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Webinar: What’s New in Hairy Cell Leukemia?

March 25, 2019

Hosted by the Hairy Cell Leukemia Foundation with guest speaker, Dr. Robert J. Kreitman, National Institutes of Health


Transcript

Welcome and Introductions

Brief introduction from Marc Stadtmauer, HCLF Board of Directors

Presentation

Robert Kreitman:

A little unusual that this would happen, but sometimes there are other bone marrow disorders that are good to know about before you start treatment, particularly chemotherapy. One main goal of diagnosis though is to rule out hairy cell variant. So what is hairy cell variant? I think that's important to clarify at the very beginning.

So you can see here that hairy cell variant comprises between 10 and 40% of hairy cell cases depending on what epidemiologic studies you read. The rest of the patients are classic hairy cell. The spleen enlargement is particularly severe with hairy cell variant and patients could have lymph nodes which are rare with classic hairy cell.

The normal blood counts are at a normal level often in hairy cell variant and they're low in classic hairy cell, whereas the leukemic cells are high in the blood in hairy cell variant and they're low in classic hairy cell. Hairy cell variant is defined by an absence of CD25, an important marker on hairy cells, and recently also by not having the BRAF V600E mutation.

So again, hairy cell variant, we call HCLv. It comprises 10 to 40% of hairy cell and where the spleen enlargement is particularly severe. There can be lymph nodes in hairy cell variant, unusual for classic hairy cell.

The normal blood counts are low in classic hairy cell, often normal in variant. Whereas the leukemic cells in the blood are high in variant and low in classic hairy cell. CD25 is absent in hairy cell variant and BRAF is unmutated in variant and has the classic V600E mutation in classic hairy cell.

Okay. The response to cladribine or to pentostatin is poor in variant hairy cell and very good in classic hairy cell.

So I want to start by introducing this regimen of cladribine plus rituximab for hairy cell variant. This is where we combine the cladribine, given daily for five doses, with eight weekly dose rituximab. In this case, we're starting the rituximab on the same day as the first dose of the cladribine. We found that from looking at the literature and almost 50 cases of variant hairy cell, that the complete remission rate to cladribine alone is only about 9%. And with this regimen or cladribine plus rituximab the complete remission rate is 95%.

We believe that based on this data that single agent cladribine or pentostatin would not be used for hairy cell variant and this is why it's important to get a good diagnosis to make sure you don't have hairy cell variant before you get single agent cladribine for classic hairy cell.

So what about getting this regimen for classic hairy cell? This is something that people are doing more often these days. Most people are still getting cladribine alone for classic hairy cell. This has been the standard treatment for about 30 years now, but more people are getting this combination. This shows that often the combination is started the same day, the rituximab is started the same day as the cladribine. Here the rituximab is started in a delayed fashion, either a month or five months or six months after the cladribine.

So what we find is that while the complete remission rate with cladribine alone is about 88%, the complete remission rate is 100% whether the rituximab is started early or delayed. So we know that rituximab can increase the complete remission rate from cladribine.

So the next question is what does complete remission mean and why is this important? So complete remission means that there's no hairy cell visible by the standard stains. Also that you have resolution of enlarged spleen and lymph nodes and also of low blood counts that patients have when they start out. Also, that the high hairy cell counts in the blood are also resolved. This is what we mean by complete remission.

But recently, we've been able to detect minimal residual disease and we call this MRD. So this stands for minimal residual disease. I'll try to remind you through this that MRD is minimal residual disease. What it is, is traces of hairy cells that can be detected by special stains of the bone marrow biopsy by flow cytometry of the blood or the most sensitive test, by flow cytometry of the bone marrow aspirate. There are more research studies that have been used to detect MRD like PCR. We believe that complete remission (CR) may last longer if the MRD is negative.

Though if you look at what I just showed and you add a column for the CR without MRD and how often people can achieve that, while we see that cladribine alone for hairy cell versus cladribine plus rituximab gives a slight improvement in complete remission rate, there's a huge improvement in CR without MRD. This is based on several studies, one of which was done at MD Anderson. So rituximab can increase the rate of CR without MRD and a clinical trial in once relapsed hairy cell is still ongoing at the NIH to determine how well immediate rituximab can benefit patients by getting them MRD-free.

So what about patients with multiply relapsed hairy cell? So in patients who've had several courses of purine analogue and usually we find that patients have had a couple courses of cladribine. We try not to use cladribine a third time. We try to use a regime called bendamustine or pentostatin. These are purine analoguess that are slightly different from cladribine and we believe there's a better chance that they will work in patients who are resistant to cladribine.

So what we do is we combine these with rituximab either with bendamustine given on day one and two, pentostatin given on day one and 15, but in both cases the rituximab is given every other week, every 15 days. We give six cycles or 12 doses of treatment on our protocol here at the NIH. We find a 75 to 85% complete remission rate. Most complete remissions are MRD-free. But while highly effective, this approach may be toxic due to the chemo. The chemo's being given at least the third or more often period of time.

So one could question can MRD-free complete remission be achieved without chemo? And then even more importantly, what's the benefit of being MRD-free? Is it just having these tests negative or does the patient really benefit by it?

Okay so from there I want to introduce a method that we can get patients MRD-free without chemo. So I want to contrast treatment with rituximab which has been around a long time, since 1995. It binds to CD20. It kills cells after binding to CD20. It has a complete remission rate of 13% without chemotherapy in patients with relapsed hairy cell. So it has very modest activity as a single agent.

Moxetumomab Pasudotox, as we call Moxe, is a engineered protein which has an antibody fragment shown here in blue, that binds to CD22 which is connected to a toxin. And the toxin is this yellow and red structure here. It kills cells after getting inside. You can see inside it splits up and the yellow and red part that's shown here goes inside the cell, gets to the cytoplasm and there it's very powerful in killing the cell. This drug, Moxe, has a CR rate, complete remission rate, of 50 to 65% in patients who are multiply relapsed. Most of the complete remissions are MRD-free. This drug was approved last September for relapsed hairy cell under the name of Lumoxiti.

So this is a way that we can eliminate MRD without chemotherapy. So but the question is, what does this mean? What's the benefit of this? So this shows that in the phase one trial of Moxe, 11 patients had MRD-free CR and only one relapsed. You can tell this group in green of 11 patients, one relapsed because the green line goes down one notch. The rest of the patients, the rest of these 11 patients are shown up here in the orange vertical bars at different time points after getting into complete remission. These patients are still in complete remission.

Whereas the patients who were MRD positive in blue, eight relapsed. You can see this curve going down eight times and there's only one patient still in complete remission shown at this time point. So Moxe is given by 30 minute infusions on days one, three and five. These cycles are repeated every four weeks.

So this curve shows that of seven patients who got one to four extra cycles, we call these consolidation cycles. That's a tough word but let's call this, for this purpose, extra cycles, after complete remission was documented. None of these patients relapsed. You can see this curve continues on and these seven patients are shown here by these orange bars. With regard to these 14 patients in blue who did not get extra cycles, most of these patients did relapse.

So CR duration, complete remission duration, is longer if the Moxe can clear MRD. This requires extra cycles. And that's our conclusion based on the study. We believe this is also the case with other treatments in hairy cell but it takes longer often to prove it because you have to follow the patients very carefully and you have to wait for them to relapse from complete remission.

So I want to show what we mean by minimal residual disease and just very superficially to show that complete remission shown here, this shows before cycle one, there's a monotonous collection of hairy cells in the bone marrow. And before cycle two, in other words, after two cycles of Moxe, these monotonous cells are replaced by normal bone marrow cells. You can see the immunohistochemistry, IHC, that shows the bone marrow cells with much greater contrast. You can see this red very clearly. That is gone after two cycles of Moxe, in other words prior to cycle three. Then we can see that the MRD seen by blood flow and bone marrow aspirate flow even more sensitive also disappears prior to cycle three.

This patient is still MRD free eight and a half years later. But it's too early to say that this patient is cured. We want to follow this patient another five to 10 years to really be more confident that this patient is cured and is not just going to relapse later.

So why can't some patients get complete remission from Moxe? 4 to 9% of patients get a toxicity called hemolytic uremic syndrome that we call HUS, where the platelets decrease and the creatinine increases. This creatinine is measuring kidney function. When it increases the kidney function decreases. But fortunately, HUS is temporary. The problem with it is that most patients who get it cannot be retreated. So it limits the number of extra cycles. Remember we said that these extra cycles are important for keeping patients into complete remission by getting rid of the MRD.

So that's a problem with HUS. Another problem with Moxe that limits patients from getting complete remission is that because the toxin in Moxe comes from a bacteria, the immune system can recognize the toxin and reject it. So the more cycles the patient needs for CR, the more chance the immune system has of interfering with Moxe and preventing these extra cycles from working. So if there's a lot of hairy cell, especially big lymph nodes, it takes longer for the Moxe to work, more cycles. And this gives the immune system more chance to reject the Moxe.

So in the phase three trial, a maximum of six cycles were allowed. So it would be best if we could achieve complete remission by two cycles and have four extra cycles to get rid of MRD.

Okay. So then I want to talk about a strategy for how we might do that, how we might get complete remission earlier using Moxe. That is shown on this slide. Where we want to target both CD20 and CD22 in hairy cell. So we want to use rituximab, which binds to CD20, remember, and also Moxe which binds to CD22. So a clinical trial is beginning at NIH in which rituximab will be given with Moxe and the first goal is for rituximab to reduce the amount of hairy cells so that Moxe can achieve CR more quickly.

A second goal is for the rituximab to reduce normal B-cells and prevent the immune system from rejecting Moxe. If successful, Moxe and rituximab could be tried for untreated hairy cell and that would be a chemo-free treatment.

So the next way that patients are treated with hairy cell now is taking advantage of this BRAF mutation that we talked about at the very beginning, where we're targeting the BRAF pathway with oral drugs. So in normal cells, BRAF, and this is shown starting here in green, the BRAF stimulates MEK which stimulates ERK and ERK results in normal cell growth and division. In hairy cell, BRAF containing the V600E mutation which is shown here in red, it over-stimulates MEK and then MEK over-stimulates ERK. That leads to increased cell growth and cancer. And the reason I say cancer and not just hairy cell is that this same mutation is seen in malignant melanoma and many other cancers as well.

So Vemurafenib, which is an approved drug, oral drug for melanoma, it inhibits BRAF V600E and this resulted in 35 to 45% CRs in the hairy cell trial. Dabrafenib is another drug that inhibits BRAF V600E and that drug, in combination with Trametinib that inhibits MEK. So now we're inhibiting both BRAF V600E in red and MEK in yellow. Both drugs together were more effective and less toxic than Vemurafenib for melanoma and they also appear very effective in hairy cell. Although hairy cells is probably not common enough to do a comparison trial like you can do in melanoma.

But these drugs, either Vemurafenib or Dabrafenib or Trametinib, they don't appear to eliminate MRD. Now to eliminate MRD, a trial led by Memorial Sloan Kettering for untreated hairy cell combines Vemurafenib with Obinutuzumab, which like rituximab, binds to CD20. And a similar trial in Italy is combining Vemurafenib and Obinutuzumab with a MEK inhibitor Cobimetinib. That's for relapsed hairy cell. These agents can have side effects including skin rashes and skin cancers for Vemurafenib, fever and chills for Dabrafenib, just to name the most common side effects of these drugs.

The oral drug, Ibrutinib, is also being used for hairy cell. Ibrutinib was approved for chronic lymphocytic leukemia and also mantle cell lymphoma. It inhibits a protein called Bruton's Tyrosine Kinase. Ibrutinib is reported to achieve up to 20% complete remissions approximately. Most of them MRD positive. So like the BRAF inhibitors, it doesn't seem to get rid of MRD in most cases and it can also be used however in hairy cell variant, even when you don't have the BRAF mutation. Because it doesn't target the BRAF mutation, it targets BTK, Bruton's Tyrosine Kinase.

So this drug, Ibrutinib, works better in hairy cell than in hairy cell variant. It can cause atrial fibrillation and can increase the risk of bleeding and infections. In general though, Ibrutinib is better tolerated than the BRAF/MEK inhibitors. Ibrutinib can take many months and even years to work in hairy cell. It works much more slowly in hairy cell than in CLL and NCL. So it should not be given to patients with severely low blood counts that need something that works immediately. A trial led by Ohio State University is still enrolling patients there and also here at NIH and MD Anderson, Karmanos and at the Mayo Clinic.

So in conclusion, untreated hairy cell is still treated with single agent purine analogues, but increasingly patients are using cladribine plus rituximab to eliminate MRD and to possibly prevent relapse. Hairy cell variant lacks CD25 and the BRAF mutation, and should not be treated with purine analogue alone. Thirdly, purine analogues including Pentostatin and Bendamustine can be combined with rituximab to eliminate MRD in relapsed hairy cell, albeit with chemotherapy toxicity.

Moxetumomab Pasudotox is approved for hairy cell and is the only chemo-free regimen with a high rate of MRD-free CR. BRAF and/or MEK inhibitors can rapidly achieve CR but generally cannot eliminate MRD. The oral inhibitor of Ibrutinib works very slowly in hairy cell but can also achieve complete remissions generally without eliminating MRD. And I want to end by saying that participation in clinical trials is encouraged for all patients.

These are the clinical trials featured on the Hairy Cell Leukemia Foundation website. Cladribine and rituximab at the NIH, Ibrutinib at many centers, Rituximab plus Bendamustine or Pentostatin at NIH. Moxe, Vemurafenib and Cobimetinib and/or Obinutuzumab. So with that I'd like to open it up for questions.

Question and Answer Session

Marc Stadtmauer: Okay great. So this is Marc. Dr. Kreitman thank you for that very informative presentation.

So first I’d like to start by asking a question of my own, and that is, you mentioned MRD, minimal residual disease. So Dr. Kreitman, why is that important to a patient? Why should we care about minimal residual disease? What does that mean for a patient?

Robert Kreitman: Well, if the minimal residual disease is where you get the relapse from, then the patient won't relapse, at least not as early. So that means that the next treatment may not be necessary and if it is necessary it may happen later than otherwise if the patient was MRD positive.

Marc Stadtmauer: Let's ask another question. If the patient is treated with cladribine and has made complete remission, but with MRD, should Moxe be administered to eliminate residual disease?

Robert Kreitman: Can you repeat that question there?

Marc Stadtmauer: Of course. [A patient has had] Cladribine and is in complete remission, but with minimal residual disease, can Moxe be administered to eliminate minimal residual disease?

Robert Kreitman: So this is something that could be possible, but it's not something that the FDA has approved Moxe for. It may be the subject of future research.

Marc Stadtmauer: So let me ask a question Dr. Kreitman. You mentioned cladribine, which of course is a chemotherapy. Can you explain why it's important to have other treatments beyond cladribine? Why is it important to get away from chemotherapy if at all possible? What are the advantages?

Robert Kreitman: So the problem with cladribine as well as other chemotherapy drugs, is that as you use them more and more, they don't kill all the hairy cells and the cells that survive, the hairy cells that survive come out smarter. These are the cells that learned how to in a sense, they're the ones who survived so those are the cells that are more resistant. So you're basically selecting for a more resistant population each time.

Therefore, the efficacy gets worse and worse. In other words, the change of complete remission goes down, the length of the complete remission goes down with each course. Also, the toxicity is compounded. There is an accumulative toxicity for these drugs. That's why we want to avoid using cladribine too many times. The official recommendations would say that if cladribine had a complete remission for more than four years, it's good to use it again. But patients are opting for other treatments, even if that's the case. Because it's clear that the chance that a second course of cladribine will work for the same time as the first course is not as good.

There are other agents to try and so we're seeing patients not opting for the same drug that didn't work the first time.

Marc Stadtmauer: Those other agents that you just mentioned, is that what you would call a targeted BRAF?

Robert Kreitman: Yes, so the BRAF drugs are targeted to BRAF mutation. The Ibrutinib is targeted to BTK, Bruton's Tyrosine Kinase. Rituximab is targeted to CD20 and Moxe is targeted to CD22. These are all we would call targeted drugs.

Marc Stadtmauer: Do these targeted drugs by and large, do they avoid some of the problems that you mentioned with the chemotherapy?

Robert Kreitman: Yes. So the main problems with chemotherapy are killing stem cells and killing fast-growing cells including the cells of the immune system. It kills normal T-cells, normal B-cells. This can bring the counts down, the normal platelets, normal red cells, normal white cells, and when they recover they may be lower amounts than patients were when they started.

Also there are incidents of myotrophy, a nerve damage that happens in about 15% of patients with the first course of cladribine or pentostatin. But this rate increases when patients are retreated.

Marc Stadtmauer: Now you also mentioned rituximab and first of all, is that used ever separately from another drug or is that only used in combination when dealing with hairy cell?

Robert Kreitman: So it's often used as a single drug and as I showed in my slides, the complete remission rate as a single agent is only 13%. So we believe that for most patients, you should avoid getting rituximab as a single agent and its real efficacy is when it's combined with other drugs. So if it's combined with cladribine it has a much better activity than if either the cladribine or the rituximab is used alone.

So we recommend combining to use rituximab in combination with a different drug.

Marc Stadtmauer: So what is the current state of the science so to speak for newly diagnosed patients? Is it just one drug or are you now recommending a combination of drugs for newly diagnosed patients?

Robert Kreitman: For newly diagnosed patients the standard treatment is still single agent cladribine. So there is no definite randomized trial reported yet that shows that combination is better. So the FDA would say that there's only single agent cladribine or single agent pentostatin for newly diagnosed hairy cell. But there are many clinical trials being done to determine if a combination with or without chemotherapy and what kind of combination will be shown to improve outcome in first hairy cell. That remains to be determined.

As I said, more patients are being treated with additional drugs, not just the purine analogues.

Webinar participant: The patient is 29-years-old. He's been diagnosed three months ago. He's BRAF negative. His CD markings are positive for classic hairy cell leukemia. He's been treated [with] cladribine, four weekly rituximab.

Last week when we were in Toronto with his oncologist, we asked her can she help us to determine if he is classic or variant. She said that she doesn't know. What is your opinion on that?

Robert Kreitman: With the classic form of hairy cell, this means that CD25 is positive. But the BRAF mutation is wild type, which means that it's not present. It's unmutated.

Webinar participant: Unmutated, correct.

Robert Kreitman: And so the patient was treated with a combination of cladribine plus rituximab and then followed by what we call rituximab maintenance. Getting rituximab on an infrequent basis as opposed to every week thereafter. So the question is, what else can be done for such a patient?

Okay so my feeling is that in some cases the patient is actually BRAF mutant but the PCR reaction didn't work because there is additional mutation that is causing some technical problems and prevents the PCR reaction from working.

So it's important to do very careful sequencing in the patient, to make sure that there isn't a technical problem with the PCR. The BRAF test is not only done by PCR. It's also done by on the bone marrow by immunohistochemistry. There's a special stain that can be done to look for BRAF mutation. Both effectively should be done before saying that the patient is BRAF wild type or doesn't have a BRAF mutation.

There's another syndrome that we see which is called V600E hairy cell leukemia. That it looks like classic hairy cell, in other words it has CD25, but the hairy cell is very aggressive and it requires this combination of cladribine and rituximab. So that requires some molecular testing and sequencing also to diagnose that. So there are other cases of classic hairy cell that do not have the BRAF mutation and so they will not benefit by the combination of Dabrafenib or Trametinib or Vemurafenib. Some of these patients are being treated with Trametinib alone, MEK inhibitors. But this is an area where there are some clinical trials being done.

In these patients, the combination of cladribine plus rituximab and also pentostatin/rituximab and Dabrafenib/rituximab, they sometimes can get very good results with these patients.

Marc Stadtmauer: Okay let me just read a couple questions that came in while you were answering that. Here's one. Dr. Kreitman do you need to be on a clinical trial to be treated with Moxe?

Robert Kreitman: No. This trial is available at several centers. I know that Ohio State has administered this drug. There are other centers that have been able to administer this drug both in the United States and in other countries.

Yeah it is approved by the FDA so it is available, at least in the United States.

Marc Stadtmauer: Here's a question.

If somebody's on their third treatment, so I guess that would be somebody that's relapsed at least twice, how would you decide what type of treatment to use? What would be the factors to make a determination as to which kind of treatment would be used for somebody that's on his third treatment?

Robert Kreitman: Okay so I would want to know what sort of responses they got with cladribine before. If they got cladribine before, what kind of chemotherapy they've had before, I want to avoid that, those same drugs the third time around. If the patient never received rituximab, they might respond very well to combination of purine analogue plus rituximab. Those patients can be treated with Moxe.

I mentioned the toxicity of HUS, hemolytic uremic syndrome, where there's a problem with kidney function. So I'd want to make sure that the patient had good kidney function. If the patient had good kidney function, then I would recommend Moxe as a third line treatment where it's approved by the FDA.

If the patient has the BRAF mutation, they could also consider the Vemurafenib drug or the combination of Dabrafenib/Trametinib. These are approved drugs for melanoma. They're not approved for hairy cell but oftentimes patients are still able to get these drugs. Then also Ibrutinib is another option that some patients are getting in third line, meaning third line means third time around being treated.

Marc Stadtmauer: We've got a number of questions about the cause of hairy cell. The questions are whether radiation has any connection with hairy cell and what progress has been made on making a determination as to what might cause hairy cell?

Robert Kreitman: So we know what causes hairy cell, at least superficially. We know that in most cases of classic hairy cell they have the BRAF mutation. So we know that it's a mutation that switches one nuclear type base for another and this causes a V600E mutation. We know that that increases proliferation, cell proliferation. It's the same mutation that happens with a skin cell that turns the skin cell into melanoma and they can turn a colon cell into colon cancer. And it turns the B-cell into hairy cell.

What causes mutations? We know that this happens at a low rate due to oxygen due to ionizing radiation. So radiation yes can cause mutations and therefore maybe some cases of hairy cell are caused by radiation. But we find that there's a lot of patients that have chemical exposure, pesticides. We've seen patients with Agent Orange exposure. We've seen many other occupational hazards in patients who have hairy cell. However, there are probably many people that have these exposures that don't have hairy cell. So it's very difficult to prove that someone's occupational exposure actually caused their hairy cell because no one was witnessing the actual mutation when it happened.

So these can be done only by proper large epidemiological studies and it's hard to do that when you have a disease that's not very common, like hairy cell.

Marc Stadtmauer: There's been a couple questions about pentostatin and apparently there are rumors that it's in short supply. Have you heard anything about that?

Robert Kreitman: I know from time to time that supply of pentostatin is low. That is a drug that was specifically approved for hairy cell and it's not in common use for other cancers. So that may be why it's occasionally in short supply. But hopefully those short supply periods of time will be transient and then the drug will be available. If it can't be used then cladribine can often be used.

Marc Stadtmauer: You also mentioned in your presentation that participation in clinical trials is encouraged for hairy cell patients. Can you elaborate on that? Tell us why you believe that participation in clinical trials is important.

Robert Kreitman: Well I think when you're participating in a clinical trial for hairy cell, you're getting number one, cutting edge treatment. But the other reason to participate in the clinical trials is that you're getting to see hairy cell experts that have seen more than just a few patients in their lifetime with hairy cell. It's not a common disease and therefore especially when you've had one or two relapses, it's important to see someone who has a lot of experience in this disease.

That I think you get more commonly with a clinical trial.

Marc Stadtmauer: We have a question about a drug I've never heard of this before, neupogen.

Robert Kreitman: Oh Neupogen, yes. Neupogen is a drug that increases the neutrophil cell count. This can be used to try to increase the normal blood counts when the counts go low because of chemotherapy. It should be used at least 24 hours after chemotherapy is over. You don't want to stimulate the normal cells when the chemotherapy is killing them. But when the chemotherapy is finished, Neupogen can be very helpful to elevate the normal blood counts and the normal neutrophil count and hopefully decrease the risk of infection, particularly in a patient who's already had an infection or having neutrophilic fever.

Marc Stadtmauer: Okay. So I think we've covered a lot of ground today. I want to give everybody a little time to think about it and I want to thank Dr. Kreitman once again for sharing his invaluable time and experience with the hairy cell patients. I think that as hairy cell patients, we are extremely lucky to have somebody like Dr. Kreitman on our side. A person every day who treats the hairy cell patients and does research to find new treatments for hairy cell.

I want to encourage everybody to please remember the foundation when they can and to support our work and to support the work of your researchers and the facilities

If anybody needs a copy of the slides that we looked at today, feel free to email Anna and I'm sure that she'll be able to get you the slides. If anybody has any individual questions about their own situation, just please be in touch with Anna. We'll certainly put you in touch with whoever's best to quickly get to your individual questions.

Again thank you all for participating. It's been a pleasure to have this call with you and our first webinar. This is one that I hope will be the first of many. Again I want to thank everybody for participating. Bye.

Transcript edited for clarity.