Understanding HCL Webinar Series: HCL in 2022
February 28, 2022
Hosted by the Hairy Cell Leukemia Foundation with speaker Dr. Tim Call from Mayo Clinic. Moderated by Anna Lambertson, HCLF Executive Director
Presentation Materials
Note: A recording and slides from Dr. Call’s presentation can be accessed using the links below. Each link will open the file via a new window or you can download the file. You do not need a Box account to view these files.
Transcript of Webinar Presentation
Dr. Tim Call:
Thank you Anna for that introduction, thank you Anna for all you do for the Hairy Cell Foundation. It's been a pleasure to work with the Hairy Cell Foundation, it's one of the most organized organizations I've ever been involved with. Greetings to each of you, wherever you're listening from and thank you for joining us.
I've got about 20 slides I want to walk through with you and then we can take questions. I'll try to go slow and not talk too fast. I don't have any financial conflicts to disclose.
If you were to see me in my office, after I have examined you and kind of looked at everything, I'd pull out a piece of paper with this diagram on it. I want to start with that because I think it's important that we know how our blood is made. If you were to take a round steak bone and you would look at it, you have hard supporting bone and inside there is liquid marrow. We're created in a way that our stem cells will differentiate into bone stem cells, skin stem cells. But there are bone marrow stem cells that will differentiate into precursor cells within the marrow and then from there we see the factory output of the bone marrow which is your red blood cells which carry oxygen, your white blood cells which are primarily infection and inflammatory fighters, and the platelets.
We also make other cells such as plasma cells which generate antibody and we can see that if any one of these cells has mutations or develops a clone, then that can be a form of leukemia. So we have acute leukemias, we have chronic leukemias. So there's chronic neutrophilic or granulocytic leukemia, there's chronic lymphocytic leukemia.
For the purposes of today's talk, we're going to be talking about a subclass of what are called the lymphocytes and specifically the hairy cells.
So again, when you look at your total white blood cells, they're made up of various subgroups that are present in a certain proportion. Among the lymphocytes, there are B cell lymphocytes, T cell lymphocytes, and NK, or natural killer cell lymphocytes.
Within each of those subgroups, there are multiple subtypes. So what the type of leukemia is will depend in the lymphoid area what cells it derived from.
Dr. Tim Call:
So this is just a case; everyone's story is different, but this is just one case.
It's a 48-year-old farmer from Iowa who went to the emergency room down in Iowa on a Friday with a cough, fever, and had a pneumonia. He was getting married the next day, so he refused to be admitted. He was recommended to be admitted, the emergency room in Iowa gave him an antibiotic by mouth and he went home, got married about noon, and by about 5:00 or 6:00 p.m., he was life-flighted to Mayo Rochester in respiratory failure.
His blood counts when he came in, and he had a pneumonia on x-ray and on CT, but he was anemic. Here you see the normal values. His platelets were low and his white blood count was low. Within the white count, he had a low neutrophil count, a low monocyte count, and had a relative increase in his lymphocytes. He was treated, turned out he had Legionnaires' disease. After about a week, he started to improve. He was on a ventilator for a couple weeks and eventually got better, but I got a call on a Saturday to come and see this gentleman because even three weeks out as he was rehabbing, he still had anemia, he still had a low white count, and he still had low platelets.
So we evaluated him and noted that his spleen was slightly enlarged and that was seen in retrospect on his chest CT. His blood smear showed what's a big word, leukoerythroblastic. It just means there were immature cells out there in the blood, and it was recommended that he have a bone marrow biopsy.
So just below where it says hairy cell leukemia, you'll see a blue box pointing to a pink slide and this is a normal bone marrow biopsy. Bone marrows contain both cells and fat. The amount of fat is about proportional to your age, so if you're 50, you should have about 50% cells, 50% fat. So this would be normal. In the background you see various different cell types which are normal. We're not going to go down to high power and identify them, but if you look here then on the left side of the slide, you will see that it says aspirate dry tap. What that means is that when ... Marrow is primarily liquid, but when they pulled back on the syringe to get the marrow, they got just very ... A little bit of blood, but not much marrow, and so we normally do both a aspirate where we aspirate the marrow and a biopsy. And on the biopsy, this was the pattern.
So again, very little fat, lots of cells, probably 95% of the marrow was cells, and if you look at this, you see these cells with a little bit of space, pathologists call this a starry sky appearance, and there's a little bit of fibrous tissue or scar tissue that occurs that goes away when treated, but that’s what makes it harder to aspirate the liquid marrow.
On the right lower side, you see a typical hairy cell. So you see red blood cells here and then you also have the hairy cell with a larger nucleus, cytoplasm, but the border of the cytoplasm is irregular. And that's where it got the name, prior to any of our major molecular markers, hairy cell leukemia.
Dr. Tim Call:
Anna does have a copy of the slides and she will make those available to you. This is a busy slide and I'm giving it as a reference slide, but it goes through how we would determine the diagnosis by looking at the blood count, looking at the blood smear.
We do use what's called flow cytometry, it can be done of the blood or the marrow. I'll come back to that in a couple slides from now. Bone marrow exam. And often I normally will get a chest x-ray just because we can sometimes see mild asymptomatic pneumonias. We just want to know prior to any treatment if there's any infections. And then the big thing in red letters I wrote is expert pathology review.
Most hairy cell leukemia is hairy cell leukemia if it's been diagnosed correctly, but there are mimickers or other cousin diseases in the bone marrow and the lymph nodes and the spleen that can look very similar. Among those is a rare form of hairy cell called the variant form. A more common confusing picture is what's called splenic marginal zone, where they may have some what are called villous lymphocytes or shaggy border, and then there's another rare disease called splenic red pulp lymphoma.
So it's very important that the pathologist looking at the sample is very sure what they're doing. If they're not, you can actually request or your doctor can request a second opinion for pathology only. Places like the National Cancer Institute and most major medical centers will provide slide review, pathology review, through their reference laboratories.
At the very bottom, it's listed when we would treat. Sometimes we don't have to treat right away, we can observe if there are no symptoms and the counts are mild, but if the hemoglobin is getting lower in the range of 10 or so, platelets or less in 100,000, or 90 to 100,000, or what's called the neutrophil count, those are the main infection fighters for bacteria, are less than 1,000 or 1.0, or if there are other symptoms like enlarging spleen causing pressure, weight loss. And as I'm sure many of you can attest, there are also symptoms like unusual bone pains and things. So monitoring without treatment is allowable if there's no symptoms or signs, but if there are things that we can improve, we should treat.
Dr. Tim Call:
I said I would be coming back to flow cytometry. So how do we determine that it is hairy cell? There are different molecular markers in the cell, around the cell membrane that can help us determine that. I compare it for my patients to a bar code. There is a specific code on the cells that we can try to analyze and determine if this is hairy cell or it's not hairy cell. So I just listed down here hairy cells tend to be larger than normal lymphocytes, and they express these various antigens. So these are on the surface of the cells, we can find these various markers around the cell that are there.
The hairy cell variant has a different pattern and is what's called BRAF negative. Almost all hairy cells are BRAF positive. It's a molecular marker that is almost 100% expressed. So if you read how do we get these results, we use what's called a flow cytometry.
So this is a laboratory/computerized test. So what we do in the laboratory, we take a blood sample, we have a way of spinning down and collecting what are called the mononuclear cells which would contain your white blood cells, and then that is incubated with antibodies that are labeled with various fluorescein colors or characteristics. Following that, the sample is washed and put through an analyzer which basically shines a fluorescent light through this layer of cells, it's usually a single layer of cells going through a tube. And on the other side, there is light scatter and the characteristics are captured in a sensor, and then computerized.
So if you look at this marker where there's blue dots, purple dots, red dots, each of those dots is an event, and that signifies a cell. And so you can then, knowing what markers you put on, that you have in your system, you can identify either ... Generally it's a series of several tubes that they run, they can identify what the pattern they're seeing, is it a normal pattern of lymphocytes or as if you look on this there's this red pattern. Again, the red is artificial, it's just a way of determining the difference but they see a clustering of a lot of cells which normally wouldn't be there. So that's just a picture of how that test is done.
Dr. Tim Call:
Just some basic statistics. HCL is rare, about 1 to 2% of adult leukemia, more common in males. For most leukemias we're used to having high white blood cells count, but only about 15% of hairy cell have a white blood count. Most of the time it is low white blood count and you can, again, looking back to that bone marrow that's completely packed, you're not generating enough of the normal white blood cells.
The spleen may be enlarged, there may be bone pain, there may be infection. However, it could just be you went in for a ... You're going to have a hip surgery, they say we want a blood count and you haven't had one for a couple years and they find it as an abnormality.
I'm just going to give a high overview of treatment and not go into a lot of specifics, because everyone's case is different. In the treatment, historically, splenectomy was used for many years. It was a temporary help, it might benefit for one year, five years. I've had some patients I've had early in my practice who had multiple years. The drug Interferon could be used and still can be used, but then in about the late 80s early 90s, our colleagues at Scripps Institute in La Jolla, San Diego developed cladribine and this (cladribine) revolutionized treatment.
Cladribine historically was given as a seven-day continuous infusion, but currently we primarily use it as a two-hour infusion daily for five days. There are certain countries that have subcutaneous available. There are oral formulations. So those of you from the European countries may have had subq or oral. In the United States, we're primarily dealing with the intravenous form.
High response rate, 98%. High complete response rate. We do know and I'll come to it in a minute that the complete response has increased with the addition of rituximab. But the wonderful thing is the response is durable and at 20 to 25 years, roughly two-thirds of people are still in remission, clinical remission that we don't see signs.
Now we don't go back and redo the bone marrow to see if there's 1 or 2%, but we just go on clinically and so there's a lot of hope in that.
It takes time for this to work. We can see the blood counts improve quickly, but to look at the bone marrow, we generally delay and don't do a bone marrow before six to nine months, which is different than a lot of the chemos and we need to sometimes tell the hematologists in private practice, don't just give a week and then recheck a marrow in a month and go ahead and give another week, you have to generally give (cladribine) time.
Dr. Tim Call:
Pentostatin is another excellent drug. It's a cousin drug to cladribine. It has a high response rate, it's FDA-approved, it's given not just for five days, it's given like every two weeks for about three to four months and again has a high response rate.
Rituximab is a monoclonal antibody directed against what's called CD20. It can be used alone and it has a pretty reasonable response rate of about 80%. But what's called relapse-free survival, when I use the survival terms, I'm not talking alive or dead. It's like how long did it last. So how long were you without recurrence was only about 27 months. So it can be a temporizing agent, but it's not generally a long term remitting agent.
About two years ago, Dr. Kreitman's group published an excellent study comparing adding Rituxan to cladribine and if you gave it concurrently, so starting both at the same time, it was superior to if we gave the cladribine first and the Rituxan later. Very high response rate with the concurrent, and much higher MRD negative.
Now MRD means minimal residual disease. So if we use our fanciest tests, can we find any cells in the marrow? Generally the (less) MRD you have, the longer the remission. A note at the bottom that if it is the rare case of hairy cell variant, you generally cannot use cladribine alone but need to combine it with rituximab.
What's been changing in the last decade is targeted agents for relapse. Probably the most interesting has been Vemurafenib. Vemurafenib is a drug that's approved for malignant melanoma, an aggressive skin tumor. So it's on the market, we can use it what's called off-label which means the FDA hasn't approved it for hairy cell but the drug is available so we can get it and sometimes we might have to appeal to an insurer.
Most hairy cells are BRAF positive. Vemurafenib has a very high response rate and it works quickly. About a third of people will go into complete response. The “but” is that the general duration of response is nine to eighteen months. So it works good, but it doesn't last long.
Dr. Tim Call:
A lot of very exciting work has been done by Dr. Tiacci's group from Italy combining Vemurafenib with rituximab, showing a very high complete response rate and showing that at 37 months, 78% are still in remission. So this is an excellent result, especially for relapse, and so we don't know what's called the median or what's the average time of benefit yet.
Dr. Jae Park and the group at Memorial Sloan Kettering are also working (on this) and they presented recently Vemurafenib plus obinutuzumab. Obinutuzumab is a cousin drug to rituximab and may have, in CLL it does have a higher single agent response. Again, high response rate, but the duration of time in the study was ... Median duration was 16, 17 months. 100% were still in remission, but again the time is short, so this has to mature.
Dr. Tim Call:
Ibrutinib is a drug that's used in CLL. Dr. Kerry Rogers from Ohio State University published a study that was coordinated through the Hairy Cell Leukemia Foundation with Ibrutinib showing a 54% response rate. It often is delayed, it takes time, and at 36 months, 73% were still in remission. The thing with this drug is it's very well-tolerated, and in addition to the response rate, there were a number of people with stable disease. That means there was a partial response but it didn't meet the criteria of a complete response and were still benefiting. So it has activity. Again primarily we're using these drugs in people who have failed or recurred with cladribine or repetitive cladribine.
The FDA has approved moxetumomab which is an immunotoxin that then targets CD22 which is one of the markers in hairy cell. 71% response rate, 41% CR. Again, the median time, many of these people are still responding. It does have some unusual toxicity, so it really needs to be used by someone who's used to it. What's called capillary leak syndrome where there could be significant fluid retention and edema or hemolytic uremic syndrome, which is a rare condition affecting blood and kidney.
Dr. Tim Call:
Now currently in the COVID situation, there have been modifications in what I've just told you, in that because cladribine targets lymphocytes, it does suppress the immune system and the ability to respond to viral infections. So this article, you can see the reference there, was published by our group with the best we could come up with ideas and options for physicians treating hairy cell during COVID-19. Trying to balance getting a good response versus minimizing immune suppression. And so I think to summarize this, during the last two years, we have decreased the amount of cladribine and pentostatin we've used. We've increased the amount of Vemurafenib, especially Vemurafenib plus Rituxan we've used. Because Vemurafenib plus Rituxan does not have a significant immune suppressant except that Rituxan decreases B cells, which is going to decrease antibody or vaccination response. So we've had to kind of vary this.
I would say that in the COVID-19 era, every case needs to be looked at individually. Let me give you an example. In June of last year, when COVID was relatively low in Minnesota, I had two patients who presented in the same week. One was a 43-year-old woman who was vaccinated, very diligent, was able to self-isolate, didn't want to face this again, and we treated her with a cladribine-based approach. Another was an individual who worked in a high risk for exposure job to people with COVID and would not accept vaccination. Because I felt the risk for him was higher, I treated him with Vemurafenib and Rituxan. The first lady is followed in a different institution now, this other gentleman has responded nicely and is remaining in remission. So (treatment) needs to be individualized.
Dr. Tim Call:
Following therapy, we monitor the blood counts until they have recovered. We watch for any signs of infection. Do you need a bone marrow biopsy after treatment to establish a benefit? I can tell you that this is not a uniform recommendation. Some people feel that you can do it, but it isn't going to change because we're not going to turn around and give you more treatment if we find .5% hairy cell in the marrow, we'll just give it time, and there's data showing improvement in the marrow even up to a year and a half out. Other people feel like, "Well it's good to know so we can see if down the road there is any sign of progression or recurrence." So I tend to lean towards biopsy at about six to nine months (after treatment), but it's not mandatory.
We can talk about the complexity of the bone marrow in the blood, but we can also talk about the incredible complexity of our immune system. During COVID, there's been a lot of questions regarding immunity, how to boost my immunity, but I think that we should really look at what is our immune system. I mean our immune system actually starts with our cutaneous system, our mucosa system, that will help to prevent infection, prevent invasion, stomach acid may neutralize certain bacteria; we'd probably have a lot more gastroenteritis if it wasn't. So that's the first line.
The second line of defense is various cells that the bone marrow makes. So the macrophages, the neutrophils, the various types of lymphocytes.
The third line really is how do you adapt to exposure and so you have T cells that will respond to infection, B cells that will respond to infection.
This is a diagram I find helpful. On the left side, you see what's called your innate immune system. This is the factory putting out the cells and you need a certain number of these various cells, for instance neutrophils, to fight infections. On the right hand side of the slide is what's called the adaptive immune system. These are cells that can be stimulated, challenged, and produce either antibodies, produce T cells that will remember prior illness and try to attack it. So again, I won't go through all these, but just to say our immune system is both innate, based on how many of whatever we have, and how well it responds to challenges.
With hairy cell and immunity, we know that following cladribine and Rituxan, what's called the CD4 T cell count may be suppressed for at least six to twelve months, perhaps longer. So we often will give antibiotics preventatively to cut down a rare pneumonia called pneumocystis, or an antiviral to cut down shingles.
Dr. Tim Call:
More recently, if I were to go back now and treat the patient that I started this presentation with, the gentleman who was hospitalized in the ICU on the day he was married, I would use Vemurafenib. Because Vemurafenib can rapidly improve the blood counts; we could treat his infection, and then down the road, we could use a cladribine-based approach. So this is an approach we often now take in a patient who comes in with a significant infection.
These slides are just simply for our reference, listing some of the immune effects. This comes from a paper; it's referenced there. Immune Effects of Hairy Cell on Your Immune System, so it can affect some of these various things and often with response and treatment, it can improve. And then this is just a chart that lists the immune changes due to our therapies and I mentioned about cladribine and the CD4 count, that there's less immunosuppression with Vemurafenib.
There's also less immunosuppression with moxetumomab.
With vaccinations, what happens is you're vaccinated with an antigen. These then cause inflammation, where at the site, what are called dendritic cells process that. They present them to the T cells, which can develop into T cell immunity or the T cells will also present them to the B cells which will develop into antibody mediated immunity.
Dr. Tim Call:
The Leukemia Lymphoma Society, some of you may have participated in this study with COVID, looked at samples that were in individuals who had mostly hematologic malignancies. And so what they did is they got individuals who had had two vaccines, had a sample to check for antibody levels and then a small proportion had a third dose to check for sample for antibody.
Now there will be more information coming from this study, but these are slides from Dr. Greenberger that was also presented at the American Society of Hematology in December. So then they did what's called an anti-spike antibody to look at the level. What they found was there was a variability between what hematologic disease it was and how well they responded, and they looked at 2,200 individuals, but there were only 13 hairy cell patients in this initial cohort. I think there will be more as they do further analysis and get more samples. But it showed that 92% of hairy cell patients did develop COVID antibodies. So as compared to CLL which is a cousin disease, only about 68%. When they looked at those individuals who had had a third vaccine, unfortunately there were no hairy cell patients who were in that cohort.
So with that, I will turn this back to Anna and try to answer questions.
Transcript of Question & Answer Session
Anna Lambertson:
One of the most frequently asked questions that we receive from patients is about when they should initiate treatment. You referenced the 2017 Consensus Guidelines that were published by a group of HCL experts including yourself and you noted that blood counts as well as the presence of symptoms are taken into consideration before deciding to start treatment. We had two patients ask a question, they're both in a watch and wait mode.
One patient said that you had mentioned that 85% of HCL patients have a low white blood cell count. Does that indicate something important for a patient who is in the watch and wait mode who hasn't yet received treatment? Or what type of clinical decision might that influence for you with regards to a patient's treatment?
Dr. Tim Call:
Good question, you might have caught me not being quite as clear as I should have been. 15% of individuals with hairy cell have a high white blood count. The rest I should correct myself and say was either normal or low. But what's important is what is the neutrophil count. Neutrophils are bacterial fighting cells, so they are what help protect us from overwhelming infections. And if the white neutrophils are low, we call it neutropenia. And neutropenic infections are something we worry about.
Now normal neutrophil count is about 1.6 to 1.7 in most laboratories. If you look at the risk of infection looking at the degree of what's called neutropenia, if the neutrophil count is between 1.0 and the lower limits of normal, there is a very slight increased risk of infection. If the neutrophil count is between 1.0 and 0.5, the risk of infection begins to increase. So then I'm talking about unusual infections, pneumonias. If the neutrophil count is less than 0.5, then the risk of an opportunistic infection is significantly elevated. Therefore, we generally ... Some of the slides, it varies how they report the number, either a neutrophil count of 1.0 by one unit or 1,000 by another unit, is generally our cutoff. So anyone who goes less than that, I would recommend therapy.
Anna Lambertson:
Keeping within the theme of how you time treatment. This other individual, also on watch and wait, blood levels have been somewhat static, they haven't changed dramatically, but this individual has experienced a lot of fatigue and breathlessness. Their question is from a quality of life perspective, how much do you take that into consideration when you're deciding when to treat the patient?
Dr. Tim Call:
Again, a good question. Fatigue ... so if a person because of hairy cell is becoming anemic, the signs of anemia, low hemoglobin, is shortness of breath with exertion. It doesn't necessarily mean fatigue at rest. One of my patients has had a quarter mile walk with an incline to his mailbox. His hemoglobin went from 13 to 12 to 11 to 10 and 1/2 and he would have to walk, rest, walk, rest. So shortness of breath with exertion is the classic sign of anemia, which again, that would be clearly an indication in most cases, especially if the hemoglobin is less than 11.
Fatigue itself, I'm tired all the time, there we have to be a little bit more careful. The most common cause of excessive daytime somnolence in the U.S. at this point is disordered sleep. So thyroid function. So if I'm going to treat, I'm not saying I won't treat based on fatigue. I think we have to be open that everyone responds differently. But doing many second opinions over the last 25 years here at Mayo, I've obviously seen people who got treated for fatigue, were in remission and were still having fatigue because it wasn't related to. But I've also seen those who have had fatigue and sometimes as a patient you don't even know how to describe what you're feeling, where there has been clear benefit. But I think before I would advise in that situation that making sure that the thyroid function is okay, if there is any possibility of excessive snoring or disordered sleep, getting a sleep study.
So again, I think as a hematologist, we need to dissect out a little bit what do you mean by fatigue? I'm never going to say I wouldn't treat, because I have, but I also want to be careful I'm not treating iron deficiency, low thyroid, or sleep apnea with chemo.
Anna Lambertson:
We have received some questions about how blood counts or cells recover after treatment. One patient is specifically asking about T cells and how long it might take for them to see recovery in that area, and another patient is asking about white blood cells and when they might return to what you might consider to be normal levels. So if you could speak to blood count recovery.
Dr. Tim Call:
Absolutely. So let me cover the T cells first. The T cells will stay down longer and we do not routinely test the T cells early during the course. Now I'm talking about with cladribine. With Vemurafenib, it doesn't significantly drop the T cells. So with cladribine or pentostatin, what you see is often your neutrophil count, that's what we're monitoring there, will increase and improve. It may be still low the first week, but generally by the second, third, fourth, fifth weeks, it is climbing up into a safe level of neutrophils. So it tends not to take very long.
Some individuals, if it's felt that you have a high risk of infection, you're starting out with a very low neutrophil count, we can give an injection called granulocyte stimulating factor, Neupogen or Neulasta, to try to get that up quicker. It's a transient effect but it can help during that amount of time.
So the neutrophils tend to respond often within the first month, you are seeing improvement of them. As I mentioned in one of my slides, T cells, especially the CD4 cell, especially with opportunistic infections, and that can really remain low for six, twelve, eighteen months and we generally look for a CD4 level of greater than 200 as being our cutoff when we'll stop the preventative antibiotics.
The CD4 count isn't that involved with neutropenic infection. It's more like atypical viral infections, like shingles reactivation or what's called pneumocystis which is an irregular lung infection or a cytomegalovirus. Those are the types of things. Those are less common, but we do watch for those.
Anna Lambertson:
We've received a number of questions about COVID. Some individuals are wondering what your recommendation is regarding a second booster. I'm sure that many of the individuals participating today are fully vaccinated, they may have already received a first booster and they're thinking about getting a second and would welcome your thoughts on that. And then also Evusheld, we've received a number of questions from patients about Evusheld and whether you are recommending this for patients who are immunocompromised or who have HCL.
Dr. Tim Call:
As I showed you, we don't have a lot of data on responses in hairy cell patients. However, there's an important thing that came out from the study of CLL patients in Israel and what they showed was important; if you had not had therapy and/or you had therapy and you were in remission, your chance of developing an antibody response was the best. It wasn't as high as a normal person who didn't have CLL or was in remission. And then if you were on active therapy or within a year of rituximab your response was down in the 20% range.
I don't have the data, but I suspect if you're a hairy cell patient who has either not been treated yet or has been in remission for 5, 10, 15, 20 years, you may very well have a good response.
So the second booster, yes. I think anyone who has an immunocompromised situation; I think now the FDA and the CDC has suggested that a fourth dose be given.
Evusheld has been a very interesting story. Now when you think of a vaccination, what you're using then is you're using our adaptive immune system, which requires an active immune system, to be stimulated and develop an antibody. So that's what a vaccine is. Your body is going to create the antibody. Evusheld is two injections, at the same setting, of two monoclonal antibodies. This is what's called a passive immunization.
So somebody with no immune system you're giving antibody to. So everyone's going to have a weight-based, depending on the dosing, you're going to have a response. You don't have to worry about what your immune system is going to do.
So yes to a fourth dose unless you had some reason not or some contraindication.
Evusheld is, as those of you who have looked into it, in fairly restricted supply. I would say if it came to you that you could get it, it seems to be safe and well-tolerated, it provides about six months of benefit and likely it could be re-approved. If you meet the criteria, I would suggest it.
Anna Lambertson:
Many individuals are asking; they're vaccinated, they're getting all the boosters, they're taking all the precautions, they may already have gotten in line to get Evusheld, etcetera. What can you advise them about their risk for COVID at this point? If they'd been in remission for a while, they're otherwise vaccinated, can they go back to a somewhat normal life? What do you advise your patients?
Dr. Tim Call:
Well I get two questions. One is what do we do at family reunions or events or weddings and all that type of thing. It all depends where you are and what the numbers are.
I think self-testing can help to determine, until we really get down to where there's like minimal COVID or just baseline COVID. I think the other question I get a lot is can I go to, it's winter here in Minnesota, can I go to Arizona, do this, do that. I think that if you're careful, if the rates keep coming down, I think people can begin moving. What I caution my patients is this is probably not the time to go to places that are medically resource poor. I would stay in areas where you can get to healthcare if you were to need it.
Webinar participant:
I've been in remission since 2010 and my question is what symptoms and signs will I have if (my HCL) would come back? Would it be very similar to before?
Dr. Tim Call:
Did you have any bone pain or aches or anything like that?
Webinar participant, responding to Dr. Call’s question:
I had major fatigue. I had nosebleeds. Those kind of things. I had a lot of nausea. I don't remember any bone pain. But my platelet count was way low, my white count was way low.
Dr. Tim Call:
Yeah, so great question, and what I would say is that if you had specific symptoms and you have them again, pay attention. They probably are related. Now again, other things can cause fatigue, so you'd want to check it out. I generally recommend continued blood count analysis even in someone like you on a once a year basis. What am I looking for? I'm looking for a trend developing. Let's say your platelets post-treatment were 150,000 and then two years ago they were 130,000 and now they're 110,000. Let's say your neutrophils are drifting, going down. Even if they're not that low, there's another cell we watch called the monocyte. Monocytes for some reason tend to be a good harbinger of recurrence, so if you treat and you go in remission, we see the monocytes rapidly come up and if down the road we see the monocytes starting to drop, then that's something that makes us pay attention. Not that we have to treat right away, but I think the best thing is we'll monitor. I'll generally monitor quarterly for the first year, then every six months for maybe four or five years. But if I see nothing at the end of that, I still have people either come back and see us once a year in our leukemia clinic or make sure that it's very clear that their primary care knows what to watch for. So pay attention to your prior symptoms, but also look for trends in your blood counts.
Webinar participant:
I was scheduled to have a bone marrow biopsy and I came down with COVID. I'm wondering if because I tested positive for COVID, if that's going to affect any kind of response that I might get from Evusheld if I can actually get it because of the restricted supply.
Dr. Tim Call:
No, it wouldn't. The response will be the response because again it's a passive immunization. So it's like me giving you an infusion of saline that's going to last six months. It basically gets into your system, and antibodies have a long half-life, so they stay around for a period of time. So having had it won't do it. You do have to separate it from a fourth vaccine by at least two weeks, so if like say the door opens up and you can get Evusheld today, you might want to wait a couple weeks to get your vaccine. Or if it looks like there's no Evusheld available, then consider getting your vaccine now so that you would be in queue.
The other thing you can do prior to getting Evusheld, you can have your doctors check a COVID spike antibody. This is the test that was done in the Leukemia and Lymphoma Society study I shared from Dr. Greenberger's data; that's what they tested to see if you have a strong antibody response or not. We don't know for sure what number is really protective, we really don't have that data.
Anna Lambertson relaying question from webinar participant:
The patient says they were treated two weeks ago with cladribine. Their doctor wants to add rituximab after the blood counts are back to normal ranges. What would be your advice in administering rituximab after the cladribine and should the patient consider doing the rituximab sooner given the research in rituximab and cladribine being done concurrently?
Dr. Tim Call:
I'm just going to give you a reference and you can write this down. It would be the Journal of Clinical Oncology, Volume 38, Issue 14, and the first author is Chihara. The title is, Randomized Phase II Study of First-Line Cladribine with Concurrent or Delayed Rituximab in Patients With Hairy Cell Leukemia.
It appears that adding Rituxan either concurrent or delayed adds additional response to the cladribine. This study showed that the concurrent was superior to delayed in terms of the overall responses. The best I can tell you is to discuss that with your doctor and how they would interpret that. So you and they will have to make those decisions based on the data.
Anna Lambertson:
I would like to encourage you for a few minutes to talk about HCL variant.
Dr. Tim Call:
So we have a rare leukemia and then we have an even rarer variant of the leukemia. The first thing is I can't stress enough that your pathology be reviewed by an expert and that they're 100% comfortable with it being a variant. I say that based on cases I've seen through the years.
Anna Lambertson:
We have received a number of questions about Vemurafenib. One individual wants to know if they did not tolerate rituximab previously, would Vemurafenib be a good option for them? In your experience could a patient tolerate Vemurafenib more easily than rituximab?
Dr. Tim Call:
It depends on the dose. I say this because a lot of the studies are written with a dose of Vemurafenib at, I think it's 960 milligrams twice a day. For Vemurafenib, the main side effects can be a slightly increased risk of skin cancer, so we generally recommend careful skin exam before and within six months after treatment. Vemurafenib can sometimes cause some inflammation in the pancreas, again very, very rare, I haven't seen it, but it can cause a lot of achiness.
The Italians’ (Dr. Tiacci), they're able to get three, four months of full dose Vemurafenib. Personally we were starting at 480 which is half dose, but I'd say for most of our patients we're giving 240 and they tolerate it really well. So the tolerance of Vemurafenib may vary, but in my mind, if you start at a high dose, don't abandon it if the side effects are there. Drop the dose down, because we've seen very good responses to lower doses, especially when combined with Rituxan.
Now taking it as a single agent, it responds rapidly, but you're going to need something beyond Vemurafenib to keep you in remission because it's only going to last for nine to eighteen months. So in that case, let's say you weren't responding, that's where you might move towards Ibrutinib or if you have someone who's skilled in giving the moxetumomab. But single agent, it's good for giving us a period of time to get an infection under control, to get things stabilized, but then there generally has to be a follow-on.
Now I have had a patient who had gone through every treatment. Every treatment and some two or three times. I would treat him with Vemurafenib for three months, it worked for a while and quit. We have cases where we've just left them on low dose like 240 milligrams twice a day indefinitely. For him it lasted about four and a half years and he became resistant to it. But again you have to monitor, there can be some hair changes, some nail changes, and you have to monitor for skin cancer.
Anna Lambertson:
Really quickly, are you able to speak to dabrafenib plus trametinib as an option for a patient who can't take Vemurafenib?
Dr. Tim Call:
It's another, what is called a MEK inhibitor. Again these both have been used in malignant melanoma and the response rates are higher and the responses may be more durable.
Transcript has been edited for clarity.