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HCL Patient Seminar - Columbus, OH

In September 2024, the HCLF hosted a full-day, hybrid HCL patient seminar on the campus of the Ohio State University in Columbus. Speakers included Dr. Michael Grever, Dr. Kerry Rogers, and Dr. James Blachly who graciously shared their knowledge and expertise.

Seminar Recording

You can view a recording of the sessions with a synced transcript here. >>

Seminar Transcript

Welcome from Dr. Michael Grever, The Ohio State University

It's nice to see everybody get together and we can maybe answer some questions for you. I want to just briefly thank a few individuals. I want to thank the Hairy Cell Leukemia Foundation for supporting the research which has enabled us to improve the treatment of hairy cell Leukemia over the last 20 years.

Without their support, this would not have been possible. They also, in addition to supporting research, have supported many educational activities f or physicians and scientists, as well as for patients and their families. We want to thank Anna for organizing that and the Hairy Cell Leukemia Foundation for their continued support in that regard.

I also want to thank Ohio State University. This has been home to me for the last 20 years, but I was here before. When I was here before is when I had Dr Bertha Bouroncle was my mentor and she told me that I was going to be a leukemia doctor. I had other plans, but she was pretty persuasive. So I've spent the last 40 some years doing leukemia.

Presentation from Dr. Michael Grever

One of the things I would like the patients to take away from this is that there is a lot of room for optimism. Sometimes, when you're walking around with the diagnosis of leukemia, that can become overwhelming.

But there's a lot of new agents that are being developed, and there are a lot of important studies that haven't been done yet on and Because this is a rare entity, it really requires collaboration and cooperation. So some trials, for example, are straightforward trials where you just test the new idea.

Other trials that compare one treatment to another often involve randomization. So half of the patients get treatment a and the other half got treatment B. And I'll show you one example where we were able to compare pentostatin to interferon many years ago. And we had 356 patients that we had on that study that we accrued. Large studies can be done with collaboration and cooperation. It takes a lot of work to set these up.

The first descriptions of hairy cell leukemia appeared in the literature in the 1950s. Dr. Bouroncle's comprehensive review of hairy cell leukemia was entitled leukemic reticuloendotheliosis. Other investigators also called it by that same name, but it led to a more convenient term called hairy cell leukemia.

Dr. Bouroncle was an extraordinary clinician and very dedicated to patients with leukemia. And through her studies here at Ohio State, with the cooperation of a couple of other hematologists, They developed a lot of the basic information about hairy cell leukemia. As I said, she had a major influence on my career, because when I came here in 1976, I didn't intend to do that, but she convinced me to pursue this.

So for those of you who haven't seen what a hairy cell looks like. This is a very nice demonstration of a hairy cell. And this is on a film of blood that was taken.

The nucleus, which is the center portion here. You can see the characteristic projections that come from the cytoplasm, giving yield to the term hairy cell leukemia. In general, there's this unexplained male predominance. We have no idea why men are much more likely to get hairy cell leukemia than women.

Although recent publication shows that women do quite well with this disease, too. But we don't understand the male predominance. The median age is 54, which means, less than 50 percent or younger and 50 percent or more are greater than 50 years. I've had patients, though, down into their early 20s.

And this typically will come about in midlife. But there's a whole spectrum. Pancytopenia is a term that means there's white blood cells are decreased, the red blood cells are decreased. producing anemia and the platelets are decreased. That's why it's called pancytopenia. Pancytopenia is present in the overwhelming majority of people with hairy cell leukemia.

There are some noted exceptions and I'll go over that later. It used to be that 90 percent of the patients had an enlarged spleen at the time of diagnosis. We don't see that high frequency anymore. Many patients do have a large spleen, but it's not nearly 90 percent because the diagnosis is made earlier before the spleen gets to be massive in size.

The large spleen can produce some of the presenting symptoms. Some patients will present with fullness and discomfort in the left upper part of their abdomen where the spleen is located. Other people might have a lot of symptoms of regurgitation. But the most frequent presenting symptoms are fatigue and this can interfere with your daily activities.

More than half of the patients will present with an infection and that's one of the biggest risks that we face. It's very rare, but less than 5 percent can have bone lesions where the bone is eroded. So when you look at a regular x ray, you'll see the bone surrounding a hole in the bone, and that can produce pain.

Patients can present with bleeding, and this Can happen as a result of the platelet count being low. And then this term autoimmune manifestation is a broad description of some of the other things that can happen. Autoimmune manifestations might include antibodies that the patients make against their own platelets.

or antibodies that they might make against their red blood cells. So they can present with very low platelet counts as a result of a decreased production because the bone marrow is not making as many. Then if you have autoimmune antibodies against the platelets, that can make the platelets even lower.

These various autoimmune manifestations of the disease can be part of the presenting picture. Now, these next letters that are preceded by CD are markers that are on the surface of the hairy cells. The way we determine that as we send a tube of blood to the lab, and they send it through an apparatus called a flow cytometer, and they measure some of these markers that are in the presence of the cells.

Somebody with classic hairy cell leukemia will have markers positive for a lot of different things, but in particular these four: CD11C, CD25, CD103, and CD103. If there are deviations from that, then you start to think about whether or not it's a variant of hairy cell leukemia.

As Anna mentioned, Dr. Tiacci in Italy first described that this gene BRAF V600E is mutated. This is seen in 90 or more percentage of patients with hairy cell leukemia.

It is also found in other malignancies. For example, malignant melanoma is often positive for this particular gene and some other malignancies are also positive. But in the area of leukemia, this mutation is most consistent with a classic form of hairy cell leukemia, because the variant will not have this mutation.

One of the things that we found recently, when you see enough patients, is that patients might be reported back from the lab where it has negative BRAF mutation. It looks like hairy cell leukemia underneath the microscope, and the markers look positive for hairy cell leukemia, but the BRAF mutation is not present.

 We send it off to our molecular lab, and they sequence the gene. And what we found is that there are several patients who have that BRAF mutation, but it's not in the usual location. So one of the studies that we have proposed we'd like to do would be to look at these markers to determine whether or not patients who present with abnormal composition of these markers, whether or not they have a bad prognosis, or they need to have a different therapeutic approach.

Then the hairy cell leukemia variant, and as Anna mentioned, the hairy cell leukemia that has this particular VH434, the immunoglobulin gene rearrangement, if they have either the variant or this particular hairy cell leukemia with that variant, they're usually negative for the BRAF mutation.

In general, their outcome is not as good as classic hairy cell leukemia. In 2017, my colleagues helped to put together the international consensus for how patients should be diagnosed and treated. We're in the process right now with Anna's help of updating that because a lot of things have changed since 2017.

And there are other guidelines as well, from Great Britain as well as the NCCN guidelines. So there's a lot of information out there for the physicians who may not see hairy Cell Leukemia every day to follow these guidelines in terms of deciding what would be best for an individual patient. Hopefully we're gonna be able to get our consensus updated at the October meeting.

Here's another picture of another hairy cell leukemia. So you should be familiar with that by now, but to the right of it, we see an accumulation of cells that are packed in the marrow. So you can understand here where these are all hairy cells.

You can just imagine that it would be hard for that bone marrow to make normal white blood cells or platelets. it's packed like that. The other thing that's characteristic of hairy cell leukemia, classic hairy cell leukemia, is that the presence of those cells can stimulate the bone marrow to put down these shredded structures that are called fibrosis.

That makes it very difficult to get an aspirate. If you're a brand new patient with hairy cell leukemia, whenever they're doing the bone marrow biopsy, they usually will need to follow that with an aspirate. And because of the presence of these fibrotic strands, it's not easy to get to come back out on the syringe.

But it's over with quickly. And I would encourage you to go along with the doctor to perform an adequate evaluation. And then if you take a look at the bone marrow stained with markers, you'll see that these cells are not normal cells, but they have a stain that will show that they're leukemic cells.

So some of the patients will have extensive involvement of the bone marrow, and you can understand how those patients would have trouble maintaining a normal blood count because there's no room for the normal cells. The other thing that can happen is if the spleen is enlarged, the blood cells can get trapped in the spleen, and so that can contribute to the counts being low.

This shows a bone marrow where there's hardly any cells, and you can see that there's a lot of fat cells here in the bone marrow. So this would be from a bone marrow biopsy. 10 percent of patients with hairy cell leukemia, if they have low counts, when you do the bone marrow biopsy, it almost looks like aplastic anemia.

And that could be a mistaken diagnosis, huh? When I was at Johns Hopkins, we had a fellow who had trained here at Ohio State University. He was practicing in West Virginia, and he sent a patient down to Hopkins for hairy cell leukemia treatment, and the bone marrow transplant team thought that the patient really had aplastic anemia.

But, the hematopathologist there was outstanding and he applied the stains that would mark the hairy cells. And so here you see these cells that are marked with a stain. There's a couple of different stains that can be used, but the presence of these hairy cells in the bone marrow actually suppressed the normal cellular development.

So trying to sort out the cause for the counts being low can be complicated. But that's why some people try and talk me out of doing a bone marrow biopsy. They say, I'd rather not have that. Well, the more information we have, the better we can formulate a plan for the patient. This was something that only happens in about 10 percent of the patients.

When you treat patients with hairy cell leukemia- specific therapy and you get the hairy cells to go away, then the bone marrow repopulates and you get normal cells back. So just so you're aware of that.

So over the last 60 years, a lot of progress has been made.

In 1958, the first descriptions of this clinical entity were made. In the late 1970s, the only treatment that they routinely used was to remove the spleen. That would temporarily improve the blood counts. But the problem is not just in the spleen, it's in the bone marrow too. So, it would give a transient or temporary improvement in the blood counts and maybe make people feel a little bit better.

But then the problem with red blood cell, white blood cell, and platelet production would come back as the disease progressed. In 1984, this was a remarkable time where they showed that alpha interferon could really improve the performance of the bone marrow because it would cause the hairy cells to regress and then the normal cells to come back.

We were working on Pentostatin in the lab here at Ohio State when I was a junior member of the faculty a long time ago. And we were trying to determine the dose of Pentostatin that it would take to get rid of a target enzyme in the leukemic cells. Because we knew that if you gave too much, you're going to have toxicity. If you gave too little, you wouldn't get a response.

So we spent a lot of time trying to determine what the optimal dose and schedule of administration of Pentostatin was. Meanwhile, in the 1990s, the group out in California, Dr Saven and his colleagues, described the really outstanding results with cladribine.

So we had two agents that were looking very promising in addition to interferon. In the 1990s, towards the end of the 1990s, lot of emphasis was placed on what would be the long term follow up, because as much as we would like to cure this disease, we can't cure it yet. It's not curable, but it is treatable.

And what we know is if you relapse, we have other strategies now, and we have increasing numbers of strategies for putting people back into remission. So one of the things we like to think about is even though we can't cure it we may be able to control it for an extended period of time And what we hope is that we can control it long enough that you're going to live as long as you might have lived otherwise.

Dr. Kreitman and his colleagues developed this moxetumomab, which was a combination of immunotoxin and a conjugate that would go towards the hairy cells and get some patients who had relapsed disease into a very good remission. Unfortunately, that's no longer available in most places.

We've already talked about the discovery of the BRAF mutation, and that's important not only for establishing the diagnosis of classic hairy cell leukemia, but it also is a target for agents that will interfere with that BRAF mutation.

 If that BRAF mutation is turned off by these targeted agents, then the bone marrow can return it to its normal production. And then over the last several years, Dr. Kreitman, in particular, and Dr. Ravandi down at MD Anderson have done a number of studies combining Rituxan, which is a monoclonal antibody, with cladribine. And what they show is that this is very effective in terms of getting, remissions in people who have relapsed. And then Dr. Jae Park at Memorial Hospital in New York has explored another monoclonal antibody that's very similar to Rituxan

it's called Obinutuzumab, and he's combined this with Vemurafenib and has shown that they're able to get very good responses in people who have relapsed.

So there's a lot of new agents. Dr Kerry Rogers is here today and we're going to ask her to give us some wisdom about these. She's a very valued colleague and frequent consultant.

She'll give you some ideas about some of the other newer agents that are coming along. But the message here should be twofold. This progress that we've made have only been accomplished because of clinical research.

But in order to maintain a long remission, we still have a lot of work to do in terms of continued research. The second part of that message is that there's a lot of hope. There's even more agents than the ones I've listed here that may be valuable in treating patients once they've relapsed.

So what's the natural history before 1984? It's still uncurable, but it's much more responsive to therapy. It's no longer unresponsive to therapy. The commonly used treatments before 1984 involved chemotherapy. That didn't work very well, and it had a lot of side effects. Removing the spleen, we talked about that.

It would improve some of the symptoms, but the disease would usually come back within a matter of years in terms of the bone marrow failure. The average survival back in 1984 was about 4.5 years after diagnosis. So, the deaths at that time were due either to infection or due to the low counts, the cytopenias, and bleeding.

Second malignancies also can happen to these patients because they do have an impaired immune system as part of the leukemia. And so you do need to be followed. I have a number of patients who have asked me, how about me just getting the blood count done and you can tell me whether or not I have to come back to see it.

And my answer to that is I'll do the blood count, but you shouldn't be taking too many shortcuts here because it's not just a simple thing of following your blood counts, although that's important, but it's not the only thing we need to look at.

So where were the landmarks made in terms of changing the natural history of hairy cell leukemia?

 Dr. Quesada and his colleagues in 1984 showed the value of using interferon. Three out of seven patients achieved a complete remission because before that, patients were treated with standard chemotherapy and essentially nobody got a complete remission. And then in 1987, Dr. Spears published a paper where 16 out of 27 patients who were treated with pentostatin went into a complete remission.

We published a paper shortly thereafter because we had been accumulating information on using the dose that we found in the lab. And we came out with very similar results that pentostatin was capable of getting a complete remission in many patients. It was durable. Now, one of the other things to remember is back in 1987, there were a lot of patients who were treated with a lot of other agents.

So many of these patients were heavily pretreated. Dr. Pirro, as I mentioned in California and Saven, published their results with cladribine, which really caught everybody's attention because 11 out of 12 patients went into a complete remission. One of the features of that study that everybody doesn't remember is that they excluded patients from cladribine going on to that initial study if they had an ongoing untreated infection.

Because one of the things that can happen with the cladribine is you can get a nice complete remission, but sometimes patients have to go through a period of weeks to months where their accounts are very low. And if you have an ongoing infection, it can sometimes rear its ugly head during that vulnerable period of time.

When we sat down to make our guidelines in 2017, we pointed out that cladribine is very effective. It's probably one of the most frequently used treatments to treat hairy cell leukemia because it's got some ease to its administration. Usually you give five days in a row and then you're told that everything's done.

Well, it isn't done if you get a bad infection and it can be much more complicated and prolonged. So if there's any evidence of an active infection, we usually think that has to be addressed before you use cladribine.

I conducted one of the first randomized studies with pentostatin versus interferon. We published it in 1995, but I started it long before that because we had to involve 200 hospitals. I was the head of a leukemia committee for a lot of collaborating institutions, and so I was able to get the help of all these other doctors. But we were able to get 356 patients into this study in less than three and a half years.

So this was just one slide from that study, and it shows that deoxycophermicin, which is pentostatin when it was compared to interferon, the results were pretty striking. The patients were randomized. And we did not necessarily exclude people with an active infection because we had published a couple cases where we were able to use pentostatin, which is called deoxycopheromycin.

And we were able to use that in patients even with an active infection, although we also had to treat the infection, but we were able to secure a remission. Whereas with cladribine, the worry was that the patients might not do well if they had an active infection. That study showed that the complete remission rate with pentostatin, the remission rate was over 75 to 77%.

Whereas with alpha interferon, it was only 11%. So that put the alpha interferon story for first line treatment to rest. There hasn't been any frontline comparison with pentostatin compared to cladribine. And that is something that could be done to try and take a look at the side effects. But so far people have been working on adding other things to cladribine rather than comparing it to pentostatin.

So when you see a patient, what do you do? First of all, you want to make sure that the diagnosis is correct. There are a number of different splenic lymphomas that can look like hairy cell leukemia, but you need to pursue it with the bone marrow biopsy and looking at those various targets on the leukemic cells.

And you don't want to make a diagnosis of aplastic anemia, as I showed you, because that would not lead to a good outcome.

So first of all, you want to establish that the diagnosis is correct. So while 10 percent of patients with hairy cell leukemia don't require immediate treatment, they then must be closely monitored because they can slip into a state where the infection fighting cells, which are called neutrophils, are low, putting the patient at risk for a serious infection. Or the platelets go low.

So if you're following somebody, they have to be willing to come back. I usually follow patients at least every three months, depending on what the blood counts are. If you have a patient with an active infection, this requires special treatment planning rather than just simply putting them on therapy.

You need to look at the kidney function because cladribine and pentostatin, these are the two recognized purine analogs that are used for frontline therapy. Both of these drugs are eliminated from the body by the kidneys. And so if you have an abnormal kidney function test, called creatinine, that could lead to higher blood levels and more side effects.

Also, we screen for patients who have had any history to make sure that they haven't had hepatitis in the past because sometimes these therapies, both cladribine and pentostatin, as well as rituxan, are immunosuppressive. And if you had hepatitis, you could have a resurgence of the hepatitis.

So we want to know whether or not they've had exposure to hepatitis before we embark on treatment.

And then again, it's essential to look at the bone marrow initiation and also at the end of therapy to make sure that you've got a complete remission because patients who get a complete remission are projected to have a much longer duration of the remission than if it's just a partial remission.

So when do you start therapy? Well, if somebody comes in and their infection fighting cells or their neutrophils are less than a thousand and the platelet counts under 100,000, if the hemoglobin is less than 11 or if they're having symptoms from an enlarged spleen or other manifestations of the disease.

I have a patient right now who's got overwhelming fatigue and his counts are very close to this borderline, so we're probably going to start him on therapy because the fatigue is interfering with the quality of his life. So, we also have other things we have to take into consideration. One patient has some religious objections to having any blood products.

And when we treat this disease, if you're starting off with low counts, they're going to get worse before they get better. And so if they go low and the patient isn't willing to take platelet transfusions or red blood cell transfusions, we could really be in a bind. And so we're probably going to start that patient on therapy before the counts get down to these levels.

So you have to put some planning into all this. Then you get started, but it's always important to look at the kidney function and to make sure that there's no underlying active infection.

So after you assess the patient and you're sure that he's ready or she's ready to get started, the most frequently used frontline therapy is cladribine. And probably the most frequently used way to do it is to give it intravenously over two hours for five days in a row. Then you need to anticipate following the counts because they're going to go lower before they get better.

You can also inject it underneath the skin like diabetics often do, a subcutaneous route. But cladribine can also be given once a week for six weeks. And if the counts go too low, we often hold off an extra week. That's called titrating the dose. Pentostatin is used by IV once every 2 to 3 weeks. We figured out this dose and this schedule based on all the studies that we did here at Ohio State back in the 1980s.

The other thing I would like to mention is that the therapy may be changing to recommendations to use Cladribine with simultaneous or concurrent Rituxan or Cladribine with adding Rituxan about a month after you're done with the Cladribine.

Dr. Kreitman is very much in favor of the concurrent approach. And one of the reasons he feels that this is important is after you treat the patient, we often do the bone marrow. And if there is no evidence of seeing hairy cells in the bone marrow, then we consider that a complete remission as long as the hemoglobin is above 11 and the infection fighting cells are above 1500 and the platelets above 100,000.

However, they are now using additional, more sophisticated tests to look for minimal residual disease. So it's possible that somebody is in a complete remission, but they still have some evidence of residual disease based on some of the more sophisticated tests. What Dr. Kreitman has published is that if you use the concurrent approach, you have a lower level of that minimal residual disease than if you do the sequential approach.

However, what we don't know is what the long term results of these two approaches will be. Dr. Ravandi has just published an update in 2024 of the regimen that they use at MD anderson, where they give the cladribine for five days. And then at a month, they repeat a bone marrow and if the counts are improving, they give eight doses of rituxan.

And he feels that regimen is so good because the complete remission rate is above 75 percent, and the minimal residual disease is markedly reduced, not quite as low as what Dr. Kreitman finds with the concurrent approach. What Dr Ravandi has said, those we don't know yet what the long term comparison of these two approaches would be.

This is a slide I borrowed from our colleague in London, Dr. Claire Dearden. They had 185 patients treated with pentostatin, 34 treated with cladribine. This was early on, and they followed the patients between 9 and 13 years. You can see that some of the patients had prior interferon and some of the patients had prior splenectomy.

But the overall complete remission rate with pentostatin in that large study was 81 percent and the overall complete remission with cladribine alone was 82%. Both of these agents are very effective, they're similarly effective when they're given as single agents, but there may be value in adding the additional therapy, the anti CD20 antibody rituximab or obinutuzumab to get a longer first remission.

So this is the one reference I mentioned to you with Dr. Ravandi. They had over 130 patients. Of those, because some of them were relapsed, there were 111 frontline patients. This was their first therapy and their complete remission rate was 97%.

Dr. Kreitman and his colleagues at the National Cancer Institute have very impressive delayed results with minimal residual disease being negative in over 90 percent of the patients, but we still don't know what the long term outcome will be. One of the other things to consider is in Dr. Kreitman's paper, one out of three patients, or roughly a third of the patients, had to accept the platelet transfusion. They didn't have any bleeding, but the platelets went down to 5 to 10,000 range. So, they didn't feel comfortable not giving platelet transfusions to those patients.

In my opinion, the cladribine with simultaneous rituxan is still very effective. But we have to be aware of this fact that you have to follow the patient very closely because they may need a platelet transfusion. Somebody said, well, they haven't bled. Well, that may be because they had played the transfusions as well. So you have to follow them. And This regimen is more myelosuppressive in my opinion.

So we still have to figure out how we're going to make it very concrete recommendation in the future about which of these two combined regimens to use. If you look at some of the data that came from London, Monica Else, who works with Dr. Claire Dearden, has shown that the patients who had a complete response, have a longer period of time before their disease relapses, before their disease comes back.

And patients with pentostatin did equally well as those patients who are treated with cladribine, but if you get a complete response, you're much more likely to have a prolonged relapse free period of time.

And this was based on 250 patients. So there was no difference between pentostatin or cladribine. It's pretty impressive that if you get a complete response, it's more likely to result in a durable remission. If they relapse and you're only using cladribine or you're only using pentostatin and you don't add the anti CD20 the complete remission rate the second time around is a little bit less. And if you relapse again and you're into your third relapse, then the complete remission rate is less.

So it's really important to try and get a complete remission to end up getting a more prolonged complete remission. This shows the same patient data. These are all patients on here. And so you get out to here and you see how many patients, maybe around 50 percent or a little bit higher have remained in remission.

That's out in years, and it gets progressively shorter if you only use the purine analog cladribine or pentostatin. However, if you have relapsed disease and you add an anti CD20 to the purine analog, you can get a much better second remission. And it's also important to look for other markers.

For example, some of these patients will have other targets that can be treated with some of the newer agents and so you can get a more prolonged remission. And what Dr Rogers will show you is she did a very extensive study on patients who are being treated with ibrutinib and somewhere around maybe a third of the patients may have an abnormality of an important target called P53.

And from the CLL literature, they've come up with a plan to use ibrutinib because it does work on patients who have abnormal p53. And so there's a lot of new biology that has led to adding some of these other promising agents to the frontline therapy or to those being treated for relapse and this just shows if you get into a relapse situation, and you have either pentostatin or cladribine, but you add rituxan, the complete remission rate is much higher, and the duration of the remission is much prolonged.

So this was the original article that Dr. Enrico Tiacci published in the New England Journal of Medicine in 2011. He was the one who has been one of the leaders in the world in terms of the use of vemurafenib, which targets that abnormal mutation. I had a chance to review this paper back in 2012. There's a German hematologist, Dr. Dietrich, who had a patient who had failed on cladribine and failed on pentostatin. And he was originally treated with low dose vemurafenib for resistant hairy cell leukemia, and it resulted in a complete remission by day 43. This just shows you his values. He had a fall in his white count. His neutrophils, neutrophils are the infection fighting cells, and his hemoglobin was going down, he was becoming anemic. He had cladribine, then he had pentostatin, then cladribine plus rituximab, and he just wasn't responding. And when they added Vemurafenib, here they only used 240 milligrams twice a day, they got a very marked improvement in his counts. And this shows his bone marrow, this over here shows how cellular it was because it was filled with the bad cells.

And then after treatment with the Vemurafenib, it was empty because it had to empty the bad cells before it was able to repopulate with good cells. And this just shows his peripheral blood. This box here has positive leukemia cells. And over here in the last box by day 70, there was no leukemia cells detectable in his peripheral blood.

That does not mean that he's cured. It just meant that he was in a remission. But the reason for showing you this one study is that there's some patients that can have a dramatic response to lower doses of the affirmative. Dr. Tiacci, and we contributed to this study as well, Tiacci, he feels that the doses of Vemurafenib that need to be adhered to are the original, which is 960 milligrams twice a day.

Quite a few patients have toxicity with that dose. In his studies, he had to sometimes reduce the dose and then would go back up to the original dose if possible.

So there's a lot of unanswered questions. You know, we had spent a considerable amount of time early on back in the 1980s trying to define the optimal dose of pentostatin, based on what happened in the leukemic cells. And so there's still probably some room for improvement to try and find the optimal dose of vemurafenib, which might be associated with less toxicity.

But the other way to go would be to do what Dr. Tiacci is doing, and that is combining vemurafenib with rituximab in relapsed disease. And this just shows if you put the two together, you end up getting a very prolonged remission in patients who have relapsed. And this study shows if you start off with Vemurafenib directly with Rituximab, you get a better response than if you start off with the Vemurafenib alone and add the Rituximab later on.

What are the side effects of Vemurafenib? Well, you have to be careful being in the sun because it could make you sensitive to a very serious sunburn. Many of the patients get a very extensive skin rash, and that often is the reason for reducing the dose because it could be intolerable.

Bone aches. Skin tumors. The skin tumors can be concerning. However, since they're on the surface, they can be removed. So you have to watch for this, but it's not something that can't be dealt with.

The other thing, Vemurafenib can cause some injury to the kidneys. That's what nephrotoxicity is. Nephro meaning kidney toxicity. And if you are on Vemurafenib maybe you have to follow the kidney function carefully because that alone might cause you to have to reduce the dose.

Dr. Rogers will give you more information about this, but, this was a study that was initiated here at Ohio State and she got the cooperation of other institutions to help us look at ibrutinib in patients with relapsed hairy cell leukemia or the variant.

So she'll go over the results of this in much more detail, but this was the scheme of her study. It's a drug that's taken orally. It goes after the target called BTK, which is a very important target in patients with B cell malignancies, not only hairy cell leukemia, but also chronic lymphocytic leukemia.

And, so sometimes you have to be on this medicine for quite a while before you get a response. But some of the responses can be pretty remarkable and patients who are treated after relapse with ibrutinib, many of them have not relapsed even out to several years. So this is an ongoing follow up study, but I think it's also reason to start additional studies looking at some of the other BTK inhibitors that may be equally or better tolerated and also looking at the BTK inhibitors with other drugs.

Dr. Rogers may be able to explain to you a study that she did in people who were resistant to ibrutinib with chronic lymphocytic leukemia. They added another drug called venetoclax and they were able to get rid of some of the resistant cells and get continued response.

 I have one patient who has had CLL and has had a very nice response to her other protocol. So classic hairy cell leukemia, the big deal here is dealing with infection. And about 17 percent of patients with hairy cell leukemia can present with an active infection that's complicated by low counts. The other thing I usually tell people is when we treat it, we're going to give you a medicine that could lower the counts, but they have to go down before they can get better, because it isn't going to get better on its own.

So more than 50 percent can present with infection at some point in their course. Infections are often involving unusual organisms, fungal infections or TB, or even bacterial infections. And because the chemotherapy or agents that we use can further suppress the immune system, we have to watch the patients very carefully.

Dr. Kraut, one of our colleagues here at Ohio State, published a list of all the different types of infections that he found in patients here at Ohio State. Many of them were bacterial infections and some of them were very serious. Others were atypical mycobacterial infections.

This is another organism that can affect patients with a compromised immune system. Zoster, which is shingles, particularly after treatment with the drugs, you're more susceptible to having shingles. I've lost patients to shingles. So if somebody gets any painful skin rash, they have to be seen right away. And they have to be placed on medicine that can prophylaxis against dissemination of this very deadly virus. It's important to make sure any vaccine that you get, it doesn't involve any live virus.

But the Shingrix, the only thing I'm concerned about there is if you have an impaired immune response, you may not be able to get a good response to the vaccine. So I feel much more comfortable if I'm worried about shingles, putting somebody on either Acyclovir or Valtrex. But Dr Kraut spent a lot of time characterizing all of the potential serious infections that can happen to patients with hairy cell leukemia.

This can happen before you're treated. It can happen after you're treated. And so you need to be aware of these things, and that's why patients need to be followed carefully.

This is one case. This was a middle age man. He's a patient of mine. He presented with back pain. I wasn't taking care of him at that time, and he had an infection in the spinal area in the thoracic discs.

And so he was treated by his local doctor with three months of intravenous antibiotics. and he has some improvement, but his white count was low and his infection fighting cells were 1000. His platelets were 62,000 and he was diagnosed as having hairy cell leukemia. So his local doctor gave him seven days of cladribine, which was one of the original regimens used.

And suddenly, after the purine analog cladibine was administered, he developed diffuse musculoskeletal pain, and he ended up with multiple abscesses around the spine in the sacrum. He was treated with antibiotics for three months, but he had to go to the intensive care unit because the infection was so overwhelming.

So when you're thinking about patients, they can sometimes present with an infection. And even though you have to get the hairy cell leukemia under control, you have to make sure that the infection is totally under control before you use cladribine. Alternatively, we published studies where patients with active infection have been successfully treated with Pentostatin.

And because it doesn't suppress the counts quite as low, we had another patient who presented with serious infection in Russia. She had serious fungal infection pneumonia in both lungs and was on a respirator, and her counts were very low. The Russian physicians were going to use cladribine.

And so the hairy Cell Leukemia Foundation contacted us and we got one of our colleagues in Hungary who could speak Russian and advised against the use of cladribine. They treated that patient with Vemurafenib to get the counts improved. So her pneumonia came under control. She came off of the ventilator.

They treated her with cladribine after she recovered and they took out the spleen. So they didn't leave any stone unturned. And she did very well. She came to one of our hairy cell leukemia meetings here at Ohio State a number of years ago to thank us for intervening.

So I mentioned that patients can present with staphylococcal infections and you can end up with re-exacerbation of the infection.

We published some of the results of using other ways of treating somebody with an active infection. Even though alpha interferon has a lower overall response rate, it has been used in patients with infection because it doesn't lower the counts.

We've published on reduced doses of pentostatin under those circumstances and patients have used GCSF to try and improve the white count to help get the infection under control. And then Vemurafenib used as the frontline therapy has been published in a number of circumstances as a way to get the white count up, get the infection under control, and then proceed with the more definitive treatment of the hairy cell leukemia.

Although, I think if you get everything under control, I'm not sure the splenectomy is going to really be indicated because that introduces another area of susceptibility to infection.

This is from Dr. Dearden's work in the United Kingdom. She worked with Dr. Matthew Cross, one of her colleagues, and they're studying bone lesions in patients with hairy cell leukemia.

And this can almost look like multiple myeloma because there's a lytic or an open hole in some of the bones. This can be painful. It often responds to radiation therapy for symptom control, but because it's part of the underlying hairy cell leukemia, you need to use treatment to try and treat the whole body.

And we've used this approach with just either cladribine or pentostatin and got the disease under control with improvement in the bone pain.

What about the long term consequences of being treated? Well, first of all, if you don't treat it, it's not going to go away. So you have to understand that the patients after treatment, are going to be very immunosuppressed, and they have to be put on prophylactic medicines in some cases, and have to be watched for infection.

One of the most common long term infections is shingles, and we've talked about that, but there's also a need to look for secondary cancers in these patients. The bone marrow can take a while to recover after chemotherapy, so you have to follow the patients carefully until you've given time for the bone marrow to recover. Because when you're treating it, you're not only getting rid of the bad cells, but there can be some effect on the remaining good cells as well.

The hairy cell leukemia variant has been mentioned here. About one out of 10 patients with hairy cell leukemia will have the variant. There is actually, in my opinion, more than one variant. We use this term to describe those conditions that look like hairy cell leukemia in many respects that have a more aggressive presentation.

The World Health Organization decided that they were going to pick up all these different rare splenic lymphomas and put them into a single category. And so they put them all in a category, and they called it splenic lymphoma with large nucleoli.

We published the paper. We thought we should retain the diagnosis of hairy cell leukemia variant because we do know that somewhere between 30 and 40 percent of them will have a mutation or a deletion of that important protein called P53.

Some of them will have a mutation in the map kinase pathway, which opens up opportunities to use other exciting drugs. And so we still feel it's important to maintain this category of hairy cell leukemia variant because it does allow you to identify in patients whether or not they may have a target that could be used to keep their disease and remission.

This lady was a patient that was in Dr. Dearden's presentation that she gave last year at the hairy cell leukemia meeting. It was a woman with a six month history of fevers, weight loss, night sweats and abdominal swelling distention.

She had a massive spleen that was down to the belly button. On examination, she was otherwise normal and she didn't have any lymph nodes. Her hemoglobin was 11.9. We've certainly seen people presenting with a hemoglobin of five or more, five, six, really low, but this was 11. 9. But the white count here is unusual for hairy cell leukemia because it was 68,000.

Normally patients with the classic form of hairy cell leukemia, at least 90 percent of them will present with low total white count. So the white count being 68,000 would raise your concern that this might be a variant, and it's not 68,000 good white blood cells. There was a lot of bad white blood cells.

The monocytes here are also not really low. The platelets were 134,000. So at first value, it doesn't look that bad. Her kidney function was good, and the flow cytometry showed that her cells were negative for CD25 and CD123, which is very unusual for classic hairy cell leukemia. So the presentation here is very much one of a patient with the variant of hairy cell leukemia. The bone marrow was negative when you put a stain on it for Annexin A1, which is almost always positive in people that have regular hairy cell leukemia.

The stain that they did on the marrow was negative for the V600E mutation because that is usually negative in the variant. So the diagnosis was the hairy cell leukemia variant. Here were the cells, and one of the things that you can see is in the middle of the nucleus, there's a big hole and that's called a nucleolus. You can see that the projections are there, but they're not quite the same as the long skinny ones that you see with classic hairy cell leukemia. But they're there. Nonetheless, there's also two nucleus in that one cell. So this is what you can see with somebody with the variant. And you also see how many cells there are there in this one view of the peripheral smear.

This is somebody who has a large spleen, has a very high white count, does not have a low monocyte count, which is characteristic of classic hairy cell leukemia. And she's got all the other markers that show that she had the variant of hairy cell leukemia. And she was treated with a combination of cladribine for five days and rituxan once a week for eight weeks.

It resulted in a complete normalization of her blood cells in regression of her spleen, and she had a complete remission confirmed by bone marrow and CAT scans. And she, according to Dr. Dearden, remains well and in continued remission for eight years. Which is really remarkable for the variant of hairy cell leukemia.

So in summary, the rare splenic malignancies that are characterized by enlarged spleen and elevated lymphocyte count are characteristic of the hairy cell variant. Typically, they don't respond very well to either cladabine or pentostatin alone. That's what monotherapy would be. The median survival is about nine years compared to more than 20 for the classic hairy cell leukemia.

And so standard therapy for these patients is frontline therapy would be cladribine plus rituximab. But other novel therapies could also contribute to controlling the disease. We usually send off the cells to have a molecular analysis done. We understand what mutations are present that would afford us various opportunities to include other drugs that might help with the variant.

So what about this disease? It wasn't in 1985 that the questions were all addressed. That's why we met in Chicago. There's still a lot of remaining questions that we could add to this list. So when should the anti CD20 be added? Should it be given sequentially like they do down at MD Anderson or should it be given concurrently like they do at the National Cancer Institute?

What's the optimal dose and duration? How important is minimal residual disease. It seems obvious that if you can get rid of minimal residual disease, that the long term outcome would be better. However, we need to see some confirmatory evidence, long term data, but we also have to understand what the toxicities will be with these combined therapies when they're given together.

When should the patient be referred for an investigational drug? And then since we have now have several options, how are we going to prioritize which investigational agents should be used first? And should it be used in combination?

We published a paper a number of years ago with a relatively young man who had a variant of hairy cell leukemia, and we found that he had a mutation in the map kinase pathway. We put him on a drug called trametinib, but we only at that point used trametinib and his disease was brought under pretty good control for a couple of years, but then he progressed. So in retrospect, it would have been wise to think about what other combinations could have added to the increased durability of that remission that he achieved.

What therapies are best for the variants of hairy cell leukemia? The combination of cladribine plus rituximab has the highest complete remission rate. But this merits further investigation. How do you manage patients with hairy cell leukemia in the era of COVID?

So we still have a lot of unanswered questions and I would encourage you to look at the website for the hairy cell leukemia foundation because I think it has a lot of valuable information. If you have questions please ask. Thanks for your attention.

Question and Answer Session with Drs. Michael Grever and Kerry Rogers

Audience question about ongoing monitoring, including blood counts

Certainly checking the blood counts is important, because you can see if the disease is starting to result in progressive decline and the neutrophils or the platelets before they get to a very low level, which makes treating it much more challenging.

So getting frequent blood counts. I usually try to look about a three month interval. Also examining the patient is important because infection and second malignancies are a real threat to this patient group. You can't do that just by checking your blood count.

What would you say about that, Dr Rogers?

The other thing I was just going to say is if we thought that it was only necessary to do a blood count and not see someone, we would say that and just set up local blood work. I do that when it's not necessary to have a visit.

We do try to think about what it actually takes to come to clinic and limit that whenever it's appropriate.

The other thing I'd add to that too is we don't see everybody every three months. That's just initially after treatment. So as you get more stable in your remission, I make it every four months, then I make it every six months.

Discussion about MRD with Drs. Michael Grever and Kerry Rogers

I think the question was if someone's in remission after treatment, but there's still what we call measurable residual disease, which is there's hairy cell leukemia cells detectable usually with special stains, what does that mean for them?

Obviously it's intuitive that it would be better to have negative minimal residual disease than to have detectable minimal residual disease, although the truth is we haven't cured the disease.

Even those patients who are negative for minimal residual disease may turn positive as you're following them. And the treatments to get rid of minimal residual disease are usually more intense, not always, but usually more intense. So it's a question about weighing the toxicity of the treatments to get rid of the minimal residual disease versus the long term implications of the presence of minimal residual disease. Dr Ravandi wrote a very nice, comprehensive article on detecting and managing patients with minimal residual disease in hairy cell leukemia. And it's been published with the review by all the members of the Hairy Cell Leukemia Foundation.

We don't know yet what the long term consequences are going to be of having residual disease. Intuitively, it would be better if you didn't have minimal residual disease, but whether or not you should aggressively treat that if all the other parameters have returned to normal, particularly since additional therapy can lead to additional toxicity.

So it's a judgment call in my opinion.

And we still haven't completely agreed as a field on the best way to measure this. Some of the studies that Dr. Kreitman did was measured using a very sensitive flow cytometry test. It was measured by immunohistochemistry, which is where they put special stains on the bone marrow.

And there's some investigational ways of looking at it, using either a specific immunoglobulin gene sequence in the leukemia cells or presence of a tumor free DNA for the BRAF mutation.

Most of the time you would think if there's detectable leukemia versus none that the remission might be shorter. That's true in other types of leukemia and in some situations. However, it doesn't mean that the remission won't be many years. I've seen plenty of patients that still had some detectable hairy cell in the bone marrow after treatment that still were in remission for multiple years, enjoying their life and not needing treatment. So for an individual, you do just have to see what happens and don't think that this treatment wasn't successful or that you're not going to get a very nice benefit.

I also think you have to wonder when the bone marrow biopsy is done with respect to treatment. Usually they're done four to six months after a treatment with cladribine, but occasionally there's a reason to do a bone marrow biopsy early and in fact you might see hairy cells present shortly after cladribine that aren't if you do another bone marrow biopsy later.

So you have to think about what the treatment was, if you'd still expect hairy cells there, what the trajectory of their disappearance is. So that can be a very individual question for someone that they'll have to discuss with their doctor to see what it means for them.

But unlike some other leukemias, having some detectable hairy cell doesn't mean that there won't be years of benefit from the treatment that someone received. So the question would be the pros and cons of doing a bone marrow biopsy very shortly after finishing a treatment, until later, or versus not doing one at all after treatment.

I often discuss this with the patients because if you do it too soon, you may still end up with a 2 percent or 5 percent residual hairy cell leukemia. If you wait a little bit longer, you may see a better outcome because there will be continued improvement. So I try and do it somewhere between one and four to six months after I'm done with the treatment, because a lot of patients don't want to have a repeat bone marrow after they've had the one.

I do think it's worthwhile getting a bone marrow at some point after the initial induction therapy, because if you have clear cut identifiable hairy cells, not minimal residual disease, but if you have clear cut residual leukemic cell infiltration that you could see, that's not a complete remission, even though the blood counts improve.

Those patients are predicted to have a less durable remission then you might want to add some additional therapy to take care of the residual resistant disease. So I think it's important to do it. Optimal time to do it is up for discussion and some patients would prefer not to do it.

But, if you don't want to know whether or not you're going to be likely to have a durable remission, then you don't do it. But if there's some possibility of intervening, if there's a fair amount of residual leukemia still there, I think it's worthwhile to try and assess that.

The long term importance of minimal residual disease still is a question. With other forms of leukemia, it does have a relationship to the duration of remission. I have a patient that has had a very aggressive presentation with his hairy cell leukemia after pretty extensive treatment with cladribine. He's on rituxan right now, but his post treatment had 10% observable hairy cells. So he didn't get a complete remission. So that's why we're definitely pursuing the additional eight doses of rituxan. And we're gonna have to repeat the bone marrow again.

The other thing that is important is everybody with this disease is not older. And so when you say you're gonna hopefully live as long as you're gonna live without the disease, what group are we talking about? Are we talking about octogenarians? Are we talking about people that are in their 40s? So we still have a lot to learn.

When to do a bone marrow biopsy after treatment also depends on what treatment the person received. So with cladribine, you're giving a fixed course of treatment and then you want to wait a few months to see the optimal effect.

And you can look at the clinical trials of the drug when they assessed response by bone marrow and then get an idea of what might be the good timeframe to do that for that particular treatment. Pentostatin though, is dosed every two weeks until you get a response and then you do a bone marrow biopsy to see how much hairy cells are there to decide how much more Pentostatin to give.

So it is necessary to do a bone marrow biopsy to decide how long of a course of treatment someone might need. You actually need that information to decide whether or not to continue with longer treatment or if someone's maximized the benefit and should stop treatment.

And then drugs like Vemurafenib clear out the bone marrow much faster. So if you look at the studies done with the Vemurafenib-based treatment or the Vemurafenib and Rituximab, bone marrow biopsies are done shortly after treatment. So you can go back and look at how the regimen was studied originally and when a bone marrow biopsy might be needed to assess the response best.

You look at a drug like ibrutinib, we're going to talk about later, it doesn't clear the hairy cell out of the bone marrow fast at all. And removing that from the bone marrow is not necessary to enjoy the benefit of it or to have a benefit from it. So I think this is really dependent on what the treatment is, so there's no standard answer.

I also have a couple of patients that do not have any hairy cell in the bone marrow. It's all outside the bone marrow and other parts of their body. And so doing another bone marrow biopsy is really not something I'd suggest because that's not going to help us understand it better.

And then the last point I want to make is if the blood counts aren't like you expect, then it's really important to do a bone marrow biopsy to know why. So if say you were to give someone cladribine and you find that their hemoglobin and white blood cell count recovered to normal but their platelets are still quite low, you want to make sure you know why that happened.

Is it that there's ongoing effects of the chemotherapy on the bone marrow? Is there still hairy cell in the bone marrow? Is it actually an immune destruction of platelets, which is something called ITP? So sometimes there's a need to do a bone marrow at a time other than everyone was expecting, because you need to figure out what's going on with the blood counts.

So I think one thing that is important is if someone recommends a bone marrow biopsy, make sure you know, why it's recommended then and what information specifically the physician is looking for.

When we did the original study comparing alpha interferon to pentostatin, the study was written, since it was a randomized study, to treat for six months and then to do the bone marrow to find out whether or not there was improvement. And if there was no improvement, they would switch over to the other side so that nobody was eliminated from getting active therapy. And if there was residual disease at six months, we would then continue with an additional six months of therapy.

And so if you don't do a bone marrow biopsy, you're not going to know whether or not there's residual disease that requires some more therapy.

If there's some residual, you have to use some judgment. If it's just trace, then you have to discuss with the patient. You don't want to give Pentostatin indefinitely. We don't recommend indefinite Pentostatin. But if you don't do the bone marrow at the end of six months, sometime around there, you're not going to know what you're left with.

Audience Question about Creatinine Levels

One individual had a question about creatinine levels and what significance that might have for them. They've already completed treatment and they're curious at what level might you become concerned for a patient who otherwise is doing well?

Discussion with Drs. Michael Grever and Kerry Rogers

Since these drugs are cleared through the kidney, you have to be careful. You have to be careful about the doses because patients can get marrow suppression that's pretty impressive if the exposure to cladribine prolongs. I have to talk usually to the pharmacist to make some decision based on individual cases.

I don't feel comfortable saying what creatinine level, but it's something that you have to pay attention to because that's how the drug is eliminated from the body.

 It does require a discussion about careful dosing of medications in collaboration with specialty pharmacists that help us with this. A choice of which drug might be most appropriate for the person, sometimes it depends on renal function. Drugs like vemurafenib don't need good renal function to take them.

The other thing that you can do, if you use pentostatin, you can use a lower dose. Pentostatin can be given every 14 to 21 days. So there's other ways to try and work your way around it, but it involves planning and discussion with the pharmacy.

Audience Question about Immunosuppression

I think in part because of the amazing education that you and other hematologists provide to patients, we see a lot of awareness around immunosuppression.

There was a question that came through online. If you're in the 10 percent of patients who don't need treatment, are you still classified as immunocompromised?

Discussion with Drs. Michael Grever and Kerry Rogers

My answer to that would be yes, because one of the other things that happens with classic hairy cell leukemia is monocytopenia. You can't forget about those cells. They're important for fighting off infections, particularly fungal infections. So even though you're being followed because your granulocyte count might be 1200, a lot of those patients will have low monocyte counts.

So the intrinsic immunosuppression related to the disease is still there. One of the other things that goes along with that is before you start treating patients, if they're in that watch and wait 10 percent group, you should probably pay attention to getting them adequately immunized against things before you're going to be treating them with something like Rituxan or the purine analogs, which will make it more difficult to get a good response to the vaccine.

 I think they are still immunocompromised and they may not be as immunocompromised as somebody who's flat out severely requiring therapy, but they still are immunocompromised. So if you're going to try and get them prepared to take one of these drugs that can add to temporarily to the immunosuppression, it would be better to get those vaccines in before you have to treat them.

I would also say yes. And even in remission after treatment, there's a degree of immunocompromised, right? You're immunocompromised to a degree. I certainly don't recommend that people live in a bubble and don't go out and do their things or the vast majority of things they want to do.

I think you have to be reasonable, but you certainly want to continue with activities that they are living and enjoying your family and not becoming a hermit.

If somebody has active shingles, you shouldn't be with them in close proximity.

I think the other thing is probably even more relevant is exposure to COVID. So I think you have to be reasonable when if you're around a crowd of unknowns, in a crowded area, it might be worthwhile to wear a mask.

Audience Question about Being Prepared for Treatment

So someone is starting treatment tomorrow. What advice do you give this patient who's just about to start treatment?

Discussion with Drs. Michael Grever and Kerry Rogers

To watch out for any signs of infection and to report it as soon as you have any concerns to your doctor. And also, to get as many questions answered as you can possibly think of before you get started.

They should know what the potential side effects are going to be and what they need to look out for. And they also need to know what kind of things the doctor will want to know about. Some people are very religious about checking their temperatures and other people don't.

So I think if they're, if you're going through a vulnerable period with your counts going down low, I would advise people to check their temperatures, maybe in the evening, and not to take Tylenol for any reason before you check your temperature because it's going to mask a low grade fever.

So watching out for infection and asking the doctor what you should do if you do get a fever. Because if it's on a Friday evening and you can't get through to his office until Monday, what does he recommend that you do if you get a temperature or shaking chills is often a sign of infection. So if you get signs of infection while you're on therapy or even before you start therapy, what does he recommend that you do?

I think one of them is make sure you understand what additional medications you've been given and prescribed and what they're for to make sure that your health care team has an updated medication list. I've also seen some people decide to take supplements during treatment to help with side effects, which majorly increased the drug levels of the medication they were taking.

Or people prescribed preventative medications for things like shingles that didn't know what it was for. And that's our fault for not explaining it correctly. But I think there's so much information people forget or you get home with prescriptions and you're like, Hey, what is this?

So just make sure that everyone knows what medications you're taking, like your healthcare team does. And that if you're prescribed medications, which ones are as needed and what to do with them. I also think that if someone is starting treatment, you can't think of every possible question before you start treatment.

So make sure you can contact your healthcare team to ask questions, right? It is completely fine to reach out and ask those questions. If it is not that serious, you can reach out at 2 pm. If it's very serious, most people have answering services, you can get someone 24 hours a day.

And then, if something feels horribly wrong to you as a person, get care immediately, even if it's not on the list of stuff that someone told you could be a side effect.

Introduction of Panelists

We are going to begin our next and final session, which will be a panel discussion. We won't have slides. This will be three outstanding hematologists and researchers taking a deeper dive into some of the topics that we explored during the first session.

So I'm just going to do a quick name introduction. We have, of course, Dr. Mike Grever, who you heard from this morning, Dr. Kerry Rogers, who graciously participated in the Q&A and Dr. James Blachly. All three are at the Ohio State University.

We at the Hairy Cell Leukemia Foundation turn to all three of these people and many more doctors at Hairy Cell Leukemia Centers of Excellence for presentations like the one today, as well as difficult questions that may come in from patients from time to time.

Panel Discussion with Drs. Michael Grever, Kerry Rogers and James Blachly

We're very grateful that we have both Dr. Blachly and Dr. Rogers here today. But I use both of them frequently for getting advice about patients. And the team at Ohio State also involves Dr. Seema Bhat, who couldn't be here today. And we have some really outstanding hematopathologists and Dr. Chris Oakes, who's one of the basic scientists who works with us trying to find out important prognostic parameters with respect to response. And one of the things that I really appreciate is we have a meeting at least every two weeks to discuss interesting patients. And that way we can get a consensus of what might be the best way to go.

We have a phenomenal team here and you mentioned pathology. We have a hematopathologist, Dr. Gerard Lozanski. I think that's really important feature of a number of the centers of excellence is not only a clinical team, but pathologists dedicated to the study of hairy cell leukemia and their expertise is really invaluable.

And then actually on the clinic side, all of our clinic teams like nurses and nurse practitioners or physician assistants and our pharmacists. Hairy cell leukemia is rare and a lot of them work with us to provide truly outstanding clinical care and are really familiar with some of the drugs and treatments that we are discussing.

 I think that's really relevant to when you have a center of excellence to have other clinical medical professionals that are familiar with Hairy cell leukemia.

It's a real team effort, and that's really essential because no one individual has all the right answers. And so whenever we discuss these complicated cases, we take valuable insight from them.

The first topic is what disadvantages are there for standard of care treatment? For example, from the standpoint of side effects, difficult cases, challenging and managing patient response and for responses among various subsets. What are the disadvantages of just applying a format of standard of care?

That's a really good question. You have talked about or alluded to a number of these things, but just, the word chemotherapy means we're giving literal toxic poison, and it was a great start to the field of oncology. But the field of oncology is moving away from chemotherapy.

And ever since the 1990s, we've realized that we can use sometimes oral medications that target specific proteins, the proteins that are making the distinct cancers tick. And we're really fortunate that we have a target in hairy cell leukemia. And so chemotherapy itself is a disadvantage, I guess would be the answer to the question.

There are side effects that are really, unique. And of course, any medication can have side effects, but the side effects of chemotherapy, I think everybody in this room is aware, can be particularly profound, and some of them can occur many years later. One of the most troublesome side effects of chemotherapy is problems with your bone marrow a decade hence.

And you know that, and for many other reasons we would like to move away from things like cladribine and Pentostatin, as wonderful and as effective as they have been to, more directly targeted therapies. And I include rituximab in that, in terms of targeted therapy.

Pentostatin and cladribine are by no means the worst chemotherapies we make. The other thing to keep in mind is that when Dr. Grever gave this great talk, he's talking about purine analogs, both Pentostatin and cladribine, and how big an impact that had in hairy cell leukemia, with people living their whole natural lifespan with a hairy cell leukemia and how much better this is than anything we had previously. But it's not a hundred percent response rate for everybody.

The average time is actually median. If you don't know what a median is, you can think of it a little bit like time to needing a second treatment after getting either Pentostatin or cladribine is between seven and eight years in most studies. So this means that if someone's going to live with hairy cell leukemia for three decades, they might need treatments repeatedly during that time.

 The other thing that is true is sometimes people don't get seven or eight years before they need a next treatment. Maybe it's two years, they get the treatment again. It's two years, they get cladribine again. It's two years and you don't want to just keep giving people cladribine indefinitely, every two years.

So there are some people for whatever biologic reason, their hairy cell isn't really getting a huge benefit from Pentostatin or cladribine the way many hairy cell leukemia patients get a huge benefit from it. And those are cases where using a targeted or a different approach is really important. Or even if it is working well, but someone's taking this treatment three times, you wonder, maybe with side effects and other things, it would be better to try a different approach.

So while these drugs are highly successful, they're not fixing things for everybody for the remainder of their natural lifespan. And there are some people who really do need a different approach for their hairy cell leukemia. And then we didn't really talk about hairy cell leukemia variant, but the responses and benefit from purine analogs for people who have variant hairy cell leukemia are not as good as they are for classic, which is what I was talking about in terms of that data.

So there is a subset of people that really do need a different approach to have healthy, productive lives with hairy cell.

I would say one other thing about chemotherapy, which is, you're going to get worse before you get better. And, as mentioned this morning, it's very immunosuppressive.

And, for people with infections, which is common in hairy cell leukemia, the notion that you're going to make the immune system worse before it gets better is, laughable. And it can be very dangerous, as I think has been said to treat patients with chemotherapy, immunosuppressive chemotherapy in the context of infection.

And in fact, it's expressly recommended in guidelines to not treat or to be very cautious and selective about which treatment patients who have active or suspected infections at the time that they need treatment for hairy cell leukemia. Whereas that disadvantage is not present with some of the targeted molecules that we have, for example, the BRAF inhibitors can be safely given to patients who have infection.

One of my friends from residency had a patient she was caring for that had been in the ICU for four months with severe COVID 19 that t hey assumed was due to this person's critical illness from COVID. A long story short, they ended up getting a bone marrow biopsy and actually had classic hairy cell leukemia and didn't know it. However, their blood counts were low and no one thought it would be acceptable or appropriate to give this person who'd been in the ICU for three months, a purine analog therapy.

I ended up speaking with a hematologist who got BRAF testing, gave this person Vemurafenib. This person was able to be discharged from the hospital to a rehab facility for ongoing rehab care. So that's an extreme example, but I think it just proves a point that some of these targeted therapies can help people where chemotherapy would likely just make situations worse for them.

 That was a good example and it reminded me of another case. I was to see this gentleman in his mid 60s as a new patient because he had been diagnosed with hairy cell leukemia on the basis of low blood counts and detectable hairy cells in his peripheral blood, very clear cut diagnosis.

I looked at the records and there's something missing. He hasn't had a bone marrow biopsy. We already know what the diagnosis is. Why do we need a bone marrow biopsy? And the answer is that, his blood counts were not only suppressed due to his hairy cell leukemia, but his entire bone marrow was infiltrated with a fungal infection called histoplasmosis.

The histoplasma blastomyces and a number of other infections are endemic to this part of the country, the Ohio River Valley and the Mississippi River Valley. And, treatment with either cladribine or pentostatin would have wiped out his immune system and he probably would have died immediately of an fungal infection.

At that time we didn't have Vemurafenib established as a therapy, but luckily we were able to treat him with antifungal therapy. Get him transferred here and then he was able to get treatment. He's alive and well, and he still travels from a neighboring state to see me, and he's doing great.

That's just an example. The key disadvantage of making things worse before it gets better. It can have a profound implications. It definitely would have killed this guy.

Well, and if Vemurafenib were available, you probably could have started that sooner along with anti fungal therapy and help the person recover faster than they did.

So conventional therapies, Dr. Grever, are very challenging, for reasons of immune related reasons in particular.

 You said immune, but mostly cladribine and Pentostatin are tolerable, but there are people to get neurotoxicity from it and absolutely should not receive that again.

So there are other side effects that are rare that people have gotten from it that really mean alternatives are better.

Exactly. Some patients have developed peripheral neuropathy with the administration of the Purine analog. So I think you've made a point that more knowledge about what's going on in the bone marrow is worth having a bone marrow biopsy. It doesn't take very long and it's not nearly as frightening as everybody seems to think that it is. I've had them by the way, so I can tell you that I've survived. But the information that you get can be very helpful. So with targeted therapy, what would you, think? How should we entertain the introduction of new protocols? Should we just abandon the frontline therapy with the purine analogs? How would you recommend that we approach bringing new therapies forward?

Yeah, great question. As is common in almost all cancers, new treatments and targeted treatments are first studied in the relapsed or refractory setting. So the answer to should we abandon frontline therapies is definitely no, not without comparative studies. One thing that's difficult in this disease is, of course, the period of time between somebody gets a response and when the disease comes back or the relapse free survival. And being such a long time as again we said this morning you know studying these outcomes can be career spanning and so it is a difficult thing to do we can look at other surrogate markers like minimal or measurable residual disease MRD that was mentioned this morning. So I would say no we shouldn't throw it out right away but randomized long term studies are also hard to come by.

And so you know, in lieu of that, we have non randomized phase two studies looking at alternative therapies like Rituximab or Obinutuzumab plus Vemurafenib. And we can look then at historical data and make our best guess. But no, I wouldn't throw the baby out with the bathwater, certainly. And as Dr. Rogers has mentioned, it differs depending on which therapy you're talking about. So while the BRAF inhibitors in combination with a CD 20 antibody like rituximab or obinutuzumab can give very deep MRD negative responses that we think might put people in remission for years and years, that same thing may not be true of all other types of targeted therapies.

 I was going to say too, Vemurafenib, even people that had no detectable Hairy's left or treatment didn't stay in remission for seven, eight, nine years. The amount of time before the disease returned was more on the order of less than two years.

So treatment with targeted agents actually has different biologic effects than treatment with chemotherapies. And so when you think about should we replace initial therapy with some of those, you've got to take into account that having undetectable leukemia might mean something different after a targeted agent than after chemotherapy.

And then, it was said earlier, but with that concurrent cladribine and rituximab versus cladribine with delayed rituximab, 7. 7 years of follow up and there's no difference in progression free survival because everyone's doing well. And then you have to think, should we not offer this new treatment type to patients yet because we don't have enough follow up to know that it's definitively better in terms of progression free survival.

Or do we think that looking at leukemia free survival is enough that we think this will be better in the future and start offering it to people. So I think that's always a challenge too on the physician side and usually requires some discussion with the person who's going to be taking the treatment.

I have the privilege of taking care of someone in his 90s who is not very concerned about a 30 year outlook on something. He's more concerned about feeling better and not getting a bunch of side effects from treatment. So I do think that like someone's natural lifespan plays a difference too because people in their 40s obviously have a different perspective on what they like out of something.

But there's randomized studies now comparing the Vemurafenib that James is talking about with an anti CD 20 antibody. And so I think those are really important to do, but I worry about how long it will take to see a difference and at what point we should start saying that this might be better and offering it to people.

One of the things you pointed out, which is important is with some of the studies with Vemurafenib alone. Just by itself. And we participated in the early studies. The complete remission rate is maybe 40 percent but over 60 percent of the patients benefit, but only the patients with a complete remission will have a more durable remission.

Even those patients tend to relapse within about a year and a half. We don't have all of the story in yet on the combination of Vemurafmib plus Rituximab, nor the combination of Vemurafmib plus Obinutuzumab. So we'll have to follow this along. And your generation will have to be there to interpret things.

I'm not sure I'll still be on the face of the earth, but those kinds of things will have to be looked at before we and end the current frontline therapy. But it will be important to try and figure out how we're going to introduce new strategies, because even with the very nice results that you've had, there are other BTK inhibitors that might be equally interesting and equally important to include with some additional therapy. You did one study in resistant CLL, where patients were becoming refractory to ibrutinib and you added venetoclax and you've had some nice long standing responses to that.

Yeah, I think one space where it's much easier to say that people will be benefiting from a non chemotherapy approach is what we were saying earlier is people that shouldn't be receiving chemotherapy. If you look at someone with an infection, like we were discussing, obviously that person, even if it's an initial therapy, you don't want to give cladribine, right? I think the other space is people whose hairy cell leukemia isn't really benefiting the way we want from purine analogs, which is cladribine and Pentostatin, where they're getting treatment like every couple years.

And people with the variant of hairy cell leukemia because you don't get the same benefit from it. So it's much easier to say that we should try a non chemotherapy approach for people who we know their leukemia is not going to get a really nice result from it. Vemurafenib actually can have better results there, especially with rituximab, than you'd expect from purine analogs.

Moxetumomab pasudotox, which is no longer on the market for manufacturing reasons, was in that category. And then the most recent one is, as we heard, ibrutinib, which targets a protein called BTK. It is a very slow therapy though. It takes a long time to work. It's approved in this class of drugs approved in other chronic B cell cancer, chronic lymphocytic leukemia, lymphoplasmic lymphoma, sometimes Waldenstrom's macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma. Across the board with all these cancers, hairy cell leukemia, it's similar. It takes years to develop an optimal response to it.

So people feel better quickly. Their blood counts normalized quickly. It controls the kind of notable effects of leukemia quickly. But if you do bone marrow biopsies, there's still a substantial amount of leukemia in the bone marrow, years into treatment, so it's actually an indefinite treatment.

So people take the drug until either it stops working or something else changes with their health and they have to quit taking it or they develop a side effect and it doesn't make sense to continue. And so when you have something, responses, people feel better quickly but take a long time to get an optimal response even years.

And it's a long term treatment. That's probably not something that will replace a limited duration treatment as a first therapy, so people want to take something they can finish and enjoy years of remission without treatment. We should clarify because I didn't mention it earlier that most of the studies looking at BRAF inhibitors are time limited.

So you don't get the BRAF inhibitor in perpetuity. You may get it for as short as eight weeks or four months. And that's for classic hairy cell leukemia where the results are good. I do think for patients with the hairy cell leukemia variant, taking it as a first treatment is actually completely reasonable depending on the biologic features of that.

So I should clarify if something like a purine analog or if a short course of vemurafenib with an antibody is going to be extremely effective, then you probably wouldn't consider taking a drug that's continuously dosed. However, it's been very important for people with Hairy cell leukemia and would not be expected to benefit from purine analog.

The study that we did here was led at Ohio State, but it's actually a multi site study, including MD Anderson, the NIH, Mayo Clinic and Karmanos. We had 44 patients. Less than a third had the variant form of hairy cell leukemia. The median number of prior treatments people had taken when they enrolled in the study was four. And the kind of median amount of time they've been living with hairy cell leukemia was 10 years. So the study was enrolling people who had taken other treatments and were not expected to get a huge benefit from purine analogs.

Many of those patients had taken BRAF inhibitors like vemurafenib previously. So it was known that that wasn't going to really get a very long term remission. So the goal was to try to treat people who weren't going to get a huge benefit from these other treatment options with this. And we actually had very good results.

Somewhere around three quarters of the people participating had a very long term benefit, including the median progression free survival not being reached yet. And we have for some people up to six years of follow up. I take care of people in the study who didn't get a long term benefit from any other treatments that have been on ibrutinib for 10 years, and it's working really well for them.

So that is an excellent option. But when we're talking about should we replace an initial therapy standard for classic hairy cell leukemia? Probably not. The really nice thing about that, the study wasn't designed to look at this specifically, but we did an exploratory analysis to try to look at was there a difference in how people with classic versus hairy cell leukemia variant did in the study.

And it looked like there was no difference in how well it worked for those groups of patients, which I think is great because typically, people with the variant hairy cell leukemia don't get the same benefit from treatments like purine analog. So that was really exciting. There are two newer or second generation BTK inhibitors that are approved.

Ibrutinib is not approved in hairy cell leukemia, however, so it can be used off label, meaning it's approved for something else. However, it is in standard treatment guidelines, so it is something that is usually approved by insurance for treatment of hairy cell leukemia. There are two newer BTK inhibitors, a drug called AcalIbrutinib and one called XanIbrutinib that work in the same way, but have fewer cardiovascular or heart related side effects, so are generally preferable. I think it would be important to try to study those in hairy cell leukemia, however, I do recommend those over ibrutinib for people with hairy cell leukemia just because of the better safety profile and in other cancers it's equally effective to ibrutinib.

One last, one last partial answer to your question, which is that it also differs whether you're talking about classic hairy cell or hairy cell leukemia variant, and I would be willing to accept a much lower bulk of evidence in order to, say, change my practice in the frontline treatment of hairy cell leukemia variant than I would for a classic hairy cell for, I think, some of the reasons that have been articulated already.

And the Ibrutinib study did allow treatment for people with hairy cell leukemia variant who had never had a treatment previously due to the less good outcomes with purine analogs. And I think that's very appropriate.

I have one patient who's a older woman who has hairy cell leukemia variant and her local hematologist has been treating her with pentostatin a couple of times. Her spleen would shrink and then grow right back as soon as they stopped the pentostatin. It turns out that she had an abnormality of P 53 plus an abnormal chromosome 17.

And so when we put this patient on ibrutinib with rituxan, she's been in a complete remission with negative minimal residual disease now at three years. So this is encouraging that some of the newer approaches will have a benefit for people with the variant, but they need to be studied in a larger patient population before we can make definitive statements.

I know we talked about this too, about what other studies have yet to be done. For example, in patients who present with an extraordinarily high soluble IL-2 level, should we be treating them longer or with different therapy to get a more sustainable remission, or does a phenomenally increased soluble IL-2 always coincide with aggressive presentation. And should we treat those patients, or should we study those patients to see whether a different approach to therapy is best?

Are there markers of the hairy cell leukemia that would be consistent with a shorter remission? And one of those markers needs to be further evaluated, like soluble IL-2 levels. And in patients who present with extraordinarily worrisome markers, should they be treated differently than somebody who presents with a typical presentation?

I'll say a little bit more about soluble IL-2 receptor because some of your physicians may be ordering this as a tumor marker. Others may not be. I also make it a habit of ordering soluble IL-2 receptor. This is just a protein that's produced by the hairy cell leukemia cells. And in fact, it is the same thing as the CD25 marker that is measured on the surface of the hairy cells, just ejected into the blood and floating around, and it's a protein that we can measure.

Many cancers have tumor markers. You might have heard of things like PSA for prostate cancer, or CEA for colon cancer, and so forth and so on. A soluble IL-2 receptor is a really good surrogate of how much hairy cell leukemia there is in the body. And and so whether or not you're doing repeated bone marrow assessments, you can get an idea of the amount of hairy cell might be going up on serial visits, even if the blood counts aren't changing. And so the question that you're asking is, what could this be predictive of? What I found is that these patients have very high soluble IL-2 receptor levels. And consequently, we infer to have very high tumor mass.

Because hairy cell leukemia is a liquid tumor, it doesn't exist all in one place, but you can still think of it as mass or volume in the same way as somebody with a very large lung tumor, for instance. So patients with very high tumor mass are less likely to get a really good deep response with a standard five days of Cladribine, say, or, six cycles of pentostatin.

And this is one of the things that I think would be phenomenal to use the Hairy Cell Leukemia Registry for is to answer questions like this. In patients who have these very high levels of tumor marker, are they more likely to have only a partial response? Or are they more likely to have a CR but one that's MRD positive?

Are they more likely to have a shorter relapse free survival or meaning their disease comes back sooner. I can say anecdotally the answer is yes and again anecdotally the patients that I have in my clinic who have these really super high levels all tend to be young people and I don't know if that's a biological effect or not.

I'd say anecdotally means our experience but there's no scientific evidence is what we're talking about.

 In other cases, people just don't like seeing doctors sometimes, which I get. So sometimes people have had symptoms for a really long time, but were just busy and didn't get it checked out. So it could be that this happened over time, although I do think it's probably more rapidly growing hairy cell than people that don't end up with these high levels of it.

And then actually I think younger individuals, especially with anemia, might not notice it as much because their physiology will compensate for it better. So I think sometimes we see this in younger individuals just because more things have to be wrong before they actually feel poorly and go get this looked at.

Soluble IL-2 does have some limitations, so extremely high levels are usually because hairy cell leukemia cells are releasing it. Remember, hairy cell leukemia is a cancer of B lymphocytes, which are immune system cells. So it is a hormone that can be released by healthy immune system cells into the blood in response to infection.

So you can see slight elevations in it in response to viral infections, like other things that stimulate the immune system. So you really have to look at the trend of it overall. And not any one individual day if it's slightly elevated. Even healthy adults will get slight elevations in it if the immune system's activated against something.

Audience question about whether Soluble IL-2 test should be performed routinely on patients in remission

Discussion with Drs. Michael Grever, James Blachly and Kerry Rogers

In my opinion, the answer is yes, because as Dr. Rogers said, it's not any single value that matters as much as the trend over time. In some cases I've been able to anticipate people who are going to need therapy soon, even before their blood counts have dropped in such a way that they meet criteria for retreatment.

 The level of the soluble IL-2 receptor is not a reason to start treatment. I also like to monitor it routinely. There are some drawbacks to it. One is if it's like slightly elevated, people worry what's going to happen. And it could be that they had a viral infection; they come back six months later and it's back down to normal levels. So it does create some worry. I also think it's helpful to regularly look at the trend of it. And then also if you're not seeing someone very often and maybe their blood counts are just slightly different and this is going up there, okay maybe come back a little sooner than you would have otherwise so that we can monitor these trends better or start having a discussion about maybe what next treatment options might be even though it's in no way time for that.

Follow-up question from audience member about how often soluble IL-2 levels should be checked

Discussion with Drs. Michael Grever, James Blachly and Kerry Rogers

It totally depends on the person so if people are coming once a year then annual should be fine if it looks like they're in remission and everything's normal. But then again if blood counts are changing and people are coming more often or you're trying to figure out the trajectory, more might help.

I would agree with that. If the anticipated visits are going to be far apart, if you see that the soluble IL-2 level is creeping up, you may want to shorten the intervals or get a more frequent blood count just to make sure that they don't get into a more dangerous situation because when the counts go real low then it's more dangerous to treat.

But I would agree completely that you don't treat the soluble IL-2 level. You just use it as a marker. And there I'd also like to add, there's probably a lot of hematologists that don't do this because it's not firmly established in the guidelines that it needs to be done.

It's hard because it's not an easy assay to do to measure and so if you're not at a referral center, maybe it's not even easy to get done.

I will say that when I started, it was a very niche and obscure test limited to immunologists and subset of hematologists. It has emerged as a very important lab that is checked in patients getting CAR T cell therapy, the chimeric antigen receptor T cells. You've probably all heard about the little girl who had refractory ALL, and it went away with these engineered T cells that she got. So soluble IL-2 receptor is, as Dr. Rogers said, produced by normal cells of the immune system. And so it's an important marker of inflammation.

One of the toxicities of CAR T therapy, which we might even talk about in the context of hairy cells, is soluble IL-2 receptor. Therefore it's available at more and more centers and there's more knowledge that this test even exists. So it is becoming easier to obtain.

 I think send out labs are also easier to obtain in this day and age. So sending blood to a reference lab or another center. Mayo Clinic just has a huge reference lab.

There's some rural communities here where they can't even do labs that are very easily done here. And in a general oncology practice, you might have one patient with hairy cell leukemia. It's not something that's easily done in all practice settings.

Audience questions about HCL variant

Could we take a few minutes to do a deeper dive into HCL variant?

Some of the questions that have been coming through are different treatment options: what's new, what's being thought about for HCL variant? What's the prognosis difference between HCL variant and classic?

Discussion with Drs. Michael Grever, James Blachly and Kerry Rogers

I'll start maybe a little bit. What is it? So hairy cell leukemia variant is so named because under the microscope it looks very much like classic hairy cell leukemia, but when we measure proteins on the surface of the cell they're different in some ways.

It's still pretty close. It's closer than some other similar blood cancers like diffuse large B cell lymphoma or CLL, but there's some differences. And so we've known for a while that the biology is different and we're now starting to understand what some of the causes of the disease are and how they differ in terms of signaling pathways and how the cell works on the inside.

So even though the cell looks the same on the outside, it looks like a hairy cell, it's really a distinct disease that shares some common activation pathways, which is one of the reasons that it looks the same. But the causes of those pathways being activated are different. Therefore, we have to find different ways to target it.

For example, classic hairy cell leukemia tends to have this BRAF V600E mutation that has been discussed. Variant hairy cell does not. It does not have this mutation. In fact, I would go so far as to say if it has the mutation, it's definitely not variant hairy cell leukemia. And if it doesn't have the mutation. Some people disagree with me, it is not classic hairy cell leukemia. Nevertheless, there are similar mutations that can activate the same pathways in the cell, and we have to find alternative medications to target them, things like MEK inhibitors. On the other hand, we can look at other commonalities like the final common pathway of expressing proteins on the surface, and there may be antibodies that could target both of them.

When Dr. Blachly said causes, he didn't mean what a person was exposed to or something they did to cause the cancer. He's talking about causes inside the cell or ways the cell broke to become a cancer cell. It's not that it's caused by something in particular.

Our colleague Chris Oakes has done a huge biologic study. The cell of origin of these cancers is the B lymphocyte. He's done a huge biologic study of different B cell cancers and classic hairy cell leukemia is in one group by itself. Variant hairy cell leukemia actually has a couple different subtypes and is more similar to some types of slow growing lymphomas. So the name comes from it looking like classic hairy cell leukemia, but some of the biology is more similar to other lymphomas than classic hairy cell leukemia, which I think is really interesting.

I think the other question that was asked is are outcomes different with variant cell leukemia?

And yes, they are different than with classic hairy cell leukemia, although variant cell leukemia is even rarer than classic hairy cell leukemia, so it's harder to get a handle on how people do in general. And it is a mix with some people doing very well with it and some people doing less well.

But when you have very few people to rely on to provide accurate information, when you're looking at what happens to a population of people with it, it's harder to make as many statements about what to expect. We do know the purine analogs work less well. So if you treat 10 patients with classic hairy cell leukemia and 10 patients with variant with cladribine alone, You'll see the people with classic caroselicemia do much better.

We know it's about average of seven to eight years until they would need another treatment if they're going to need one. Some people again two decades later haven't needed treatment and are still in remission. You don't have that same expectation with variant. A lot of them have a mutation or the loss of a gene called TP53, which is a tumor suppressor gene, which across the spectrum of cancers predicts very poor response to traditional chemotherapies.

So this is definitely a group where there's no consensus on what the standard initial treatment is. And I think discussing with your physician about what might be best for you as a person is really important if that's something that you're living. Certainly, I would suggest participation in a clinical trial for patients with this very rare subtype of disease.

Yes, and the ibrutinib trial enrolled patients with variant cell leukemia. We are going to shortly have open a study with venetoclax, which is a targeting approach called BCL2. That will include people with variant hairy cell leukemia. That's being led by Dr. Kreitman at the NCI that we're going to have that available here.

And moxetumomab pasudotox had patients with the variant enrolled who did well.

So I think when we have novel therapies that might be suitable for both classic and variant hairy cell leukemia, allowing people with a variant to participate is really important.

 Just in general, to answer the rest of the question, given the high incidence of TP53 mutations in variant hairy cell leukemia, I really encourage the use of non chemotherapy approaches, whether it's a monoclonal antibody or an immune activating therapy like a BiTE or a DaRT, or a BTK inhibitor. Really try to stay away from chemotherapy in variant hairy cell.

When we're trying to think about what really impacts how well people with classic hairy cell leukemia do and also to help people with the variant of hairy cell leukemia do well over their lifespan, I think this is going to be a really important use of the patient data registry in years to come, especially when you have variant, which is even rarer.

Before I was working in hematology, they were looking at features when people are diagnosed with classic hairy cell leukemia that predicted worse outcomes, those things like severe anemia. I think that needs to be redone now with what we know about treatments. And I think that's an important use of the patient data registry. I think looking at how people do with a variant and what treatments they took and how that worked out for them is going to be a very important use of the patient data registry, which does allow participation for people with variants.

My patient that has had such a dramatic and impressive response to the variant; she not only got ibrutinib, but we also gave her six weekly doses of rituximab. And that emphasizes, in my opinion, that we do need to be looking at strategic combinations. And the reason why we only gave six weeks of rituximab is, she had somebody very close to her die with COVID.

And so you have to be careful giving rituximab when the incidence of COVID is rising. It raises the ongoing discussion that I have with a lot of patients and that is they're more distrustful about getting vaccinated.

So it's not a good idea to give Rituximab and then try to vaccinate somebody. You got to factor all these things in and discuss it with the patients. You have to rely on their wishes, but there are important aspects here to combined therapies probably better than single therapy.

Just to add a little bit to that for the people online wanting to know more about variant hairy cell leukemia. One of the differences in classic and variant hairy cell leukemia is that CD 20, which is the target of rituximab, is expressed much more brightly, or at a higher level, on the surface of variant hairy cells. Therefore, these cells may be more responsive to the same dose of Rituximab.

Discussion with Drs. Michael Grever, James Blachly, and Kerry Rogers about IGHV4-34 variant

Can you add a few more words about the IGHV4-34 variant. You might not even know it exists if you don't have it, but for those who do, they're concerned about what their options are.

IGHV4-34 is just a specific gene segment that is expressed in hairy cells or other B cells. So, the immune system is a miracle and we are able to recognize billions and trillions of different foreign proteins. One of the ways is the way in which B cells, remembering that B cell is the normal counterpart of hairy cells, can make antibodies in various combinations. So all of us have hundreds of different gene segments, which are given numeric identifiers that recombine in different ways to form an antibody.

Antibodies can either be secreted or antibodies can be expressed on the surface of a B cell as a receptor. And these gene segments recognize different things. The IGHV4-34 is just one among many gene segments that can form an antibody. What we've noticed is that when present, not only in hairy cell leukemia, but also in other similar diseases like CLL, chronic lymphocytic leukemia, it seems to signal more powerfully to the cell that the cell should activate itself. The V434 when present in the immunoglobulin receptor on the surface of a B cell activates that B cell much more strongly than when others.

They activate the cells at a very high level and this serves as an additional source of drive or gas pedal, right? So cancers are counterparts of normal cells where somebody has just got their foot on the gas at all times. And this is one mechanism that cancer uses to have its foot on the gas.

It's like a marker for something that's a more biologically aggressive form of hairy cell leukemia, still within the spectrum of a lower grade leukemia.

I think more information is really needed, how to optimally address that with treatment, things like that. One last comment is that because this is an independent way of cancer having its foot on the gas, these patients who have the 4-34 may not have a BRAF mutation and that's been shown by Dr. Kreitman and others.

Often they have other ways of activating that same pathway, like map kinase mutations. And as the cells are promoted to be more active and grow, it just makes it harder to bring them under control. Those patients who have that, as they said, tend to be BRAF negative in terms of the mutation. So they tend to have a worse profile for response.

And mostly when we talk about mutations like the BRAF V600E mutation or TP53 mutations, we think of these mutations as changes in a gene, like a mutation of a normal gene that's bad or helps it be a cancer. What Dr. Blachly was talking about with these gene segments being rearranged or mutating; that's actually a normal process that B cells undergo. So mutation in this context is something they're supposed to do so that you can make immunoglobulins against all the things that are dangerous using one DNA blueprint.

So sometimes it gets really confusing when you talk about mutations in the context of something where the cell is supposed to go through a process to mutate this one specific gene versus mostly when we talk about mutations as something that's bad or negative that's happened to a healthy cell to help it become a cancer.

Audience question about vaccines

There was a question that came in about vaccines. When you're helping a patient manage their care, how do you help them make decisions about which vaccines they should absolutely get, how to time those vaccines with their treatment and what considerations they need to explore with their physician.

Discussion with Drs. Michael Grever, James Blachly and Kerry Rogers

In general, in order to get the best response to a vaccine, it would be better to get it before you've been treated with chemotherapy or targeted therapy or antibody therapy. Because, once patients have had treatment with, Rituxan, for example, it could be many months before they can reorganize and get a good response to a vaccine.

There is a couple of vaccines that are particularly important for people with chronic lymphocytic leukemia as well as hairy cell leukemia: vaccines against pneumococcus. I've had patients who refused or didn't get their pneumonia vaccine, and they had overwhelming sepsis with bacteria caused by the common cause of pneumonia, which is the pneumococcus. And so I think it's important that the patients get the latest version of the pneumonia vaccine. And right now, I believe what we're recommending is Prevnar 20 for patients who haven't had other anti pneumococcal vaccines.

I think it's also important to get an annual flu vaccine because they try and design those to be appropriate for the most prevalent form of flu. And certainly with COVID, there's been a lot of mistrust of the COVID vaccines, but, we've seen marked improvement in survival over the last couple of years in dealing with the COVID vaccine and this probably reflects the fact what there probably are changes within the virus itself, but there are many more people now in the community that are vaccinated against COVID. And some people have had COVID develop their own antibodies against COVID.

 I usually try and focus in on the pneumonia vaccine. In general, these are just very approximate suggestions, but I usually try and look and make sure people have been vaccinated within the last five years at least. Annually we try and encourage them to get the flu vaccine. I've been trying to encourage them to stay abreast of the most important new COVID vaccines.

There are other vaccines that are also important. I know a lot of people take the position that they'd like to get the Shingrix and I think that's reasonable. I don't know how much protection everybody gets with the Shingrix.

So even if they have had the Shingrix, once you start somebody on therapy, they're probably going to be more immunosuppressed. I always put patients either on Valtrex or acyclovir prophylactic doses to prevent shingles, probably because I've had a few patients that have died from shingles.

It's not a benign vaccine. The tv commercials tell you that most of us have the virus asleep within our bodies because of our exposure as children. And when the immune system goes down, this can become overwhelming. I've had patients die from disseminated shingles or disseminated infection with that virus.

I was going to reemphasize the shingles vaccination. And when I first started here, 10, 12, years ago, there was still a live attenuated shingles vaccine on the market, which was pretty terrifying for patients who are immunocompromised. And we had to caution patients.

Not only don't get this, but you can't even be around people who have recently received live attenuated shingles vaccine. There are still a few other live attenuated vaccines on the market, typically in pediatric indications. And so patients who have had purine analogs need to stay away from people who have had live attenuated vaccines.

Live attenuated means there is a live, real active virus. It's just been dialed down. But for people with no immune system or a weak immune system, it can still be transmitted, potentially deadly. I'm a big advocate of the shingles vaccine, which may not even decrease the number of people who get shingles, but it decreases the incidence of post herpetic neuralgia or permanent chronic pain from shingles, which is a horrible complication.

I like to say get all the vaccines that are owed to you. There's a RSV vaccine, which RSV is not usually fatal for adults, but it is highly unpleasant. And so for anyone over 60, you can get the RSV vaccine. I say get all the vaccines that are owed to you, but avoid live vaccines. If you're not sure if something's a live vaccine or not, the person offering you the vaccine should know that answer.

 As an immunocompetent adult, I try to get all my vaccines that are owed to me too. I got my updated COVID vaccine and flu shot early this year, or as early as I could, because I was going to Spain and I don't want to get COVID in Europe.

Especially in a population of people who are immunocompromised for infections, even if they don't result in being in the hospital, are going to be much more unpleasant. It's a good idea to make sure you get all the vaccines owed to you, whether or not you need treatment now.

Audience question about revaccination

Discussion with Drs. Michael Grever, James Blachly, and Kerry Rogers

So absent a bone marrow transplant, we don't typically re vaccinate people, even those who get immunosuppressive therapies because we have both memory B cells and memory T cells which serve as a reservoir that can keep you alive. There's something called the anamnestic response, where even if you haven't been exposed to something in a long time, if you once upon a time had immunity to it, then that can grow back out.

It might be delayed a little bit, but we don't recommend revaccination in general unless you've had a stem cell transplant, which we're not typically doing for hairy cell.

Discussion about Prophylaxis

I routinely use zoster prophylaxis in patients that are being treated and even after treatment.

There was one report that said that once your CD4 cells were over 200 that you could stop the prophylaxis for shingles. I'm not so sure. It may work for patients who have HIV, but I had a patient who was adamant about getting off of the Valtrex, even though it wasn't causing her any problems.

She waited until her CD4 count was 210 and then she stopped it and then she got shingles. I tend to keep people on the Valtrex until they start to get a normal lymphocyte count back and we're well beyond the therapy.

With respect to PCP prophylaxis, that's an important question. One of the more common ways to prevent pneumocystis pneumonia from taking a hold on patients after therapy is to use Bactrim. However, Bactrim can also retard the recovery of the bone marrow. I don't routinely start everybody on spectrum, but I worry about it all the time.

There are other ways that you can prophylaxis people. One is by using dapsone. That also has some things you have to watch, because it can cause abnormalities in the hemoglobin. And there is a way to use pentamidine to try and prevent it. But that's not so easy. So I caution patients if they are coming off of therapy and their lymphocytes are low, that they have to be aware that there is this entity called pneumocystis pneumonia that can be very aggressive and present with rapid progression. And if they get any fever or cough or shortness of breath, they need to go to the emergency room to make sure that they don't have a developing pneumonia.

I think to o what preventative anti infection agents to use depends on like the patient and what treatment you're doing. I also usually use acyclovir to prevent shingles. In fact, even when people aren't on treatment or haven't been for a while, if they get recurrent shingles, sometimes it's worth just staying on the drug. Those drugs are very safe, relatively inexpensive, and don't have a lot of side effects. I always recommend continuing them for either six months or a year after treatment, because that's where we start to see the risk of shingles dropping.

I don't use PJP prophylaxis unless someone's also been on high dose steroids. And that's with the purine analogs not with those targeted drugs.

I don't use regular antibiotics like levaquin or fluconazole except for some sort of unusual circumstance because you don't see those infections or those helping.

I've had some cases of disseminated zoster even after 18 months, and it seems to be worse with cladribine plus rituximab, anecdotally again. So now I'm a little bit more aggressive about continuing Valtrex through 18 to 24 months post therapy. Again, no data, but I've had several patients who've had horrible shingles. It was disseminated.

I'm doing less and less Bactrim. I've actually never seen a case in my hairy cell patients, I have in some of my other patients of Pneumocystis Pneumonia; it can be a little bit hard on the bone marrow in terms of recovery.

It's more common among HIV AIDS patients who have CD4 count less than 200 for years and years. Whereas, it may just be 12 to 18 months that the CD4 count is depressed in a patient with hairy cell who got chemotherapy.

The last thing I would say is I've had several consults come in, patients had chemotherapy, cladribine typically, somewhere else. And they come to see me because their blood counts are really slow in recovering. And those are the type of people that I would put on levofloxacin, Levaquin, because their neutrophil count is still struggling to get up to 500 or up to a thousand.

When the absolute neutrophil count is 500 or less, the chances of getting a serious bacterial infection go up pretty significantly. So I would use antibacterial prophylaxis. I have in patients whose absolute neutrophil count is below 500 and looks like it's going to stay there for a while.

I did that large study many years ago with hairy cell patients, where we had 356 patients. We didn't see very many cases. This was in 200 different hospitals.

We didn't see very many cases at all of pneumocystis. But what we weren't routinely capturing was how many of those patients were on prophylaxis. I haven't routinely been adding the bactrim unless unless patients had a recent course of steroids like hairy cell.

Additional discussion with audience

So they're asking, can the vaccine replace the antiviral or should you do them both? I get asked all the time, can I get shingrix and stop taking Valtrex? I think of them as completely different things. So if you get a treatment that is immunosuppressive enough, the immune effect or benefit from the vaccine is going to be low enough that you should get the antiviral during that time too.

You want to time the vaccine either before treatment when you're going to benefit or far enough out from treatment that you'll benefit. So I wouldn't start the treatment, start taking Valtrex and get a vaccine a week later. So if someone hasn't gotten Shingrix, then you take the preventative antiviral and get Shingrix once you have immune recovery.

Audience question about bone marrow transplants

There's one question that has come through three times in today's Zoom, and I think it's worth talking about for a few minutes. There's no cure for hairy cell leukemia yet. It's a chronic disease, manageable, but chronic, and we don't yet have a cure.

Why not just consider a bone marrow transplant, particularly in HCL variant, where you have fewer treatment options?

Discussion with Drs. Michael Grever, James Blachly, and Kerry Rogers

That is a really good question, and in particular, in the context of hairy cell leukemia variant. That may be the one type of hairy cell patient who could benefit from a bone marrow transplant.

But I want to paint bone marrow transplant not as a savior, but the bad guy. And just very broad numbers obviously it differs based on age and a lot of other factors. When I'm talking to a patient about a bone marrow transplant, I will tell them that about a third of patients will have a successful outcome.

They'll be in remission and they'll have a pretty good quality of life. Might be a couple of side effects that are lingering or long term. About a third of patients will die from the bone marrow transplantation procedure itself. It is a very toxic and dangerous thing. And then the last third of patients, may get a remission or they may not, but they're going to have such horrible side effects that they probably wish they would have not undergone the bone marrow transplantation.

So when deciding when to offer it, we look at what are your outcomes from the available treatments likely to be. And if your outcomes from the available treatments are looking worse than the numbers I just quoted, then it could be a really good alternative. That happens sometimes in very refractory chronic lymphocytic leukemia, for instance, it's very uncommon.

When you hear stem cell transplant, what we're talking about here is a stem cell transplant where you get stem cells from a donor. So a stem cell transplant where you get your own stem cells back is a way to give high dose chemotherapy. And that's not what we're talking about.

The goal of it actually is to have the donor's immune system live in your body and attack your leukemia. It's an immunotherapy. Not only is it a dangerous process to go through because for a while, nobody's bone marrow is working and you're at risk for infections. Your transfusion dependent. But also the donor's immune system, you want it to attack your leukemia, which may or may not happen. It can attack your healthy tissues, which is something called graft versus host disease, and it is completely devastating.

A donor stem cell transplant might cure me. Yes. But when you look at your options of having a normal lifespan, but needing repeated treatments, which could take some time away from your life and are expected to have some side effects, but that you're unlikely to die from and are likely to work. Or to get a therapy that has a 30 percent chance of killing you and more than likely you're going to end up with chronic medical conditions that require more appointments, more side effects, and more treatment burden than living with the hairy cell leukemia variant. You're probably not going to want to do the thing that has a chance to cure you, but is more likely to either hurt you or end up with you needing more chronic medical care, pills, side effects, than if you were to just take repeated therapy for something that's not likely to cure you.

So if you look at the treatment burden in terms of visits, costs, side effects people are living with, and certainly quality of life, it is going to be better with treatments than with a stem cell transplant.

Audience question about benefit of removing the spleen

Discussion with Drs. Michael Grever, James Blachly and Kerry Rogers

With hairy cell, because it's a blood cancer, it's throughout the body, so if you remove the spleen, because you need to, the hairy cell throughout the body will eventually cause problems.

Think of it as a patient with, I use the example again of metastatic lung cancer. If you have a big tumor, you might still benefit from taking it out, doesn't mean that it's not in some other places. So it's a way to, what we say, debulk the disease.

Splenectomy can be really helpful in debulking the disease. Maybe you'll remove 90 plus percent of the hairy cell that's in that person's body. Certainly it's not a cure, but it can provide important symptomatic relief.

Panelists' concluding remarks

Before we wrap up, this session was really to talk about the future and we're running short on time. But I could say just really briefly, the future is really bright. There's a lot of exciting things on the horizon. I took the opportunity to peruse clinicaltrials.Gov earlier today before I came up here to see what's open where and there's so much going on for a disease that's both rare as well as thought of mistakenly, in my opinion, a fixed or solved problem.

There sure is a lot of great work going on at a number of different centers of excellence throughout the United States. And these range from everything from brand new BTK inhibitors, to immune activating therapies, to engineered T cells, CAR T therapies, as well as randomized studies looking to answer questions like the one Dr. Grever asked, should we be giving cladribine and rituximab together, or should we be giving a novel combination therapy? So we're really answering a lot of questions, answering them in high quality ways. There's active ongoing research in this disease, and I tell patients that by the time you need treatment again, whether that's in two years or 10 years, the treatment landscape will be totally different.

So be hopeful for the future.

This transcript has been edited for accuracy.