Understanding Hairy Cell Leukemia: Current Therapies and New Developments in Treatment
May 23, 2022
Hosted by the Hairy Cell Leukemia Foundation with speaker Dr. Robert Kreitman from NIH. Moderated by Anna Lambertson, HCLF Executive Director
Presentation Materials
A recording and slides from Dr. Kreitman’s presentation can be accessed using the links below. Each link will open via a new window or you can download the file. You do not need a Box account to view these materials.
The recording does not include the Q&A. You can revisit the Q&A in the written transcript below.
Transcript of Webinar Presentation
Dr. Robert Kreitman:
Today, we are going to talk about understanding hairy cell leukemia, current therapies, and new developments in treatment. Just a review, hairy cell is a B-cell malignancy, 2% of all leukemias, and based on the 2022 statistics, around 1,210 new cases per year in the US. Normal blood counts in patients presenting are low. Patients have large spleens. There are these cytoplasmic projections that look like hairs. They're not real hairs, obviously.
The cells are bright positive for CD22, CD20, and CD103. If it's classic hairy cell, they're also positive for CD25. We know, thanks to the work of the group led by Enrico Tiacci and Brunangelo Falini, that hairy cell is driven by the BRAF V600E mutation.
The standard treatment remains Cladribine and Pentostatin, purine analogs that induce long term complete remissions, but are not known to be curative and have decreased efficacy with each repeated course. There are variants of hairy cell that lack CD25, we call that hairy cell variant, or HCLv, or that express unmutated IGHV4-34 immunoglobulin rearrangement. And either of these respond poorly to treatment. The diagnosis involves flow cytometry at the blood or bone marrow. This is done to exclude other disorders also, and we want to determine whether it's classic or variant hairy cell. That's a major goal when you get diagnosed.
This contrasts the different types of hairy cell.
Dr. Robert Kreitman:
Hairy cell classic is in the first column, and it's most of hairy cell patients compared to hairy cell variant. The hairy cell variant patients are more rare. They have larger spleens. The lymph nodes are more often present. The normal blood counts tend to be normal rather than low in hairy cell variant, but the leukemic cells in the blood are more numerous. The CD25 is negative. The BRAF mutation is not present, and the response to Cladribine or Pentostatin purine analogs is poor, even in first line. Now, the IGHV4-34 variant involves CD25 positivity like classic hairy cell, but otherwise, the patients are like hairy cell variant. They can still have severe spleen enlargement, although their normal blood counts are often low. Again, they don't respond well to initial treatment with chemotherapy alone.
Variant hairy cell tends to be more common among patients with relapsed or refractory hairy cell. This shows the protocol that we tested starting in 2010, starting the Cladribine for five daily doses, at the same time as Rituximab weekly for eight doses. Dr. Ravandi had previously, at MD Anderson, tested this combination where the Rituximab begins one month later than the Cladribine starts. But we found that out of 20 patients, the complete remission rate was 95% compared to only 7% of 42 patients in the literature who were getting Cladribine alone.
Single agent Cladribine or Pentostatin, which is similar to Cladribine, should not be used for hairy cell variant. You need to use something combined with the Cladribine or Pentostatin, like Rituximab.
Dr. Robert Kreitman:
Now, what does complete remission mean, before we go on? It means that there are no hairy cell visible by standard stains. This could be a hematoxylin eosin or H&E stain of the bone marrow, or Wright's stain of the blood. You can see that the monotonous hairy cells in this H&E stain are converted after complete remission to normal precursors of normal blood cells. There has to also be resolution of large spleen lymph nodes, high hairy cell counts, and normalization of blood counts to a neutrophil count of at least 1.5, hemoglobin of at least 11, platelet count at least 100.
The need for treatment is one of the three, ANC less than one, this is absolute neutrophil count, hemoglobin less than 10, or platelet count less than 100. You have to have one of these. If you don't have one of these, patients could still be eligible for treatment if they have a painful spleen, growing lymph nodes. There are a few other indications as well.
Dr. Robert Kreitman:
Now, complete remission is often with minimal residual disease. These are traces of hairy cells. It could be detected by a number of tests, including special stains of the bone marrow biopsy, flow cytometry of the blood, flow cytometry of the bone marrow aspirate.
This is the most sensitive standard test, and there are molecular studies like PCR that can detect MRD. The importance of MRD is that the complete remission may last longer if the MRD is negative.
Now, this shows long term results of the trial that I began talking about, of Cladribine or Rituximab. We call this CDAR for HCLV. 95%, as I mentioned, of 20 patients achieved CR and 80% of the 20 patients achieved MRD free complete remission. Although 80% achieved MRD free CR, only seven of these patients long term, or 35%, stayed MRD free so far.
In patients with MRD free CR who became MRD positive, we found that delayed Rituximab, if they got a delayed course of Rituximab, you could see that here starting at least six months after the first course of Rituximab or when hairy cell variant cells were detectable in the blood by flow cytometry, we found that it was often successful in re-achieving MRD free CR for many years. Some of these patients still are MRD negative.
But this shows the importance of MRD negative CR, and another marker called TP53 in hairy cell variant.
Dr. Robert Kreitman:
I want to go through this up in the upper left corner so that you can understand how we interpret Kaplan-Meier curves.
This shows four patients. This is the 20% that didn't get MRD free CR. That's four patients out of 20 that actually died. This shows the percent surviving, so you can see over the number of months, after starting treatment, the number of patients dying is at 25% lower here, at 75%. That's one patient. This is another patient dying, another patient, and another patient, all four patients, unfortunately, died. Of the patients who were MRD negative at six months in blue, you could see that only three of these patients died, number one here, two here, and three here. The patients still living are shown by the vertical blue bars.
You can see that many of these patients are out longer than 120 months. That means more than 10 years. We think that some of these patients could actually be cured.
Now, this shows that patients who are MRD negative at one month also have this characteristic that they're more likely to survive than patients who are not MRD negative. In other words, they're MRD positive at one month after starting Cladribine and Rituximab. This shows the P value means that the chance that this could happen due to chance alone, if there's no real difference between these two groups, is less than 100th of 1%.
Now, this in the lower left is important because many patients don't get bone marrows. This shows that of the three patients that were MRD positive in the blood at six months, all these patients died, and fewer patients died if they were MRD negative in the blood at six months. Now, this shows that TP53, if it's mutated, and that's in red, patients were more likely to die than patients who had normal TP53.
Dr. Robert Kreitman:
What about classic hairy cell, untreated classic hairy cell? This is what many patients have when they're first diagnosed. This shows a randomized trial that we did where we compare the same CDAR regimen that I just showed for Cladribine and Rituximab for hairy cell variant, versus just getting Cladribine alone. Then, getting Rituximab later, if needed for the MRD. This shows the complete remission rate wasn't that different, 100% versus 88%, but the MRD free CR was much different, 97% versus 24% for Cladribine alone. If you follow these patients a median of six and a half years, the MRD free CR rate here drops only to 94% versus dropping all the way down to 12% for patients getting Cladribine alone. The patients stay in MRD free CR better if they have the CR regimen up front, but not everyone needs it. There's a few patients that didn't have their MRD come back.
Dr. Robert Kreitman:
This shows that delayed Rituximab, and you can see that each of these groups got delayed Rituximab at least six months after the first course of Rituximab, if and when hairy cells were visible in the blood by flow cytometry. This raised the MRD free CR rate up to 47% in patients who got Cladribine alone and then got delayed Rituximab. The important point though is by either approach, zero to 3% of the patients needed more treatment by six and a half years. Compared to 28% of patients six and a half years after getting Cladribine alone, and then just waiting for relapse. This, for several decades, was the standard approach.
We believe that either of our two approaches, either CDAR or Cladribine followed by delayed Rituximab is superior, because patients have less chance of relapsing at least by six and a half years.
Now, in patients who are multiply relapsed, we've tested Bendamustine and Rituximab versus Pentostatin and Rituximab. The complete remission rates in these patients are 65% to 73%. Most of these CRs are MRD free. While this is highly effective, this approach may be more toxic due to chemotherapy toxicity, and as I mentioned, these patients are multiply relapsed. They've already had chemotherapy.
Rituximab by itself, though, if you didn't add chemo to Rituximab, it achieves complete remission and only 13% of relapsed hairy cell. This was shown by a trial run by Dr. Saven many years ago.
Dr. Robert Kreitman:
Our question is, can MRD free CR be achieved without chemotherapy?
This shows targeting CD22 in hairy cell with Moxetumomab pasudotox. We abbreviate this Moxe. It's an engineered protein. You can see a picture, a cartoon of the protein here on the right, which has an antibody fragment shown in blue that binds to CD22. It's connected to a toxin, shown in yellow and red, that kills the cell after getting inside. This shows it getting inside and killing the cell.
Moxe is given by 30-minute infusion on days one, three, and five, and repeated every four weeks. Moxe has a complete remission rate of 41% to 73%, depending on what trial the data come from. Most of the CRs from Moxe are MRD free, and it was approved by the FDA in 2018 for relapsed hairy cell leukemia. This shows the importance of MRD free CR. In the phase one trial of Moxe, 11 patients shown in green on the left here had MRD free CR and only one of these patients relapsed, shown by this vertical depression in the curve, in the green. Nine patients, however, had MRD positive CR and eight of these patients relapsed.
Now, the patients who are still in complete remission are shown by these orange vertical bars. Seven patients, shown here on the right, who got one to four extra cycles after complete remission, we call these consolidation cycles, did not relapse, whereas of 14 patients who did not get extra cycles, most of these patients relapsed, and that's shown in the blue. CR duration is longer if Moxe can clear MRD. That requires more cycles.
Now, the toxicity of Moxe includes HUS and CLS. HUS is hemolytic uremic syndrome. This is where the creatinine goes up, the kidney function goes down, and the platelet count goes down. Fortunately, this resolves within one to two weeks, and we think that this is precipitated or predisposed by CLS, which is leaking, when patients get dehydrated due to the fact that the toxin pokes holes in the blood vessels in order to get out of the blood vessels. We actually like that to happen so that the toxin can get to the cells outside the blood vessels, but you have to drink a lot of water to prevent dehydration, and that dehydration can lead to the HUS, we believe. The IV fluid, if you give too much IV fluid, it can cause fluid overload, but oral water is rapidly regulated. We recommend taking one cup per hour, even at nighttime, during this time.
Many patients will get up every two hours, drink a couple cups of water, and then go back to sleep during the night. That prevents this leaking that happens 24 hours a day. We find that the nausea or headache that sometimes happens in a minority of patients after Moxe responds rapidly to Dexamethasone four milligrams orally. That allows patients to continue drinking normally.
At this point, we are targeting both CD20 with Rituximab and CD22 with Moxe for two goals, we're doing this at a trial at the NIH, to reduce normal B-cells and prevent antibodies from rejecting the Moxe. That can happen because the Moxe is a bacterial protein, and normal people can recognize this as being foreign and make antibodies to it. Hairy cell patients are less likely to do that, but still, that's the reason that most patients don't get, or for most of the patients not being able to get the best response, which is MRD free CR. A second goal with the Rituximab is to reduce the amount of hairy cell so that Moxe can achieve CR more quickly. This Moxe R regimen, Moxe Rituximab, is being tested in multiply relapsed hairy cell at the NIH. But we believe that this could be used in earlier line, like first or second line treatment of hairy cell.
Our goal is to give four cycles past MRD free CR, so that even when patients are MRD free, they could still have some cells that are hiding, that we can kill with several more cycles of Moxe Rituximab. We'd give a maximum of four cycles so that if the patient's MRD free after two cycles, they would get four more cycles. Now, this shows that on the first cycle, cycle one, we start the Rituximab at least three days before the Moxe to give the Rituximab adequate time for the Rituximab to get rid of the normal B-cells and allow less chance of antibodies. On the subsequent cycles, the Moxe and the Rituximab can be started on day one. So far, as we reported at ASCO last year, out of the first nine patients, 78% of them had MRD free CR, which is much higher than MRD free CR rate with Moxe alone.
Dr. Robert Kreitman:
Now, what about targeting the BRAF pathway? This was first reported by the Tiacci group to be highly effective. The BRAF containing V600E mutation, it overstimulates the BRAF MEK and ERK pathway. You can see that here on the right where the mutated BRAF is in red, and there's over stimulation or over phosphorylation leading to cancer. This can happen in melanoma, it can happen in hairy cell, and a few other diseases. In the BRAF of normal cells, there's not this overstimulation.
Dr. Robert Kreitman:
We know that Vemurafenib inhibits BRAF V600E and it resulted in 35% to 45% complete remissions in hairy cell, but all of these were MRD positive. Dabrafenib inhibits BRAF V600E also. Trametinib inhibits MEK. While Dabrafenib alone achieves 30% CRs in hairy cell, both drugs were more effective and less toxic in melanoma patients with a combination compared to melanoma patients getting Vemurafenib. It achieves complete remission rates that are still usually MRD positive. To eliminate MRD, a trial led by Memorial Sloan Kettering for untreated hairy cell combines Vemurafenib with Obinutuzumab, which like Rituximab binds to CD20.
Dr. Robert Kreitman:
Now, in Italy, the Tiacci group reported that Vemurafenib and Rituximab achieved 96% CRs and 65% were MRD free CRs in relapsed hairy cells. Rituximab improves the MRD free CR rate to Vemurafenib like it does with Cladribine. Now, these agents can have side effects, including skin rashes and skin cancer for Vemurafenib, fever and chills for Dabrafenib and Trametinib. Another combination Encorafenib and Binimetinib are currently being tested at NIH.
Now, what about Ibrutinib? Ibrutinib is approved for CLL and mantle cell lymphoma, and it inhibits Bruton's tyrosine kinase. It achieves 19% CRs in hairy cell that are mostly MRD positive. It's also effective in hairy cell variant, unlike the BRAF inhibitors that don't work in hairy cell variant. The Ibrutinib can cause atrial fibrillation, increase the risk of bleeding and infections, but in general is better tolerated than the BRAF MEK inhibitors. Ibrutinib can take many months and even years to work in hairy cell. It should not be given to patients with severely low blood counts who need a very rapid response. Those patients should get some other treatment.
Dr. Robert Kreitman:
Conclusions for hairy cell and hairy cell variant is that first line treatment is purine analog. Now, the NCCN guidelines, accept Cladribine with Rituximab.
Cladribine with Rituximab eliminates MRD. It decreases relapse long term compared to Cladribine alone. Hairy cell variant, which lacks CD25 and BRAF V600E mutation should not be treated with purine analog alone. Purine analogs, including Cladribine and Rituximab and Bendamustine can be combined with Rituximab to eliminate MRD and relapsed hairy cell, albeit with chemotherapy toxicity. But Moxe, which is approved for hairy cell, is the only chemo free single agent with a high rate of MRD free CR. Moxe and Rituximab is highly effective and is currently being tested. BRAF and/or MEK oral inhibitors can rapidly achieve CR, but usually need Rituximab to eliminate MRD.
The oral inhibitor Ibrutinib works very slowly in hairy cell that can also achieve CR generally without eliminating MRD. Participation in clinical trials is encouraged for all patients.
Dr. Robert Kreitman:
Also, there's a CAR T-cell protocol that just opened here at the NIH, where patients have blood removed and their T-cells are engineered to bind to CD22. You can grow millions of these. They are infused back to the patient, and they can kill the CD22 positive cells.
This works in ALL, in childhood leukemia, and we believe this will work very well in hairy cell.
I want to end by talking about COVID. COVID vaccines produce antibodies in T-cells that protect from infection, hospitalization, and death. Antibodies could be low or absent after purine analogs, Ibrutinib, or Rituximab. After Rituximab, it could take six to 12 months for antibodies to be able to be made. They could decrease more quickly after these agents. Hairy cell patients should have antibodies measured according to hairy cell experts. Low or absent normal B-cells can lead to poor antibody response. Hairy cell patients can have low or absent antibodies, but since the last vaccine dose have a recovery of normal B-cells, should get another vaccine dose. It doesn't matter if it's a fifth or sixth vaccine dose. Those patients should get another vaccine, and they may have a nice antibody response.
Dr. Robert Kreitman:
Hairy cell patients with persistently low normal B-cells may require drugs like Paxlovid or Remdesivir, or infusion of antibodies, but one should not compromise hairy cell treatment due to COVID 19. But consider delaying initial treatment to achieve the highest antibody level possible before starting treatment, particularly Rituximab. This shows the different trials that are featured on the Hairy Cell Leukemia Foundation website. With that, I'll turn it over to questions.
Transcript of Q&A Session
Anna Lambertson:
Thank you, Dr. Kreitman. We really appreciate, as always, how substantive your presentations are. There have been a number of questions that have come through the Q&A, so I'm going to jump right into those. Because you ended on COVID in HCL, if you don't mind, I might jump into a few questions on that topic.
I think there's a general curiosity about how patients with HCL have fared amidst the COVID pandemic. Are you aware of patients with HCL who have died because of COVID or what are some of the complications that you've encountered with patients who specifically had HCL?
Dr. Robert Kreitman:
In the days before we had effective monoclonal antibodies and before we had vaccines, there were patients, there was one patient I know of with hairy cell who actually died, other patients with severe infection.
But since the advent of vaccines and monoclonal antibodies, I haven't seen any patients dying with hairy cell, but patients can get sick. They can get COVID multiple times. They can get COVID and then get COVID a few months later, because they may not respond or they may not make antibodies to the COVID that they get by vaccine or by infection. It's still something that patients need to be concerned about, but it hasn't been as severe.
Another reason for that is that the Omicron variant is less severe than the Delta and previous variants with regard to pneumonia. It mainly localizes in the upper respiratory tract, the nose, the throat, and less in the lungs. While patients, certainly, hundreds of patients are dying per day in the United States of COVID, the Omicron variant, it's a lot less common than previous variants of COVID.
Anna Lambertson:
Have you tracked patient's symptoms? Those that have been vaccinated perhaps compared to those who have not been vaccinated and seen that patients with HCL, that their symptoms are not as severe, if they have received the appropriate vaccinations and booster shots?
Dr. Robert Kreitman:
Absolutely. Patients who are vaccinated have much less symptoms of COVID. They're able to recover from COVID much more easily. They're less likely to need antibody treatment. But patients who have not been vaccinated, if they get the right antibody, they're able to recover. But obviously, we all recommend vaccination to be able to get immunity.
There are some hairy cell patients who present with very high hairy cell counts in the blood and very low normal B-cells. They have very poor response to vaccine even upfront. Those patients may not have good response to vaccine and may actually need to be treated just to be able to respond to vaccine.
In the old days, we used to suggest that maybe these patients should get Vemurafenib to be able to beat down their hairy cells, improve their normal B-cells, and then get vaccinated. Then, once their hairy cells come up again, to get Cladribine and Rituximab or something more definitive for hairy cell after they have already made antibodies. I think that that is something that certainly some people are doing now, but with the advent of the monoclonal antibodies, that may not be as necessary. But again, this hasn't been worked out with randomized trials, which is the best path to go on.
Anna Lambertson:
Can you talk a little bit more about Evusheld in terms of the timing? You're advising patients to ideally be vaccinated prior to being treated, because we know that Rituximab and Cladribine can both impair the body's ability to produce antibodies. What about Evusheld? Do you advise patients to receive it before Rituximab, after Rituximab, or do you test their antibodies first and then decide when to administer it?
Dr. Robert Kreitman:
Evusheld will raise the antibody level, in our assay, a couple thousand, maybe 4,000. This is IUs per ML units.
The patients who have good antibody responses, they'll go up to about 25,000 IUs per ML or higher, and we won't be able to determine the amount because it'll be greater than the amount that we can measure, which is 25,000. If patients have a level of 25,000, it really doesn't make any sense to use Evusheld. It's not going to raise it that much higher. The other thing that Evusheld does is it obscures the antibody level because it'll show up as that you have antibody, but you haven't really made that antibody.
If you want to know whether you're able to respond to a vaccine and you get a vaccine, and then you check your level of antibody, you don't want to take Evusheld before you check your level, because otherwise you'll get a positive result, but it could be from the Evusheld. You won't know if it's due to the vaccine or the Evusheld.
But patients who can't have good responses to vaccines, they can get Evusheld prophylactically, or they can get it after getting or after contracting COVID, and it'll work either way. That's the case with Evusheld, and the other antibodies are similar.
Anna Lambertson:
Two more questions specifically about COVID; one is about how antibodies are tested. Can you just quickly name the tests that are being used for the antibodies so that the patients know what they could ask their doctor for?
Dr. Robert Kreitman:
The two different types of tests are for nucleocapsid antibodies and spike antibodies. Most labs now can test for each one. If you have a positive nucleocapsid antibody, that means that you are exposed to COVID. If you have a positive spike antibody, it means you could either be exposed to COVID or a vaccine. Therefore, if you have a negative nucleocapsid antibody and a positive spike antibody, it means you must have gotten the vaccine, right? Well, not always, because the nucleocapsid antibody drops with time a little bit more quickly than the spike antibody.
If a patient never got a vaccine, they could still have a negative nucleocapsid antibody and a positive spike antibody. But usually, a positive nucleocapsid antibody means that a patient was exposed to COVID, whereas a positive spike antibody means that they got either COVID or the vaccine.
Anna Lambertson:
Some people on the webinar today have just been diagnosed. Others have been in remission for 10 years, for 20 years. They're getting vaccinated, they're getting their booster shots. They're doing absolutely everything they can to keep themselves safe and to keep their family members safe. They're trying to get their heads around how much at risk are they still, being that they are in remission. What are you advising the individuals who you see at NIH in this regard, particularly those who are in remission?
Dr. Robert Kreitman:
We recommend checking antibodies, and that was a consensus recommendation by the hairy cell experts in a publication that was recent. However, if patients have good antibodies, we don't necessarily use that information and tell them, "No, you shouldn't get a vaccine booster." If a patient's due to get a booster, it may not be proper to use antibody information to say, "You shouldn't get a booster." What we do is if a patient is contemplating a fifth or sixth dose of vaccine, and they have low normal B-cells, and it looks like they're not going to respond, we don't necessarily recommend a fifth or a sixth dose, but I think checking antibodies is very helpful.
If a patient has normal, high antibody levels, despite getting treatment for hairy cell, it means their COVID immunity is good and shouldn't worry too much. However, having said that, even normal people with normal immunity can still get COVID despite very high antibody levels, even too high to measure.
That's because the path of infection, where someone is talking in your face and the COVID goes right into your nose, there's no blood there in between, so there's no way that antibodies are going to help you prevent infection. The antibodies can prevent you from getting sick, but they may not be able to help you from getting infected.
That you have to rely on masks, and distancing, and the other things that we've been inundated with for years with COVID that we get tired of. But nevertheless, those things are very effective in preventing infection.
Anna Lambertson:
You've spoken a lot about MRD and there are some individuals on the webinar who are less familiar with what that term means. Could you quickly define MRD and also how you identify MRD in a patient, what tests you use, what is the best method?
Dr. Robert Kreitman:
MRD is just nothing more than traces of hairy cells. A few hairy cells floating around in the blood, it could be as low as a 10th of a hairy cell per cubic millimeter or 0.002% of hairy cells in the bone marrow aspirate flow cytometry. The bone marrow aspirate flow cytometry is the most sensitive test for hairy cell MRD. Minimal residual disease is just that. The more convenient test is flow cytometry of the blood. The special stains of the bone marrow biopsy can be used if you have a bone marrow that's already been done a month ago or a year ago, or 10 years ago, and you want to determine if there was MRD there.
You can have special stains cut of that bone marrow and send it to a place like NIH. We can tell you whether there was MRD at diagnosis, but many bone marrow reports now give this information as well.
But it's important to not get MRD confused with partial response or not being in complete remission. For example, a patient has, let's say, 5% of the bone marrow cellularity being hairy cell, but on the H&E stain, it looks normal. That patient is in complete remission and just has MRD. It doesn't mean that they've had a failure of treatment.
Anna Lambertson:
A lot of people are curious about the Cladribine and Rituximab combination therapy. Many people on the webinar today have received this combination therapy. They're trying to understand what they should expect in the next few weeks after that treatment is complete. How should they be feeling? What are some of the side effects that they can expect?
How careful do they need to be to keep themselves safe now that they've completed this combination treatment?
Others are hearing about the effectiveness of adding the Rituximab, and they’re asking whether it's worth adding the Rituximab several months down the road or a year down the road.
Dr. Robert Kreitman:
The first part is, what to expect after you get Cladribine and Rituximab. We find that at the four-week time point, the neutrophil counts have recovered and they're actually higher than the neutrophil counts in patients who get Cladribine alone. The platelet counts are also higher in patients who get Cladribine and Rituximab versus Cladribine alone. Although, patients have very low platelet counts 24 hours after starting Rituximab with Cladribine. But that improves very quickly on its own and only a minority of patients would need a platelet transfusion, for example. Generally speaking, patients might feel better four weeks after the Cladribine and Rituximab.
But in that two-week period after starting, patients might be more likely to have infection. That's important because a lot of people have fever with Rituximab, and if you have fever and you are also neutropenic, you have low neutrophils, you really need to think of infection, not just blame the fever on the Rituximab. That's the first issue.
The second issue is, what about long after the Cladribine alone? I don't know if you could still see the slide, but if you got Cladribine and then at least six months or years later you have hairy cells appear in the blood by flow cytometry, we believe that based on our data, giving delayed Rituximab is beneficial. Because our patients who are treated that way don't relapse compared to, we expect about 28% of patients to relapse if they're treated with Cladribine alone and just wait by the six and a half year time point.
I think there is a benefit for delayed Rituximab. However, we wait until the patients really need it, and that is when the blood is MRD positive. In other words, we can see hairy cells in the blood. Let's say it's been several years after you get Cladribine and your blood counts are normal. You're still in complete remission, but you have this positive MRD in the blood, on a flow cytometry of the blood. I believe that our data would support delayed Rituximab in that case.
What about if you're several years out and your counts are low, and you find that you have a lot of hairy cell in the blood and bone marrow? Well, you've relapsed, and at that point, if you get delayed Rituximab, that's less likely to give you a complete remission. Only about 13%, as I mentioned, of patients who get Rituximab for actual hairy cell that you have to treat, get complete remission. Many of those are not MRD negative. We would only recommend the delayed Rituximab if patients are still in complete remission, they just have MRD show up in the blood.
Anna Lambertson:
In terms of safety, in your assessment, is there a difference in safety in terms of doing the concurrent Rituximab versus the delayed Rituximab?
Dr. Robert Kreitman:
As I mentioned, the platelet count and the neutrophil count is better at the four-week time point than with the CDAR, the concurrent Cladribine and Rituximab versus the Cladribine alone. I think in that sense, there may be a benefit, safety wise, because the counts are better. But there certainly could be some ... if a platelet count is extremely low, one has to monitor that carefully and give a platelet transfusion if needed, if the platelet count is extremely low after Cladribine and Rituximab together. I think that could really take care of most of the problems that would be seen.
I don't think that there's a safety issue beyond that. We tested the safety of these two regimens in a randomized fashion. The only one that really stood out was that patients have lower platelet counts within 24 hours after getting the combination.
Anna Lambertson:
We've also received a number of questions about how long patients need to wait until they have had what would be considered a successful response to treatment. One patient's question is about Cladribine and Rituximab. They completed that treatment two years ago, but some of their counts remain low, white blood cells, lymphocytes. Do you expect two years after Cladribine and Rituximab combination for the counts to continue to improve or is this a situation where they might just continue to have low counts?
Dr. Robert Kreitman:
Cladribine is a stem cell toxin. In other words, it kills stem cells. You're going to end up with a new normal white count, for example, which is lower than the white count that you might have had 10 or 20 years before you got diagnosed with hairy cell. It takes about four years, median, to recover the CD4 T-cell count that you had before Cladribine. That was shown by Seymour after Cladribine or Pentostatin back in the 1990s. This is a well known fact that the Cladribine causes long term decreases in normal T-cells. You shouldn't be alarmed when the T-cell counts are low.
If they're lower than 200, especially if they're lower than 150, we recommend a prophylactic drug to prevent herpes zoster or shingles, particularly in patients who haven't been immunized against shingles. If they're over 200, a lot of patients don't get that drug, which is either Acyclovir or Valtrex. Some of those patients can still get shingles if they're above 200 CD4 count, so the counts can be low. Now, the platelet count is rarely low after Cladribine and Rituximab long term. The neutrophil counts, they're also rarely low. If a patient has a very good response but a low neutrophil count, sometimes a little bit of Neupogen for a few days is all that's needed to get the neutrophil count up to a normal level.
Anna Lambertson:
You mentioned the side effects or long term effects of the chemotherapy. I want to relay a few questions in that topic area. There are at least two individuals who have said that since completing Cladribine one specifically said that they had it 18 months ago. Another individual said it was two and a half years ago, but they continue to experience chronic fatigue. What is that about? Do you hear this from patients often? Is that related to the chemotherapy? Is it something else? How can the patients work with their medical team to address this chronic fatigue that they experience? Again, one individual completed Cladribine 18 months ago, another one, two and a half years ago, but I've heard this from people all across the US and beyond, chronic fatigue years after completing Cladribine.
Dr. Robert Kreitman:
Yeah, we've heard this too, and we've heard chemo brain, we've heard chronic fatigue. It could be that some of this is due to deconditioning, that during the time that you get chemotherapy you lay low. You stop the exercise that you're used to doing. I have hairy cell patients who, when they get diagnosed, they are runners, and they're running several miles with a hemoglobin of five. Then, most people stop running or stop exercises during chemo, and they may feel tired after chemo and may not start up exercise again. Fatigue, chronic fatigue, is not well understood. It's not easily treated, but one of the things that does work is exercise. If you get on an exercise program and gradually ramp up to improving exercise, that can go a long way to treating and resolving chronic fatigue.
On the other hand, there are some patients that have fatigue and it's very hard to figure out what it's from, but keep in mind that there is neurotoxicity that can happen due to Cladribine. Some patients can get tingling of the nerves in the feet, in the hands. It can happen in about 15% of cases after the first course of Cladribine or Pentostatin or Bendamustine. It may compound with multiple courses.
This is the reason why we try to avoid and we try to use things like Cladribine and Rituximab, to prevent the need for more Cladribine or more chemo in patients. Because there could be neurotoxicity, and it's possible that some of the neurotoxicity leads to chronic fatigue, but we really don't know that for sure.
Anna Lambertson:
What about thrombocytopenia? Have you seen this in patients who had Cladribine decades ago, 10, 20 years ago, and they continue to have this issue?
Dr. Robert Kreitman:
I see thrombocytopenia in patients who have MRD and sometimes we blame the thrombocytopenia on the fact that they have MRD. Unless you get rid of the MRD, you don't really know if the thrombocytopenia is due to the MRD. But sometimes, when you give those patients Rituximab, their platelet counts will normalize, but other patients, their platelet counts will be at a new normal, let's say, 120, 130, whereas, years before diagnosis, they'd be normal around over 154. Similar to the white counts, the platelet counts can remain low-ish.
But in cases where patients are MRD free, they ought to have a platelet count above a hundred. We find, however, in patients who have multiply relapsed hairy cell, after many courses of chemotherapy, even if they're MRD free, they can have a platelet count in the seventies or eighties, and that's just fine. That's all they can manage because they've had stem cell damage due to all the chemo in the past.
And it's not due to hairy cell.
Anna Lambertson:
I'm going to move on to Vemurafenib. We've received a dozen questions about Vemurafenib. What dose and duration of Vemurafenib might you advise for your patients? If it's frontline, if you were to consider Vemurafenib at frontline, what dose or duration would you use? If this were at relapse, what dose and duration would you use for Vemurafenib?
Dr. Robert Kreitman:
The 960 milligrams twice a day is the one that was published in the New England Journal. That achieves the 35% to 45% complete remission rates. It's a single agent. It's been published that lower doses are effective for short time periods, but the data show that these patients relapsed. When you relapse, you have less chance of getting back into a complete remission. I think that I would advise the published dose of Vemurafenib, and then quickly decrease the dose if needed due to toxicity. Certainly, there are many patients who have an excellent response with a very low dose of Vemurafenib, even a one quarter of the dose, 240 milligrams twice a day, compared to the standard dose, which is 960 twice a day.
Anna Lambertson:
You mentioned earlier that when COVID was at its worst, doctors were using Vemurafenib almost as a bridge. It continues to be used by many doctors who are concerned about the risks for COVID that their patients with HCL have. One individual specifically says their doctor wants them to have Vemurafenib. They've just been diagnosed and this is their frontline treatment. They want the patient to have Vemurafenib, assess their response, and perhaps do Rituximab later. What are your thoughts on this?
Dr. Robert Kreitman:
I think that patients should be treated in an evidence-based manner. In other words, I think that if there are clinical trials that have shown in a reasonable number of patients that a certain treatment works, that's the way to treat patients. I think that some patients, I find, getting Rituximab alone for newly diagnosed hairy cell or getting Vemurafenib alone, then saying, "That's the way we're going to treat you. Then, we'll wait and see what happens when you relapse." That's not really an optimal way to treat. However, as I mentioned in the COVID age, there may be an advantage in some patients who can't make antibodies to getting Vemurafenib alone.
Then, following that patient closely and checking normal B-cells, getting the patient vaccinated effectively, and then, once they need treatment again, in other words, once their counts go down and their hairy cells go up, and they go out of complete remission, treat them with something more definitive. I think in that way, Vemurafenib is useful.
Now, Vemurafenib plus Obinutuzumab, another CD20 antibody, as I mentioned, is being tested at Memorial Sloan Kettering. We're waiting for that data. That could very much change the standard of care for newly diagnosed hairy cell, but we have to really scrutinize that data once it becomes available.
There may be an advantage to treating patients with a chemo free treatment, even in first line, like Obinutuzumab and Vemurafenib, or Vemurafenib plus Rituximab or, it hasn't been tested in first line, but Moxe plus Rituximab. We feel that that may be useful to test as well. I think that the potential advantage of chemo free primary treatments is that there's less damage to normal T-cells and less toxicity from the Cladribine. But this is not something where we're at, at the moment. At the moment, primary treatment involves purine analogs with or without Rituximab for hairy cell.
Anna Lambertson, relaying question from webinar participant:
A patient asks what can be done to raise lymphocytes? In this case, treatment was about eight months ago.
Dr. Robert Kreitman:
We know from the CLL literature, that it can take six to 12 months for normal B-cells to come up after Rituximab. We find that it sometimes takes even longer. That's why we recommend that patients get the highest COVID level possible before they start Rituximab, because it may be a very long time, even several years, before they can have effective normal B-cells. Without effective normal B-cells, you really don't have the ability to respond to vaccines. There really is not a good substitute for that. You do have a T-cell immunity though, but we just don't measure that routinely.
It could be that the vaccines that you get after not having normal B-cells can still give you a good T-cell response to COVID, but we don't have a good way of helping the normal B-cells come back more quickly. There's no B-cell stimulant like there is for granulocytes with Neupogen at this point.
Anna Lambertson:
A number of people have asked about how frequently they should have their blood checked or how often they should be checked. I would say two scenarios, one, the individual has been diagnosed and they're on watch and wait, so active monitoring, not yet treated. How frequently should their blood be checked? Then, for an individual who has completed treatment, how often should they be checked? How often flow cytometry should be done to monitor their response?
Dr. Robert Kreitman:
It's a good question. We typically will check CBCs every three months and flow cytometry of the blood every six months for the first two and a half years after the treatment starts. After two and a half years, we cut it in half. In other words, we'll check flow cytometry only once a year. We'll check CBCs once every six months. In patients who are needing treatment, we'll check CBCs at least every three months. In patients who are rapidly getting worse, they may need to check their CBC more frequently. But generally, three months is the ballpark figure that you want to be checking quickly after treatment.
Obviously, when you're immediately after treatment and the platelet counts are low and you want to know whether you need platelet transfusions, there, you may be checking CBC several times a week. But in general, once the counts recover, it's less frequently.
Webinar participant:
Well, my question is about the indication for treatment for a patient with classic hairy cell leukemia who has three years remission with no clinical symptoms, no spleen enlargement, normal white and blood cells count. Only during the last three, six months low platelets count, like 80,000, 70,000. In this COVID time, what is an indication to treat or is it better to wait until the counts drop worse.
Dr. Robert Kreitman:
I think that it may be helpful to get a bone marrow to determine what the low platelet count is due to.
If patients after treatment, several years after treatment, have a low platelet count, generally a bone marrow is done. If there's no hairy cells there, patients are in a very good, complete remission. They may have no MRD. They may have a large spleen, and the spleen may not have any hairy cell in it. It just may be large because it was large before treatment. Those patients should not have their spleen taken out. There was a study that was done several years ago that had three patients getting their spleens taken out because of low platelet count after treatment. In all those cases, they couldn't find hairy cell in the spleens.
It doesn't really need to be done. Sometimes patients who have very large spleens, you can get rid of the hairy cell in the spleen, but the normal elements that make up a large spleen, the scar tissue, the fibrosis, that doesn't always go away so fast. That spleen architecture can cause a low platelet count, but it's not clinically significant.
Anna Lambertson:
We did get one question that I thought you could respond to quickly. We know that there's a four to one, male to women ratio in HCL, but we are seeing a lot more women with HCL, including women who are pregnant. Do you feel that that four to one ratio in HCL is still true, or is it changing?
Dr. Robert Kreitman:
I think it's still true. I do think that there are more hairy cell variant patients that are getting diagnosed now. In the hairy cell variant, the female to male ratio is not one to four, it's a little bit more even. But I think it's still four to one, male to female in classic hairy cell. It's not clear exactly what's causing that, but there are some interesting theories.
Anna Lambertson:
We have reached the end of our time. Thank you, Dr. Kreitman, for the time today to do the presentation and respond to questions. I want to say thank you to everyone who joined the webinar. We had folks from across the United States, Canada, Europe, and beyond. Wishing you and everyone here a wonderful day.
Transcript edited for clarity.