2023 HCLF PATIENT SEMINAR
In October 2023, the HCLF hosted a full-day, hybrid seminar for people with HCL and their family members. The seminar was held in London, UK with participation via Zoom for individuals unable to travel. Recordings and slides from portions of the seminar are linked below, along with a transcript of the slide presentations. The seminar included a panel discussion, but a recording of that panel will not be posted.
Seminar Slides and Recordings
Understanding Hairy Cell Leukemia: Diagnosis and Management
Overview: Participants will learn about typical HCL presentation and diagnosis
Presenter: Dr. Claire Dearden, The Royal Marsden Hospital
View a recording of Dr. Dearden’s presentation. >>
View Dr. Dearden’s slide presentation. >>
A transcript of Dr. Dearden’s presentation can be read below.
Standard HCL Treatment
Overview: Participants will learn about standard therapies used in frontline HCL treatment and at relapse, as well as treatment available to patients who don’t respond to other options.
Presenter: Dr. Dima El-Sharkawi, The Royal Marsden Hospital
View a recording of Dr. El-Sharkawi’s presentation. >>
View Dr. El-Sharkawi’s slide presentation. >>
A transcript of Dr. El-Sharkawi’s presentation can be read below.
Transcript of Presentations from Dr. Dearden and Dr. El-Sharkawi
Understanding Hairy Cell Leukemia: Diagnosis and Management
Presenter: Dr. Claire Dearden, The Royal Marsden Hospital
TRANSCRIPT
I'll start with a brief overview of the disease and then go through the history. It's very inspiring to see where we've come in 60 years since the disease was first described. I'm not going to go into details of treatment. I will say a little bit about clinical presentation and diagnosis, mention some of the unusual clinical manifestations, in particular bone lesions, and then say something about infection. Then, lastly, I'll mention a few things about the hairy cell leukemia variant.
Hairy Cell Leukemia
One of the most striking characteristics of hairy cell leukemia is the male predominance. For every female, there are four males with this disease. We've never explained why that is, but it's very consistent since the first description of the disease. The median age at presentation is about two decades younger than in chronic lymphocytic leukemia (CLL), where the median age is in the early 70s. So, the HCL population is relatively younger.
HCL patients present with pancytopenia and splenomegaly. Pancytopenia means low blood counts; 'pan' means all the blood counts are low.
We see odd phenomena, which we loosely call paraneoplastic, which means they're not directly due to hairy cells but are associated with the disease. They go away when you treat the disease and tend to be odd skin lesions.
We can make the diagnosis easily if we have the right material because the hairy cells express particular proteins, and we can detect those using technology easily now. It's like having a barcode; your hairy cell has a unique barcode that we can detect.
A unique mutation is also present in all the hairy cells in classical hairy cell leukemia. Hairy cell variant and a small proportion of classical hairy cell leukemia patient cases with an odd expression of the immunoglobulin gene don't have the BRAF mutation, and they behave differently. We are trying to separate those from the classical hairy cell leukemia characterized by a mutation in the BRAF gene.
An international consensus guideline was produced in 2017, which is in the process of being updated. A lot has happened since 2017, and we need an update, which hopefully will come out next year. And we have a British consensus guideline, published in 2020 during Covid.
History of HCL, Disease Discovery and Treatment Development
The first recognized clinical description of hairy cell leukemia was about 65 years ago by Dr. Bertha Bouroncle at the Ohio State University. Prior, there had been some case reports, but it wasn't until 1958 that HCL was first recognized as a disease, and it took almost another decade before it gained the term' hairy cell leukemia.'
Around that time, the only treatment that worked was splenectomy. Then, in the mid-1980s, systemic treatment became available that was effective. That was initially interferon and then followed by the purine analogs, pentostatin and Cladribine. Pentostatin and Cladribine have been around for a long time now, and even a decade after their introduction, we had good follow-up data showing how effective these drugs were and how long people remained in remission.
In this century, we've developed novel agents such as antibodies and immunotoxins, which are antibodies linked to a toxic substance. We've discovered the BRAF mutation and introduced the BRAF inhibitors and the combinations of some of these drugs, notably the purine analogs with an antibody.
So, what happened to patients before we had systemic treatment? They died, and the disease was regarded as incurable. It didn't respond to the drugs that were available then, mainly a class of drugs called alkylating agents. These drugs were used, but they didn't work in HCL.
Splenectomy had some benefits, particularly for some patients. Certainly, the counts improved after splenectomy, but the median survival was four and a half years. Now, in some context, that might sound quite good, but from what we know now, that was a dismal outlook. People would die from infection and other complications due to low blood counts.
Secondary malignancies in HCL patients were identified before any of the novel treatments. Secondary malignancies are therefore probably not treatment-related; they may be inherent to the disease.
Here is a story of a keen sailor. He was out sailing; the boom came across, hit his side and ruptured his spleen. When they took the spleen out and looked at it histologically, they found hairy cell leukemia. He did very well after having his spleen out. His counts normalized, and he had 28 years in remission and relapsed. He then had Cladribine and did very well.
Overall survival in that era was four years.
In 2018, we published this data, a master series of 250 patients. You can see that 95% of the patients were still alive at four years. What we see is that the overall survival at 15 years is the same as that of an age-matched population. If you look at the general population and match it to age, you'll get the same curve, which means that people aren't generally dying from hairy cell leukemia.
We see very good outcomes now for patients with hairy cell leukemia.
Purine analogs: cladribine, pentostatin, and interferon
Here are the landmarks in HCL: 1984 interferon, 1987 pentostatin, which was first called deoxycoformycin, and Cladribine or 2CDA. These first publications were published in the New England Journal of Medicine Journal. That was the first hint in just a handful of patients of how effective these drugs were going to be. You could see that back in the late 80s and early 90s, and we are still reaping the benefits.
It wasn't until 1995 that a randomized control trial in hairy cell leukemia was conducted, looking at pentostatin versus interferon, interferon being the standard treatment at the time. This is a patient who had interferon, and you can see how well they did; the hairy cells came down, platelets and hemoglobin went up, and that was all very well whilst they stayed on interferon. But the problem with interferon was once you stopped it, patients relapsed quite quickly because they only achieved partial remission in the bone marrow. The other problem with interferon was a lot of people didn't tolerate it very well. It's an injection.
We do still occasionally use interferon. It's effective in the disease and can be used circumstances. Some people use it during pregnancy.
Pentostatin and cladribin are purine analogs that work in the same way and have the same results. Pentostatin is used less often now and is much less available. But you can switch between the two, and they're not mutually resistant. So, in patients who are resistant to Cladribine, we have seen good responses to pentostatin. It's worth knowing that both can be used and give exactly the same results.
Length of response
Patients who get a complete response will stay in remission for much longer than patients who only get a partial response. And you can get a longer response with a second treatment in hairy cell leukemia if you get a better response. That's very unusual in hematological cancers. In hematological cancers, your best chance of good treatment is the first treatment you have, but that's not the case in hairy cell leukemia. In HCL, you can often get a better response to the subsequent line of treatment than you did with the first.
The median relapse-free survival, 16 years in our series, and for those patients who were in complete remission (CR), is over 20 years.
If you use the same treatment again and again, the duration of the complete response decreases with each subsequent treatment. If you get 16 years of remission with the first line of treatment, you might get 11 years with the second line and six years with the third line.
BRAF
Identifying the BRAF mutation in HCL by Dr. Enrico Tiacci and Dr. Brunangelo Falini’s group in Italy was a major landmark in hairy cell leukemia. These genetic findings were converted into therapeutic application in HCL.
BRAF is common in other malignancies, notably melanoma. Melanoma was a completely untreatable disease until people found that half the patients had a BRAF mutation. There was then a big drive to produce an inhibitor of BRAF to treat melanoma. Because of that progress in melanoma, we were able to use BRAF inhibitors in HCL.
BRAF is an activating mutation. This means that the BRAF is over-expressed, and these cells love and grow on it. If you block it with vemurafenib, which is a blocker of or an inhibitor of BRAF, the first thing that happens is that they lose the hairs. You take their hairs off and then they die. And so, it shows how dependent these hairy cells are on this mutation.
We treated the first patient with vemurafenib more than ten years ago. The patient had had about eight lines of treatment with very refractory disease. The patient came up from Wales, and his bone marrow was full of disease. Six months after his vemurafenib treatment, he had cleared the bone marrow of the disease.
Clinical presentation and diagnosis of HCL
The classical clinical feature of HCL is low blood counts, which is often picked up as an incidental finding. Many people have blood draws and blood counts done, and the blood count is low. Sometimes, not much attention is initially paid to the low counts. We know this because you can look back and see that patients have had low blood counts for quite a long time before the diagnosis of HCL is made.
Monocytopenia is a classic feature of hairy cell leukemia, and it explains some of the types of infections we see in HCL that we wouldn't typically see in other diseases that retain monocytes, diseases such as mycobacteria TB-type infections, or related organisms.
Splenomegaly is less common as a presentation now in HCL because the HCL is picked up on blood counts more frequently, or the patient presents with an infection and is noted to have a low blood count. But occasionally, people have a CT scan or an abdominal ultrasound for another reason, and the splenomegaly is noted.
Diagnosis of HCL is straightforward with flow cytometry. You have a barcode that can identify and distinguish the cells from normal B-cells and other B-cell malignancies. We use the same technique to look for these proteins in tissue samples from the bone marrow and spleen. You really cannot accurately diagnose hairy cell leukemia without a bone marrow. It is essential because mistakes are made when the bone marrow hasn't been examined.
So, you have to confirm the diagnosis with a bone marrow, which you can use to accurately assess the infiltration and the BRAF. And a caveat about the BRAF mutation: a test is only as good as the sample that you give the lab to test. The absence of a BRAF mutation does not necessarily mean that it's not classical hairy cell leukemia or that it doesn't harbor a BRAF mutation. It may be that the right tissue hasn't been sent. When you try to aspirate bone marrow, it can be very difficult to get a bone marrow aspirate. You may not have any hairy cells in it. And even in the peripheral blood, you may not have very many circulating hairy cells. It depends on the sensitivity of the method that's used, the lab that's doing it, how quickly they get the sample, and the quality of the sample.
Here is an image of the hairy cells in the blood. We call this a reniform nucleus because it looks a bit like a kidney. And then in the bone marrow, this is often being referred to as a fried egg appearance because you have the nuclei which look black and then you have quite a big space around them, which is where all this cytoplasm was. So again, it has a very distinctive appearance. You don't really see that in any other leukemia.
And the reason you can't often get an aspirate is because there's a lot of what we call reticulin in the bone marrow. It's fibrosis, like scar tissue. You get these strands of fibers across the bone marrow, which trap the cells in there. This is why you can't aspirate them and it's probably why they aren't circulating very much in the blood either. You do see fibrosis in some other types of hematological malignancies, but it's very typical in hairy cell leukemia.
So, first we make sure you've got the right diagnosis. We do occasionally get people sent to our clinic who have had the wrong diagnosis. I've seen patients diagnosed with aplastic anemia that have hairy cell leukemia. And it’s important to distinguish classic HCL from the variant.
A proportion of patients may not need treatment straight away. HCL can be picked up in a patient who's asymptomatic, where a blood count shows modest reduction in the cells and it would be possible to monitor that patient, but closely.
Infection
Sometimes patients will be diagnosed with HCL when they've presented with an active infection. These patients do need to be managed differently. The infection must take priority; identifying the infection and treating it effectively is the first step. There are treatments you can use in HCL that are not chemotherapy, that are not otherwise myelosuppressive and might be safer in that context. But it's really important that attention is paid to the presentation with infection. We look at kidney function. We always look to see if people have been exposed to hepatitis in case that needs to be managed, if we're going to give drugs which will risk reactivation of the hepatitis.
When to initiate treatment?
From the guidelines, there are parameters that would trigger a need for treatment. That goes hand in hand with people who may be asymptomatic or have a very big spleen or other things that may merit treatment initiation.
We nearly always have somebody who will have an unusual clinical manifestation. Lymphadenopathy is an unusual clinical manifestation. We would very rarely ever be able to palpate large lymph nodes in a patient presenting with hairy cell leukemia. Occasionally, we'll see enlarged abdominal nodes on a scan.
The liver nearly always has some involvement. If you biopsy the liver, you would see hairy cells in the liver, but we would very rarely see that compromising to liver function. Hairy cells are in the blood and circulating; they could infiltrate anywhere. We have one patient who had a solitary lesion in the left apex of the lung that looked exactly like lung cancer. Without a biopsy, no one would've known that it was hairy cell leukemia. There are autoimmune disorders, including the ones affecting the blood, like autoimmune hemolytic anemia and rare infections.
Focal bone lesions are a very rare presentation in hairy cell leukemia. We think the reported incidence is about 3%, but it's likely under-reported because we don't routinely do that sort of imaging in hairy cell leukemia. It's very rare as the first presentation. It's usually something we see later in the disease and the lesions are usually lytic. It is often associated with other unusual disease features like nodal presentation or extra nodal disease involved site radiotherapy.
Radiotherapy to the location can be useful for symptom control. If the lesions are quite widespread then systemic treatments are needed; these lesions usually respond very well to the same systemic treatment you would give if you were treating a standard hairy cell leukemia patient. But there may be bone destruction that doesn't repair afterwards, so there may be evidence of longstanding bone.
A 42-year-old gentleman presented to us years ago with a history of a right occipital swelling and he had a big lump on his head. He also had some pain in his ribs and a history of headache. The MRI showed he had this big soft tissue mass in his skull which was eroding the bone. He had other soft tissue masses and bony lesions. We were able to demonstrate on the MRI that there was leptomeningeal disease, which means disease of the membrane surrounding the brain and spinal cord. And much to our surprise on the initial biopsy of his skull lesion, it was hairy cell leukemia and the bone marrow biopsy confirmed that.
But he had an excellent response. He had radiotherapy, steroids to reduce the compression, intrathecal chemotherapy to get rid of the disease within the central nervous system and Cladribine in the standard way that we would normally give it for hairy cell leukemia. And he went into a complete remission at all sites.
Infection is a relatively common presentation. People present with an infection, sometimes it's just a pneumonia, but when the blood counts come back, they're unusually low and that leads to a call to the hematologist.
Remember that infections can be atypical, so they won't necessarily be the bacterial sepsis that you see with a low neutrophil count. We've seen all sorts of unusual infections; the whole immune system is compromised in someone with hairy cell leukemia. It's not just the monocytopenia; the T-cells and NK cells are not functioning normally. Often the neutrophil count, which is very important in bacterial infections, is low.
This does unfortunately get a little worse when we initiate treatment in terms of the myelosuppression and prolonged immunosuppression from some of the therapies that we use. Having said that, the biggest risk for patients of infection is before diagnosis and in the immediate period after diagnosis until all the blood counts recover.
We rarely see late infections now other than shingles, and we've got a way of managing that. So, this is a case of a middle-aged man who presented with fatigue and headache and the blood count showed neutropenia: low neutrophil count of 0.8, monocytes zero and platelets were low. Bone marrow was full of hairy cells, which typed with the barcode for classic hairy cell leukemia. The patient was treated with Cladribine.
We wouldn't now normally give IV for seven days and we wouldn't normally give fluconazole prophylaxis for a month. But he had fluconazole prophylaxis and did well, but then the fluconazole was stopped and he subsequently developed a fever and headache and the lumbar puncture and brain biopsy showed cryptococcus, which is an unusual fungal infection. It was probably there at the time he presented with headache and had been damped down by the fluconazole, which is an antifungal drug, and then just resurged afterwards. But he was treated successfully with antifungals and achieved a complete remission.
So, some of the long-term consequences already mentioned, prolonged immunosuppression with reduced T cells in particular, the most common long-term infection is shingles. But we do have a non-live vaccine for shingles called Shingrix. It's offered in the UK to people over the age of 65, but also to people who are in special circumstances. We don't have data on Shingrix in patients who are immunocompromised, but it isn't a live vaccine and there's now been such widespread use in the US that we would probably be aware if there were some problem arising as a result. I have been advising patients to get it.
The risk of secondary malignancies is a bit iffy. In our own series, we saw non-melanoma skin cancer, which tends to come up in all lymphoid leukemias. But it's worth remembering that if you keep using a purine analog sequentially, there is a possibility of bone marrow toxicity.
To sum up before I mention the HCL variant, hairy cell leukemia is a B-cell leukemia that presents typically with cytopenias and splenomegaly. Diagnosis is based on blood and bone marrow, the appearances and immunophenotypes, and the BRAF mutation.
The one message I like people to take away is that the overall survival in our series, and I can only speak for our series, is the same as in the general population.
HCL variant
The HCL variant was first described in 1980 by someone who worked in Liverpool and was shown quite quickly to be biologically distinct from classical hairy cell leukemia. So, there's never been any doubt that this was a different disease even before we had BRAF mutations to confirm it. It's interesting that our molecular tests confirm what we already knew from other clues. For every 10 patients with hairy cell leukemia, there'll be one patient with the variant.
The incidence of the variant is very small. Previously when we collected data, we had 39 patients and the male to female distribution is quite different. It's only two to one instead of four to one, similar to CLL. The median age is older by two decades and that's again similar to CLL.
This is a patient who presented when she was 78 with a six-month history of fevers, weight loss, night sweats, and abdominal distension, so symptomatic already in a way that we wouldn't typically see in hairy cell leukemia. She was otherwise very well for her age with no other medical problems or significant travel history. On examination she had massive splenomegaly right down to the other side of her abdomen. But the examination was otherwise normal, she had no lymphadenopathy, and her blood count showed a high white count. She was mildly anemic, had a high white count and a high monocyte count.
She had quite a well-maintained hemoglobin and platelet count, and everything else was fine, but the immunophenotyping of the peripheral blood leukocytes showed that she was positive for CD103 but negative for CD25 and CD123.
That isn't the barcode for hairy cell leukemia. It's a different barcode. Also, the bone marrow infiltrate didn't express the markers we would expect for classical hairy cell leukemia and notably she did not have the BRAF mutation. So, we diagnosed hairy cell leukemia variant.
So, the characteristic features of HCL variant are this massive splenomegaly, which we don't often see in classical hairy cell leukemia, and the leukocytosis, which we rarely see in classical. This patient was treated with Cladribine plus rituximab, which would be our standard for the variant, and her blood normalized and her spleen disappeared. Eight years later, she still doesn't have a spleen and still has a normal blood count. There are some patients out there with the variant who do very well.
HCL variant is rare and typically it's resistant to purine analogs. But when you combine the purine analogs with a monoclonal antibody, the patients do much better.
Standard HCL Treatment
Presenter: Dr. Dima El-Sharkawi, The Royal Marsden Hospital
TRANSCRIPT
I'm going to talk about treatment. I'm not going to talk about all the clinical trials that have been published in hairy cell leukemia. I do want to highlight some of the key treatments and talk to you about the graphs and how you interpret them. So, if you are interested in reading papers, you can start to understand some of the terminology, words, and diagrams.
Why do we treat hairy cell leukemia?
The ideal reason to treat HCL is to cure you. We would, in an ideal world, be able to give you a treatment that would get rid of it and the disease would never come back. But we know that whilst people can have very deep remissions or very long remissions, the current therapies are not curative.
So given that we can't cure you from the hairy cell leukemia, the other reasons that we would want to treat is for survival. We want you to live for as long as possible to avoid death from the hairy cell leukemia itself. We don't want you to die from the hairy cell leukemia or importantly the complications of the disease, but also the treatment we give. We don't want to give treatments that are going to themselves cause complications that can be life-threatening.
And it's not just about the length of life. We want you to have good quality life as well. We want you to not have symptoms from the disease so you can have a good active life, that HCL isn't dictating your life, but also that the treatment is not causing side effects. So, these are the ideals.
So, when you see clinical trials, you'll see something called overall survival and that means how long someone lives. At what point do we measure the overall survival from? And depending on where they put their time point, it's either from the point of diagnosis or, usually in clinical trials, it's from the point when you start treatment. So that's point zero if you like. And overall survival is how long someone lives for. You might hear about words that are median overall survival, and that basically means how long do 50% of that population that are being studied live for. So if for example, you saw that there was a study with 20 people in it and the median overall survival was 20 years, that means that 10 people at that 20 year time point were still alive.
What do we use to treat hairy cell leukemia?
When treatments are tested in hairy cell leukemia, what often we call endpoints are being measured in the clinical trials. Because with something like hairy cell leukemia where people luckily do live for many years after treatment, no one wants to be running a trial from 20 years ago and wait 20 years to publish. They want to publish their results from their trials quickly. So rather than waiting those 20, 30 years to see what the overall survival is, we're trying to look for quicker time points to assess how effective the therapies are.
Often the depth of response is given as the main endpoint of the trial. When I say depth of response, I mean how much of the disease has gone. There are different ways that we can assess that. So we can look at what we call hematological response. A lot of you if you've had treatment, will have had treatment because you had low blood counts. So we can see, did the blood counts correct or not? And that can be called hematological response. So has your hemoglobin gone from low to a normal range? Similarly, your platelets and your white cells. If you've got an enlarged spleen, has that returned to the normal size? And then again, what's complete response? What's partial response? That's looking to see what percentage of hairy cells that were seen in the bone marrow, how many of them have disappeared. And if you can't see them anymore, that's a complete response. If you've had over a 50% reduction, that's a partial response.
Now that our techniques for detecting hairy cells are much better than they used to be, there are these very sensitive techniques that we can use, and they're sometimes referred to as MRD or minimal residual disease. And these are very powerful techniques that can detect up to one in 10,000 cells. So in every 10,000 normal blood cells it will pick up one hairy cell. So, for example, someone could have a complete response by our older ways of looking for hairy cell. But by these very specialized techniques, we can pick up very low levels of hairy cells. So, we might say someone's in complete remission, but they are MRD positive as in, we can pick it up at that very low level, or that they're MRD negative because we can't pick it up even by those very sensitive techniques.
These endpoints are very helpful. They give us an idea and an indication of how good a drug is at treating the hairy cell leukemia, but they may or may not correlate with any of your goals. So, for example, some treatments can cause a very deep response, but just because we can get rid of a lot of the hairy cells doesn't necessarily always mean that it's going to last for a very long time. For some drugs we can correlate the depth of response with the length of response, but it's not always the case.
It's great having a drug that can reduce the hairy cell leukemia, get rid of it, and cause a complete remission, but if the drugs themselves are causing lots of side effects and toxicities then it may not be the ideal drug to push forward. So, when we’re looking at clinical trials, we're not just looking at how effective it is for the hairy cell leukemia, we're also looking at the side effects and toxicity of the drugs.
Even when we get these trials that show effective therapies and advances in the field, it doesn't mean that they're automatically available, particularly in the UK where all drugs go through different regulatory authorities. First, they have to be licensed and approved in hairy cell leukemia or for other diseases, and then we can use them in hairy cell leukemia. Then another body has to approve the funding of the drug.
In rare diseases like HCL, this is where we can run into problems in accessing the drugs. That's when we often need the patients to put their support forward about how important it is to have access to these drugs.
Let’s talk about current treatment options.
First, active surveillance. It can be a useful treatment strategy, or I should say useful rather-than-treatment strategy. In some patients we may pick up the hairy cell leukemia incidentally. And if we know the survival is long, you're not getting symptoms from the disease, and the drugs aren't going to cure you (but we can keep them for when your disease is causing problems), then it may well be that no therapy is the best thing.
But when we want to give therapy, the therapies that we give through your body (tablets), your veins, or injections under the skin, those therapies are either targeting the surface of the hairy cells or they're targeting enzymes which are in the middle of the cells.
So, they may be targeting one of those enzymes that are overactive. In the middle of the cell is what we call the nucleus, and that's where your DNA is, that's where all the genes are. That's what eventually causes the cell to split and divide and grow into more cells. The therapies could target that middle, the DNA, as well. So, the treatments can target any one of those parts.
We've got chemotherapy, which I always think of as a blunt instrument because it's targeting the splitting and the dividing of cells and all the cells that are growing. The chemotherapy will affect the hairy cell (the leukemia cells), but it'll also affect other cells in your body that are potentially growing as well. But we know that the chemotherapy that we've got for hairy cell can be very effective. Generally, the ones that we give are cladribine and pentostatin. They're affecting the DNA growth and splitting and the cells growing.
The antibody therapy that we've got is sometimes called monoclonal antibodies; they're targeting the proteins that are on the surface of the cell, like the CD20. We've got antibodies that can bind onto these different proteins and cause the killing of the cell that way. These are antibody therapies; you might have heard of rituximab or obinutuzumab that are targeting CD20. There's also a drug called moxetumomab which targets a protein called CD22, but the antibody is attached to a toxin and that causes the death of the cell. So, it's a more targeted way of treating the hairy cell leukemia.
Then we've got the targeted therapies. Most patients with classic hairy cell leukemia will have a mutation that causes one of those internal enzymes to be overactive. And we can give tablets that will target that specific enzyme, block its pathway and block the signal to the middle of the nucleus that keeps telling the cell to divide and to grow. So, the drug can kill it that way.
Having a spleen removed may be appropriate if the systemic therapies either can't be used or have been used and are no longer working. We may want to take out the spleen where patients have a significant burden of disease, but that is rarely done now with all the other therapies.
These are what we call survival curves. Survival curves, it's when people go onto a clinical trial. Obviously not everyone goes onto the trial on the same day. Some people will have started it last year, some people will be starting it next year. So, we have to group everyone together.
When everyone starts the clinical trial, they're at year zero. So, we go across the x-axis will always have the time on trial. Now in hairy cell leukemia, we're normally looking at years. But look at the x-axis because it might be weeks, it might be months. So different trials will report for different lengths of time. Then on the Y-axis, so the one running up and down, everyone starts at the top, that's the hundred percent. And then you need to look at is it progression-free survival, is it relapse-free survival, or is it overall survival? If it's overall survival, did someone die or not? And if they die, then the bar goes down a bit. If it's progression-free survival, then the event is either they've died or the disease has come back and that would be considered an event and then that goes down a step. So the further it goes down, the more events have happened.
Relapse-free survival. So, these are people that have all had either cladribine or pentostatin, and each time a patient's disease has come back or they haven't responded, then the bar goes down. So, we want these bars to be as high as possible because that means none of the events have happened. But you can see here that at 10 years from treatment, with either pentostatin or cladribine, about 50% of the people who've had the treatment, so that's 188 in the pentostatin arm or 54 in the cladribine arm, have still got to that 10-year point and are relapse free, whereas 50% of patients will have their disease come back.
It's always worth remembering that these give us guides as to how good the drugs are as an average on a population. But there will be many patients who are at the 20-year mark who are still relapse free. So, if we talk about a median relapse of about 10 or 16 years, then that means 50% will be relapse free. But you will see from that bar coming down, there will be a handful of people who relapse early. We can never say for the individual how long you will have from a particular drug before the disease comes back. We can only talk in averages to give you ballpark figures. Some people will do better, some people will do worse.
But we can see that with these treatments, the depth of response does correlate with the duration of response. For cladribine and pentostatin, if you achieve a complete response, so when we look at the bone marrow six months after treatment and we can't pick up any hairy cells there, then you are likely to have a longer time until the disease comes back again than if you only get a partial response, and then the disease is likely to grow again slightly quicker. But even in those patients that have got a partial response, you'll see that even at 15 years out, for just under 20% of them, the disease still hasn't come back to an extent that they need therapy again. So even with a partial response, there are a proportion of people who will get prolonged survival. So, there are a lot of survival curves when clinical trials are reported.
Depth of response. The majority of people will get a complete response the first time they have cladribine or pentostatin. The second time and the third time, we will still get a high proportion of people achieving a complete response, which is quite unusual. We don't see this with other blood cancers where we can give the same treatment and it can still be very effective. We can see that the proportion of people who achieve a complete response does tend to go down the more times that you are treated, but people will still get good responses. And if you get a deep response the second time and the third time, then as we've shown already on the relapse free survival curve, you are going to get another period of time where the response is going to be durable.
Median time to relapse. The time it takes for 50% of the patients to relapse is about 16 years in the first line setting, 11 years in the second line setting, and six and a half years in the third line setting. These drugs are quite old and so therefore quite cheap as well. And when we think about the UK and how they fund drugs, they will also always compare new drugs to what our current standard is. Some of the newer drugs and trials that you see, even if the trial is in the frontline setting, it would be hard pressed to beat such good remission rates. So, at least in the NHS, we might never get these newer drugs in the frontline setting. With the results that we get now, it's not necessarily that new is always better.
As I mentioned, rituximab is an antibody that targets the surface of the hairy cells. I've picked one trial that was published recently that looked at giving rituximab in patients with hairy cell leukemia who have either relapsed or refractory disease. What that means is the disease has gone away and now it's come back, and it needs therapy again. If it's refractory, it means it hadn't responded to the previous treatment.
In this Italian study, 33 patients with hairy cell leukemia had rituximab for their disease that was either relapse or refractory. So they had previously had therapy and in fact the majority of patients had already had two other lines of therapy before so this was their third line of therapy. The overall response rate, and usually overall response rate counts all the complete responses and the partial responses, was 71%. So approximately seven out of 10 patients achieved either a partial or a complete response with rituximab on its own. The median progression-free survival, the length of time until the disease started to get worse again, was about two years for this as a single agent.
We've already mentioned moxetumomab, which was the first licensed drug specifically for hairy cell that was available in the US although we were able to access it on clinical trial whilst the trials were running. This targets a protein that's on the surface of the cells called CD22, and it's got a toxin attached that helps kill the cells. The endpoint for this specific trial was how many people had a durable CR, so rather than looking at how many people got a complete remission at six months after their treatment, they were trying to make it more clinically meaningful by talking about durable CR's, so complete remissions that lasted at least 180 days, and a third of patients had this durable CR. Unfortunately, even in the US now, this drug is no longer available.
Another newer class of drugs are the BRAF inhibitors. We’ve known for over 10 years now that the majority of patients with hairy cell leukemia will have an active mutation in BRAF. That’s not a mutation you're born with. It's one that develops in the hairy cells themselves. We've got drugs that can target this enzyme and cause the death of the cell that are used in other cancers but have also been investigated in hairy cell leukemia.
There have been several trials looking at different BRAF inhibitors. The two most common ones that have been trialed in hairy cell leukemia, one called Dabrafenib, and another one is called Vemurafenib. They've either been used on their own or in combination with rituximab. There are going to be new trials coming out in combination with other antibody therapies. They've been used in the relapsed refractory setting, so patients who've already had therapy, but there are trials that are coming up in the US and Italy where they're going to be tested in the frontline setting, for patients that have never had therapy for their hairy cell leukemia.
This is an example of one of the trials that has been published where patients were given Vemurafenib as a single agent for between three to six months depending on how well they responded. And the overall response rate with the initial treatment with Vemurafenib was 86%. So about 86% of patients, and there were 36 patients on this trial, achieved a response to the Vemurafenib. But as you can see with this short duration of therapies, that progression-free survival curve does go down. So, these can provide responses, but they're not necessarily going to be very long-lasting responses in this setting. But what's reassuring is that even when the disease comes back, we can treat again with the same drug and again get good responses. Even with re-treatment, the overall response rate was about the same.
There have been a couple of trials using targeted drugs that target different enzymes. One that's had a couple of publications is a class of drug called BTK inhibitors.
We use BTK inhibitors in other B lymphoid cancers, such as CLL and other blood cancers that affect the B lymphocytes. And there are a number of BTK inhibitors on the market. But the two that have been tested and published specifically in hairy cell leukemia: one called Ibrutinib and there's another one called zanubrutinib.
One of our American colleagues published their experience with Ibrutinib in patients with hairy cell leukemia whose disease had been treated before. There were 37 patients on the trial. The red line is the progression-free survival and the blue line is the overall survival. A lot of patients, again, are remaining in remission with Ibrutinib At the bottom, the x-axis is in months. At that five-year time point, about 70% of patients remain on the drug. This is a drug that's given continuously, so they stay on this drug for as long as they're responding. About 70% of patients are still taking the drug, are still in remission and their disease is still in control. The blue line is the overall survival, so how many of the patients are still alive. When you look at overall survival curves, that doesn't reflect necessarily deaths specifically due to the hairy cell leukemia; the deaths may be because of other medical problems as well.
A swimmer's plot is often used to describe small trials where there are very few numbers of patients and where you look at each individual patient and their response to a drug. This trial is using Zanubrutinib, another drug that targets the BTK enzyme. There were about 11 patients on this trial, and they all had slightly different doses. The length of the bar is how long these patients are remaining on the drug. Studies are often published whilst patients are still taking the drug, so there will be further publications later if people have been on it for longer. We can see that patients are going on the drug; they are responding, and they are managing to stay on the drug, so getting durable responses.
It's great having all these drugs, and we've already touched on the fact that access to drugs will be something that we need to focus on here in the UK, but they don't necessarily tell us the best way to use these drugs. So, for example, what the best doses of drugs are, what the best combinations are. So, we have used rituximab with purine analogs, we can use rituximab with some of the targeted inhibitors as well. There will be trials going forward, where we'll see different combinations of these drugs.
For some of these targeted inhibitors, sometimes we use them for as long as people are responding and they're not getting intolerable side effects. But for others we have run studies where they're used for short periods of time, so we don't know for how long we should be using these drugs for. And we know that some of these drugs can cause some side effects as well. So, the ideal would be a drug that we could give for a short period of time, that you're not going to get side effects for many years, but that is going to lead to a durable length of remission.
Combination therapies
I wanted to touch on publications that have used different combinations. So, this is one where rather than just using cladribine or pentostatin, we're using a combination of cladribine plus rituximab. The combination often can lead to a deeper response. Again, this is a swimmer's plot. So each line represents a different patient. A blue bar means that we can't pick up any hairy cell in their blood or their bone marrow. The green bar means that the disease has gone in their blood, but we can still pick it up in their bone marrow and blood. We can pick it up in both. The red bar means that we can pick it up in both the blood and the bone marrow. And you'll see that the combination of the rituximab and the purine analog, so whether it be cladribine or pentostatin, leads to very deep remission. The majority of patients having the two get the negative or complete remission, that means we can't pick up the hairy cell at all by quite sensitive tests.
Another combination is a combination of different targeted inhibitors. I've already mentioned dabrafenib, which is a BRAF inhibitor. Trametinib is another targeted inhibitor that targets another enzyme on the same pathway. And the combination of the two has led to good progression-free survival curves in a small series of patients.
What are the new therapies on the horizon?
There are newer ways to target old targets. I've already mentioned a couple of drugs that can target this enzyme called BTK, but there are newer drugs coming up that are being used in other B-cell malignancies that can target BTK in a different way. Even when your hairy cells stop responding to Ibrutinib or Zanubrutinib, we may be able to access these drugs that may have an effect. There may be new targets as well, new enzymes that can also be targeted that will be effective for hairy cell leukemia.
We know some of these strategies are effective in other B lymphoid malignancies, and there are increasing reports that they can be used in hairy cell leukemia. And you might hear about newer therapies that are being used in other malignancies.
Where there's a lot of excitement is using your own T cells to fight the cancer cells. There are two classes of drugs. There's one called bispecifics. These are antibody therapies that target the B lymphoid cells. So, like the rituximab, bispecifics target something on the B cells and something on the T cells, and they bring your T cells to the B cells and say, "Here, kill them." Now obviously, that's a very simplistic way of thinking about them. But they've been shown to be effective in other lymphoid malignancies, and some of the trials are including patients with hairy cell leukemia. It’s often patients that have exhausted the standard lines of therapies and their disease is no longer responding to the standard therapies, who we would put forward for these clinical trials because we don't know how effective they're going to be in hairy cell leukemia.
The other way of using T-cells that you might hear about is something called CAR T therapy. This is where we take T cells outside your body. We collect them from your bloodstream and manipulate them in the lab to express a receptor that will home in on the B lymphoid cell. So we increase the number of cells in the lab, and then they get reinfused back. We're making your own immune cells stronger to fight the hairy cells. This has been used successfully in other lymphoid malignancies and there are some trials with CAR T therapy that are including patients with hairy cell leukemia.
Treat the person, not the disease
I wanted to end by saying that we need to treat the person with the hairy cell leukemia rather than just focus on the hairy cell and the disease itself. We want you to have active, fulfilling lives. The important thing is working with you as a partnership, getting for you the best treatment for the disease, helping you think about other things that the hairy cell can indirectly affect as well, and ensuring that we give support where we can, through the amazing work from the charities, or in terms of coping with some of the anxieties that are normal. So, I think you need to find a doctor and a team of people around you that treat you as the person rather than just the disease.
This transcript has been edited for clarity.