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Webinar: Understanding Hairy Cell Leukemia (HCL)

August 2025

This webinar was hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Leslie Andritsos from The University of New Mexico Comprehensive Cancer Center. This presentation is part of the HCLF’s ‘Understanding Hairy Cell Leukemia’ webinar series. Each webinar features a presentation by an HCL expert and an overview of diagnosis, standard treatments, and alternative therapies.

View Dr. Andritsos’ slides >>

View a recording of Dr. Andritsos’ presentation below.

Transcript of Dr. Andritsos’ Presentation

Dr. Leslie Andritsos:

Thank you so much for having me. I'm so happy to be back here with friends, new and old. I meet new Hairy Cell friends all the time, and I'm delighted to have a chance to talk about our work.

These are my disclosures. I do receive research support from the foundation via the patient data registry. I'm also going to be discussing off-label use of some of the newer treatments for hairy cell leukemia.

The objectives of today’s talk are going to be, number one, to understand the designation as a leukemia, because this is something that might be confusing to some people who are recently diagnosed with this. We will briefly review the biology and epidemiology of hairy cell, how we make an accurate diagnosis, what our current treatment options are, and what we see as the future of management in hairy cell.

Is hairy cell a leukemia? The answer is yes and no. Technically, it is a lymphoma. About 10% of patients with hairy cell do have hairy cells in the bloodstream that were identified early in the discovery of the disease. And whenever we see tumor cells in the bloodstream, even if they're not leukemia-type cells that we would normally call leukemias, they're designated leukemias. And so, that's how hairy cell leukemia got called leukemia, but really biologically it is a lymphoma.

So just a little bit about the hairy cell, cell of origin. Where does it come from in our bodies? I have a little graphic of B cell development here, on the left, and this first cell is a hematopoietic stem cell, and this is the parent cell of all of our blood cells in our body. The hematopoietic stem cell can either divide and make another one of itself, or it can differentiate into other types of blood cells.

In the case of hairy cell leukemia, the stem cell starts down the B cell development pathway and goes all the way to this memory B cell, and we know that hairy cell leukemia is a B cell lymphoproliferative disorder; the cell of origin is felt to be a late-activated memory B cell.

Some very elegant studies were done that showed that some patients with BRAF mutations actually have that mutation seen as early as the hematopoietic stem cell. And so, it seems possible that this disease is starting very early in the blood development process.

The majority of patients with hairy cell will have a BRAF V600E driver mutation. The way that we know it is causing tumor growth is because it will be present in the entire tumor clone. So, every hairy cell will have the same mutation, and if the disease does relapse, we will also see that same mutation at the time of relapse in the cancer cells.

We also know that there are alternative mutations that can act as driver mutations, including alternative BRAF mutations. These are sometimes very difficult to identify if you don't have specialty testing in your hematology lab and could require expert consultation. There are also other high-risk mutations that can drive the disease, and it's really good to know if these are present.

There’s a whole host of mutations that have been identified in hairy cell leukemia, and so sometimes we have to consider next-generation sequencing if we're just not sure what's going on or if we're looking for additional targets that could be treated.

So, who gets hairy cell leukemia? This is the million-dollar question because we don't always know why it happens. It is one of the more rare hematologic malignancies. It's only 2% of all lymphomas. We usually see it in what I consider younger patients, which is 55 to 60 years of age.

There is a male predominance, which is also seen in some of the other indolent lymphomas that are similar to hairy cell. We know that there is a higher incidence among Caucasians and lower incidences in Asian, African, and Arab populations. We absolutely do see a higher incidence in first-degree relatives of patients with hairy cell. And we also see other lymphoproliferative disorders happening sometimes in first-degree relatives of patients with HCL. That would indicate the possibility of a familial type of hairy cell or some type of environmental exposure that is happening among families. Our group showed a few years ago that there is an improved progression-free survival in U.S. women after treatment, and this appears to be a little bit different in the French population. So, it'll be very interesting to see, as the registry grows, which of these findings hold up when we're able to look at very large populations of people with hairy cell.

There are some studies showing possible associations with environmental exposures. People who are involved in farming may have a higher incidence of hairy cell, and that has also been shown with exposures to pesticides and herbicides, which probably all kind of go together with farming.
We know that people who have high levels of diesel exposure have a higher incidence, and also some people with exposure to ionizing radiation. So, whether that was nuclear energy or medical devices, things people are exposed to were potential factors.

I wanted to talk a little bit about why sometimes we go down the path of trying to identify whether somebody has hairy cell. Typically, somebody will be found to have low blood counts, and sometimes that's in somebody who has absolutely no symptoms, or sometimes they're being seen because they're sick.

We also find in hairy cell that there is a tendency for the monocytes, which are part of the white blood cells, to be either low or undetectable. Nobody really knows why this happens, but it's felt that that may contribute to the fact that hairy cell leukemia tends to be a relatively immunosuppressing condition.

Patients might have enlargement of the spleen at diagnosis, or that may evolve over time before treatment is started, and it's pretty common for people to come to evaluation when they're found to have an infection. A lot of times these can be unusual infections such as really severe pneumonia, sinusitis, or skin infections, things like that. Things that are unexpected. Some patients may have unexplained fevers or weight loss, and less commonly we do see circulating hairy cells in the bloodstream that might indicate a need for further evaluation. But if any of these things are present in the setting of low blood counts, typically we need to do a bone marrow biopsy to define what's going on.

Back in 2017, I'm sure everybody on this webinar is familiar with Mike Griever; he really led the charge in developing consensus guidelines for the diagnosis and management of Hairy Cell. Before this publication, there was no consensus, and I think it has really been helpful for both doctors and patients to have a uniform method for making sure that we're doing the right thing for patients. I would encourage everybody to have a look at this paper. Some things are already—I don't want to say out of date—but we’ve moved on or made things a little bit more specific. But this is a great place to start if you want to learn more about hairy cell.

These consensus guidelines establish the first standards for diagnosis, indications for treatment response assessments, and then recommended therapies, either in the first-line setting or at the time of relapse.

I wanted to talk a little bit about what we're doing with the tissue. If you have any type of biopsy, there are several different steps that occur where testing is done to try to arrive at what is going on. So, the first thing that happens is we look at the tissue morphology, and that is what the tissue looks like under the microscope.Typically, the tissue has to be stained and sectioned and put on a slide. This can be done on blood, bone marrow, or any other tissue that somebody got a piece of. We can also look at what proteins are being expressed on the outside of the cell, either with a special machine called a flow cytometer, or the slides can be stained with chemicals to do immunohistochemical staining. Genetic testing can also be performed.

When we talk about the immunophenotype, what we're talking about is what proteins and receptors are being expressed on the outside of the cell. We can also look at proteins on the inside of the cell, but this is kind of like a little graphic representation of a cross section of a cell. And you can see that there are all these proteins that stick out and all these receptors, and we expect to see them in a certain configuration to say, yes, we think this is probably hairy cell leukemia.

The first two rows here are kind of like the original immunohistochemical proteins that we used for a diagnosis of hairy cell, and it was felt that these had to all be positive or it wasn't hairy cell. This was the best that the testing could get. Over the years, we've added proteins that we know are commonly expressed and also other more specific testing that I'll discuss next.

Probably, if you have hairy cell leukemia, you've had a bone marrow biopsy. This is a picture of the core biopsy. It has been decalcified and stained, in its decalcified state. We can apply different chemicals to try to see if they stick to the cells. Here, this is a CD20 stain.

You can see the chocolate donuts. This is a positive stain. As you can imagine, since this is just stains sticking onto the tumor cells if they're positive, sometimes they can be falsely negative or maybe not show up very bright. But we do have stains that we commonly use in hairy cell, mostly CD20 and Annexin-1, and VE1.

I wanted to talk a little bit also about BRAF testing. Back in 2011, there was this seminal paper where Doctors Falini and Tiacci found that the vast majority, if not 100% of people with hairy cell leukemia, have a BRAF mutation. That is a driver mutation we just talked about for hairy cell, and it should be positive in hairy cell leukemia.

We can either look at the mutation testing by PCR, or by staining. If you want to think about it— I don't know if anybody ever had a COVID test, probably everybody did—when we first had the COVID test, you could only get a COVID PCR. You had to go to a testing center, and they would swab your nose and put it in this little sample container and look for DNA segments. That is very, very sensitive testing.

There's also testing for BRAF by staining. This is an example of a positive BRAF stain. The stain only works for V600E. So, if that stain is negative and your PCR is negative, it's actually possible that the test is not picking up what you actually have.

Alternative BRAF mutation analysis may be required. That can be done through whole exome sequencing and other testing. At that point, I think it would be time to see somebody at a center of excellence. In the case of an atypical finding, the diagnosis is usually made based on the most diagnostic features.

For example, if you had a hairy cell sample, it looked pretty similar to hairy cell, but one of the immunohistochemical proteins was not present, but it was also BRAF positive, it would still likely be called hairy cell leukemia with atypical features. If the diagnosis is truly unclear, I think it would be really great to reach out to the Hairy Cell Foundation and find a center of excellence near you for an expert consultation, because I think that's where, honestly, we are the most helpful.

I did want to touch on variant hairy cell. I'm really not going to talk too much about the diagnosis and treatment of variant, but I did want to bring to light that the name of Variant Hairy Cell has changed. We now call it, according to the WHO classification from 2022, Splenic B-Cell Lymphoma/Leukemia with Prominent Nucleoli.

That has been a little bit controversial because we get upset when our names of diseases are changed. But that is how it is classified now. So, there are a lot of people out there now with this diagnosis. It used to be called variant hairy cell. It tends to behave more aggressively than hairy cell leukemia, and by definition is BRAF V600E negative.

That's why I'm bringing it up—because there’s always the worry that if somebody has a negative BRAF test, they will be classified as a variant or a splenic B-cell lymphoma diagnosis, and it's really important to get that diagnosis correct.

If there's an alternative BRAF mutation, that’s different. Also, this was originally felt to always be CD25 negative. We now know that sometimes CD25 can fall off, especially after treatment, because it is a pre-apoptotic signal when that protein disappears. That's another reason to be seen at a center of excellence.

If CD25 is negative and the diagnosis is unclear, this is considered to be a completely separate disease from hairy cell. I'm not going to address the treatment, but there is a lot of overlap with the exception of BRAF inhibitors. They're not used in this.

Most of the time, at the time of diagnosis, imaging is not necessary to make the diagnosis. But sometimes it's useful, especially if there’s concern for lymph node enlargement or something else. The options are: we can do an ultrasound to get spleen measurements. The nice thing about that is it's easy, you don't have to fast or anything, and there’s no radiation exposure.

With CAT scans, we obviously get more information. We can look for any enlarged lymph nodes, enlarged spleen, or liver, and also if the hairy cell is somewhere outside of the places we normally see them. Sometimes people can actually get bone involvement with hairy cell.

So the scans are nice if we're looking for a reason for a symptom that's unusual. I don't know if anybody on this meeting has had a PET CT scan. This is a way to do functional imaging and we can actually look and see where the lymph nodes are active or if the spleen is very active.

You can look for involvement in extranodal sites such as the bone. The downside to this is there’s currently no consensus on how hairy cell typically looks on a PET scan. So, it may not be the best choice of imaging unless there was something very specific the team was looking for because we don't really know how to define hairy cell on a PET scan. We typically would recommend doing some type of imaging prior to starting treatment so that we have a baseline and we know what the measurements of any enlarged spleen or liver are, and any enlarged lymph nodes.

The treatment of hairy cell is a true success story. Back when the disease was first recognized, there were very limited treatments. They would usually do splenectomy. Some oral chemotherapies became available, but the median survival was only four years. So, on average, people only lived four years once they were diagnosed with hairy cell.

And then, as new treatments became available, the life expectancy really soared. I wanted to go over some of the treatment options so that people know what to expect. I think that time before treatment—not knowing what the treatment is going to look like and what to expect—is one of the more stressful periods in the disease.

So hopefully this will help people understand what to expect.

According to the guidelines, not everybody needs treatment at the time of diagnosis, but the truth is that most people do. Only about 10% of patients will be monitored on observation at the time of diagnosis. We typically consider treatment when the hemoglobin is less than 11, the platelet count is less than 100,000, the absolute neutrophil count is less than 1,000, and if there is symptomatic splenomegaly.

The reason for this is because these problems don't typically get better without treatment. Sometimes there will be fluctuations, so it's not necessary to react to one blood count value or something temporary that's happening. But if these are persistent and getting worse, they typically do not get better until treatment is started.

The goals of treatment are obviously to normalize the blood counts or get them as near normal as possible, to shrink the spleen if it's enlarged, and to resolve the symptoms that the disease is causing. We now know from studies that were done during COVID that treatment of the underlying disease can sometimes improve the immune system.

People who were in that period of time after treatment and in remission tended to do better during COVID in terms of not getting very sick. Treatment is not yet curative, that’s what we're all dreaming of—but it's highly effective. And because it is not curative, we don't want to treat when it's not needed. We're always looking for the longest remission possible and the safest possible way. And treatment is now very customizable.

The classes of treatment I'm going to go over are: chemotherapy, immunotherapy (which are the anti-CD20 monoclonals), targeted therapies, and then I wanted to give a very small review on the cell-based therapies in hairy cell.

For chemotherapy, you have two options: either Cladribine or Pentostatin. These can be given as single agents, and that's how they were used for a long time because there wasn't enough data to add Rituxan until recently. These two options are highly effective in both the upfront and relapse settings.

They're not curative, but the remissions can be very long in many cases. The drugs are basically equivalent. They have equivalent responses and equivalent long-term outcomes. So, I would say one is not necessarily better than the other. We know that with either chemotherapy, we can see responses in up to 100% of patients, with anywhere from 70 to 90% complete response rates.

The five-year progression-free survival across the board is around 70%. Life expectancy has become near-normalized because of these two chemotherapies, but still about 40% of patients will eventually relapse and need something else.

So, I just put up a little comparison slide between Cladribine and Pentostatin.

On the left, Cladribine: there are a bunch of different ways to give it. It can either be given as a continuous infusion—we don't really do this much anymore. Most of the time it's given for five days, either IV or subcutaneously. It can also be given IV once weekly for six weeks.

It turns out there's actually no difference in responses based on the schedule. So, there's not a wrong answer here. Sometimes it comes down to patient preference, physician preference, and facility resources.

Pentostatin is typically given IV every two weeks for 12 doses, so that's sort of a six-month course of therapy. At the end, we usually give two additional doses if people are in a CR to kind of consolidate that remission. The one thing about Pentostatin that's nice is the dose can be reduced in the middle of treatment. If there's a reason to, you can lengthen the treatment interval. Let's say somebody has surgery—you can stop treatment, let them get the surgery, and then it can be restarted.

You can hold treatment if somebody gets sick. There was a time when it was actually unavailable. I'm told it is now once again available, but I think honestly Cladribine is the chemotherapy that most providers use.

Regardless of which chemotherapy is administered, really the most important thing is whether or not a complete response is achieved. You'll see this is the proportion remaining relapse-free over time. People who only achieve a partial response are going to tend to relapse earlier, whereas those who obtain a complete response tend to stay in remission much longer.

And that's with either Pentostatin or Cladribine.

Before I go on to the combination therapies, I just wanted to give a little overview of the anti-CD20 immunotherapy. This is either Rituxan or Obinutuzumab, and these target CD20 on the cell surface. So here's your B cell: you have your CD20 receptor here, and when you give Rituxan or Obinutuzumab, they have a lot of different ways that they engage the immune system.

They can either directly kill the cell, as you see here, or they can bring in other aspects of the immune system to also kill the cell. You can use them alone, or in combination with other therapies. There is growing data for their use in hairy cell, and these agents have been studied both in the upfront and relapse settings.

There was this recent paper in Blood Advances by Dr. Broccoli and his group, looking at single-agent Rituxan as an effective salvage therapy in people who have relapsed. They just looked at all their patients who got Rituxan by itself. I just wanted to show this because I think it is important to realize that maybe it's not the most sophisticated therapy, or something that we would normally do routinely, but giving Rituxan at the time of relapse can lead to prolonged remissions in some patients.

So, it is honestly not a crazy thing to do if there's a reason to avoid either chemotherapy or a targeted therapy, and it can be very beneficial. I just wanted to put that out there in case this has been recommended for anybody.

Obinutuzumab, also an anti-CD20, has a similar mechanism of action. It was developed to be more potent, and it actually is. We do see better responses when Obinutuzumab is given in combination with therapies than when Rituxan is given with other therapies, but that's not always the most important consideration. Still, we know that is definitely the case.

Now that we've covered the main things, I wanted to just talk a bit about combination therapies, which I would say are the new standard of care.

Dr. Kreitman published this study, which was really absolutely practice-changing. He was the senior author, Dai Chihara actually trained here at UNM. They looked at patients who got Cladribine either with Rituxan at the start of treatment or delayed to the end of the Cladribine and then they got their Rituxan.

So they randomized patients one-to-one to either of these arms. The concurrent patients got days one to five of Cladribine plus Rituximab for eight weekly doses, or it was delayed if MRD was detected.

What they found was that six months after treatment, the patients that got the upfront Rituxan with Cladribine had 100% complete responses, with 97% of patients being MRD negative. The patients who just got Cladribine—only 24% of them achieved MRD negativity when the Rituxan was added after the Cladribine.

And this was statistically significant, and it held up over time. So 96 months later, you still saw better outcomes in the patients that got the concurrent therapy compared to just Cladribine followed by Rituxan if MRD was positive.

We know that giving delayed Rituxan led to lower rates of durability of MRD negativity. Also, the concurrent approach was associated with faster blood count recovery, so it may actually be a safer approach, although some of those patients did need platelet transfusions.

Then a little bit about targeted therapies. Many people are receiving BRAF inhibitors now for treatment of hairy cell if there's a BRAF mutation.

Just a word about the BRAF pathway: there is a receptor on the outside of the cell, and typically what happens is something has to activate this receptor to start this pathway, revving up the cell cycle.

When you have a BRAF mutation, it can turn itself on, and so you have constitutive activation through this pathway. It's always running, and that drives the tumor growth.

We have BRAF inhibitors on the shelf because these were already developed for other tumors that have BRAF mutations. And so we have at least four trials, or maybe more now, looking at BRAF inhibitors as single agents in hairy cell. It's a limited duration of therapy, three to five months. Across the studies, the overall response rates were about 90%, with up to 35% complete response rates. The median duration of those responses was one and a half years—not as durable as we would normally like to see.

But again, if the circumstances warrant, it is a very reasonable option for treatment.

The BRAF inhibitors have a unique advantage, or a couple: the first one being that they can lead to rapid increases in neutrophil counts. They are not immunosuppressive in and of themselves. They can be used in people who are not eligible for chemotherapy, or during critical illness.

Dr. Park, one of our amazing colleagues, published this paper recently in the New England Journal looking at Vemurafenib with Obinutuzumab as frontline therapy. Again, I consider this to be a practice-changing study. It was a phase 2 multicenter study, and they gave oral Vemurafenib twice a day.

Beginning cycle two, they added Obinutuzumab, and the study did allow Vemurafenib dose reductions. What they saw is that 90% of patients achieved a CR. Ninety-six percent of those CRs were MRD negative. The median duration of remission was more than two years. Some patients did require a dose reduction of Vemurafenib because of rash, joint pain, or fatigue.

We know that this regimen is effective in both the frontline and relapse settings. The nice thing about this is it is a chemotherapy-free regimen. Again, some people just cannot get chemotherapy for whatever reason, and so this gives a really reasonable option in both the upfront and relapse settings.

Just a small word about the BTK inhibitors. We keep getting more and more of them. This is kind of the same concept where you have this receptor. Normally something would need to trigger that to turn itself on, but in B-cell lymphomas, the BTK protein is just kind of present and driving the cell through the cell cycle.

So we have these targeted therapies. I didn’t put the study in here, but I think it is actually on the hairy cell website. More and more studies are coming with these BTK inhibitors, either as single agents or in combination with anti-CD20.

I also wanted to mention Venetoclax, which was recently studied. It was a small study, but the initial results showed it is effective both as a single agent and in combination. This is a very well-tolerated medication. It's widely studied in leukemias and lymphomas, and used very commonly. I would expect to see, over time, combination studies with this drug because of its excellent side effect profile. So there will definitely be more to come with Venetoclax.

Doctors Falini and Tiacci had a beautiful review article in the New England Journal looking at proposed algorithms for initial treatment and relapse.

So, with a new diagnosis of hairy cell: if you're asymptomatic, you don't necessarily need treatment. If you have symptoms or low blood counts, you should proceed with first-line therapy, chemotherapy with or without Rituximab, and I think that's what most people are doing. If there's an active infection, you can consider a BRAF inhibitor, which is a new recommendation I think we'll probably see in the next guidelines. Patients who are pregnant should be treated with interferon-alpha.

For treatment at relapse, one of the more important things is looking at the duration of the first response. So if there was no response, or the remission was less than two years, then looking at Vemurafenib, the BRAF inhibitor, with or without anti-CD20—I would say with—makes sense. This takes you through all of these scenarios. I think this was very thoughtfully done and will really help providers who are not necessarily experts in hairy cell leukemia to navigate some of these more difficult situations.

I want to talk just a little bit about cellular-based therapies.

In CAR-T, the patient’s own T cells are trained to kill the tumor cells. Hairy cell actually has several potential targets for CAR-T. I love this little picture of the T cell engulfing the tumor cell—it’s a great way to think about what our immune system is supposed to be doing, and it can be trained to do that.

At the current time, there is a phase 1 study of CAR-T at the NIH with Dr. Kreitman. The target is CD22, which is pretty much universally expressed on hairy cells. This study is currently enrolling. They recently reported early outcomes in four patients, and one patient is in a complete remission who had very refractory disease.

I also wanted to highlight the Hairy Cell Foundation. The HCL 2025 initiative funded two CAR-T products. One is at Case Western Reserve, targeting BAFF, and the other one is with Dr. Ruella at Penn, targeting IGHD4-30.

And then last but not least, the bispecific engagers. We will be hearing more about these. I'm sorry my image is a little blurry, but this is kind of like—if you want to think of it this way—an off-the-shelf CAR-T. So it does similar work to CAR-T, but basically uses a little molecule that grabs hold of the tumor antigens on the outside of the tumor cell and brings over a T cell and connects them.

Then the T cell will kill the tumor cell. These don’t require processing of the patient’s lymphocytes, so it's a much more standardizable treatment option. In fact, Dr. Tamar Tadmor, who’s another one of our hairy cell colleagues, just recently published the first bispecific in hairy cell with this drug that I'm sure we’ll be hearing a lot more about, with great success. So, more to come for sure on that.

In conclusion: I want everybody to know that there are highly effective therapies in hairy cell, and more to come. The chemotherapy-based regimens still have the longest progression-free survival, but for those people who cannot get chemotherapy—if they're very ill or in the ICU—there are options for alternative therapies. Some people may not tolerate the targeted therapies and need to go back to chemotherapy.

These decisions are made with careful consideration of the patient’s overall health, the treatment goals, and also other things that are going on in the world. If there’s a global pandemic, all these things have to be factored into the treatment decision.

So, I'm going to end now and take questions. I want to thank the Hairy Cell Foundation for all the work that they've done and all the patients who contributed to this work.

It was my pleasure to be here. I look forward to coming back soon. Thank you so much.