at the marrow after treatment.
Relapse by definition would be that you see hairy cells either in the blood or in the bone marrow and that the blood counts start to show some deterioration. But relapse actually is confirmed by looking at the bone marrow because if you can morphologically identify hairy cells coming back, then the patient has actually relapsed. So then the question is often, well, if they relapsed, when do they need to be retreated? What's the point at which you say it's worth taking the risks of using more immunosuppressive therapy? I think a lot of people use those same criteria that you decide to retreat somebody using the same criteria that you did for initial treatment. Or if they go into a protocol, there may in the future be a provision for people who have bone marrow.
I had one patient who was going to go on one of the original BRAF inhibitor studies in New York, and her bone marrow was 85% hairy cell involvement, but her neutrophils were 2000 and her platelets were about 120,000 and her hemoglobin was over was 11.5. So she didn't meet the absolute criteria for treating that we use, and she was very upset. She said, we know that 80% of my marrow contains hairy cells. And I followed this woman now for seven years and she's never met the criteria for re-treatment. And she's led a very normal productive life realizing that there's still hairy cell leukemia in her bone marrow, but she's never dropped her counts. She's probably unusual in that regard. So that's what I have to say about it. We could see what our colleagues have to say about it.
Dr. Leslie Andritsos:
That was a good answer. I wanted to just add one thing to your discussion about the minimal residual disease testing because up until now we haven't really had a standardized approach to that. When hematopathologists read people's bone marrow tests, they kind of put their own interpretation on whether MRD is present or not and may use their own sort of criteria for what they consider MRD. And so hopefully this paper that's coming out will help to clarify some of that and maybe standardize things a little bit more across centers and make it easier for people to understand their bone marrow biopsy results once they've completed treatment and have their restaging testing.
Anna Lambertson:
Thank you.
Dr. Grever, maybe we could take five to 10 minutes to talk about current recommendations related to COVID?
Dr. Michael Grever:
Well, we just had a discussion in New York about how you manage hairy cell leukemia in the current environment with COVID infection. Bob has presented a lot of data and has actually volunteered to write up the results of that discussion. So if we only have 10 minutes to talk about that, why don't we start with Dr. Kreitman?
Dr. Robert Kreitman:
This COVID pandemic, as everyone knows, has been going on since March of 2020, we're coming up to about three years of this. And it started out being a very dangerous disease where people would die of pneumonia. And so we were very worried about putting patients on drugs that could make them immunosuppressed to the point where they might not get better from COVID. The other problem was that once we got the vaccines in 2021, patients would not make antibodies to COVID from vaccines if they had gotten rituximab in the past six months, sometimes in the past year or longer. We were surprised to see that sometimes patients after rituximab would take several years to be able to make antibodies to COVID. So we made some recommendations a couple years ago regarding how you might want to modify treatment during the COVID pandemic.
But what's happened over the last several years with COVID, as I'm sure many people are well aware, is that COVID has changed to the point where it's now more infectious and less lethal because it tends to grow in the oropharynx, the mouth, the nose, and less in the lungs. There's still patients unfortunately who are dying of pneumonia from COVID, but they're much, much less common. COVID is becoming less lethal. And then the other fortunate thing regarding COVID is there are antibodies that can be used in patients who have very low immune system. They've gotten rituximab recently, for example, and they can't make antibodies to vaccines. This is also useful for patients who refuse to get a vaccine, and many patients are in that category, they just don't want to get vaccines for any reason. They can get a drug called Evusheld.
There are some other drugs that are available that are antibodies that can help prevent COVID in patients. We measure antibodies. We do that in our clinical trial. In patients who have very good response to the vaccine, we can measure 25,000 units per milliliter in the blood, and Evusheld one dose can bring that up about 20% of that amount. So these techniques are now available as are the vaccines, and they can help patients who can't make good antibodies because they've been treated. But having said that, before we start treatment in patients, we try to get their COVID antibodies up as high as possible by doing vaccination if possible. And the reason I say as possible is that some patients when they get diagnosed with hairy cell leukemia, they have very low numbers of normal B cells because their B cells are all hairy cells, and so they're not going to be able to make antibodies to COVID vaccine even though they've never been treated for hairy cell.
And so for those patients, they may need to be treated first and then they can make antibodies to COVID. And this could be done in several ways. They could get cladribine alone, for example, and they can get a response within a few months and then their normal B cells will come up, and they can respond to vaccine. Patients can get Vemurafenib, which is a new treatment that we really haven't talked about, but it can be used in patients who have the BRAF mutation. It's not chemotherapy and oftentimes the normal B cells will come up very well for that. So those are several points that we've used in trying to eliminate problems after COVID.
Dr. Leslie Andritsos:
And just as a very practical suggestion, because I don't know how things are around the rest of the country, but in New Mexico right now we have influenza A, RSV, and COVID circulating right now. So if you develop sometimes a respiratory virus infection, you should go get tested with what we call a respiratory virus panel because it's really important to know if you have one of the treatable viruses. So we have treatment for influenza, which is Tamiflu, and we have treatment for COVID, which may be Paxlovid or one of the monoclonal antibodies. We don't have treatment for RSV, but you probably would also want to know if you had that. The treatments are time limited, so you have to start them within five days of symptoms developing. And so definitely get that test early in your symptoms so that you can get treated because it really makes a huge difference for both influenza and COVID.
Dr. Michael Grever:
The other thing I would add that's important to get is not sit at home and try and wonder whether this is influenza or whether it's COVID, but get tested. Earlier is much better. The other thing I try and encourage the patients to do is also get up to date on their pneumococcal vaccination and also flu vaccines. It's unfortunate that there's a group of individuals who are adverse to getting vaccines, and it's just hard to understand whenever you have a compromised immune system, even though we're not sure that you'll get a great response, it would certainly help the patients if they have some ability to help fight off these potentially serious viral infections.
Anna Lambertson:
Thank you so much. As we've been having this discussion, I've been monitoring the Q&A, and I've been doing the best I can to integrate many of the very, very important questions that have been coming in. I just want to say very quickly that we have had a few requests for more information about the patient data registry, and I will in a followup send a link to our registry page so that those who may want to get involved and add their data can do so. There's also been a request for links to the research that you've mentioned today during the panel, and I will also pull that together and send that out to everybody in a summarized fashion.
In the time that remains, Dr. Grever, there's a lot of interest in what's new. For example, we know that cladribine alone, and cladribine and rituximab combined, are being used. Can you talk a little bit more about some of the newer therapies or newer studies?
For example, MSK's study with Vemurafenib plus Obinutuzumab. Dr. Kreitman, you specifically mentioned Vemurafenib, and I think there's a lot of interest in the benefits of Vemurafenib for patients. And don't forget, we do have individuals on the webinar today who have hairy cell leukemia variant, so if you could include some information about treatment options for them as well.
Dr. Michael Grever:
This is very important because even though we've made tremendous progress, there's still a lot of work to be done. The job is not done, and the original studies looking at the BRAF inhibitor, Vemurafenib, sort of extrapolated the dose of Vemurafenib from the melanoma literature. And so there have been a number of investigators across the globe who have explored lower doses of Vemurafenib because even though the Vemurafenib is very effective, it does have some side effects. The one that is most troubling to some patients is a skin rash. It can be pretty extensive. And so trying to determine what is the optimal dose of the BRAF inhibitor is an area that will need continued work. The first selection of 960 milligrams twice a day was I think derived predominantly from the doses that were being used in the treatment of patients with malignant melanoma.
There have been patients I've used lower doses at times in certain patients, and lower doses can be effective. The question now though is what's the optimal dose of Vemurafenib to add to the anti-CD20 monoclonal antibodies? There will be some additional work there that's going to be needed. Some of the data that's being explored by Dr. Jae Park at (Memorial Sloan Kettering) was very exciting, where he's incorporating obinutuzumab along with Vemurafenib. He's also put together a structure where they get treated for about a month with the Vemurafenib alone, and then the obinutuzumab comes in in month two, I believe. And that may have some similarities to what Bob has described about bringing that monoclonal antibody so close to the initial BRAF inhibitor that you get some drop in the platelet counts. And so trying to find out the optimal combination and schedule of administration; the BRAF advances were predominantly used in patients who had relapsed.
However, there's a certain group of patients with hairy cell leukemia who present a real challenge because they have an ongoing active infection. For those patients using cladribine, a five day administration of cladribine can be dangerous. In those circumstances we have used low dose pentostatin because the treatment is every 14 days. They don't get the same degree of marrow suppression for the white blood cell count as you can get with five days of cladribine. So if there's an active infection, you have to again use clinical judgment. There are a number of us who have used the BRAF inhibitors as initial therapy when somebody has an active infection because it doesn't tend to lower infection fighting cells, and it gets an improvement in the infection fighting cells quicker. So there are some groups of patients, for example, patients who have an active infection that still need to have some further definition of what's the optimal therapy approach.
And then when you talk about hairy cell leukemia variant, these patients won't have the advantage of having BRAF mutation, so they're going to require some other innovative therapies. I know Bob did a lot of work on this by treating those patients with cladribine plus rituximab. But the further we look at the variant of hairy cell leukemia, and we see that there are other targetable mutations, it raises the possibility. We published a paper early on, Dr. Andritsos and I, on using a MEK inhibitor for a patient with the hairy cell leukemia variant. And he responded very well for almost a year and a half. And unfortunately at that time we were still working with one drug at a time. And just like patients in general do better with more than one agent, the MEK inhibitor probably will be further explored in patients who have that specific additional mutation.
So there is a lot of research that's necessary to try and improve the treatment for the hairy cell leukemia variant. I just hate to see those patients not included in specific studies because they tend to have a more aggressive disease, and they need our continued commitment to new drug development. And so the last thing I would say is Dr. Jae Park at Memorial Sloan Kettering is doing some very interesting work with the combination of Vemurafenib and obinutuzumab as frontline therapy, and he's got some very encouraging early results. So when we first formed this group of people working in the Hairy Cell Leukemia Foundation back in the era around 2008, I was approached by some of the patients, and they said, has everything been done that can be done for hairy cell leukemia? And I said, absolutely not. There's still a lot of road to travel, and so we have to be committed to finding effective new drugs that are targeted therapies.
The last thing I would say is that the thing that worries me is that because we have small numbers of patients, some of the pharmaceutical companies need to be committed to staying the course because when we develop effective therapy and because it's a small patient population, we need to work with them so that they don't abandon production because we have to have access to these drugs in order to be effective. Bob, you know a lot about some of the therapeutic studies you're doing. You may want to mention them or Leslie you may want to mention these too.
Dr. Robert Kreitman:
For hairy cell variant, I do want to make a point very strongly that I don't feel that these patients should be treated with cladribine alone or pentostatin alone because their response rate is so poor. We find that in looking at hairy cell variant, if you look at cases in the literature put together about 42 patients from the literature, only about 8% had complete remission compared to if you give them cladribine with rituximab, you get a complete remission rate of 95%, so that's a huge difference. I think in 2022, no patient should be getting a purine analog alone, cladribine or pentostatin alone, for hairy cell variant. And that's one of the reasons why it's really important to get a good diagnosis.
Now what's being done now for hairy cell variant besides cladribine and rituximab, when those patients relapse, they're eligible for a MEK inhibitor trial.
We are doing that at the NIH. And because it's an oral drug, it's binimetinib, it's approved for melanoma along with encorafenib. But patients can get Vemurafenib, and they can come to the NIH very infrequently and be mainly treated by their local doctors and followed by us through telehealth for that particular trial. Patients with hairy cell variant, as we said, are not eligible for Vemurafenib or any other BRAF inhibitors. We have a clinical trial for patients with mutant classic hairy cell, BRAF mutant classic hairy cell with encorafenib and binimetinib. That trial's going very well. Most of the patients have complete remission. But really focusing on hairy cell variant, we also are running a trial of CAR T-cells, which is a type of procedure where you use the T-cells to kill the hairy cells.
And this is a little bit more aggressive than drugs to treat variant hairy cells, but this is something that patients are also eligible for. There is a drug that I've been working on for several decades and got approved by the FDA in 2018, moxetumomab pasudotox. We recently found that when we combine that with rituximab it works much better. Unfortunately that drug is going off the market because the drug company is not interested in continuing. And we're hoping that another drug company will take that over. That drug targets CD22, and obviously that will work also in patients with hairy cell variant. So there's a number of options for hairy cell variant that we're hoping can be developed and we're developing now because these patients really have a more aggressive form of hairy cell leukemia and need better options.
Dr. Leslie Andritsos:
I think the only treatment I would add to that summary is ibrutinib. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, and hairy cell patients were included on the initial clinical trial. The complete response rates were not as high as what has been seen with other therapies, but there was significant clinical benefit. I think that's a drug that should be considered in people who have relapsed either classical or variant hairy cell leukemia who need an oral treatment option or may have already relapsed following the more traditional treatments .
Dr. Michael Grever:
To go along with both Leslie and Bob here, I have a patient who was being treated for hairy cell leukemia variant by her primary hematologist. First of all, she shouldn't have been treated with just one agent like Bob said. This person was being treated with pentostatin alone, and she had a very transient response as what you would predict, and that goes along with what Bob said. So when we saw her, we looked for some of these markers, and not only did she lose one in her leukemic cells, they lost one chromosome 17. So she only had one of the two normal chromosome 17. But even the one that she had left had a mutation in P53. I didn't even bother putting her on cladribine because patients who have, Bob may not agree with this, but patients who have an abnormality of P53 in general don't have the same kind of great response to the purine analog.
So I put her on ibrutinib as Leslie said, and we added Rituxan. She got treated with not just one agent, but she got ibrutinib and six doses of Rituxan and she's been in a clinical remission now for a year, and her spleen is normal size. Her blood counts are perfectly normal and she's really had a major response to that combination of ibrutinib plus an anti-CD20. I have to do the bone marrow on her now to prove that she's still in a complete remission. I think a lot of work still needs to be done on the variant, but I agree with Leslie that the BTK inhibitors are promising in terms of the patients with the disease that needs to be treated. But using the BTK inhibitors alone may be effective but may not be as effective as combining them with another agent. And so we still have a lot of work to do there, but it's encouraging that we have some options to work with.
Dr. Robert Kreitman:
The nice thing about ibrutinib is that it's effective in both hairy cell variant and classic hairy cell.
Dr. Michael Grever:
Yeah, we did a study with over 30 patients, and some of these responses take a while to happen, but then they're pretty durable. So using the study we did had just looked at ibrutinib alone, but we really need to take the next step and add another good partner to the ibrutinib.
Anna Lambertson:
We have unfortunately reached the end of our allotted time for this panel. I want to thank all the people who registered and who joined us today.
I also want to say thank you to Dr. Michael Grever, Dr. Leslie Andritsos and Dr. Robert Kreitman. We are so grateful for the leadership and the information that you bring to the Foundation, for your ongoing commitment to study in hairy cell leukemia, to treating patients, to participating in programs like this. I know that this eases a lot of anxiety for many people knowing that you're out there rooting for them, working for them, researching for them. We at the Foundation are equally committed and supportive of all that you do so that we can one day find a cure for hairy cell leukemia.
This transcript has been edited for clarity.