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Webinar: Understanding Hairy Cell Leukemia

December 1, 2020

Hosted by the Hairy Cell Leukemia Foundation with expert speaker Dr. Farhad Ravandi from the University of Texas-M.D. Anderson Cancer Center. Moderated by Anna Lambertson, HCLF Executive Director.

Webinar Transcript

Presentation by Dr. Farhad Ravandi

Dr. Farhad Ravandi:

Hairy cell leukemia is what we call an indolent, and that means generally very slow growing, lymphoid leukemia. Emphasis on lymphoid because it arises from within the lymphoid part of the compartment of bone marrow. So there are myeloid cells and lymphoid cells and many of you may have heard of acute myeloid leukemia or acute lymphoid leukemia. Hairy cell leukemia is an indolent, chronic disease and because of that, generally in most patients it's not an immediate medical emergency. People hear about leukemia and have the worst images in their head of something catastrophic that has happened or about to happen and they're going to have very severe chemotherapy and they think about bone marrow transplant.

In the case of hairy cell leukemia, and there are other lymphoid indolent leukemias and other myeloid indolent leukemias, it is not an immediate emergency. In the past, we did sometimes see patients who would come in with very low blood counts and a huge, massive enlargement of their spleen. We don't see that very often these days. When I was in medical school in England, we used to have all these patients with massive spleens brought to us with diagnosis of hairy cell, but in my practice in the last couple of decades, I hardly ever see any patients with splenomegaly. That's because in the U.S., most of us have routine health checks and somebody sees there's something a bit wrong in your blood counts and this leads to eventual diagnosis of hairy cell leukemia.

Dr. Farhad Ravandi:

But because it does cause lowering of the blood counts if it's left untreated, it is a disease that needs therapy. There are guidelines published by hairy cell experts regarding the time that we need to start therapy. A lot of it is dependent on the blood counts, so if there's a significant lowering of the blood counts - platelets below 100, hemoglobin below 11 or 10 and the neutrophil count below one, that is an indication to start treatment.

Also, severe symptoms. Some patients do develop severe fatigue, weight loss, what we call constitutional symptoms. Fevers and night sweats. Even if their blood counts are reasonable, we would still consider starting therapy. But it's important to note that some of these symptoms could be caused by other things. So severe fatigue, it's not impossible for a patient to have early hairy cell leukemia, but also undiagnosed hypothyroidism, low thyroid. So you can't just assume everything is hairy cell. If you come to my clinic and your blood counts are essentially within the normal range and you've been diagnosed with hairy cell, I don't say, "Well, we have to drop everything and start you on chemotherapy." We need to make sure there are not other things. 

Sleeping is important and there are things like obstructive sleep apnea that could be a cause of the fatigue. But again, we do like to treat hairy cell leukemia because as I mentioned, if left untreated eventually you develop very low blood counts and in a really extreme case you can develop massive splenomegaly. The spleen is the organ on the left side of your abdomen that becomes huge if you don't treat this disease. 

So the treatment of this disease has gone through a tremendous evolution over the last four or five decades. Many years ago, the only treatment available was splenectomy and that would actually improve the blood counts, but it would not cure the disease and so everybody would definitely relapse. Then a drug called interferon came around and that was effective somewhat.

Then in the late '90s, cladribine and pentostatin came around, which are both highly effective in producing complete responses. Many various studies between 80 to even 100% responses have been reported with these drugs. And because of that, interest and research in hairy cell leukemia waned a little bit. People felt that we've got the cure and why do we need to worry about hairy cell anymore? I'm talking about the academic community.

Then a drug came around called rituximab in the late '90s, which was truly a revolutionary drug in hematological cancers, because it was an antibody. It was the first antibody that was effective and it was actually used in virtually all hematological cancers, including many lymphomas and many lymphoid leukemias. So people used it in hairy cell in the relapse setting and it was shown to have some activity. I would certainly not think of it as my first choice as a front line therapy, but then the decision was made to combine this with cladribine. So studies were done that gave cladribine followed by rituximab and they have been very effective in producing responses close to 100% or even 100% responses and in general these responses have been more durable than what we used to see with cladribine alone. Remember, as I mentioned, very high responses with cladribine, which is considered the standard of care.

Dr. Farhad Ravandi:

But if you follow up patients who have been treated with cladribine or pentostatin, the other drug, over years, 40 to 50% will eventually relapse. Now, the median age of diagnosis, that's the middle number of age for all patients, is in the mid-50s. So I think most of you would agree that if you're 45 and are diagnosed with hairy cell leukemia and somebody says, "Take this drug. It gives you an 80 to 100% response, but there is about 40% chance that over the next 10 to 15 years it will come back and then we'll deal with it." Many of you may say, "Well, that's fine," but some of you would say, "Well, is there any way we can just do it something that would get rid of hairy cell forever and not to worry about it?"

And there are studies that suggest that the responses with the combination of cladribine or pentostatin with rituximab are deeper and last longer. Unfortunately this has not been proven in a randomized trial and because of that, it's still not the standard of care. The standard of care in the U.S. remains single agent cladribine or single agent pentostatin.

Dr. Farhad Ravandi:

In all hematological cancers and in all leukemias, we have actually started delving into the biology of the disease, what creates the disease. The reason why we develop any cancers is because something goes abnormal in the genes and chromosomes of the cells in that tissue. In breast cancer it's breast tissue. In leukemia, it's bone marrow. Some of these cells become abnormal and you develop various forms of leukemia.

What happened in about 2010, Italian investigators, Dr. Falini and colleagues, described the mutation that happens in the cells that creates this hairy cell leukemia. By the way, the reason why we call it hairy cell leukemia is because there are these projections or these hair-like projections from the hairy cell leukemia cells. So when this mutation happens, the cells develop these hairs and they essentially develop a hairy cell leukemia, which then takes over the bone marrow and causes the lowering of the blood counts.

It is important, because this mutation, which is called BRAF, has also been described in other cancers, most notably in a form of skin cancer called melanoma, which is actually widely prevalent. Hairy cell is a very rare disease up to about 1,000 cases in U.S. every year. I don't have the exact numbers for melanoma, but it is in tens of thousands. So it's a much more common disease. As we all know, it's because of sun exposure. And why it's important, because when you have a common disease, there is unfortunately for whatever reason, there is more interest to develop a drug against it.

So they did develop these drugs called Vemurafenib and then more recently dabrafenib and trametinib, which are very effective in blocking this mutation or making this mutation disappear, essentially. So the Italian investigators again studied this Vemurafenib, which was available for melanoma, but not for hairy cell. They studied it in patients with hairy cell and they found that it is very effective. Unfortunately it's not 100%. If you take it as a single agent, I would say it's not even as good as cladribine or pentostatin. But it is an oral agent and it does not cause lowering of the other blood counts. 

Cladribine and pentostatin are both chemotherapeutic agents and when you take it, at least for the first month, you actually get very significant lowering of your blood counts. If you start with a platelet count of 80, it will go down to less than 10. If you start with a neutrophil count of 1000, it will go down to 100. So it is what we call very myelosuppressive. That means lowers the blood counts, and immunosuppressive. It reduces your immune system, because it also lowers your lymphoid cells, which are an important component of your immune system.

So the reason why Vemurafenib is of interest is because it's not myelosuppressive and it's not, to a great degree, immunosuppressive. So the next step, which again has been done by the Italian group, is to combine Vemurafenib with rituximab and they are doing that. They have shown much, much higher responses, much better activity, but as I mentioned, rituximab is also, to some degree, immunosuppressive.

Dr. Farhad Ravandi:

Why am I talking about these things? Because there's obviously some interest in using these agents now that there is COVID-19 as opposed to cladribine alone or cladribine plus rituximab and clearly this is something that many of us are dealing with and discussing amongst ourselves and also with the patients. I have had several hairy cell patients over the last few months and I think many of them have opted to go with cladribine, because they felt that they are going to be essentially completely socially distant and they're not going to risk anything to expose them to COVID.

There is also another combination called dabrafenib plus trametinib and these are also oral agents and they also are effective. Again, against the BRAF mutation. But again, that's not FDA approved for hairy cell.

Dr. Farhad Ravandi:

Again, I think the importance of the whole situation now is the COVID-19 and the risks it causes for all of us, but particularly for hairy cell patients as well as all other patients with leukemia. I continue to treat other leukemias. I have patients who are getting very intensive chemotherapy. You have to remember that patients with leukemia have known forever that they are at risk of infection, so there are other bad viruses out there that if you're undergoing treatment for leukemia, we tell you to just be extremely careful. Not to go to work. If your child has a rash, send your child to your sister's house or something like that. But we have been dealing with infections for leukemia forever.

With COVID, this is also an important issue. As I said, I have treated patients with cladribine and rituximab over the last five or six months, but they have been completely socially distant. The first month particularly, they have avoided anyone, but then if they're getting the rituximab, which is another two months of therapy, they continue to remain socially distant and I will tell you, hairy cell leukemia itself, even before you start therapy, is an immunosuppressive state. As in if you have the disease, your immune system is down, and it will stay down even if you achieve a complete remission. Your immune system will be down for at least six months to a year after therapy. 

So if you get the treatment for hairy cell leukemia, even if you get the non-myelosuppressive agents that I mentioned, your immune system is going to be down for six months to a year and I certainly would highly recommend for you to be socially distant.

Question & Answer Session

 Anna Lambertson:

Everyone who's participating in the webinar today has been watching the news about all the vaccines that are being developed and that may be available, perhaps even in the United States, as early as December. I'm sure your patients are asking you this question. Can you, at this stage, recommend one of those vaccines for someone who has hairy cell leukemia? What do you know? What don't you know? What are you recommending for your patients?

Dr. Farhad Ravandi:

We do recommend all of our patients to have a flu vaccine, but we always recommend you should receive inactive vaccines and no live vaccines. There are some live vaccines. I think one of the shingles vaccines is a live attenuated virus. In immunosuppressed patients, you should never receive any form of live vaccine. 

When you vaccinate someone, you rely on their immune system because that's the whole point of vaccine, to activate the immune system. Of course if you have a disease or you've been receiving therapy that has made you immunosuppressed, your response to the vaccine is going to be attenuated. We still recommend patients receiving vaccines, even despite the fact that they probably are going to have a suboptimal response to the vaccine in terms of the protection, immune protection.

In terms of COVID-19 vaccine, I would definitely advise you to make sure all the available vaccines that are going to be coming are not live vaccines, that they're not active virus or attenuated virus. I would recommend you receiving them if you're offered them, but again, just always make sure that you're not receiving any form of live vaccine.

In terms of flu vaccine, I highly recommend you all get a flu vaccine if you haven't yet. I think the nasal form is a live attenuated vaccine. I would not get that. You would always want to get a dead, inactive vaccine in any form.

Anna Lambertson:

At this stage, there isn't one vaccine that you would necessarily recommend for any of your patients. Your primary guidance is to make sure that whatever vaccine they take, be it for COVID, for flu or shingles, that it's a dead vaccine. It's a non-live vaccine?

Dr. Farhad Ravandi:

Unfortunately, I don't have the vaccine expertise to recommend one COVID-19 vaccine over the other. Once they become available and they offer it to us, the healthcare workers, we are probably going to get it, one of the first groups of people who will get it. We can opt out of it, but I certainly will not opt out. They might give me the Pfizer vaccine or Moderna and I'm not going to say, "Well, I don't want to take the Moderna. I want to take the Pfizer." They won't give you a choice, as far as I know.

Anna Lambertson:

You said that as far as you know, hairy cell leukemia is in the genes. I think you were speaking specifically about the BRAF mutation. We do receive questions from patients who want to know can they or will they pass hairy cell leukemia on to their children? Is it hereditary? So when you say it's in the genes, are you saying it's hereditary or are you speaking about the BRAF? If you could clarify that for everyone listening.

Dr. Farhad Ravandi:

When I say it's in the genes, any cancer develops from an event in the genes of presumably one cell initially. There are some familial cancers. There are some unfortunate families who have a hereditary predisposition to cancer. Some of them have been known for a long time and one of them is called Li-Fraumeni syndrome that many members of the family have various forms of cancer because of a defective gene that is passed on among the family members. But hairy cell leukemia is not known to be a hereditary cancer.

Now, these hereditary cancers actually have been helpful in us understanding that cancer is a genetic disease. Doesn't mean that every individual's leukemia is a hereditary cancer, it just means that every leukemia or every cancer develops because some event causes malfunction of a gene in a cell in that specific patient, which has nothing to do with hereditary.

The examples of that are prior chemotherapy for other cancers that cause unfortunately defects within the bone marrow stem cells and cause leukemia. Or radiation therapy, or the worst example is the atomic bomb survivors in Japan. They all had developed cancers in Hiroshima and Nagasaki because the radiation caused defects in the genes of their body tissues.

There are some hereditary cancers, some predispositions to cancer and leukemia and we are understanding more and more about those, but hairy cell leukemia is not known to be a hereditary cancer and is not passed on between generations. As far as I know, there haven't been any familial cases reported. There are some other leukemias that people report familial clusters, but not in hairy cell. So it's not if you have it, it's not something that you're going to pass on to your children.

Anna Lambertson:

We know that most patients with classic hairy cell leukemia have the BRAF mutation and you talked about some of the BRAF inhibitors. Vemurafenib, dabrafenib and others. Can you tell us a little bit more about patients who have the variant form of hairy cell leukemia? What's their prognosis compared to patients with classic? Do they fare better? What treatment works better for them? 

Dr. Farhad Ravandi:

So as you remember, I said initial diagnosis and recognition of this disease, hairy cell leukemia, is because of the hairs. The projections on the surface of these cells. This is not the only hematological cancer that produces hairs. So there is another condition called SLVL or splenic lymphoma villous lymphocytes or more recently called marginal lymphoma, marginal zone lymphoma, that the cells have projections. The way we distinguish these diseases from each other. The pathologist first looks at the shape of the cells, the history, but also they look at some markers on the surface of these cells. The case of hairy cell, these markers are very established. Like five or six of them that easily tell the pathologist it is hairy cell leukemia. Variant hairy cell has the projections, so when the pathologist looks at the cells, it looks like hairy cell.

But the reason why it's called variant is because the markers are not the same as hairy cell. Why does this matter is several things. One, patients with variant hairy cell tend to be a bit older. So remember, I said the median age in hairy cell is about mid-50s. It is late-60s in variant hairy cell. They're a bit older. Second, they don't respond as well to cladribine or pentostatin. So remember I said the response rate to those in classical hairy cell is 80 to 100%. In variant hairy cell, it's only about 50%. And their responses don't last as long in variant hairy cell.

So it's a more difficult disease to treat and to actually produce longer lasting responses. That's one of the diseases the addition of rituximab, the antibody, is definitely useful. So I don't think anybody would argue that if you have a patient with variant hairy cell, you should do a combination strategy. So it's important to know this. It's important for the pathologist.

Now, the other disease that I mentioned, SLVL, the pathologist and everybody would look at the markers and once you diagnose that, that's treated completely differently. Just with single agent rituximab, which is highly effective. So we do need to know these variants, this is why you need the experts. That's why you need a diagnosis in an expert facility, because they are treated differently as well and they have different prognosis.

One other thing, variant hairy cell leukemia, as mentioned, does not express the BRAF mutation. That's another thing that distinguishes it from the classical hairy cell.

Anna Lambertson:

We had one patient who reached out to ask about BRAF wild type. Have you treated patients with the BRAF wild type? If so, how do those patients seem to fare over time compared to patients with the classic hairy cell leukemia?

Dr. Farhad Ravandi:

What wild type means is there's no mutation. So if you have a patient with BRAF wild type disease, it means they don't have the mutation. Now, one of the things about hairy cell is when you do a bone marrow exam in a patient with hairy cell, this is in all the classical medical textbooks, they commonly have what we call a dry tap. That means that the person who is doing the bone marrow on your back is pulling and is not getting any of the liquid in the bone marrow. They do a biopsy and that helps with the diagnosis, but if you want to test for the BRAF in the bone marrow, you need that liquid. So sometimes, and many patients with hairy cell don't have a high peripheral blood count, as in the white counts are usually very low and so you can't pick it up in the peripheral blood.

There are situations, if you do test, you send a specimen and it is inadequate, the pathology lab, wherever you sent it, comes back and says, "BRAF mutation not detected," or "BRAF wild type." Wild type essentially means mutation not detected.

Now, we have had that situation and the patient comes to see us and then we do a bone marrow and we do get the sample and it comes up as positive, or you can actually do a staining of the bone marrow biopsy that some places do and shows the BRAF mutation in a different way. Essentially when you do not have a BRAF mutation, it's unlikely that you have the classical hairy cell leukemia. You're likely to have a variant hairy cell or one of the rare subtypes of classical called VH434, which I'm not going to go into detail, because it's too complicated. But classical hairy cell, in over 99% of cases, should have the BRAF mutation. If it is not there, it could be just because your testing was inadequate, not because of any fault, but it's just you have the dry tap.

Anna Lambertson:

So if someone seems to have what might be considered the classic type, not the variant type, even if they are BRAF negative or the BRAF mutation was unable to be determined, that person may very well fare as well as somebody who has been determined certainly, 100%, to be classic? 

Dr. Farhad Ravandi:

Yeah. If the pathologist looks at all the markers, everything looks perfectly hairy cell and you had a dry tap and they couldn't get the BRAF mutation, it's possible that it just hasn't been tested adequately.

You should do as well as a classical, but again, there are ways of testing for this, even if your specimen is inadequate.

Anna Lambertson:

Earlier on in your remarks, you talked about the watch and wait. You talked about how unlike other malignancies or other cancers, you may be able to monitor a patient with hairy cell leukemia and you may not have to treat immediately unless they're showing certain symptoms or their blood counts have reached certain levels. Can you talk a little bit more about how long can a patient be on watch and wait? Have you seen patients on watch and wait for years? Is that normal? 

Dr. Farhad Ravandi:

I have had patients who I didn't treat for a couple of years. If the blood counts are adequate and actually it's not just the adequate blood counts. You follow the patient and if three months, six months, nine months, 12 months later the counts are very much the same and the patient is doing well and no problems, no constitutional symptoms, there is no need to start the therapy. Sometimes I actually have deferred therapy because the patient had reasonable counts. Of course, when I do that, I continue to monitor the patient and I ask them to continue to monitor the blood counts.

But essentially the whole thing means that it is not unreasonable to monitor the patient, as long as they have reasonable blood counts and they don't have significant constitutional symptoms.

Anna Lambertson:

There are a number of patients who are on the webinar today who have been recently diagnosed. They are struggling with should they go ahead and be treated or should they wait until there's a vaccine for COVID? This, as you can imagine, is a really grave concern for a lot of patients. You talked a little bit about the consensus guidelines and those thresholds. If a patient's platelets, for example, are 75,000 and white blood cell counts are at 2.7, they're not having any symptoms. How would you navigate that situation with that patient?

Dr. Farhad Ravandi:

First, the disease diagnosis itself is immunosuppressive. So if you don't get started on treatment, don't assume that you have no risk of COVID. I have a risk of COVID. Anybody has a risk of COVID. If you have just diagnosis of hairy cell, it means that your immune cells are somewhat malfunctional. Of course if you have a platelet count of 75,000, that's a reasonable platelet count, but still, if you are unfortunately in a car accident, you are going to bleed a lot more than anybody else who was in the car.

So 75,000, it's a lot better than 10,000. If you have severe low counts like platelets in the 20s and 30s and if you definitely have a neutrophil count less than 0.5 and your hemoglobin is eight, there's no point in not proceeding, even with COVID. Because the only way those things are going to get better is by getting rid of the leukemia.

And fortunately, with hairy cell, we have very effective therapies. Now, if you had a disease that only produced 20% response, you might say, "Well, what am I going to gain from this?" But if you have  very low counts and you were diagnosed today, there is no point saying, "Well, I'm going to hang around until the COVID vaccine comes," because that month that you're hanging around, by the end of the month you could actually be back in normal counts if you start the treatment.

It’s not just the counts. It's also the decline. If every month you check and the counts are getting down by 10 or 20, that means that things are getting worse, whereas if they're always stable, then in the low 100s, high 90s, then it is reasonable to say, "Okay, I'm just going to wait for two or three more months. See if I can get the COVID vaccine and then start treatment."

It really is a decision that has to be made by your doctor and yourself in terms of, what is the risk and benefits of either decision.

Anna Lambertson:

Many patients and their families are very concerned about COVID. So many doctors are doing telemedicine. Others aren't able to do telemedicine for new patients, but many patients are unwilling to travel. They worry about risking exposure to COVID by traveling to go see a doctor. What are you recommending to your patients? Is it worth the risk to travel out of state to go see a hairy cell leukemia expert in person and be seen and get a second or third opinion? What is your recommendation for patients who are really kind of struggling with whether or not they want to further risk exposure?

Dr. Farhad Ravandi:

I think one of the tragedies of COVID is that people are scared of going to hospitals and for good reasons, but I think the risk of dying from a heart condition or cancer or something if left untreated is worse than COVID. So you should not just completely blank out doctors just because there's COVID out there. You can't just ignore health just because there is COVID. You have to be very careful. You have to wear a mask. Anything that makes you a lot more safe and go. Now, with regards to traveling out of state, it all depends on how confident are you with your doctor?

If you are in a major academic center, there may not be many hairy cell experts, but there are leukemia experts there and if they have any questions, they can always communicate. But if you are in a small community hospital where the doctor has never seen a hairy cell and doesn't even know what a hairy cell is, I think it's better for you to go to an expert, at least for initial opinion regarding what I just said, whether you need to start therapy or not, to get expert advice.

So you should always get good advice, but you should not risk too much and you should not avoid doctors in general. We all have to look at the risk benefits and when it comes to health, you should not ignore your health problems because of COVID.

Anna Lambertson:

Even if a patient is in remission, so they've already completed treatment, will they remain immunosuppressed or immunocompromised for the duration of their life? Even if they're in remission for hairy cell leukemia? How long does that generally last?

Dr. Farhad Ravandi:

No, as I mentioned earlier, it's only about six months to a year. That's with cladribine and pentostatin, because those drugs really attack all lymphoid cells, cancerous or leukemic or non-leukemic. Unfortunately, many of the cancer therapy drugs are not highly discriminative against just the cancer cells. They attack normal cells as well. So cladribine and pentostatin attack normal lymphoid cells as well as leukemic lymphoid cells.

So with those drugs, your immune system stays down for about a year until your normal lymphoid cells fully recover and that actually predisposes you mainly to viruses, because you need those lymphoid cells against viruses. In the first month of cladribine therapy, not only your lymphoid cells go down, but also your myeloid cells. So that's when you're neutropenic. Your neutrophils are low. Neutrophils are the soldiers that fight any infection and that's the month that you're extreme high risk of all infections. Bacterial, viral, fungal, et cetera. So the first month after cladribine, you are going to be very myelosuppressed and immunosuppressed, but the immunosuppression is for six to 12 months.

Anna Lambertson:

We do have quite a few questions about moxetumomab pasudotox or Lumoxiti. Can you talk about your experience with moxe? Whether you have used it with patients, what the side effects are? We know that it's one of the newest drugs for hairy cell leukemia, it was approved by the FDA in 2018, and there's a lot of curiosity from patients about your experience in using it with patients.

Dr. Farhad Ravandi:

I haven't used it extensively. It is an active drug. It definitely needs expertise in terms of its administration, because there are a couple of side effects that can be serious and they need appropriate management. You do need to take, for example, a lot of fluid during the administration of moxetumomab. You need to keep drinking a lot of water and the two side effects, one is called hemolytic uremic syndrome, which can cause kidney problems, which are generally reversible as in even if you get it, it doesn't mean you get kidney failure for life. And the other one is called capillary leak syndrome and that's the reason why you have to take a lot of water.

It needs to be monitored, but it can be very effective. It's approved for second salvage, as in you have relapsed once and you get into remission again and you relapse a second time. So it is available commercially. The advantage over, let's say vemurafenib, is vemurafenib is not available commercially for hairy cell. These cancer pills are extremely expensive. So a course of vemurafenib could be in tens of thousands of dollars and if your insurance doesn't pay for it, I don't think many people are going to go and sell their car to get vemurafenib.

Moxetumomab is approved for second salvage, so your insurance cannot decline it.

Anna Lambertson:

There is a median age for hairy cell leukemia in the mid-50s, but there are some patients diagnosed much younger. Diagnosed in their 40s, 30s, we've even heard of patients being diagnosed in their 20s. What do you see over the long term in terms of treatment for some of those younger patients? What do you foresee coming on the horizon? You were mentioning vemurafenib is something that's being used, but doesn't have FDA approval. There's dabrafenib and trametinib and these others. Do you see any new therapies coming online for some of these younger patients who may experience a few relapses over the course of their life?

Dr. Farhad Ravandi:

I'm a bit biased here, because our regimen of cladribine plus rituximab, I think our longest CR duration is now about 17 years and this is in a patient who was a salvage patient. As in she had cladribine before and relapsed after a reasonable time. She relapsed after about eight or nine years and then we gave the cladribine plus rituximab and she has been in remission for 17 years.

This has been also somewhat confirmed by the NIH group; they did a randomized study of cladribine with immediate rituxan or cladribine followed by rituxan if there is MRD or minimal residual disease. And they showed that additional rituxan does produce deeper responses. So in a younger patient, I have no qualms about stressing the need of cladribine plus rituxan.

You mentioned vemurafenib plus rituxan. It seems to be a very effective strategy, but the question is, first there is not a lot of long term data on that yet and the other issue is the cost. How long are we going to take the vemurafenib and again, the issue with insurance. Cladribine, we already have 30 years of data. It's a completely known and it's extremely cheap drug.

So in a young patient, I have no qualms about recommending the combination therapy. There are other agents that we mentioned. Dabrafenib plus trametinib. So there are other agents that can be potentially effective that have been developed in other leukemias.

I would tell anyone is that there are so many options now in hairy cell, options that people haven't tried and are likely to be effective. Some of these markers that I mentioned are expressed on other leukemias. So for example, acute lymphoblastic leukemia. And drugs that are new drugs that are effective in acute lymphoblastic leukemia. If you have a patient that has failed four or five, six therapies, you can at least try one of these agents for other leukemias to put them back in remission. So there are many, many options.

Anna Lambertson:

For the cladribine rituximab combo, do you feel that these fairly long, durable remissions are because the rituximab is just doing a better job of clearing out that minimal residual disease? Is that why? And are there risks to rituximab combined with cladribine greater or less compared to cladribine alone?

Dr. Farhad Ravandi:

So your first question, rituximab targets the CD20, which is expressed on most lymphoid cells and that's why it's almost universally used in lymphomas and lymphoid leukemias. Now, hairy cells have the highest expression of CD20 amongst all hematological cancers. So that is why rituxan is pretty effective against hairy cell. I think the benefit is really from the combination. Now, our original study for various reasons we gave cladribine first, followed by rituximab later, but I think it's probably even more effective if you start them both at the same time, concomitantly, and that has been done by the NIH group.

The reason for that is in every cancer that we have ever treated, we combine two or three agents to essentially beat the cancer cells and avoid them developing resistance. So it's made sense combining rituximab with other agents in other leukemias. For example, in chronic lymphocytic leukemia or in follicular lymphoma or various large cell lymphoma. They are not additive. When you put them together, they attack the leukemia cells in an exponential way, as in it's not just one plus one equals two. It's one plus one equals 10 and that's why it's more effective.

Again, that has not been proven in a randomized trial in hairy cell and unfortunately there will never be a randomized trial in hairy cell, because it’s a very small population of patients. But in a young patient, that's why I would advocate. Not all of my colleagues would. Now, in terms of risks, yes, rituxan is also immunosuppressive and cladribine is immunosuppressive, so you are increasing the risk of immunosuppression.

If you use rituximab, you will see in the package insert there are risk of reactivation of viruses like hepatitis C or extremely rare cases of this uncommon condition called progressive multifocal leukoencephalopathy. It's extremely rare, but it's there. I would also tell you, rituximab is used extensively around U.S. and Europe and most countries in the world. It's widespread, its use. So any drug has these rare toxicities, but rituximab has been used extensively over the last three decades. So nobody is going to say this combination is absolutely safe, but there is enormous number of patients who have received those drugs.

Webinar participant, asking a question:

The question is, when you have the classic HCL, does it make you predisposed to secondary cancers? I was recently diagnosed with prostate cancer. My HCL was diagnosed four years ago. I've had skin cancer, pre-cancerous skin cells on my arm, so I'm wondering, does it predispose me to secondary cancers or increase the chances of other cancers?

Dr. Farhad Ravandi:

So this has been a very long debate for about three or four decades. I think it's reasonable to think that the immunosuppressed state does increase the risk of cancers. We have started to think about cancer in general as being this genetic defect that happens in one cell and normally your intact immune system finds these defects. I think we all probably have cancerous cells within our body at this moment, but your intact immune system will go and find those cancer cells and gets rid of them. So it is reasonable to consider that if you have any form of immunosuppression, your risk of cancer increases, and this has also been well described for example in HIV patients. There are various unusual cancers in patients who get organ transplant. There are post-transplant cancers.

There may be a somewhat slight, I would probably call it slightly increased risk of cancer, but the other issue is that hairy cell, as I said, a lot of patients are in their 50s and 60s and 70s, so once you get diagnosed with a leukemia, I think everybody becomes much more aware of their health and you go to the doctor a lot more often. You do your testing much more frequently. So you expose yourself to finding all these things that you probably would have ignored for a long time.

The cancers you mentioned, prostate cancer, unfortunately all of us males will eventually get cancer if we live long enough. But did you increase your general health awareness after the diagnosis of hairy cell? Probably you did. So I think it's a combination of both. There is probably some truth about increased risk, but I don't think anybody has ever been able to absolutely confirm that.

Anna Lambertson:

There are some questions about how long you wait between treatments. So let's say someone is treated with cladribine, then they relapse. Given the risk, the toxicity and perhaps risk for other cancers that may or may not be exacerbated by cladribine, how long would you wait before treating that patient again with a purine analog like cladribine?

Dr. Farhad Ravandi:

I don't think there's any length that you need to wait, a specific length of time. If you have a course of cladribine this month and somebody does a bone marrow exam on you three months later and there are a few hairy cells, I would not give you another course. You receive one cycle, most people are in remission and if three or four months later your counts are normal, your bone marrow just shows a few hairy cells, I would tell you if you repeat that bone marrow six months later they will all be gone. Somebody is going to give you a second course of cladribine just because there are a few hairy cells somewhere, there should be some degree of anxiety not to do that. 

However, if it is absolutely necessary, there's no specific time period. I would be thinking why am I getting this second course of cladribine?

Webinar participant asking a question:

I'd just like to ask about two questions. One is around the waiting. The why wait. I still don't quite understand. I can understand seasonal, you're more likely to get infected during the winter periods, for example, and of course there's the COVID issue, but apart from that, if you could just put that aside for the moment, isn't it better to start treatment as soon as possible? Because your blood counts will, even if it slowly will start to decline and therefore it's better to take the treatment while you're in a better condition than wait until your blood counts are actually going to quite a lower level when you're less able then to fight off the potential effects of the treatment in terms of infection or something?

Dr. Farhad Ravandi:

For a long time we have not had curative strategies in any leukemia. So the watch and wait is not just for hairy cell. So for example, in chronic lymphocytic leukemia, if the patient doesn't have a lot of problems, we watch and wait. There is follicular lymphomas that we watch and wait. Your argument is reasonable that, especially if you have a very highly effective strategy, why wait? And it's a very reasonable thing, but the only point about that I bring is that there is no rush. So if you have essentially normal counts, you're not that immunosuppressed and if you have to have a wedding party in a month, I wouldn't rush you to treatment now. I'd say go and enjoy your wedding party and come back two months later. Do you see what I mean? As long as your counts are not significantly low.

I think you're right that eventually most patients will end up needing the treatment, but the whole point about this is that I think you should not feel this is like acute leukemia. If a patient with acute leukemia sees me today, you can be sure that they're going to be in hospital within maximum two or three days, if not the same day, depending on their situation.

I think the whole point is look at the circumstances. Even if the circumstances are social circumstances, there is no rush, unless there are significantly low counts. Now, again, there are these guidelines and most people like to abide by them, so that is why people say, "Well, if the counts are not that low and you don't have any constitutional symptoms, I'm not going to start treating you until you get those. But that means that we need to monitor you." I would monitor your blood counts at least monthly.

Anna Lambertson:

I'm going to relay one more question from the Q&A and this is about febrile neutropenia. This patient was hospitalized for febrile neutropenia when they were first diagnosed with hairy cell leukemia. What are the chances that that could occur again if and when they relapse? And are there additional risks that they need to consider given COVID-19?

Dr. Farhad Ravandi:

The important point about febrile neutropenia is the neutropenia part. So the way I describe this to my patients is that your neutrophils are your soldiers and you can think of yourself as a medieval castle and your neutrophils are the soldiers that are all around the walls at the top and the bottom that are standing guard and the castle door is closed and the enemy is outside. The enemy being bacteria or other infections. Let's say suddenly all your soldiers disappear for whatever reason. Now, as long as the enemy doesn't realize that and doesn't open the door of the castle and doesn't enter, you're fine. But the moment the enemy soldiers, one of them is brave and goes and opens the castle door and sees there's absolutely no defending soldiers, so he calls all the other enemy soldiers and then they invade the castle within three seconds and completely destroy the castle.

This is why neutrophils are important, because they are essentially your soldiers against infection. Unfortunately, as you know, the castle could be still invaded even if you have functioning soldiers. You can still lose. But if you don't have any soldiers, it's a defeat within minutes. This is why we tell patients if you are neutropenic, if you get a fever that means the enemy is invading. You need to be within hospital within an hour at most, even less than that, because you need the reinforcement of very strong intravenous antibiotics to fight that infection.

So in terms of your question, if you become neutropenic, any patient who is neutropenic is always going to be at risk of getting neutropenic febrile infections and the quicker you act on it, the less likely they could become life threatening, because the quicker you act on it, the strong antibiotics that we have these days, they would replace the need for the neutrophils. They will essentially destroy the enemy bacteria or fungus or whatever infection there is.

Anna Lambertson:

We've reached the end of our time. I want to thank you on behalf of the Hairy Cell Leukemia Foundation and on behalf of all the patients who were on today's webinar. Thank you for taking time to share your expertise and your knowledge.

This transcript has been edited for clarity.