General HCL Webinar Series: Understanding Hairy Cell Leukemia and Variants of Hairy Cell Leukemia
May 3, 2021
Hosted by the Hairy Cell Leukemia Foundation with expert speaker Dr. Robert J. Kreitman from the National Cancer Institute, NIH. Moderated by Anna Lambertson, HCLF Executive Director.
Presentation Materials
Note: Slides and a recording of Dr. Kreitman’s presentation can be accessed using the links below. Each link will open the file via a new window. You do not need a Box account to view these files.
Transcript of Webinar Presentation and Q&A
Presentation from Dr. Robert Kreitman
Anna Lambertson:
Today’s speaker is Dr. Robert Kreitman. Dr. Kreitman is a senior investigator in the laboratory of molecular biology at the National Cancer Institute. He's also head of the clinical immunotherapy section where he specializes in the treatment of HCL with neurotoxins and other agents. I've spoken with many of you who have participated in clinical trials at the NIH or who have reached out to Dr. Kreitman's lab with questions. We know that Dr. Kreitman brings significant expertise in HCL and as many of you can personally attest to, he also brings very deep commitment to patient support and to improving outcomes for patients who are living with HCL. So we're really grateful, as we always are, to Dr. Kreitman for all that he does in research and for the time that he takes such as today in speaking to patients during this webinar.
Dr. Robert Kreitman:
So today, I'm going to be talking about Understanding Hairy Cell Leukemia and Variants of Hairy Cell Leukemia. Hairy cell leukemia is a B cell malignancy. It comprises two percent of all leukemias and in 2021, it amounts to about 1200 new cases per year.
Patients have low blood counts, they have large spleens, and the cells have these cytoplasmic projections, which are very characteristic. The cells are bright positive for CD22 and CD20 and if they're classic hairy cell, they have CD25. Hairy cell leukemia we know is driven by BRAF V600E mutation.
Treatment, which is standard, is considered cladribine and pentostatin. These are purine analogs, which can induce long term complete remissions. But they're not known to be curative and they have decreased efficacy with each repeated course.
There are variants of hairy cell that lack CD25, we call that HCLv, or that express unmutated IGHV4-34, immunoglobulin rearrangement. Either of these variants responds very poorly to chemotherapy, so they're important to diagnose. And diagnosis of hairy cell can best be done by flow cytometry of the blood or bone marrow. The goal is to exclude other disorders and to determine if you have classic hairy cell or a variant.
Now, let’s contrast hairy cell here on this column with the two right columns which are variants. And we can see that the spleen enlargement is much more severe in the variants. The variants can have lymph node enlargement. Normal blood counts can be either normal with HCLv or they can be low like classic hairy cell with the IGHV4-34 variant.
Now, the leukemic cells in the blood tend to be very high in these variants. CD25 is positive like classic hairy cell with the IGHV4-34, but it's negative with hairy cell variant. And BRAF is unmutated and a response is poor to cladribine or pentostatin chemotherapy with the variants. And they tend to be more common, the variants, in patients who have relapsed or refractory hairy cell. So we need to rule those out.
Now, this shows a trial for treating patients with hairy cell variant. Where instead of using cladribine alone, shown in green, we use rituximab weekly for eight doses, where we start the first dose of the rituximab the same day as a first dose of the cladribine. Some people start this a month later. And you can see, there's a huge difference in complete remission rate. Nine percent with cladribine alone versus 95% with a combination. So single agent cladribine or pentostatin should no longer be used for HCLv.
What does complete remission (CR) mean? So it means that there's no hairy cell visible by standard stains, that’s H&E stain (Hematoxylin and eosin) or Wright stain of the bone marrow and blood. And you can see that the complete remission involves the conversion of these monotonous appearing hairy cells on the left to the normal hematopoietic precursors on the right. You also have to have resolution of enlarged spleens, lymph nodes, and high hairy cell counts. And normalization of the normal blood counts to a neutrophil count of at least 1.5, hemoglobin of at least 11, and platelet count at least 100.
To need treatment, we go by the one, 10, and 100 rule, which means that you have to have either an ANC less than one, hemoglobin less than 10, or a platelet count less than 100. But you can also need treatment due to a painful spleen or growing lymph nodes.
Patients can have complete remission with minimal residual disease. What is that? That's traces of hairy cells that can cause relapse. And you can detect those by special stains of the bone marrow biopsy, flow cytometry of the blood, or bone marrow aspirate, which the latter one is the most sensitive. And you can also detect MRD by molecular studies like PCR. Complete remission (CR) can last longer if the MRD is negative.
Now, how do you get MRD negative from the very beginning? This is a trial that we did using cladribine and rituximab to eliminate MRD for newly diagnosed hairy cell. This is in first line. And you can see that we randomized patients against the cladribine alone, which is here on the bottom, the green, daily for five doses. Versus the cladribine plus weekly rituximab for eight doses started on the first day of cladribine. And you can see that there's a slight improvement in complete remission rate from 88 to 100%. But there's a huge difference in MRD-free complete remission rate from 24% to 97% at six months.
If you follow these patients for six and a half years without further treatment, 94% of them are still in MRD-free CR after cladribine plus rituximab, we call this CDAR. And with cladribine alone, only 12%. So, there's a huge difference there in MRD-free.
Now, you can treat these patients who have cladribine alone with delayed rituximab and this is shown here. We treated with up to two courses of eight weekly doses of delayed rituximab and this is effective. You can get 47% of the patients MRD-free at the six and a half year time point using delayed rituximab. That’s not as high as 94%, but it's very significant. The important thing is that, regardless of which method you use, whether it's delayed or early rituximab, zero to three percent of these patients needed more treatment at the six and half year time point. Compared to historically, 28% of patients at six and a half years, if you just use purine analog like pentostatin or cladribine and you wait until they need more treatment. So 28% of patients at 6.5 years already have relapsed, have low blood counts, they need more treatment. But only zero to three percent of these patients did. So that's a huge difference not only in MRD-free CR rate, but also what's more important, need for next treatment.
Now in the multiply relapse setting, this is third line and beyond, we use pentostatin or bendamustine, chemotherapy drugs, purine analogs, combined with rituximab. You can see that either way, the rituximab is given every two weeks. By either method, we get complete remission rates of 65 to 75% with most of the CRs MRD-free.
While this is highly effective, this approach may be toxic due to the chemo to patients who've already had chemo. So the question is whether MRD-free CR can be achieved without chemo and what's the benefit to being MRD-free?
So this shows that rituximab over here on the left, which kills cells after binding to CD20, has a CR rate of only 13% without chemo in patients with relapsed hairy cell. So it's really not a very good agent for patients who need treatment after having had chemo.
Moxetumomab pasudotox on the right is an engineered protein that has an antibody fragment that binds to CD22. The antibody fragment is in blue. It's connected to a toxin shown in yellow and red that kills the cells after getting inside. And this is highly effective. Moxe has a CR rate of 41 to 73% and most of these CRs are MRD-free. It was approved by the FDA for relapsed hairy cell under the name of Lumoxiti in 2018. And this shows that in the phase one trial, 11 patients here on the left had MRD-free CR and only one relapsed, where nine patients had MRD-positive CR shown in blue and eight of these patients relapsed. Moxe is given by 30 minute infusions on day one, three, and five and it's repeated every four weeks.
And why do we give these extra cycles?
You can see here that when we gave one to four extra cycles, these are consolidation cycles, cycles beyond where we detect no minimal residual disease, that of these seven patients, none of these patients relapsed. Whereas, when we don't give consolidation cycles, most of these patients relapse. The patients still in complete remission are shown by these orange vertical bars. So CR duration is longer if moxe can clear MRD, which requires extra cycles to get rid of the hairy cells that are hiding in the bone marrow or the liver or spleen, areas where they're not detected in the blood or bone marrow. So, it turns out that patients on moxe can get a toxicity called HUS, where their platelets go down, their creatinine goes up, kidney function goes down. This resolves, fortunately, by itself within about a week. The biggest problem with it is, that they can't get these consolidation cycles. They have to stop treatment.
We have a good way of preventing this now and it's based on the fact that blood vessels are constantly leaking, allowing the moxe to get out. It's actually a good thing because we want the moxe to get out of the blood vessels and as it's getting out of these blood vessels, which are lined by living endothelial cells. It goes inside the cells so the toxin kills the cell, causes some leaking. But the blood vessels heal themselves pretty rapidly, and so this leaking stops. And we call this leaking, capillary leak syndrome, CLS. We find that IV fluid is not a good way to prevent dehydration because it causes fluid overload. And so, we want to prevent dehydration and we find that oral water, just drinking water, is rapidly regulated. So the body prevents oral water from causing fluid overload. One cup per hour of oral water works very well during the week of treatment. And we keep lapses in drinking to less than two to three hours. This is surprisingly easy for patients to tolerate and we find that this works well.
We find that the nausea or headache that sometimes can happen after moxe responds rapidly to Dexamethasone, four milligrams orally. This is a low dose of steroid and it allows patients to continue drinking to prevent dehydration. Before we used these precautions, the rate of grade three, or severe HUS, was three out of the first nine patients. And then after we used these precautions, zero out of 17 next patients had this problem. So, we are definitely using theseprecautions and they're highly effective.
Now, what about targeting both CD20 and CD22 with rituximab and moxe? Our first goal of doing this is to reduce normal B cells because that's what rituximab does. It depletes both normal and malignant B cells. And it therefore presents anti-drug antibodies, the antibodies that the body can make to reject the moxe.
And the second goal is to reduce the amount of hairy cell so that the moxe can achieve CR more quickly by binding to all the hairy cells. Remember, it has to bind to the hairy cells to go inside and kill the cell. And so, moxe rituximab is now being tested here at the NIH. We're giving four cycles past MRD-free complete remission or giving a maximum of eight cycles.
And you can see here that on the first cycle, we give rituximab three days before moxe to give it a head start to decrease normal B cells and also the hairy cells. And then on subsequent cycles, you can see on re-treatment cycles, we can start the rituximab and the moxe on the same day. And so, if a patient were to get an MRD-free CR after two cycles like many patients do, we would just give four more cycles so they get a total of six cycles, as we did on the phase three trial.
Now, let me shift and talk about the BRAF pathway and targeting that with oral drugs. In classic hairy cell, BRAF carrying the V600E mutation shown in red here, overstimulates or over-phosphorylates the BRAF-MEK-ERK pathway. You can see that the BRAF overstimulates or over-phosphorylates MEK, which then in turn, over-phosphorylates ERK and that leads to cancer.
Now, if it's in a B cell, it causes hairy cell, if it's in a skin cell, a melanocyte, it causes melanoma. If it's in a colon cell, it can cause colon cancer, if it's in a lung cell, it can cause lung cancer. So Vemurafenib inhibits BRAF V600E and resulted in 35 to 45% complete remissions in hairy cell, all MRD-positive, however.
Dabrafenib inhibits BRAF V600E. And Trametinib is and oral drug that inhibits MEK.
Now, Dabrafenib alone achieves a fairly low complete remission rate, 30% in 10 hairy cell patients. But both drugs, Dabrafenib and Trametinib, were more effective and less toxic in melanoma than Vemurafenib alone. And they're also very effective in hairy cell. However, these drugs usually spare MRD. The patients are left with an MRD-positive complete remission.
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. In Italy, Vemurafenib and rituximab achieved 96% complete remissions and 65% of the patients had MRD-free complete remission. Vemurafenib and Obinutuzumab is also being tested with the MEK inhibitor, Cobimetinib. So these agents can have many side effects, including skin rashes, skin cancer from Vemurafenib and fever and chills for Dabrafenib and Trametinib. So the BRAF inhibitor, Encorafenib and MEK inhibitor Binimetinib is currently being tested as an alternative at NIH.
Now, what about Ibrutinib? Ibrutinib is approved for chronic lymphocytic leukemia and mantle cell lymphoma and inhibits Bruton's tyrosine kinase. It's reported to achieve 19% complete remissions; most of these are MRD-positive. It can also be used in hairy cell variant, but it does work better in hairy cell classic. Ibrutinib can cause atrial fibrillation, it can increase the risk of bleeding and infections, but in general, it's better tolerated than the BRAF and MEK inhibitors. Ibrutinib can take many months and even years to work in hairy cell. So it should not be given to patients with severely low blood counts who need a fast response.
In conclusion, first line treatment is still single agent purine analog, but it's getting more popular to use a combination of these with rituximab. Since it eliminates MRD and decreases relapse long term. Hairy cell variant lacking CD25 and BRAF V600E should not be treated with purine analog alone. Purine analogs including cladribine and pentostatin and bendamustine can be combined with rituximab to eliminate MRD in relapsed hairy cell, albeit with chemotherapy toxicities. Moxetumomab pasudotox, we call it moxe, is approved for hairy cell and is the only chemo-free single agent with a high rate of MRD-free CR. Moxe and rituximab is highly effective and is being tested. BRAF and/or MEK oral inhibitors can rapidly achieve complete remission, but usually need rituximab to eliminate MRD. The oral inhibitor Ibrutinib works very slowly in hairy cell, but can also achieve complete remission, generally without eliminating MRD.
And participating in clinical trials is encouraged for all patients. I want to mention that a trial was just approved here at the NIH using the CAR-T cell approach. This is where we remove blood from patients to get their normal T cells and we make CAR-T cells in the lab using gene splicing techniques to insert a chimeric antigen receptor, this is the CAR. And we make it against CD22 and grow millions of these patients' normal T cells. We give back the CAR-T cells to the patients. These CAR-T cells bind to the cancer cells and kill them. This is an approach, which targeting CD22, can get patients with ALL, acute lymphoblastic leukemia, into long term complete remissions. And we hope that this will work well in hairy cell patients as well who have a need for treatment after failing other treatments.
And so, these are the clinical trials on the Hairy Cell Leukemia Foundation website. I want to open the presentation to questions, thank you.
Question & Answer Session with Webinar Participants
Anna Lambertson:
I'm going to go ahead and dive into some of the questions that have been coming through in the Q&A.
When it comes to the watch and wait, doctors are making decisions based on whether or not the patient has symptoms, as they might be described in the guidelines and/or what the blood counts are and how low they are. When are treatment decisions made, when is treatment necessary for a patient? How long can they be monitored before treatment begins?
Dr. Robert Kreitman:
I mentioned near the beginning that we use 1, 10, and 100 rule where the ANC is less than 1, or hemoglobin less than 10, or platelet count less than 100. You only need one of those to qualify for treatment. Patients who don't have any of those indications, but their spleen is enlarging, it's very large - this may be seen in a hairy cell variant where their normal blood counts are preserved but their disease is growing out of control in the spleen and maybe lymph nodes. That's an indication for treatment. You don't want lymph nodes to be growing out of control and compress the kidneys and things like that.
But in patients who have classic hairy cell that have, let's say, a platelet count of 90, 80, and it's been stable for several years and they want to go on vacation and they don't want to get treated right away, there's really no problem in waiting. A platelet count of 90 or 80 is not really much of a problem.
An ANC of 0.9 is usually not a problem. It is a relative risk factor for getting infections if patients are going to delay treatment while their neutrophil count is 0.9, they just have to be aware not to get sick. But there is a little bit risk of pneumonia in that case. We've seen patients get pneumonias with ANCs in the 0.8 region. But if it gets down to 0.5, you really want to think about treatment for that low ANC. And the reason is that, especially if you're getting treated with chemotherapy, that the counts are going to go down further. We see this with Ibrutinib too. The counts go down further and you don't want to have the counts go down to less than 0.1 where it's very common to get infections and some of those can be life threatening.
Anna Lambertson:
We frequently hear from individuals who are told that they're asymptomatic, they're told that their blood counts are at a certain level, that they're being monitored before treatment begins. But then, they're also told that the percentage of hairy cells is a certain percentage and so, they're asking themselves well, “How does that factor into a doctor's decision on when their treatment will begin?”
Dr. Robert Kreitman:
The amount of hairy cells by itself is not considered a major reason to start treatment. However, if you have doubling of hairy cells in a very short time; for example, you have a high risk variant like hairy cell variant or the IGHV4-34 immunoglobulin rearrangement, which has a poor prognosis. You might want to start treatment earlier if you have doubling of the percentage of hairy cells in the blood or the bone marrow. But in general, we don't tend to put a lot of weight in the percentage of hairy cells so much as what it's doing to your blood counts. And the reason for that is, everyone seems to have different levels of hairy cells in the blood and it has to do with how sticky the hairy cells are. It differs in different patients. That alone is not really an indication for treatment.
Anna Lambertson:
We've received a variety of questions about rituximab. How long can you delay rituximab after cladribine (or bendamustine)? Is there a period of time after cladribine after which adding rituximab would have no effect or benefit for the patient?
Dr. Robert Kreitman:
We compared starting rituximab at the day one time point, in other words, starting it the same day as cladribine, with starting at least six months later. Many of our patients were treated at the six month time point because their blood was MRD-positive at that point and by protocol, they qualified for delayed rituximab at the six month time point. So we find that there's a big difference in terms of MRD-free CR rate as I mentioned, with starting the rituximab early versus delaying it. And the reason for that difference, we believe, has to do with the experiments that were done to show that the reason you get synergy - synergy means one drug plus one drug is like more than two drugs. They work together to accomplish a goal which is not possible with either one alone or really more than what would be predicted with the two drugs together. And this is because the rituximab makes the cells more sensitive to the purine analog.
So, whether it's bendamustine or cladribine, when you give rituximab, the cells are more sensitive to the chemotherapy. The problem is, if you wait for one month, which is what many people do before starting the rituximab, the purine analog is long gone by then. However, there are still clumps of hairy cells in the bone marrow at the one month time point. And many of those clumps are going to be gone if you wait for the six month time point, before starting the rituximab. So, what we do is, when we delay rituximab to the six month time point, we are delaying it to the time when the hairy cell clumps are at their minimum, and so the rituximab can bind to all the hairy cells, as they are individual cells, there are no clumps by that point and it can work the best. But you don't have synergy at that point. You have synergy when you're starting at the very beginning with the chemotherapy because the rituximab makes the cells more sensitive to the chemotherapy and this chemotherapy is gotten rid of by the body within a day or two of each dose.
Now if you're giving rituximab, rituximab hangs on for six months after the last dose, so that stays in the body a long time. But it can't be synergistic with the chemo, when the chemotherapy is gone within a few days. I showed the slides about the bendamustine and the pentostatin and this is designed for synergy because every dose of chemotherapy is being used with rituximab. And so, we're really maximally taking advantage of the synergy. So that's the reason that we favor using rituximab at the day one time point of chemotherapy and not delaying it. But if you do delay it, we prefer delaying it to the point when the hairy cells are at their least number and you can get the best response with the rituximab.
And there are some reasons to delay. Some patients don't want to get rituximab and they may not need it. The cladribine may be just okay, but they're using rituximab in reserve. So that's a reason why some people don't want to get rituximab up front. Another reason is COVID. They want to get the COVID vaccine and they're worried they won't respond if they get the rituximab at that time. So, they don't want to delay treatment and they get the cladribine alone.
I have to say that, and I'm getting to another subject that I'm sure everyone's interested in, cladribine alone is also something that can prevent you from making a response to the COVID vaccine. So you have to be careful about getting these vaccines when you're immunosuppressed.
Anna Lambertson:
One of the things that's on people's minds right now is that the CDC in the United States, Centers For Disease Control, has issued revised guidelines about safety precautions. How do you feel about individuals with hairy cell leukemia in remission following those modified guidelines from the CDC?
Dr. Robert Kreitman:
I think that five years after treatment in a patient who is in complete remission with no minimal residual disease, their immune systems are fairly normal and I think that they can behave like a patient who never had hairy cell. And you could make the similar argument for someone who is in complete remission with a tiny bit of minimal residual disease, meaning there are no hairy cells in the blood by flow cytometry.
But the guidelines that we put out under Dr. Michael Grever's leadership, suggests that patients with hairy cell who get the vaccine should get confirmation that they actually made antibodies to the vaccine and they actually do have immunity.
Patients who have never been treated with hairy cell, but they have a very high number of hairy cells in the blood, so they don't have normal B cells. They may also not make antibodies to the COVID vaccine. If you're in the middle of treatment, if you've finished treatment within the last few years, we are doing a trial where we're checking antibody levels in patients and we're making sure that our patients have antibodies.
This is a little confusing if you're trying to get an antibody test, you want to get a spike antibody test. You don't want to get a nucleocapsid antibody test. Most antibody tests now are still nucleocapsid tests and they only tell you whether you have antibodies to the virus, not antibodies to the vaccine. So, you've got to make sure that you get a spike antibody test to see if you have antibodies to the vaccine, and if the vaccine produced spike antibodies.
Anna Lambertson:
Do you feel that someone who has not responded to the vaccine based on the antibody test will have an opportunity to take the vaccine again? And then secondly, what precautions should these individuals take if they don't have a response to the vaccine?
Dr. Robert Kreitman:
If you don't have a response to the vaccine, I think that you have to be careful. It's possible you might still have some immunity from your T cells, even if you have no antibodies against the vaccine, but you can't count on that and it's a difficult assay to do it. You have to assume the worst, that you just don't have immunity and you have to operate like you did before there was a vaccine. Which is like six months ago. So that's that issue.
Now, I think that it's important to check with your doctor to see if you can get another vaccine if you don't respond to the one that you're about to get. Because if it's been less than six months after the last rituximab or even six to 12 months since the last rituximab, you may not have normal B cells in your blood. You can check for normal B cells in the blood by a lymphocyte subset test. You can ask your doctor to check that and they can tell you whether you have normal B cells present. If you do have normal B cells, you're probably more likely to make antibodies. But if you don't have any, I would check to see to make sure you can get another round of vaccine later, several months later. Let's say the rituximab is out of your system or your immune system is better, and if you can't, you might want to wait before getting that COVID vaccine. But if you can get the vaccine again, then there really is no theoretical reason why you can't get the vaccine again and then test again to see if you've made antibodies.
Anna Lambertson:
Do you consider rituximab to still be a safe option for patients in the context of COVID? And do you feel that rituximab could eventually be used as a monotherapy, perhaps as a bridge, until a patient could handle cladribine?
Dr. Robert Kreitman:
There is no evidence that rituximab by itself works well in newly diagnosed hairy cell and my experience with it is that it works very poorly. And I think that's predictable by the fact that it doesn't get into tightly packed tumor cells and very large clumps that are present in patients with newly diagnosed hairy cell. I would stay away from rituximab alone as a bridge. It’s counterproductive to use rituximab at all in patients who, you're wanting to get a good response to the COVID vaccine with. A more realistic question is, why not use cladribine alone? Because with cladribine, you don't have to wait for six months after the last dose before having a better immune system like you do with rituximab.
I feel that right now in May of 2021, things are safer for patients getting rituximab than they were six months ago because now, we're approaching herd immunity. The likelihood that your neighbor is going to infect you with COVID is less because they've probably been vaccinated. If you're on rituximab, you really need to be careful, you need to wear a mask and socially distance. But I think in general, things are better now than they were because so much higher of the population, percentage wise, has been vaccinated. I don't think we're back to where we were in 2019, but we've come a long way. I don't think that treatment decisions in hairy cell should be strictly made based on rituximab or no rituximab and the need for getting antibodies to the vaccine. I think that you should really make your decision on what will be the best treatment for hairy cell now. And part of that reason is that we've made a lot of progress in getting the population vaccinated.
Anna Lambertson:
You are doing a trial at NIH related to COVID. Could you speak a little bit about that and what you're hoping to learn from those studies?
Dr. Robert Kreitman:
So, we're checking antibody levels in patients after vaccination and correlating that with their levels of immunoglobulin and normal B cells. It's quite simple to do that. We're checking both the spike antibodies and nucleocapsid antibodies. We do find that a fair number of hairy cell patients have been exposed to COVID, many were asymptomatic. But there's another trial being done here at the NIH by the Cancer Therapy Evaluation Program (CTEP), which is looking at T cells that are specifically anti-COVID T cells, which is a little bit more complicated. It gives the patients the Moderna vaccine. That's a protocol that's just opening that we're working with. But we're specifically looking at hairy cell patients to make sure that they've had good immunity.
Anna Lambertson:
And when will that study conclude? When do you feel you'll have some more information that you could share with individuals who are curious what response they might have?
Dr. Robert Kreitman:
We’re analyzing our data now and I think we're winding down in that most patients have already been vaccinated now. We’re still waiting for some patients for at least two to four weeks after the last vaccine dose. Some of our patients have not been vaccinated yet and some patients have to be convinced to be vaccinated; they don't trust the vaccine. We're trying to be advocates for the vaccine. Some patients have shown poor levels of vaccine and those patients are going to be getting another round of vaccines and some of them we're checking again to make sure that they have immunity.
Anna Lambertson:
So, a patient has been treated once with cladribine, and now they're thinking about what treatment they might need to have in the future if and when they relapse. What recommendation might you hypothetically offer to this type of patient for their second round of treatment? If and when they relapse.
Dr. Robert Kreitman:
I rationalize my decision based on the randomized trial where we found that using rituximab with cladribine was not very toxic. It depletes the platelet count for a couple days, but patients don't really notice that. If you look at the neutrophil counts and platelet counts at the four week time point after starting cladribine, they're better if you use rituximab than if you don't use rituximab. So I don't really see much of a downside to using rituximab with cladribine either in the first line or certainly in the relapse setting.
Now in the relapse setting, we do have a trial at the NIH where we're comparing the cladribine alone with delayed rituximab versus cladribine with immediate rituximab. And both groups are getting 100% complete remission rate. This is a very important trial. We believe that each of these approaches is very good, but if you don't use rituximab up front, you need to be followed fairly carefully to be able to give the delayed rituximab when you see the hairy cells in the blood. So that trial is currently ongoing and is available for patients if they're interested. And it's only for patients who've had one prior course of cladribine. They can have vemurafanib and some other things, but not two courses of cladribine and they can't have had prior rituximab.
But we feel that just getting cladribine alone and forgetting about it, in other words just waiting for relapse, is really not appropriate in this day and age for someone who's already had cladribine. Because the chances are, you're not going to get as good a response as you did to the first course of cladribine and really, you can do so much better nowadays with hairy cell treatment than that.
There are recommendations that if you've had more than a two year or more than a four year remission with the first course of cladribine, that it's okay to get the same thing again, the cladribine alone again. And that is probably still in the guidelines. But we don't favor that at the NIH because there's so many better things to do that can work for longer than doing the same thing again.
The other thing I should mention is, there is some toxicity with cladribine. There is some damage to stem cells, there is some neuropathy, some nerve damage with cladribine. It is only about 15% in patients who get the first course. But in patients who get multiple courses, that incidence goes up. So our goal is, if we're going to give a second course of cladribine, we certainly want that to be their last treatment and we think that is a higher chance if we give it with rituximab so that we can eliminate MRD.
Anna Lambertson:
We’ve had a few people ask about moxe and rituximab for second line treatment. It might be helpful for everyone listening for you to clarify when moxe can be used and whether moxe and rituximab could possibly be used for second line treatment for a patient.
Dr. Robert Kreitman:
Our trial is open for patients who've had one prior cladribine and at least one other treatment. They could have another course of cladribine or they could have a BRAF inhibitor like Vemurafenib or they could have just rituximab alone. Those patients would qualify for our moxe rituximab trial. We're very good at the NIH in preventing this HUS toxicity. You want to be really, really careful when you take moxe that you don't get dehydrated and we make sure that patients don't get dehydrated. But there are people giving moxe that are really not aware of these precautions.
So in second line, meaning that the patient has had no treatment other than one course of cladribine, we are not using moxe in that setting. It's only approved in the third line and beyond setting where you've had at least two prior treatments. But they don't have to be two prior chemos. They could be cladribine and then followed by rituximab or a BRAF inhibitor, or even Ibrutinib could be considered a second treatment that, after which, you could use moxe with or without rituximab.
Webinar participant:
I was diagnosed last year and am about to undergo cladribine next week after having had the Moderna shot a week ago. The question is about the rituximab, it seems the big debate here is whether to do it or not do it. It seems you're, in my mind, trying to avoid complications. In your sense, with the vaccine already administered, if you go onto the rituximab, do you think there will be a more favorable response to COVID with the vaccine shot having been given prior to the cladribine?
Dr. Robert Kreitman:
After treatment with cladribine or cladribine plus rituximab, whichever you decide, I would stay away from COVID and be careful because either way, that cladribine is going to make you susceptible to getting complications with COVID. That's point number one. I'm aware of someone who's had a severe, severe course of COVID with just cladribine alone. Having had cladribine alone and then getting COVID. You really want to stay away from anyone who's had COVID, regardless of whether or not you take rituximab.
I think that the remissions with rituximab are much better than without rituximab. This is data not only from us, but also MD Anderson by Farhad Ravandi, that whether you start the rituximab delayed or at the immediate time point on day one, or if it's started one month later as MD Anderson does, you get higher complete remission rates and you get a reasonably high MRD-free CR rate, even at the one month time point.
So I think that there's no question that the long term outcome is better if you're incorporating rituximab into the treatment, either immediately or delayed. You don't want to just take the cladribine I think and wait for relapse and then be back to square one and then be thinking about taking more chemotherapy. I think even in the COVID age, incorporating rituximab into the treatment isn't a wrong idea, but you do have to be careful. For example, you want to make sure your family members have been vaccinated, you don't want to get COVID from them and these are the things that we look for.
Webinar participant:
I was diagnosed with hairy cell leukemia variant 20 years ago and the choice at the time was pentostatin or cladribine. I chose pentostatin. Since then, I have only had my normal blood counts tested twice a year and my doctor says that although there's possibly some hairy cells, since my blood counts remain normal, there's no reason for further treatment. What is the problem about having MRD? Which, he assumes I probably do have some hairy cells, but they don't seem to be affecting my blood counts.
Dr. Robert Kreitman:
Yeah, so your story is very unusual. If you'd like to send blood to us, we could probably help you with understanding why you've done so well despite having hairy cell variant. Some patients who have been diagnosed with hairy cell variant don't actually have it. They just have a low CD25, but they do have CD25 and they really have classic hairy cell. Your disease is behaving more like classic hairy cell. In other words, if your blood counts are normal and you don't have a high white count, you’re behaving like someone who's had classic hairy cell. I mentioned before that only nine percent of patients have complete remissions. It sounds like you've had that and so you're certainly in the minority of hairy cell variant patients. But if that's the case, then I think you're lucky. We don’t understand the genetics of variant hairy cell. There are some mutations that drive variant hairy cell that are different than other patients with variant hairy cell. So it may be that you have a mutation that is not associated with a fast moving disease like hairy cell variant usually is. And I think you could be thankful for that, regardless.
But this is one thing we're doing at the NIH is studying hairy cells in patients so that we can better understand this disease of hairy cell variant, which is very heterogenous. A lot of patients progress much more rapidly than others.
Anna Lambertson:
A few people have asked how they might participate in the clinical trials that are ongoing at the NIH and I just wanted to jump in and say all the clinical trials that Dr. Kreitman has mentioned are listed on the Hairy Cell Leukemia Foundation website. If you click on patient support and scroll down, you'll see the list and under each clinical trial, there's a contact name and email and phone number, so you're welcome to reach out to those individuals, either Dr. Kreitman or the nurse in charge of the trial and they can help you if you're eligible.
Webinar participant:
Just a quick question, can you get a spike antibody test after you've been given a mRNA vaccine a month ago? Is that what you're recommending to test your antibody levels, that's what you're recommending for patients with classic hairy cell leukemia?
Dr. Robert Kreitman:
Under the leadership of Dr. Grever, we published a position paper about COVID and hairy cell and we said that in general, hairy cell patients should get tested with antibody tests to make sure that they're responding to the vaccine and not just assume that the vaccine is going to work. And what you want to check is that spike antibody test, that's correct.
Anna Lambertson:
There was an individual who had asked a question earlier about after treatment, risk for exposure. If you could quickly speak to that question. Once people have been vaccinated, are their treatment options at that point open? So people are vaccinated and then they get diagnosed with HCL or they relapse, are you at that point recommending whatever treatment is necessary for the patient?
Dr. Robert Kreitman:
We actually take everything into consideration when we're going to treat a patient. For example, if there's a patient who is newly diagnosed and was vaccinated, but they end up having a very high level of hairy cells in the blood and they don't have normal B cells, they don't respond to the vaccine, even though they haven't even gotten treated yet. They have no response to the vaccine in terms of antibodies and their family member has not been vaccinated, so we really highly encourage that family member to vaccinated because at least that's something they can do. There's nothing the patient can do, he’s already been vaccinated and the vaccine doesn't work, it's probably not going to work until the patient gets treated and regains a fairly normal immune system. So I think the family members are important, that's really your herd. When you talk about herd immunity, it starts with your family.
You've got to make sure that the patient's family has been vaccinated to the extent possible. Obviously there's children that are under 16, they can't get vaccinated, but if there are children there that are above the age of 16 or 16 and over, those people should be vaccinated if they're going to be around a hairy cell patient that may or may not make antibodies to the vaccine. And that's regardless of what kind of treatment they get.
Anna Lambertson:
There’s still so much that we're learning about COVID and hopefully through trials such as the ones that are being conducted at the NIH, we can learn more and learn how doctors can better manage care for HCL survivors or those who relapse or who are first diagnosed over time.
We have reached the end of our time. Dr. Kreitman, I want to thank you so much for the time that you took today to present information and answer questions. We always receive so many more questions than we can get to. I wish all of you a wonderful remainder of your day or your evening and all the best for this week.