Webinar: Understanding Hairy Cell Leukemia (HCL)
March 5, 2025
This webinar was hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Kerry Rogers from The Ohio State University. This presentation is part of the HCLF’s ‘Understanding Hairy Cell Leukemia’ webinar series. Each webinar includes a presentation by an HCL expert and provides an overview of diagnosis, standard treatments, and alternative therapies.
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View a recording of Dr. Kerry Rogers’ presentation below.
Transcript of Dr. Rogers’ Presentation
What is Hairy Cell Leukemia?
Hairy cell leukemia is a rare chronic B cell leukemia, a type of blood cancer. It’s a cancer of immune system cells called B lymphocytes. Over the course of life, these cells become hairy cell leukemia cells.
Hairy cell leukemia is a subtype of B cell cancers and was described in the 1950s. I have a picture here of Bertha Bouroncle who was at my institution, the Ohio State University. She published, describing hairy cell leukemia.
Diagnosis and Identification of HCL
The diagnosis of hairy cell leukemia requires verifying the presence of the leukemia cells. This can be done in a variety of ways, but bone marrow biopsy is the standard for diagnosis. Even though it's leukemia, which are blood cancers that circulate in the blood, hairy cell doesn't always circulate in high amounts.
Because it's a blood cancer, the cells live in places where blood cells like to live. The hairy cells are usually in the blood and the bone marrow and can also be in the lymph nodes and the spleen. You can see an enlarged spleen in people with hairy cell leukemia because that's where the hairy cells go. They fill up and expand the spleen.
Some people have hairy cell that invades not the bone marrow, but the outer cortex part of the bone. So, it can really be anywhere that the blood is. And that doesn't mean that it's spread or worse, like we think of for solid tumors.
Morphology of HCL cells
The leukemia cells are identified using a couple different methods. The oldest method that we have is morphology - What do they look like? The hairy cells appear similar to mature lymphocytes, because they're lymphocyte cancer, but they have these hairs or cytoplasmic projections. That’s how it got the name hairy cell leukemia.
The cytoplasm is the substance of the cell. And you can see here, this picture is a blood film; that's a drop of blood that was dried on a slide and then stained so that it could be reviewed. The pink splotches are red blood cells, and those two purple things are hairy cells.
Markers and cell mutations
There are markers. That's the other thing we use to identify HCL. There are many ways to look at markers. One is special stains on bone marrow called immunohistochemistry. There is also flow cytometry, which is a test to look at markers on blood cells in the blood.
Classic hairy cell leukemia usually has the BRAF V600E mutation. That's a mutation in a gene called BRAF. That's very common in classic hairy cell leukemia. Sometimes when people are diagnosed with hairy cell leukemia, the pathologist isn't sure if it's hairy cell, splenic marginal zone, or some other type of B cell leukemia or lymphoma.
Seeing this BRAF mutation usually helps point people in the direction that it's classic hairy cell.
HCL variant
There is a variant hairy cell leukemia that has slightly different markers and different mutations. HCL variant doesn't usually have this BRAF mutation. The WHO recently reclassified HCL variant under a catch all category of splenic lymphomas with splenic B cell lymphomas, prominent nucleoli.
But there's still quite a lot of literature on variant hairy cell leukemia. Some of the other classification schemes still acknowledge it, and we certainly do.
So, you can see they have these hairy projections which look like fuzz around the outside of the cells. The arrows are pointing to the hairy cells here. This is the bone marrow and it's very common for the bone marrow in people with hairy cell leukemia to be replaced with some of these fibers.
That fibrosis or extra fibers go away after treatment, but that can also help identify hairy cell leukemia cells.
HCL is rare
So just a few facts about hairy cell leukemia. It's a rare leukemia. This is only about 2 percent of adult leukemias; about 1,100 new cases per year in the U.S.; about 0.3 new cases per 100,000 people per year. The demographics of those who experience hairy cell leukemia are more commonly men. It's got a four to one men to women ratio.
And then it's more common in white people That's true across B cell malignancies; most of them are more common in people who are white or Western European origin.
The median age at diagnosis is 55. There's a whole group of people that get it younger, in their thirties and forties, and then people that get older.
The expected survival is decades. So that means while we cannot cure it, people live with it for a very long time. In the majority of cases, it does not shorten someone's natural lifespan. So that means that this is not a leukemia we expect people to die of.
Clinical features
There are some clinical features. Many people are diagnosed with no symptoms at all or asymptomatic. A lot of people get blood counts tested for other reasons or for annual physicals.
I've had some patients with slightly low blood counts that were monitored for years. They finally got low enough that someone, thought, we've really got to get this diagnosed. They got a bone marrow biopsy and had hairy cell leukemia. So, a lot of people feel perfectly fine. But over time, if it fills up the bone marrow too much and crowds out the healthy blood producing cells in the bone marrow, then the bone marrow can't do its job making blood cells and you end up with low blood counts or cytopenias.
Slightly low blood counts or mild cytopenias are fine because everyone has more blood cells in their blood than they need. People can get very low blood cells and that would be a reason to treat hairy cell leukemia.
We believe it causes a low monocyte count. So, monocytes are a certain subtype of white blood cell that tend to be extremely low or zero in people with hairy cell leukemia, even if their other blood counts are relatively normal. You can also see people with an enlarged spleen.
That does go back towards normal with treatment. You can see enlarged lymph nodes or bone lesions. And then, because these are cancers of immune system cells, the hairy cells can release chemical mediators or cytokines, which are the same hormones released during infections. And that can really lead to things like night sweats, weight loss, or fatigue.
Lots of adults in the U. S. live with mild chronic fatigue, but some people can get fatigued severe enough that they can't do their usual personal or professional activities, and it really limits their enjoyment of their life. That does usually improve with treatment.
And then many people have an infection at time of diagnosis. Hairy cell leukemia lowers the blood counts, and since it's an immune system cancer, it interacts with the healthy immune system cells and increases risk for infection.
I alluded to this a little bit, but not everyone needs treatment right away. So, there are some people, it's roughly 10 percent at diagnosis, where they feel fine, their blood counts are pretty fine, and they're not having any problems from the hairy cell leukemia, and you don't need to treat it.
In other chronic B cell cancers that have had randomized studies in early treatment versus delayed showing, early treatment doesn't matter. That has not been done specifically in hairy cell leukemia because it's such a rare leukemia, but the same applies, where earlier treatment can lead to side effects.
In fact, if you eliminate the hairy cells sooner, a lot of the treatments are immunosuppressive and you could increase risk of infection.
When to start treatment
The standard treatment indications are low blood count. If the absolute neutrophil count (neutrophils are a bacterial infection fighting type of white blood cell) is less than a thousand - That's usually reported as one on lab reports. If you're looking at a lab report for blood counts, it says neutrophils are granulocytes and it says one, that's a thousand. Hemoglobin less than 10 or 11, platelet count less than a hundred.
So, if the counts are this way, it's from hairy cell and it's time to think about treatment. Of course, a really large spleen to the point where it's affecting someone's abdomen; that's a reason to do treatment.
Enlarged lymph nodes that are bothersome, bone lesions causing issues, and then if it is releasing chemical mediators that are causing so much fatigue people can't enjoy their life or do what they need to do, of course treatment is indicated.
Considerations before starting treatment
So, a couple of considerations for treatment. One is a bone marrow biopsy; it's pretty helpful to understand where things are at before treatment.
Definitely labs to look at kidney and liver function, and talking with someone to understand their general health and other health issues they might be experiencing. And then any testing that might be needed to make sure they don't have an infection.
And then it's really nice to talk to people about their preferences regarding treatment.
Treatment options
So, here's a brief listing of some of the treatment options. The first one is purine nucleoside analogues; these are chemotherapies. This is cladribine and pentostatin, the two most standard chemotherapies for hairy cell leukemia.
These are the most used and cladribine is more commonly used than pentostatin. These can be given multiple times over someone's lifespan, and sometimes used with anti CD20 antibodies, which is an IV antibody treatment of manufactured antibodies against a marker called CD20 that's on the hairy cells, and that can increase the effectiveness of the chemotherapy.
These purine analogs are the backbone of treatment for most patients.
However, there are studies now, one of which Jae Park is doing, looking at comparing purine analogs to non-purine analog therapies. I think that's really important to do just to make sure that we know what the standard is and how we should be treating people.
BRAF inhibitors are probably the most used non-chemotherapy treatment.
Remember classic hairy cell leukemia has the BRAF B600A mutation. This drug (vemurafenib) binds and blocks that mutant protein. Dabrafenib is (another BRAF inhibitor). These are drugs approved for melanoma that have been very well studied in hairy cell.
I'm currently in charge of a study here looking at an inhibitor of a protein called BTK, which is in B cells. And then there are a variety of investigational agents, including other RAF inhibitors, not just BRAF.
Venetoclax, which targets a protein called BCL 2, that is effective in a lot of cancers, especially B cell cancers. And then in other B cell cancers, we've had immune based therapies. That hasn't been used a whole lot in hairy cell leukemia, but I do want to cover it, especially when some of the standard therapies aren't getting the job done for (some patients).
There are older treatments that really aren't used anymore. One is a drug called interferon and the other is splenectomy. So, removing the spleen can improve the hairy cell for a couple years. These other treatments are usually safer and more effective, but there are a few cases where that has helped someone out.
Standard Chemotherapy
The purine analogs are drugs that interfere with DNA synthesis. That means that they kill the hairy cells faster than they injure your normal cells, and that's how all traditional chemotherapies work. So, there's cladribine and pentostatin, and I don't know of anyone who thinks that one is more effective than the other. They do have different administration schemes. Cladribine, which is more commonly used, is given all in one week, so either continuously for seven days or daily for five days of that week, so you get your whole chemotherapy course in one week, which is very convenient.
It does take weeks or sometimes even months to really recover, and you see the full effects around four to six months.
And then there's pentostatin, which I think tends to have fewer side effects. It's been used in cases of infection. And it's given every two weeks, until people get a response. And then you do a bone marrow biopsy to see how the response is. If it's good, then you do two more doses and quit. So, this can result in months of treatment. But it spreads the side effects out so people don't get all their chemotherapy at once. It also doesn't suppress the healthy bone marrow as much. So, for people that are having very low or severely low blood counts at diagnosis, it can really be useful. It also works very well.
Purine analog have very high remission rates. They're almost 100 percent effective in achieving some kind of remission with 80 percent achieving a complete remission, which is near normal blood counts and no visible hairy cell in the marrow. It results in two to 10 or more years of remission.
There are people who received cladribine over 20 years ago that have not had hairy cell need treatment since then. So, occasionally people have only one treatment in their whole lifespan for hairy cell. They'll die of something else, decades later, and never need treatment again.
However, about 80 percent of people do need treatment again, and the average, or median time to needing treatment again is about 7 to 8 years. That's pretty good. It's not perfect. It would be nice if we could just cure people. But in terms of cancers, having seven to eight years before needing the next treatment is a relatively long outcome and you can see people that have a complete response actually have a median of 16 years versus partial.
And unlike most cancer chemotherapies, you can get a longer remission with the second course compared to the first. That's not common in cancers.
Purine analogs, mostly cladribine, have been combined with antibodies, and those are antibodies against a marker called CD20 on B cells and on the hairy cells, and that can improve outcomes. I'm showing you some data from a study that was led at the NIH, which randomly assigned people getting a first treatment to cladribine with the addition of rituximab if hairy cell became detectable later, or cladribine with rituximab together. So, it was rituximab on the first day of cladribine and then weekly for eight weeks, (that's what CDAR is on this slide. CDAR is the abbreviation for cladribine and rituximab), versus the cladribine alone.
This is a swimmer's plot. So, you can think of the different bars as lanes in a lap pool. Everyone starts on the line and swims away in the pool. And that's how long they're followed for. The start time, when they jump in the pool, is when they start the treatment. They've colored it blue if they have no detectable hairy cell and kind of a light or aqua green or pink when they do have detectable hairy cell.
With the CDAR, which is the cladribine and rituximab, very few patients have any detectable hairy cell compared to Cladribine and then Rituximab later.
So there weren't differences in survival because everyone was alive and doing well. But there was less detectable hairy cell when you gave the drugs concurrently.
And that's why there is a discussion to use CDAR initially for patients who are getting their first treatment, especially if they're pretty healthy.
BRAF Inhibitors
I just want to say a few words about vemurafenib. This is a drug again that targets the BRAF mutant protein and it rapidly clears the bone marrow of hairy cell; response rates are extremely high.
But given for a span of just about six months, it doesn't work that long. So, it's very useful if you need a quick response, if people present with infection, it doesn't stress the immune system much, but it doesn't last very long after you stop giving it.
It's been combined with rituximab. I'm showing you a study led by Enrico Tiacci in Italy that is looking at improving how long remissions last by adding rituximab. Patients were able to stay in remission longer, so adding Rituximab does improve it.
And Vemurafenib has also been combined with Obinutuzumab, which is a different anti CD20 antibody that's likely more effective.
BTK Inhibitors
My institution has done a lot of work in Ibrutinib across B cell cancers. This targets and inhibits a protein called BTK. It's in a cell signaling pathway in B cells. Ibrutinib is a daily oral medication. It is taken indefinitely, so it's a long-term treatment that people take for years.
However, people feel pretty good and go about their life when they're taking it. It does work quite well in both hairy cell leukemia classic and variant hairy cell leukemia. And while it's not FDA approved in hairy cell leukemia, it is in the NCCN and other clinical practice guidelines. So, it can be used off label, meaning it's approved for something else.
So ibrutinib is the first in class one. There's Acalabrutinib and Zanubrutinib that are both approved in other cancers. These have fewer cardiovascular side effects.
So, this is a study that included 44 patients. This is a multi-site study; we had multiple hospitals participating, but we are the organizing site for this. Patients had hairy cell for an average of 10 years and experienced an average of four treatments.
This is for patients where purine analogs and other treatments aren't getting the benefit they need. And you can see while that overall response rate, that's what ORR is, was not super high, this bar graph is probability of being alive and with your disease controlled for the dotted line and alive for the blue line.
So, at 60 months, you had 68 percent of people still alive with their disease controlled and that's longer than some of these people had gotten from any other treatment. So, this can be effective for difficult to treat hairy cell leukemia.
Alternative Treatments, such as CAR-T Therapy
I want to mention that there are B cell targeting immune therapies out there. Hairy cell is a B cell cancer, and I've had patients that participated in studies that were enrolling anyone with a B cell cancer. They got some therapies that helped their hairy cell leukemia a lot. Sometimes when they're being studied in B cell cancers, it's a good opportunity to participate for people that need this type of therapy.
CAR T cell therapy is where the T cells are harvested. The blood is taken out of the body, spun through a machine and put back in the body, and some of the white blood cells are removed.
The T cells are separated; they use a viral vector to transform or alter the cells to express a receptor to make them target something called CD19, which is on the B cells. The patient must get chemotherapy to allow their body to accept the cells back.
Then they get their own T cells that have been genetically modified back. And those T cells grow and expand in the body to fight their cancer. And so, the marker that the most common one uses is CD19. This can work across a variety of CD19 positive cancers.
And then bispecific antibodies are the same idea, but without the CAR T. These are antibodies, but instead of regular antibodies, like the Rituximab and Obinutuzumab, they target one marker on the T cell and get the T cell to attack the tumor. And those are used across a variety of blood cancers.
Screenings for skin cancer
These are immune system cancers; people with hairy cell leukemia have a higher rate of other cancers or infections and that means that getting all the cancer screenings your primary care doctor recommends is super important.
Skin cancer is very common in hairy cell leukemia, so anyone with hairy cell should be getting skin cancer screening.
Vaccines
The recommendation is to get all the vaccines owed to you; make sure you get all your vaccines because that's what's going to protect you from infection.
Health maintenance
Remember, most hairy cell patients live for decades with it. You don't want to die of a heart attack because you stop monitoring your cholesterol or exercising.
Unanswered research questions
There are questions that we're trying to answer in the field: How to use antibodies, what chemotherapy free treatments are better, questions about the variant of hairy cell leukemia, and how other aspects of health should be supported.
This transcript has been edited for clarity.