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2021 Hairy Cell Leukemia Patient Seminar Session
Understanding Hairy Cell Leukemia - Living with HCL
October 11, 2021
Hosted by the Hairy Cell Leukemia Foundation with guest speaker Dr. Francesco Forconi from the University of Southampton Hospital Trust in the UK. Moderated by Anna Lambertson, HCLF Executive Director.
Session Materials
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Please note that the Q&A is available through the written transcript only.
Transcript of Presentation and Q&A
Transcript of Presentation from Dr. Forconi
Dr. Francesco Forconi:
Thank you so much Anna, thank you so much the Hairy Cell Leukemia Foundation for organizing these excellent meetings where we are all updated. Not only the patients, but also us doctors are updated on the tremendous progress that is currently happening in hairy cell leukemia. Really thanks to the Foundation. This is something that has been quite a push in the last years since the renovation of the foundation, something remarkable for such a rare disease. And I'm sure the output will be that all of us will learn how to better treat this condition and understand why this happens.
So having said that, my task today was to talk about what hairy cell leukemia is. And by giving on my side the clinical information on what the treatment approaches are, probably this will give you a hint on what it is living with hairy cell leukemia. I don't know that because I haven't got it, but I have experience from the patients who have got it. And the feedbacks are always quite a mixture of factors.
First of all, I will talk about definition, the demographics and the classification of hairy cell leukemia, and then I'll give you a little hint on origin and pathogenesis, which will explain why we are moving towards different treatments from chemotherapy. How we make the diagnosis, what treatments are available, and if we can say anything about prognosis.
Dr. Francesco Forconi:
So, the definition of hairy cell leukemia. There has been a huge effort by the Hairy Cell Leukemia Foundation and its medical partners that you can see across the world. You can see how many people are working together all across the world captained by the super Dr. Grever, if there is a superman in hairy cell leukemia, that is him. And we should all be (thankful for) his skills in creating such an effort for the benefit of patients. And the British community has also taken advantage of this effort by the Hairy Cell Leukemia Foundation to give a little update of what could be done in the United Kingdom.
But very briefly, you probably already know that hairy cell leukemia is a condition that hits mainly individuals during their working age. This is an important aspect because having a diagnosis of leukemia, first of all with the term leukemia, is of impact. And we all hate that word (leukemia). So, at the age of 55, it (hairy cell leukemia) is very rare, and it is quite much more common in the male individuals than in the female individuals. Not that females are spared, however.
The diagnosis of hairy cell leukemia is done when individuals have a peripheral blood count quite often now for erratic reasons, now that the blood count can be done easily. But generally because there was pancytopenia. So an individual does a blood count, and the morphologist finds these cells. These are medium-large sized cells characterized as you can read, by an abundant pale cytoplasm, please compare it to a normal lymphocyte here. So abundant means that this rim, the cytoplasm, is more than this blue rim here, with a nucleus that have a lymphoid shape, so round, or bean-shaped like monocytes.
But the really impressive thing is these hairs. These hairs are part of the mnemonic of the disease. If you see a cell like this in the peripheral blood, the diagnosis for the morphologist is done.
We will want to have a quick hint on the origin, the pathogenesis of hairy cell leukemia, because now we have more tools to be reassured about making a diagnosis, more secure with molecular tools. And I will get back into that. But talking about origin and pathogenesis, just a quick summary. The idea that has emerged from the summary of the literature that has been carried on by many people in the Hairy Cell Leukemia Foundation - doctors, including myself to a little extent at the beginning of the millennium, was that hairy cell leukemia is characterized by a very specific genetic lesion in all the tumor cells of the largest majority of the patients. And this is this BRAF mutation, V600E is the name. Which according to some, occurs quite early in the process of differentiation of a normal lymphocyte.
All our white blood cells are produced in the bone marrow, but there is a phase here in the bone marrow during which a stem cell will differentiate in many different cells - the red blood cells, the white blood cells or platelets. So this differentiation process will also lead to the production of raw B-lymphocytes, which are the precursor of any normal lymphocyte of a normal B-cell, from which the hairy cell leukemia will come, following transformation.
But it is suggested that the lesion that is found in all the hairy cells of an individual with the diagnosis of hairy cell leukemia, will acquire this lesion very early in the progeny. This is quite remarkable but not uncommon in lymphomas and leukemias. For example, to give you the name of another type of lymphoma, called follicular lymphoma. There are lesions that occur here at the pre-B cell stage called (14 18) translocation, another genetic mutation. This doesn't mean anything in terms of diagnosis.
Dr. Francesco Forconi:
So it is possible that this is a multi-step process which involves the acquisition of a lesion, and then other characteristics that tell us that the hairy cell may originate from some B-lymphocytes that have encountered an antigen that have signs of a germinal center reaction of a response to an antigen. As we documented in the early 2000s, the expression of multiple isotype as if there is a process of isotype switch. The process that the mature B-cell against the putative infective agent, becomes more effective. But that is broken up and that is frozen, and so the hairy cell leukemia will come out.
What we don't know is why the hairy cells has this hairy shape. This is the most peculiar thing, and there is a lot of work going on. But none of these institutions explain why this is happening. It does suggest that however, the ancestor cell here and their features are those of a stem cell that has maintained some characteristics of some other lineage like macrophages. We have done some work, taking advantage from the work of one of the Hairy Cell Leukemia Foundation members, Chris Oakes, who's now in Ohio. He did some excellent studies when he was in Germany, differentiating the cells by the epigenetic profile, normal B cells by epigenetic profile, which suggests that the hairy cell originates from marginal zone B-cells.
Is this important? To some extent, it is, because it will help us with the diagnosis and the treatment.
So going back to the diagnosis, there are clinical and laboratory features representation that are quite common. One of these in the majority of patients, there is either a clinical or ideologically documented splenomegaly. Typically, different from the majority of leukemia cell lymphomas, there is no lymph node involvement. Actually, if lymph nodes are involved and if you do a lymph node section of this, you will find that where hairy cells are, there is an atrophy of some structure of the lymph nodes, as if there is a counter reaction against a proper germinal center reaction, which is quite part of the mnemonic for the diagnosis. But also there is a pancytopenia, so hemoglobin levels are low, platelets are low, white blood cells are low, and typically, a reduction of a type of cells, white blood cells, called monocytes.
Obviously what you find is these hairy cells here. As you see, the shape of the cells can be again rather different, I was talking to you about the bean shaped lymph node, I was talking about the pale cytoplasm. But at the end, depending on how the smear is done, the diagnosis can be sometimes problematic. So, having some additional tools to make the diagnosis is not bad, and we can do it. All western countries can use tools that allow the diagnosis from the peripheral blood with a test called phenotype, which shows a classical pattern with expression of some markers, such as CD103 or CD13, or CD25. It is an activated B-cell phenotype. And CD25, for many of you, will be important together with the expression of CD20, that I'm not showing here, both markers of B-cells. Because these can be a target. There are other markers that help with this differentiation from other types of leukemias, that is CD200.
So, morphology plus phenotype is already quite enough. But if that is not sufficient, there are also bone marrow parameters, like stain for a specific component of the membrane called Annexin A1.
But most importantly is the presence of this mutation BRAF V600E. This was used as a tool for the diagnosis in Italy by Enrico Tiacci. Obviously there has been an evolution with PCR based technology, but all to say that BRAF mutation is indicative of a diagnosis of hairy cell, when the hairy cells are documented in the peripheral blood.
Dr. Francesco Forconi:
There are other conditions that can have BRAF mutations; these are not leukemias or lymphomas and the clinical presentation would be different. So the BRAF mutation is indicative of hairy cell leukemia.
Dr. Francesco Forconi:
Treatment in hairy cell leukemia has been a bit of a paradox. Because we have found solutions against hairy cell leukemia. The lifespan equivalent (of someone with hairy cell leukemia) compared to the lifespan of other individuals who haven't had a diagnosis of hairy cell leukemia in the normal population; before, we had a clue of what the origin of the cell was. So in the 1970s, there was splenectomy as an opportunity to palliate the symptoms, but their survival was five years. Then interferon was introduced, and that was a game changer already. The difficulty with interferon was that this drug, it's cytokine basically, it's what is released when we have an influenza. And that is the reason why we have chills, shivers, temperature; it comes down to cytokines and interferon. So injecting the interferon into the patients can cause those same side effects or flu-like syndrome.
So, sometimes patients cannot tolerate these treatments, and we need other type of treatments which are easier to be given. And that brought the opportunity of using purine analogs. Mainly two purine analogs were used, interestingly at lower doses than any other leukemias, and these were depending on the countries. Pentostatin, otherwise called deoxycoformycin, or now more common and easier to manage, cladribine, or 2-CdA (or 2-chlorodeoxyadenosine). Which can be given in many different ways. In the UK for example, we give it subcutaneously for five days. It can be given at different doses. And there are situations and circumstances where reducing the dose might be better than giving a full dose, in order to reduce the complications of the heavy cytopenia induced by the chemotherapy with the risk of infections.
In the 80s, another drug was added, rituximab, to most lymphomas and leukemias, and it happened that this was also successful in hairy cell leukemia. And I will show you how it will be very successful if given in combination with cladribine.
Dr. Francesco Forconi:
We are now moving to monoclonal antibodies, and thanks to the novel discoveries of Dr. Falini’s group in Perugia together with New York, it was found that BRAF inhibitors may play quite an essential important role against hairy cell leukemia.
Dr. Francesco Forconi:
So let’s go to cladribine. Cladribine is still the gold standard for hairy cell leukemia. Purine analogs are the gold standard for hairy cell leukemia. And most of the studies were done retrospectively, and with the effort of people collecting information from different centers and seeing retrospectively how hairy cell leukemias would go. It's impossible in hairy cell leukemia to do a big randomized study, unless structures like the Hairy Cell Leukemia Foundation decide to fund it, and have power in the studies to explain why one treatment is better than the other.
But the bottom-line here is that these are years from diagnosis and treatment. So these numbers as you see, patients who receive first-line cladribine or another purine analog like pentostatin, are expected to have an overall survival, if not almost better, than individuals who haven't had hairy cell leukemia. Exactly the same as individuals from the normal population. Or at least these deaths, if there are any, are not because of hairy cell leukemia.
Dr. Francesco Forconi:
There is a bias here that whatever we think, however, hairy cell leukemia does not plateau in terms of progression-free survival. That is, these individuals, this curve drops down, meaning that patients will relapse and require another treatment. And the relapse, the time from the first treatment to relapse is longer if the patient obtained a complete remission rather than a partial remission. This is all on average.
So what are the problems here? The problems here are one, second tumors, and we will not yet know whether the second tumors that we experience in individuals monitored for over 20 years, actually do have an increased incidence simply because we monitor them more carefully, or because there is a real increase of incidence in individuals with hairy cell leukemia compared to the normal population.
The other is infection. And the risk of infection is higher when we give treatment. So have to balance the success of treatment with purine analogs against the risk of toxicity at the time of purine analog administration.
Dr. Francesco Forconi:
So, what was the idea to improve this curve of progression-free survival? Again, from retrospective analysis done at Royal Marsden, the idea was to add rituximab to these purine analogs. And in these very short survival periods, six years. If you think about acute leukemias, six years of survival with a curve like this means cure, this doted line. In hairy cell leukemia, we measure things in decades.
And what happened was that except for one patient, all patients who receive rituximab on top of purine analogs, did not progress. This has given the opportunity for many studies, some of which were done in second-line and in first-line, not randomized by Dr. Ravandi in Texas, in Houston. Another one at NIH, where individuals were randomized to receive cladribine plus rituximab, or cladribine monotherapy. Or to receive Rituximab subsequent to cladribine.
The summary was that if you give cladribine plus rituximab, or cladribine alone, the minimal residual disease-free survival is quite different. And the chance for the disease to progress again is quite different. This is 100 months; you see patients receiving cladribine plus rituximab, have almost no chance within this timeframe to relapse.
Dr. Francesco Forconi:
We know and we have to be honest in that, that there is a chance that individuals will relapse. We are facing individuals who have an average diagnosis of 55, but there are also individuals who are diagnosed when they're 80, and if we start thinking about these timeframes, it's obviously easy to think how a treatment like this is the one, six months of our life in getting ourselves fixed, and then we won't think about it anymore.
Dr. Francesco Forconi:
So at the end of the story, what we have is one, we're talking about a B-cell. In B-cells, there are always two components. There is always one component operating, it is the B-cell receptor. The B-cell receptor is over expressed in hairy cell leukemia, in many cases, it is expressed in multiple isotypes. If we go back to this slide, a normal B-cell has one isotype, one immunoglobulin and it's called M, G, or A. Hairy cells can have up to four, can have all of them together. And they all will be able to signal into the cell to say, “proliferate”. So if they encounter an antigen, they will proliferate. And if they encounter something that triggers them, they will proliferate or survive.
So within this context, targeting the B-cell receptor is a logical way forward, and there are drugs that block the signaling cascade that I've mentioned here, and some of which have been used in hairy cell leukemia, and I will give a quick note.
Then there is another characteristic of B-cell, that is B-cell is defined also by the expression of markers called CD20, that can be targeted by rituximab. Or CD22, that is targeted by this antibody associated with some toxic agent that is internalized in sequencing. And this is called moxetumomab.
But again, within the B-cell receptor signaling pathway, there is a component that goes through a kinase called RAF or BRAF in B-cells, that in hairy cell leukemia get constitutively activated by a mutation, with the V600E. So you don't need triggering of the B-cell receptor, this mutation activates it. And so this is why considering treatment against this mutated RAF, might be a way through and I will show you evidence that it is certainly a way through.
Dr. Francesco Forconi:
The first paper by Enrico Tiacci was published in 2010, documenting that all hairy cell leukemia patients are expressing BRAF. And then, the Perugia team was able to give the patients BRAF inhibitors and showed that the patients did respond to BRAF inhibitors, to Vemurafenib. These patients were relapsed or refractory.
The response was excellent. So complete remission in 35% of individuals, and the responses in almost (all the other) individuals, were fantastic. The point is that we learned quickly that BRAF inhibitors, they lose their effect as soon as the treatment is suspended. So something more is required, otherwise even if you obtain a complete response, the patient will progress after the suspension of Vemurafenib.
Dr. Francesco Forconi:
This drug has another advantage over purine analogs and any chemotherapy. Biological treatment, small molecule inhibitors, has the power of being generally non-toxic and to be given continuously. That doesn't mean unfortunately, that they can be given forever. We're learning it from many other small molecule inhibitors. Certainly, they give us the opportunity to give a much more targeted treatment and much less toxic treatment that chemotherapy.
So one way through was by Thorsten Zenz, who suggested, wait a second, in order to reduce the toxicity, why don't we do what we have always done in hairy cell leukemia; let's give Vemurafenib at a dose that is lower than the dose that is given in other diseases. So he reduced the dose and found that the therapeutic effect was rather similar. Still, the condition progressed, but he put there a point saying, "Giving reduced dose is as effective. Don't dump and give as much as possible, we can titrate the dose." It's an important thing for a medical approach, which means we don't need to give a black and/or white approach to individuals. We can play the doctor and the patient in order to titrate the toxicity.
But the other point was that since the duration of the treatment was not forever, of the response was not forever, for an extension. Again, Perugia's team has suggested to use the combination of Vemurafenib and rituximab, and here are the results. So in patients who received the combination, then again we seem to have a plateau. Mind you, the duration of the follow up is still very short, for individuals with hairy cell leukemia, but significant to say that this treatment works.
Dr. Francesco Forconi:
Obviously, if patients have received the BRAF inhibitor before, it will work less than if you had not received a BRAF inhibitor before, or if you received a better response in MRD negativity, then the duration of the response will be much, much superior than if you're MRD positive, meaning minimal residual disease detectable.
Dr. Francesco Forconi:
So, is this the line toward which the community is moving? Certainly yes, because we are moving towards thinking about cancer, in general if we can use the C word, with pathogenetic treatment. Hairy cell leukemia is being one of the many, now, approaches, particularly in hematological cancers, where giving targeted treatments to lesions, whether they're genetic, epigenetic, or of the surface, specific of tumor cells, particularly in kinases. So something that is barricading the tumor cells, is the best effective approach because it won't have as much toxicity, and will allow us to use the drug for long.
Another drug was then proposed on the same principle, and this is Ibrutinib. Ibrutinib targets the B-cell receptor associated pathway, amongst other pathway, proper of the hairy cells. And in this study by the Ohio team, again a phase two study in classic and variant hairy cell leukemia. There wasn't such an eradication of treatment here, a complete response in blue, as there was in with BRAF inhibitors. But certainly a prolonged treatment included an increased frequency of complete remission and an increased frequency from the same patients of partial remission, with many remaining stable response. So that there was also here, an effect on overall survival and progression-free survival on heavily pre-treated patients.
Other opportunities have been considered, like moxetumomab pasudotox. This is an antibody bound to a toxic molecule at the end. So if the antibody binds to the cell, it will get internalized as it will, and the toxic agent will intoxicate the tumor cell so it will die. And through this treatment, again what we're seeing is that patients who receive moxetumomab, after at least three lines of treatment, so heavily treated patients with hairy cell leukemia will benefit. Remember that after three lines of treatment, according to all studies with purine analogs only, the median survival suggested was to be around a huge variability, so do not take it on individual basis, around three, four years. Now here, we have got a median overall survival is not reached after five, six years. So this is an important result. And again, if the patient is MRD negative, the chance of progressing is very, very low, as opposed to MRD positive.
Dr. Francesco Forconi:
So we're going now to prognosis.
So now this is all blurred by the fact that there are different approaches that can be taken in consideration. I think one factor is whether we live in a country where those approaches can be accessible.
But if we look at what happens in patients with hairy cell leukemia, there are two key factors that are relevant, I think, in order to obtain the best response. One is the starting point, so hemoglobin and platelet levels. The other one is the quality of response achieved following that treatment. This is an example of what happened following purine analogs. So if you obtain a complete remission and your hemoglobin and platelet levels are normal at the time the treatment starts, then obviously, your duration of the response is much longer than individuals who have not obtained a complete remission and have hemoglobin or platelets normal.
So there are obviously intermediate situations, but to say that we want to treat patients with hairy cell leukemia before there is deterioration of the blood counts. And we want to treat hairy cell leukemia for the purpose of reducing the tumor burden as much as possible in such instance.
Dr. Francesco Forconi:
There are other parameters. One is the white blood cell count. When you see a white blood cell count, I quite often like to think this is variant form at least in its presentation, because typically hairy cell leukemia, when you have a high white blood cell count, this is not typical for it. And as much as the tumor burden, so the presence of splenomegaly or not, by physical examination. In a clinical trial where I was using cladribine. Looking at molecular parameter associated with the status of the B-cell receptor, so the feature of the B-cell, of the tumor B-cell being mutated and unmutated. And there are studies that are validating this information, where individuals who have unmutated immunoglobulins, unmutated B-cell receptors, is not as well as individuals who have mutated immunoglobulins.
Dr. Francesco Forconi:
What is currently happening in the United Kingdom is the following. If you have a patient with hairy cell leukemia in first-line, you're allowed to give only a single agent purine analog, not together with rituximab. But if the patient is not eligible for purine analogs, you can find opportunities to start treatments with rituximab single agent. If the patient progresses, then at that time you can consider a purine analog with rituximab, given concomitantly or as a subsequent treatment.
Dr. Francesco Forconi:
There are suggestions from the studies at NIH where concomitant is better than subsequent treatment. So rituximab following cladribine. But there are also some hints that cladribine plus rituximab at the same time may give a bit more toxicity and a bit more immunosuppression, and I use the word may. In some centers where companies are more accessible, considerations for BRAF inhibitors can be done. This is hectic and sometimes it's not easy. But the second-line to be considered is the purine analog plus rituximab.
In third-line, depending on the duration of the treatment, we can either consider the same treatments that the patient has had before, or if the duration of the response has been short, we must go and look for additional opportunities. So this is where the doctor needs to find either BRAF based, BRAF inhibitor based treatments with or without rituximab, and/or anti-CD22 treatments with moxetumomab.
Opportunities like BTK inhibitors are being explored, I've shown you the study with Ibrutinib, but there are other BTK inhibitors in which I may only comment that they are not yet mature to make any consideration. Probably the one to consider at this specific moment if required, and if other options are not available, is Ibrutinib.
Question & Answer with Webinar Participants
Anna Lambertson:
We frequently receive questions about what is the right treatment for a given patient, given their situation? And then individuals often have questions about the right timing of treatment. So, as you've been presenting, we have had quite a few questions come in about what treatment might be right for this individual.
For example, one person who is in fact in the UK, has received cladribine, their blood counts didn't go back to completely normal ranges, and so they're trying to decide if they're in the UK, what are their options for adding a combination, something else to cladribine? You've touched on that in this slide, so maybe you can clarify that a little bit for someone who's in the UK, has already been treated with cladribine, and might want to look for additional treatment.
They did say that they received cladribine about five years ago, so it has been a considerable amount of time since treatment.
Dr. Francesco Forconi:
So when you have a treatment with cladribine, there are a lot of components to consider. The very first one component is that the time by which cladribine is being given, which is roughly five days, and if you're in the UK, it's possible that the patient has had it subcutaneously.
The time by which you end your treatment and you have the best effect of cladribine, can be up to six or nine months. So it's not unusual that you give cladribine, you do a bone marrow biopsy after two months, you see residual disease, you still see what is called the cytopenia, so hemoglobin and platelets are still low. But then you wait six months and you do a bone marrow biopsy again to find out that the hairy cell proportion is much less, sometimes you don't find it. And the bone marrow is much more populated, and the blood counts have improved.
Dr. Francesco Forconi:
So the second question there is, what is the consequence of cladribine on the normal marrow? When patients have received cladribine, and even worse when they receive pentostatin, it's not unusual to find a cellularity of the marrow from what should be around 80% of the normal marrow, to 10, 20%. So we find the marrow empty, and that marrow remains empty for many years. This will possibly have an impact on the production of red blood cells, platelets, and normal white blood cells in the peripheral blood. The one thing that needs to be done is to make sure that the low counts are not because there is hairy cell leukemia infiltration, but because there is instead toxicity by the cladribine treatment.
The other point that cladribine can cause is dysplasia. Dysplasia means that the marrow is fluid, but doesn't produce the end product. It is the mature red blood cell, the mature platelet, the mature normal white blood cell. This is called myelodysplasia or dysplasia, and purine analogs can cause that.
In any of these circumstances, you do not want to give another treatment to an individual. If instead the cytopenia is the result of hairy cell leukemia infiltration, then there you have to play in two directions. If the cytopenia has remained stable and non-symptomatic for those five years, you really don't want to jump on the individual, because the options that are available are short. And the longer you go away from the first-line, the more likely the second-line will be effective.
But if instead the counts are deteriorating, that is the point where the doctor has to pick the right timing in order to give another treatment before they have completely deteriorated. Because if that happens, that is the moment when the individual who is receiving the treatment is more at risk of infections. And infections are one of the major complications with morbidity and mortality in hairy cell leukemia.
Obviously, each individual will have to have a personal discussion with their doctor and make the best decision based on personal circumstances. But if I could extrapolate a general approach, I think that would be the reason.
Anna Lambertson:
So there are several questions about how doctors make clinical judgment regarding when treatment is needed for a patient. I’m going to try to aggregate them, but they're all within the same theme of timing. Let's say one patient, his other blood counts are at relatively normal levels. However, his platelets have in the last several months dropped below the normal level. So he's asking himself, "Well, should I go ahead and be retreated?" And I should point out that this patient has actually had Vemurafenib, as opposed to cladribine. So his most recent treatment has been Vemurafenib.
He's been treated with Vemurafenib, his counts went back up, and now despite that almost everything is still remaining at normal levels, but in the last several months, the platelets have surprisingly fallen quite low into the 80s. So he's thinking, well, “Should I go ahead and be treated again with Vemurafenib, or should I switch to the cladribine and rituximab?”
Dr. Francesco Forconi:
The question there is, has the patient received a cladribine before? Has the patient received the rituximab before? Has the patient received cladribine plus rituximab before? If they had received Vemurafenib in first-line, certainly cladribine and rituximab are the very best option. And there I come with more questions than answers, because I'll start asking the patient where is he from? Where is he based? If he was in the UK, he could have, it would be surprising that he would have had Vemurafenib in first-line. But if he was in the UK, and that was the option, well he could certainly have had cladribine plus rituximab.
There are individuals who have chosen not to have rituximab and leave it for the second or third-line, in combination with a purine analog, simply for professional reasons. Because giving rituximab would, in association with cladribine, require a duration of the treatment, which is quite long, at least two months, where every week the patient needs to come, to four months, if the patient having had rituximab subsequent to cladribine with an assessment of response two months after cladribine. Which again if you are running a professional busy life, it may have a big impact.
So these decisions are taken into account, and likely so for hairy cell leukemia, it can be taken into account. So I would be more curious to understand what the patient had had before Vemurafenib.
Anna Lambertson:
The individual is in the United States, did previously receive cladribine several years ago. And most recently pursued Vemurafenib, in part because of the ongoing pandemic and concerns about the immunosuppressive effects of cladribine. So had a fairly positive response to Vemurafenib, but now that the platelets have fallen, is thinking, "Well, maybe I will have to be retreated again."
But I think what you're saying is there's a variety of factors that you would have to look at. How well he responded to the cladribine when he was treated. I guess, other questions that have come in have been kind of in that same vein. So, you pointed out earlier that the consensus guidelines laid out these hematological thresholds. So platelets below this level, white counts, et cetera, if they fall below those thresholds, a doctor might consider treatment.
What several of the questions are asking is well, so only my white counts are low, or only my platelets are low. So as a clinician, you're not automatically going to jump to treatment.
Dr. Francesco Forconi:
No, there is a lot of reasoning, particularly in hairy cell leukemia. I made my answers very, very long exactly for that point. So if you read the guidelines, we have very neat cutoffs, below 100, you treat, above 100, you don't treat. I'll put it simply that way to simplify the concept and simplifications are always simplifications, they're not appropriate for everyone.
Those cutoffs are designed to give a big alarm bell. It is the time when action is required. Action could be treatment, if it is all down to hairy cell leukemia progression. It hasn't got to be considered as such if it is not because of hairy cell leukemia. You can have multiplication of problems if the patient has been treated before.
But at the end, I think it's very, very safe if the instruction is done with your GP next to you, with your hematologist next to you.
Anna Lambertson:
We've received another question. So this individual was treated a couple of years ago with subcutaneous cladribine. Some residual disease does remain in the bone marrow and the peripheral blood. So what he's trying to get his head around, is whether it would be worth doing rituximab now, so its been two years since cladribine was completed, there's some MRD. Should he do eight doses of the rituximab now, or should he wait until he relapses and then do cladribine and rituximab?
Dr. Francesco Forconi:
So my personal suggestion is definitely, if the condition is stable, no reason why at a given point you want to burn one treatment line. In those specific settings where you have stability and platelets and hemoglobin, normal white blood cells are within normal ranges, or stable or acceptable ranges, you don't want to give any treatment. You want to have your hematologist be very careful and to offer you the treatment with rituximab for example, when there is a sign of progression. So only at that time, I wouldn't certainly go randomly within a stable condition, to burn one treatment opportunity.
Anna Lambertson:
There have been several questions about those thresholds and the guidelines. Would you mind clarifying those guidelines, with the understanding that they're simply, they're guidance, and there's a variety of other questions that as a clinician you need to take into account?
Dr. Francesco Forconi:
So guidelines are always designed to seek a consensus amongst practitioners. And nowadays also to protect the doctor from justifying their decision. We have to be sometimes planned, and honestly admit that those cutoffs are arbitrary.
The figure of 100,000 platelets is designed to have a safety net between values, for example, 50 below which there is starting to be a real risk of bleeding. And the value of 100 above which there is really no risk and there is no problem. As much as a hemoglobin level of more than 100, in an individual who has had hemoglobin more than 100 for two, five, six years, that individual will not sense fatigue or lack of oxygen. There is a big adaptation of our body to what are called deficiency compared to the standards.
So the guidelines are guidelines, they guide us through a consensus within the safety net. They are not biological definition of risk. They are a clinical summary of what is best based on, in the case of hairy cell leukemia quite often, what happens also in other conditions.
Anna Lambertson:
We are unfortunately at the end of our time, and Dr. Forconi, we're always incredibly grateful for the time that you spend, for the information that you share. I want to say thank you to all the individual patients and family members who logged in and joined today's webinar.
This transcript has been edited for clarity.