Understanding Hairy Cell Leukemia Webinar Series: Accurate Diagnosis & Targeted Therapies
August 24, 2022
Hosted by the Hairy Cell Leukemia Foundation with speaker Dr. Clive Zent from the University of Rochester Wilmot Cancer Center. Moderated by Anna Lambertson, HCLF Executive Director
Presentation Materials
Slides from Dr. Zent’s presentation can be accessed using the link below. You do not need a Box account to view the slides.
Transcript of Webinar Presentation
Anna Lambertson:
I'm delighted to introduce our speaker today. Dr. Clive Zent is a highly experienced hematologist and an internationally recognized researcher and expert in the care of patients. He trained in hematology at the University of Chicago, where he studied the molecular genetics of hematological malignancies in the laboratory of Dr. Janet Rowley. His clinical and research interests started as an attending physician at the Central Arkansas Veterans Healthcare System and continued when he joined the staff of the Mayo clinic in Rochester, Minnesota in 2003.
In 2013, he was appointed to the faculty of the Wilmot Cancer Center at the University of Rochester Medical Center as professor of medicine and as director of the CLL program. The Wilmot Cancer Institute is an HCL Center of Excellence. Dr. Zent is also a member of the Hairy Cell Leukemia Foundation Scientific Advisory Committee, where he provides invaluable leadership and counsel to Foundation Board of Directors and staff. Thank you, Dr. Zent for being our speaker today. And I gladly turn the time over to you.
Dr. Clive Zent:
Thank you so much. And just to add to that, I'm a very grateful recipient of funding from the Hairy Cell Leukemia Foundation. Just for completeness, we do have NIH funding for the lab and also from industry, Acerta and TG therapeutics.
So what I'd like to talk to you about in the next 20 or 25 minutes is really about how to make an accurate diagnosis of the B-cell lymphomas that we call classical hairy cell leukemia and hairy cell leukemia variant, which are part of the splenic lymphoma group of Non-Hodgkin's lymphomas, and how some of the new targeted therapies and new uses of the older targeted chemotherapies are helping us to better treat this group of diseases.
Dr. Clive Zent:
To start off, just some basic medical school stuff, which some of you will probably know very well, but just to make sure everybody's in the same place. This is a diagram of blood production, starting off with the blood stem cells. Blood stem cells give rise to cells along the myeloid pathway on the left side of your screen, which gives rise to red cells, which carry oxygen, platelets, which plug up holes in the circulatory system, and the innate immune system cells like neutrophils and monocytes.
And you also get the adaptive immune system on this side, which is based on lymphocytes with the two major players being the T-cells, which are the controlling cells, and also the cytotoxic cells when you have to defend yourself against foreign cells of any type, and the B-lymphocytes that develop into plasma cells, which make antibodies. So keep this in mind, as we talk about lymphoma and how to treat it.
Dr. Clive Zent:
The lymphatic system is something that is not always completely intuitive. We have a fluid drainage system in the body, which drains all extra fluid that leaves the vasculature, the blood system, into the tissue, and it gets drained in a very simple network of ducts called the lymphatic ducts, which go through various checkpoints, like the groin over here, under the arms in the axilla and in the neck before draining the fluid back into the heart.
There are a couple extra sets of tissues that are part of the lymphatic system that are actually directly connected to the blood, namely the spleen, which is in the abdomen under the diaphragm on the left hand side of the belly, the tonsils, the adenoids, and so on. So these are always the important things to think about when we go through discussion of the lymphomas that we're going to be talking about today.
Dr. Clive Zent:
The latest version of the World Health Organization's classification of lymphomas, which is really where we get our diagnostic criteria and the way that we group all these different types of blood cancers, came out this year. And they've made some changes, which are very confusing to everybody, patients and providers, but are really quite important because they acknowledge an increase in understanding of these diseases. And better classification allows for better recognition and diagnosis and probably eventually better treatment. So there are four categories of splenic lymphoma and leukemias, which comprise the two diseases we're going to talk about today. So just to remind everybody, lymphomas are lymphoid malignancies and leukemias are diseases that cause an increase in abnormal white blood cells in the circulation.
Dr. Clive Zent:
So hairy cell leukemia has gone back to being hairy cell leukemia, it's not called classical anymore. And they've given a very complicated name to the disease previously known as hairy cell leukemia variant. It's now Splenic B-cell Lymphoma/Leukemia with Prominent Nucleoli. Nucleoli are little structures within the nucleus of a cell. And then the other two diseases are Marginal Zone Lymphoma of the spleen or splenic marginal zone lymphoma, which I’m not going to talk about today very much because it's really not related to hairy cell and hairy cell leukemia variant.
But there is another specific lymphoma diagnosis here that is important and it's called Splenic Diffuse Red Pulp Small B-cell Lymphoma. A very long name, but it's actually very closely related to hairy cell leukemia variant. And it's often very difficult to distinguish between these two discrete diseases unless you've got splenic tissue to examine. Now, how common are these diseases? The United States incidents, number of new cases per year, is about 1,100 for hairy cell leukemia. It's about 800 for hairy cell leukemia variant, and the splenic red pulp lymphoma together, because they're really not distinguished in the epidemiology data yet, and about 640 cases per year of splenic marginal zone lymphoma. And for most of the rest of the talk I'm going to use the old nomenclature because the new nomenclature has just come in and it's going to take a while to filter through to all our applications and data.
Dr. Clive Zent:
So how do you tell the difference between hairy cell leukemia and hairy cell leukemia variant? Because there are different diseases with different treatments and different outcomes. So if you're a very good morphologist, in other words, a pathologist who spends their whole life looking under the microscope at cells, you often think, well maybe you can tell the difference.
On the left there, on the top left is what gave hairy leukemia its name. This is a lymphocyte as opposed to a red blood cell over there. Bigger cell, big nucleus, not much cytoplasm over here, the fluid around the nucleus seen inside the cell. And then you have all these protuberances from the cytoplasm and the membrane, which are the hairs that give hairy cell its name. If you look down here, this is also a hairy cell leukemia, classical hairy cell leukemia. It's got an even bigger nucleus, it's bi-lobed, and has less cytoplasm and much sparser here. So I guess this is a semi-bald hairy cell.
Dr. Clive Zent:
Now, if you look on the right here, this is a cell coming from a patient with hairy cell leukemia variant. Now, if you look at the two top cells, it's not so hard to tell the difference if they were all like that, but they're not. So there are a few hairy cells here, they're not quite as profuse. And if you look at the bottom cell here, really there aren't many hairy cells at all, but here's this big nucleolus inside the nucleus. That gives it its new and reformulated name of splenic lymphoma with prominent nucleoli. So this wouldn't be a really good way to tell the difference between these two groups of diseases in a reliable and reproducible way.
So we use a process known as flow cytometry, and this is a lot of data on one slide, but I'll go through it very quickly with you. So what happens is you take cells from a person's blood or bone marrow, you stain them with antibodies that bind specifically to particular proteins on the surface, and then you run them through a machine which identifies which antibodies are stuck to which cells and how much antibody is stuck. And it gives you a readout. So for instance, if you go to a normal B cell over here, this cell, this is the axis that reads out CD22, which is an antibody against CD22.
And this one, this is the one that reads out on the axis of CD20. And this cell has a lot of CD20 and a lot of CD22. So it sits up here in the corner. And you'll see that the hairy cell leukemia over here and the hairy cell leukemia variant all look pretty much the same. So this is not going to help you tell the difference between these cells. On the other hand, if you look at CD103, which is on this axis over here, the normal B cell sits over right against the left. So that's negative. The hairy cell leukemia on the other hand is positive and the hairy cell leukemia variant as well.
If you look at CD25 over here, it's not particularly high. So this is quite a spread over here for the normal cell. It's positive for the hairy cell leukemia, and it's negative for the hairy cell leukemia variant. And if you look at CD123 over here, the B cells are negative and normal B cells, the hairy cell leukemia cells are positive and the hairy cell leukemia variant is negative. So if you look at the pattern of each group of cells, you can tell from the immunophenotype which cell group it belongs to quite a lot of the time, but not always.
Dr. Clive Zent:
So sometimes we have to go to histology. Histology is a study of tissue, and this is a study of a bone marrow. So this is a bone marrow from a person who has hairy cell leukemia, classical hairy leukemia as it turns out. But I wouldn't know that from this bone marrow. And what I'm seeing here is that in patients with hairy cell leukemia, you have a lot less fat. Normally a person age 50 would have about 50% fat and 50% cells. And these cells are all looking pretty much the same. I'm not seeing any cells that are big in making platelets or anything like this. So they're a prettymonotonous number of small cells.
And if I look on the right here, they've stained it with CD20, which tells you if they are B cells. And these cells are pretty much all B cells. So there's something very wrong over here. Instead of being a mix of a lot of different types of cells, this is only B cells, and there's something wrong over here. And in this, it happens to be hairy cell leukemia. So you can tell whether a person's got a lot of disease in the bone marrow and whether that's possibly affecting their ability to make normal blood. And it also tells you a little bit about what particular disease it is.
Dr. Clive Zent:
So that's pretty useful for determining both the diagnosis and you can do some additional tests by staining with antibodies and so on to tell. Now, the next step you could do if you got that bone marrow is you could test for mutations in BRAF. And most of you, or a lot of you probably heard about BRAF. So BRAF is a molecule, it's a signaling molecule, so it's a protein in an enzyme that is in a pathway which carries messages basically from the surface of the cell to the nucleus to tell the nucleus whether it should activate molecules that improve survival, growth, and possibly change over to another type or more mature cell.
So this is a very important pathway, and generally these molecules are not signaling, but they will signal when there is a message from the surface to signal. And BRAF, the B type of this molecule called RAF is generally not on most of the time in most cells and certainly not in B cells. And if there's a mutation in that cell, that makes it work all the time, all these effects will be up-regulated. So the cell will survive when it shouldn't. It will grow when it shouldn't. And it can transform when it shouldn't. And you can get a disease. And this is common. 90% of patients with classical CLL have got an activating mutation of BRAF.
Dr. Clive Zent:
So that would be very helpful in diagnosis and also in treatment, perhaps. We can also try and better characterize patients with classical hairy cell leukemia, and even variant by analyzing the mutations in the variable region of the immunoglobulin gene, which is a characteristic feature of a B cell. Looking for somatic hypermutation, and also the family of the variable region of the heavy chain over here. And we can also look in other genes for mutations in the P-53 and also in the MAP kinase. So these are all ways that you can make a diagnosis and find targets for treatment.
Dr. Clive Zent:
So how do we diagnose classical hairy cell leukemia? Well, first of all, you've got to know what the patient's symptoms are and what they have on examination. So a typical person, the median age is 58 years with a very large skewing, a four one skewing towards men, rather than women. Patients can present with nothing at all, an accidental finding, asymptomatic. They can present with infection, fatigue, drop in their blood counts, and especially an absence ofmonocytes and big spleen and liver. And as we've just gone over, you can often make a pretty convincing diagnosis on looking at circulating cells, if you've got them, and looking for specific immunophenotype, for instance, abnormal B cells, which have 11C25 CD103 and CD123 expression. If they have that BRAF mutation, that's additional confirmatory evidence. And then you can sequence, IGHV, and immunohistochemistry to determine this.
Dr. Clive Zent:
So that's the sort of things you can do to make a definitive diagnostics. On the other hand, hairy cell leukemia variant occurs in older people. It does not have that very large male to female ratio. Often, patients present with anemia or other forms of decreased blood cells often with splenomegaly. They don't often have the leukemic phase. In other words, they don't have a lot of circulating lymphocytes. And they don't usually have a low monocyte count. And unfortunately, this disease generally doesn't respond quite as well to treatment and outcomes aren't as good. The pathology is not that definitive in all people, but if a patient doesn't have CD103 on the surface of their cells ... I mean, if it has 103, but it doesn't have 25, 123 and 200, then it's reasonably convincing. Patients with this disease often have the VH4-34 gene segment in their immunoglobulin, which means that they don't respond to conventional therapy quite as well. And they often have P-53 dysfunction.
Dr. Clive Zent:
So what about targeted therapies? So therapy for hairy cell leukemia and the variant has for a long time been based on purine analogs, which are chemotherapies, which are relatively specific for B cells and especially effective in treating classical hairy cell leukemia. Monoclonal antibodies are very helpful, whether they be unconjugated, in other words, they switch on your own immune system to kill off the cells, or conjugated. And then you've got molecular targeting that can inhibit specific molecules in the B cells, whether they be specific to classical hairy cell leukemia, with the BRAF mutation, mutations in MEK, MAP kinase, or treat or inhibit normal BTK, or even BCL-2 to stop the B cells from working like they would otherwise.
Dr. Clive Zent:
So purine analogs. The one that's commonly used is Cladribine. 2CDA. Also, pentostatin. And what they do is they disrupt production of a group of components of DNA called purines and prevent them from being metabolized in a way that is most specific for lymphocytes because of the specific characteristics of metabolism in lymphocytes.
And so they're selectively toxic for lymphocytes. You can have antibodies which will bind to a specific marker, which for instance, with CD20 is only found on lymphocytes. And that can activate your immune system. Or they can carry a drug or an isotope, but specifically in classical and hairy cell leukemia variant, it can actually carry a pseudomonas bacteria derived toxin to kill the target cells. And this is just how antibodies work by activating your own immune system to kill off the bad B cells. The one that's commonly used is a drug called rituximab, which has been used for a long time. And then there's the combination of an anti CD20 antibody with a pseudomonas toxin called moxetumomab pasudotox, which is really not a word anybody should be pronouncing too often. So we just called it moxe.
Dr. Clive Zent:
Then, we've got very specific targeted therapies. And the one that we've gained the most experience with, is a drug called Vemurafenib, which combines to that mutant BRAF over here, block it and prevent the survival of the hairy cell leukemia. So that's quite an effective therapy.
For instance, as a patient, looking at the bottom here, all the CD20 cells before Vemurafenib, very few B cells left after Vemurafenib. How effective is it? Well, it works very well, but it doesn't work for very long. And as a result, we've been adding rituximab, that monoclonal antibody against CD20, to it. And we now are getting long term survival, even in patients who have failed all other therapies.
Dr. Clive Zent:
So this is something called a swimmer’s plot. So this patient over here had Vemurafenib and rituximab for a bit longer there. And now they're over five years, nearly six years out from treatment and still going on. And in this group of patients, nine patients, from our institution, we had success in treating all of them. And a lot of them have done very well and continue to do so using Vemurafenib and rituximab. And this is data from a paper published last year in the New England Journal of Medicine, showing the progression-free survival for people who get a combination of Vemurafenib and rituximab is actually very impressive given that all these patients have been previously treated.
Dr. Clive Zent:
Another big development that's come through in the last few years is the drug Ibrutinib, which blocks BTK, bruton tyrosine kinase, which is a component of the signaling pathway that keeps B cells alive. And if you look at this composite figure, for this group of patients, who were approximately one third variant and two thirds classical and had all previously been treated except for a few exceptions. That the progression free survival here is very good at 70% at over a predicted five years or above. And what was really interesting here is that patients continued to improve their remissions throughout treatment in some cases.
Dr. Clive Zent:
So what do we do for classical hairy cell leukemia? I think for a lot of the standard cases, probably either Cladribine or Pentostatin to start off with. If you have a reason why you can't get that, or you haven't responded for very long, Vemurafenib and rituximab is good. We have limited experience with the MEK inhibitors and Moxetumomab has been around for a while and has quite a consistent track record. And we are beginning to start using the BTK inhibitors.
Dr. Clive Zent:
If you've got hairy cell leukemia variant, a splenectomy has a role in diagnosis if it's not clear whether you've got hairy cell leukemia variant, which happens sometimes. We've learned that adding rituximab to cladribine gives better responses. Moxie also works. As do the MEK inhibitors, especially if you've got a MEK mutation. And the BTK inhibitors are also showing some promise.
Last point here is that it's also very important to look after yourself and to make sure that you don't get some of the complications. As you all know, both of these diseases are associated with a high risk of infections. So there are ways that you can protect yourself from infection and respond to them rapidly and effectively. Second cancers are not unusual. Smoking cessation is very important. Weight control as well. Limit alcohol, which suppresses bone marrow and especially platelet production, and exercise which has been shown to improve quality of life and probably duration of life in many diseases, including lymphoid malignancies.
Dr. Clive Zent:
So in conclusion, this is a rare and complex disease. It can be difficult to diagnose and treat, and good care and good outcomes often require a team of people. Just for example, here at the Wilmot Cancer Center, we've got a team of outstanding pathologists. We've got a scientific lab, which is trying to understand our diseases and get better ways of treating them. And we have excellent nursing and nurse practitioner support. So thank you for listening. I'm happy totake any questions.
Transcript of Q&A
Anna Lambertson:
As you were presenting, there were a number of questions that came in about HCL variant. And I think a lot of people may have been interested and perhaps even surprised by the World Health Organization's new information about how to classify variant. Could you speak to that a little bit more in terms of what that really means and how it might affect diagnosis and treatment? And then we have a few other specific questions about the variant form.
Dr. Clive Zent:
Okay. So basically, B cell malignancies are comprised of B cell malignancies that occur in cells that aren't yet mature B cells, which is basically acute leukemia. Lymphocytic leukemia. And then the B cell malignancies that are the terminally differentiated B cell, which is the plasma cell, which is multiple myeloma. And then the term non-Hodgkin's lymphoma of the B-cell type is really used to describe all the others. And there are about a hundred of them, nearly a hundred of them, which occur between the time that a cell matures and the time it becomes a plasma cell for B cells. And there is a group of four diseases which clearly affect mostly the spleen. They do not generally cause big lymph nodes. They generally do involve the bone marrow and they sometimes can be circulating. And there's a strange characteristic of the circulating cells, they've got these hairs, which we had to look at earlier on and the biology of these diseases, they are actually somewhat overlapping and they are a similar group of diseases.
So the World Health Organization is always trying to bring order to the traditional chaos of classification of these diseases.
Hairy cell leukemia is clearly a discrete disease, which has very little to do, has no more to do, with hairy cell leukemia variant probably than splenic marginal zone lymphoma or red pulp lymphoma. These are four different diseases. It's important to know the difference. So I think that taking the term hairy cell leukemia out of the variant for the future is actually going to help everybody because they won't be confused about thinking that they've got a type of hairy cell leukemia. There's the old type or the classic or the new type of the variant. No, that's not true at all. These have always been two different diseases. We just weren't smart enough to know about it originally because when they discovered hairy cell leukemia in 1959, they didn't even know there were B and T cells. All lymphocytes were thought to be the same.
So we're just catching up with the progress in the field. And I think this is good and we'll process it. And we'll ask them very nicely to give us a better name than splenic B cell lymphoma/leukemia with prominent nucleoli, which to most people means nothing at all. So they've got to come up with a better term, but it’s a good thing that they've given it a different name.
Anna Lambertson:
Thank you. One of the questions that came in about variant is ... and maybe this is a moot question now that we're looking at reclassifying variant, but our understanding has been that variant is about 10% of all HCL cases. Is that still accurate?
Dr. Clive Zent:
What used to be called hairy cell leukemia is two diseases. One is hairy cell leukemia and the other is hairy cell leukemia variant. In the past, 15, 20 years ago, the red pulp lymphomas were very often called either hairy cell leukemia or hairy cell leukemia variant. And they're not. They're not either. They are a different group of diseases. So that's why, for instance, the national epidemiology in this country doesn't distinguish between hairy cell leukemia variant and splenic red pulp lymphoma, because you have to take somebody's spleen out to find out which one they've got and they (the diseases) are quite different.
For instance, hairy cell leukemia variant, even if you take the spleen out, often people will progress with cytopenias. They will have low blood counts. Whereas, the red pulp lymphoma can often do extremely well. I'm talking many, many years or decades by just taking the spleen out. And usually, they very often present with very big spleens that are symptomatic because they're causing pain or discomfort, or because they're making the platelets very low. So these are different diseases that need to be treated differently and treating everybody with cladribine is undertreating hairy cell leukemia variant, probably, because they need rituximab as well. And then they'll be watched more closely because they're not going to do as well often. And treating patients with red pulp lymphoma with cladribine and rituximab generally doesn't work, so they get all the toxicity without the benefit. It's really, really important to be able to make good, accurate diagnosis. The fact that we now know that 90% of people with classical hairy cell leukemia have got a BRAF mutation, and we're very good at measuring that, detecting that. That has made an enormous difference to our ability to accurately diagnose those people, and those people, very often, if they've got circulating cells, we don't have to even do a bone marrow to make the diagnosis anymore. Whereas to make a definitive diagnosis of red pulp lymphoma, you've basically got to take the spleen out because it is very dangerous to biopsy a spleen because people can have serious bleeding complications with that.
Anna Lambertson:
There were a number of questions that came in about cladribine and rituximab, and I felt it was important to get through a few of those. How do you approach cladribine combined with rituximab when you're making treatment decisions for your patients? What are some of the questions that you're posing, that you're asking, that help you make that decision? And then if you do decide to add rituximab to cladribine for your patients, are you doing it concurrently or are you pursuing delayed rituximab?
Dr. Clive Zent:
The best data we have at the moment for classical hairy cell leukemia, so the real hairy cell leukemia, is that results from combining concomitant rituximab and vemurafenib is excellent. Excellent. Not as good as we'd like it to be, but it's excellent compared to what we used to see sometimes for patients who had failed cladribine or pentostatin several times and didn't have a lot of options. Those graphs I showed you, the swimmer's plot and the survival graft, are for people who have generally failed cladribine. On the other hand, we have patients that have gone 20 years from cladribine alone, and the third component of this is rituximab is not chemotherapy, but it's not benign.
People get into big trouble, and occasionally even don't survive rituximab because you can get a nasty first dose reaction, and it does suppress your bone marrow, so you become more neutropenic and you can have low platelet counts. It can cause interstitial pneumonitis, and it can suppress your immunity and give you nasty infections, herpes simplex, and occasionally even PML. This is not a benign drug, so you've got to have a really good reason to use it when your median progression-free survival on the average person with hairy cell leukemia is over 10 years. The bottom line is I don't use it. I use cladribine as a first line therapy, not because it's better than pentostatin, but because it's much easier to use.
I don't think that there's really a lot of data for first line therapy in a person who doesn't have IGHV 434, and doesn't have a P53 mutation and does have a BRAF mutation, in other words, the lowest risk of all the classical hairy cell leukemia patients, and who's fit enough to get cladribine. I'm using cladribine. I'm not adding rituximab because I don't think there's any value. There's even less data about whether concomitant or sequential is required. The data from other lymphomas is that you do better if you get it together, but you can also find people that'll argue about that, so I don't use it in hairy cell leukemia. On the other hand, in hairy cell leukemia variant I'm starting to use it in everybody and I'm using Dr. Kreitman's regimen of concomitant therapy.
Anna Lambertson:
It's not something that you generally pursue at frontline?
Dr. Clive Zent:
No.
Anna Lambertson:
When you do use the combination, your approach is to do the concomitant approach, which you find, according to the data, is more effective.
Dr. Clive Zent:
Correct. There's no definitive data that it's more effective. Nobody has looked at 500 people and given 250 of them cladribine and the other 250 cladribine and rituximab. Nobody's done that and they're not going to, because they're not that many people being treated at the same time.
Anna Lambertson:
I understand, and I do know that a lot of patients, including many people on today's webinar today who are reading and hearing about cladribine and rituximab. A lot of individuals are asking their doctor to administer that even at frontline. What I appreciate about these webinars, by inviting hematologists from our centers of excellence and from different institutions, the patients are able to hear different perspectives and to understand why different HCL experts approach treatment in different ways, so thank you very much for offering your perspective on this.
There are a few other questions about rituximab.
In light of the ongoing pandemic, patients are wondering whether rituximab should be something that they should be considering now that we're getting a little bit further away from the worst part of the COVID pandemic, given that we have vaccines and other things.
Dr. Clive Zent:
Sure. The game changer there is Evusheld. In other words, you can now get an injection of a long-acting antibody, combination of two antibodies that are highly effective against COVID, including we think the omicron, and so basically that big hole in your immunity caused by rituximab can be replaced by injections given once every six months.
We were very, very concerned about that when we didn't have a vaccine. we certainly didn't have monoclonal antibodies and we didn't have Paxlovid. I think now that if you're careful, you don't have to worry about it, so we're back to using rituximab as before, but with those precautions.
There is also obinutuzumab, which some people are using.
The other thing to remember is that cladribine will take away your T-cell immunity as well, but if you're just getting rituximab, rituximab only affects B-cells and your vaccines will still work to give a reasonably protective T-cell immunity.
Anna Lambertson:
On the topic of T-cells, one individual did ask, "What does that mean that T-cells don't completely recover after cladribine for three to four years?" What does that really mean, perhaps in more layman's terms, and how cautious should someone be after completing treatment with cladribine?
Dr. Clive Zent:
Okay, so let's start at the beginning, and the beginning is you've got a low grade B-cell lymphoma and your T-cells aren't normal and they'll never be normal again, because even if all your lymphoma goes away, you don't have a thymus, which is a gland that neonates and younger children have, that basically educates your T-cells to be high-functioning T-cells. T-cells are the cells that can recognize an abnormal protein in your body, at a molecular level, generate an immune response against it and kill any cell it sees. So a cell that's infected with the virus, a cell that's a tumor cell, and a cell that is infected by a bacteria or something else, a cell from somebody else that shouldn't be in your body.
Dr. Clive Zent:
Those cells are critically important for your cell adaptive immunity. And we don't really understand completely how it works, but there's a very sophisticated development that occurs during your early childhood, as you see antigens and develop your immune repertoire. When you get a lymphoma, that gets really badly damaged, and we do not know how to fix that. We make it a lot worse with the purine analogs, more so with cladribine than pentostatin, and it takes about six months to a year for you to get back to where you were before you got treated, but you never get back to normal, so you are always at higher risk of unusual infections, more likely to get infections and to get cancer and probably to get autoimmune diseases as well if you have any of the B-cell lymphomas, including hairy cell and hairy cell variant.
Anna Lambertson:
There are a lot of questions about some of the other drugs that you mentioned in your presentation. For example, the moxe-rituximab combination being tested right now at NIH. Maybe that's not a treatment option you can consider in your clinical practice since right now it's being studied. Two different patients have asked about the moxe and rituximab combination, and I think we all would welcome your feedback on that.
Dr. Clive Zent:
Moxe is a conjugated antibody. What it does is it carries a very potent pseudomonas-derived protein, toxin, to B-cells that express CD22, and that's a protein expressed very well by both hairy cell leukemia and variant cells. The antibody binds to the target, the whole complex gets endocytosed or eaten by the cell, and then the pseudomonas toxin is released and it kills that cell. That is a mechanism that requires CD22, and it is a mechanism that requires a toxin to work, so you’ve got to be sensitive to the toxin. Most cells are sensitive for that toxin, and you've got to have CD22 on the surface, which most hairy cells do.
That's one type of mechanism of action. CD20, even though it's an antibody, is unconjugated, so what it does is it binds to the surface of the B-cell, and then the other side of the cell, of the antibody called the constant region, will either bind to a macrophage and that cell will get eaten, or it binds to a natural killer cell, which is like an assassin cell, which will pour poisons into the target cell and kill it. Or it will activate a process known as complement, which is a protein sequence where one protein gets activated and activates the next one, draws a hole in the membrane of the cell and can kill it. They're different than what we call orthogonal ways of killing. They are non-overlapping ways of killing at pretty much all levels, and so you would expect that those two drugs, because they have different targets and because they work in different ways, would be at least additive and maybe more than additive. There's a concept in pharmacology called synergy, which very simplistically, one and one is two is additive, one and one is three is synergistic.
In other words, the sum is more than the whole, it’s more than the sum of the parts. And what Dr. Kreitman and his team are doing are really trying to find out whether it's additive effect or synergistic and what the toxicity is. Now, the toxicity could be a problem because the toxicity is not that different. In other words, when you get moxe, you can get kidney damage and you can get low blood pressure and you can activate the immune system to call what's called a cytokine storm, where you get leaky capillaries and your blood flows out of into your tissues and gets you into a whole lot of trouble. Now, it's not that common, it's only about 5%, but for those 5% of people, it can be a big issue. More than half the people that get rituximab by itself get a first dose reaction, which is also in part a cytokine storm.
It's going to be interesting to see how they manage to prevent those two toxicities from becoming additive, which is not what you want in any combination. My bottom line is, I think it's a good idea to test it. I'm really interested to see what happens. I don't think this is going to become first line therapy for classical hairy cell leukemia because the first line therapy is much better than that already, and whether it will be a salvage therapy or therapy for hairy cell leukemia variant in the future, it will depend on what it looks like when results of the studies are published or presented.
Anna Lambertson:
Thank you. We know that vemurafenib on the other hand is getting a lot of attention, certainly during the ongoing pandemic it has been used instead of cladribine because we believe it's not as immunosuppressive as cladribine. Some patients have read that vemurafenib can put a patient at greater risk for other malignancies, including skin cancer. If you might speak to those potential side effects, things that patients need to be aware of if they choose vemurafenib.
And as an aside, there's quite a lot of interest in Trametinib and Dabrafenib. One patient asked, "Why don't we talk as much about these other two drugs?" Why is vemurafenib stealing the headlines?
Dr. Clive Zent:
Okay, so very good question. Vemurafenib is only less toxic compared to cladribine or pentostatin, not less toxic compared to non-chemotherapy drugs. It is not a simple drug to use. Certainly it's famous for causing people to get skin cancer, and people can get skin cancer within weeks of starting it. They get warts, they get joint and muscle pain, they get a drop in their blood counts, they can get liver damage. That's why the drug is given for a short period generally, and sometimes at a much lower dose than is used in melanoma and renal cell cancer. And it is a very effective drug, but in combinations used for treating melanoma and renal cell, they've actually gone to combinations with MEK or MEK inhibitors. And because Vemurafenib in combination with those is actually even a lot more toxic, they've gone the less toxic route. One of the reasons we're still using it is because it has proven effectiveness, and we have ways of using Vemurafenib safely in people with hairy cell leukemia, more safely because we limit the dose. The German groups show that using a quarter of the dose is as effective, maybe, certainly much better tolerated. We use it only for a short period of time, eight to 12 weeks, depending which regimen you use. And we watch people very carefully. So I think that it's a drug that can be given quite safely, if you're careful with using it. It's not a drug that should be used without very careful observation by experienced people who know how to use it.
Dr. Clive Zent:
The MEK inhibitors are useful in people who become resistant to BRAF inhibitors. And it's also useful in some people with hairy cell leukemia variant. So really, that's the answer. Summary, Vemurafenib is the drug we have the most experience with, experience is very precious in hairy cell leukemia because they're not that many people who need to be treated, unlike for instance, melanoma, where you've got a lot of people that you can test your drugs on. So when we have experience, we like to consolidate it rather than just go to the next drug and hope that it's better, and it possibly isn't. And the MEK inhibitors are really most helpful in people who have a BRAF inhibitor resistance, or in patients who don't have a BRAF mutation and are either the rare people with classical hairy cell leukemia who've got a MEK mutation, or people with variant who've got a high rate of MEK mutations.
Anna Lambertson:
There are a few questions from patients about the risk of organ toxicity with cladribine and pentostatin, would you consider the toxicity for those two drugs to be the same? Is one less toxic or less prone to side effects than the other, particularly when it comes to classic HCL?
Dr. Clive Zent:
I don't know that you can say one is more or less toxic than the other. They're very different in their toxicity. So what they both do is they both get rid of most of your T cells, so you're very immunocompromised in that respect, and it takes about six months before you have even modestly safe T cell counts, so you're going to have to be protected against Pneumocystis and against herpes simplex and other herpes infections during that period time, watch carefully. Pentostatin is probably a little bit less immunosuppressive, but you use it for a longer period of time, so I think the net overall there is about the same. But with regard to suppressing the bone marrow, cladribine is a major suppressor, there's no question about it. People become pancytopenic almost all the time, and they become very neutropenic. That's not what we experience with pentostatin.
So cladribine's other major toxicity is neurotoxicity, which we don't see very often, except if people have renal failure without dose adjustment. So the biggest complications of cladribine are profound minor suppression, which gives you anemia, thrombocytopenia, neutropenia, neutropenia leads to infections, and loss of your adaptive immune system, because you have no normal B cells or T cells, and that lasts at least six months and longer. And then occasionally people will get neuropathies as well. Not a whole lot of other toxicities, but that's a lot. Pentostatin is a bit more diverse. So pentostatin can cause some neuropathies, and the biggest problem with it is if you don't monitor carefully, you can get renal toxicity from it as well.
Dr. Clive Zent:
So none of these drugs are particularly safe, compared to a lot of the other general chemotherapies. And they're best given by somebody who's experienced in using them, in which case you should be able to do the adjustments and monitor things to keep administration as safe as possible. And whenever a drug's not used a lot, you probably want to be treated by somebody who's used to using them a bit more than people who barely ever use them.
Anna Lambertson:
One last question, we are frequently asked by patients, how do they go about selecting their next treatment? So maybe their blood counts are starting to decline, they don't yet know if they've relapsed, that's to be determined, or maybe they've completed treatment, and they're just trying to plan ahead. How do you go about working with your patients and identifying what the next treatment would be for them? Classic hairy cell leukemia I think would be easier to respond to with this question, but if you're able to also touch on a second treatment for variant, that would be appreciated.
Dr. Clive Zent:
So the first thing is if a person has classical hairy cell leukemia, it’s their first treatment, and they've gotten a purineanalog and they've done really well, I don't think they should be wasting their time on this question because there's a very good chance they're only going to need treatment in five to 10 years, and I don't know anybody who knows what we'll be using in five to 10 years. So that's a classic story of trying to cross your bridges before they're even built, never mind before you got there. So I wouldn't waste too much time on that. If you want to stay healthy and look after yourself, you should focus on all the things we talked about earlier. Keep healthy, exercise, don't put on too much weight, look after your skin, don't get skin cancer, make sure you don't get any bad infections.
If you’ve got hairy cell leukemia variant, and you've only got a partial response, then I think you should be thinking about it. And again, because it's a disease that doesn't affect that many people, there isn't the same rigorous data that we have for a lot of other diseases. So first of all, you should keep an eye out for what's working and you must remember two things, one is the drug you get, and the person who's getting it. And you've got to know them both well. And most people, including me, are not very objective about themselves, so sometimes you’ve got to defer to an expert on that, especially about your health and ability to get drugs, and get therapy. And also it's a non-curable disease, so it doesn't help you to hurt yourself trying to get a better response if you don't really need it at the moment. And whether you have MRD negative disease or MRD detectable disease, you still have whatever your disease is and it's not gone completely, this is not a curable disease these days. Yet.
So you've really got to be judicious about the risk-benefit ratio, and all the drugs we use have got a risk, and the benefit's not always there if you've got minimal disease that's not hurting you. So I would say, look at the big picture, don't get too excited about the latest drug. Don't get too upset about finding out that every drug's got side effects, because we do eventually. And remember that it's very hard for most of us to be objective about care of ourselves, and so you should find a responsible, reliable, and trustworthy person to look after you, who you can share your concerns with and make decisions with. Get a good team to help you look after yourself.
Anna Lambertson:
Thank you. And since you did mention minimal residual disease (MRD), in terms of making treatment decisions with patients, how do you factor MRD into your decision making and what should patients be keeping in mind?
Dr. Clive Zent:
I don't, because we just don't have the data. So first of all, what is minimal residual disease? You have a disease which when you treat people, you know you can't kill all of the tumor cells yet, so it's not a question of cure, it's a question of how good you are at clearing as many cells as you can. And the more cells you clear, the longer it's going to take for that person's disease to come back. But remember, the rate at which a disease comes back, it's a biological property of the disease, not the treatment. Very few of the treatments are going to make the disease slower at coming back. And some of them could make it faster at coming back, if it selects resistant cells, which may or may not have a faster growth rate.
So the idea that if you've got no detectable minimal residual disease at the end of treatment is better than not having it for you, yes, that's absolutely true. But does it predict when you're going to need treatment again or if you'll need treatment again? No, it doesn't because we're not very good at measuring the kinetics of a person's disease, so that's the one point. The second point is, what's minimal residual disease? Minimal residual disease for some people is looking with flow cytometry or immunohistochemistry, where you can find one in 100 residual cells in the specimen. So if you think of 10 to the power of 12 and you remove two from 12, you've got 10, that's the enormous amount of disease you can still have.
Even if you go to the PCR based BRAF V600E which only works for some hairy cell patients, you are going to be able to see one in 10,000 or one in 100,000, it's still a small fraction of the tumor burden. So none of these tell you that you've got no residual disease, it's just undetectable. And all the methods of detecting are different by orders of a magnitude.
So if a person has a little bit of residual disease, we know that there's no data that treating those people again is going to make any difference. Sure, they're not going to do as well as a person who's got no residual disease, right? You can't make them negative and say, "Right, now you're negative, so you're going to do better." Because we don't know that for that person. It's sort of a prognostic marker that if you get your treatment and you've got less disease, you are probably going to do better than if you had more disease. But if you've got less disease and you need the two treatments to get there, that doesn't mean necessarily you're going to do better overall. So it's not simple, you've got to really think this through carefully and remember that re-treatment has risk, especially if you don't need treatment.
Anna Lambertson:
Dr. Zent, thank you. And thank you to everyone who joined us, from wherever you were logging in. We really appreciate you joining us today, and we hope that you'll enjoy the rest of your day.