Dr. Scandura, what is the role of the patient in making treatment decisions?
My personal philosophy is I view myself and my interactions with patients as a partnership. And I have and I bring to this partnership medical knowledge, some scientific knowledge, experience treating patients, understanding the diseases and the biology of the diseases.
What patients bring is their personal histories, what they want and need from therapy, what their expectations are, where their fears and concerns might be. And as we share our information, I think that provides the opportunity to come to an understanding where the patient can make an informed decision and I can support that decision, that we know what the groundwork has been between us. And so, I spend, often, a lot of time in the beginning with patients kind of trying to understand who they are as people and what they need and expect. And everybody, as you might imagine, is an individual.
And I present to them the information, and I try to encourage questions so that I know that they understand the information that I’m giving so that they can make a decision in their best interest. And so, I think shared decision-making is the only model I practice.
Now, patients have different needs, particularly some of my older patients. And, culturally, there are some differences where they don’t want to take that role of being the decision-maker. And so, then my role changes a little bit, and it becomes more to make sure they’re comfortable and understand the direction that we’re going in and, again, always trying to encourage people to take ownership.
I think, in New York City, that’s not so common. People are pretty well-informed and interested and more than willing to express their opinions.
And so, I would say it can be very rewarding to come to a decision where patients feel their needs are being met.
https://powerfulpatients.org/pen/wp-content/uploads/Whats-YOUR-Role-in-Making-Myelofibrosis-Treatment-Decisions_-1.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 19:01:342021-03-26 13:28:21What’s YOUR Role in Making Myelofibrosis Treatment Decisions?
Dr. Scandura, you mentioned promising research in myelofibrosis treatment. What are you most excited about right now?
I think there are a couple drugs that have been in clinical trials that have had activity in a significant subset. So, anywhere from 20 to 50 percent of patients where the bone marrow fibrosis is actually reversed.
And this is really something that we haven’t seen with other agents. And the approved agents, when that does happen, it’s really in a vast, vast minority of patients. And so, these newer drugs and, often, they’re used in combination with other approved drugs, can reverse the fibrosis in the marrow. And that is what I find most intriguing and exciting. They seem to be well-tolerated medications with predictable and reversible side effects when they do exist. And I think that time will tell if the promise is long-lived or if it’s short-lived. I mean, obviously, new drugs we don’t have the experience with that we really need.
The clinical trials that are available now with some of these agents are in the last stages before the companies go to the FDA seeking approval for use.
And so, we don’t have their results from those studies yet. They’re just opening, so sometimes the excitement doesn’t bear out when we do the rigorous clinical trials. But I’m actually quite optimistic about some of these agents, and I think that there is going to really be a sea change in how we treat patients and some of the outcomes we can expect from our therapies.
https://powerfulpatients.org/pen/wp-content/uploads/Expert-Perspective_-Promising-Myelofibrosis-Treatment-Research-1.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:58:062021-03-26 13:27:41Expert Perspective: Promising Myelofibrosis Treatment Research
Is the COVID-19 vaccine safe for patients with myelofibrosis, and how does the vaccine affect treatment?
So, I will flip that question around a little bit. I live in New York City.
If I cross the street, the decision to cross the street is potentially a life-or-death decision. And whatever minor decision you’re making, there are always risks and there are always potential benefits. So, I might get home, I might get run over by a cab. And so, I try to mitigate those risks as I can by crossing in certain streets, looking both ways. So, when we talk about vaccine, we also have to talk about the other part of it. What is the risk of not being vaccinated? And so, we know COVID-19 is a severe illness in a subset of patients, we know that if you take all people, about 1 percent of people die from COVID.
If we take all people from the vaccine who have been vaccinated, the number of serious side effects is very, very, very, very small, so, like .000, you know, something percent.
So, very low. It doesn’t mean it’s zero, but it’s very, very low. So, just looking at those numbers, I say for virtually everybody, the risk/benefit is in favor of vaccination. In patients with myelofibrosis, we’ve had the opportunity collectively across the world to gather experience and look at patients with myeloproliferative neoplasms and how they responded to COVID when they were infected with COVID. And worldwide, the toxicity of COVID in patients seems to be quite high. And so, patients with myelofibrosis may be at higher risk from COVID.
I can’t say that they absolutely are because this is imperfect data, but that’s the experience that has been published so far.
We really don’t know anything about the experience of patients to the vaccine. Actually, at my center, we have a myeloproliferative diseases center, and we are trying to collect that information because patients often ask, and I don’t have any results from that. But I think that, all told, there is no reason to expect higher symptoms in patients with myelofibrosis from vaccination. And what we do know is that the risk of not being vaccinated is probably higher than the risk of being vaccinated.
https://powerfulpatients.org/pen/wp-content/uploads/COVID-19-Vaccination_-What-Do-Myelofibrosis-Patients-Need-to-Know_-1.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:49:392021-03-26 13:28:18COVID-19 Vaccination: What Do Myelofibrosis Patients Need to Know?
What are the considerations when choosing treatment for myelofibrosis?
I would say in broad strokes, the primary considerations are the patient, what they want, the disease, what our options are, and the overall condition in terms of what are our possibilities for therapy and what is the risk/benefit of some of these different therapies. So, in myelofibrosis, although there’s been a huge amount of research over the past 10 years, really blossoming and are very impressive in, I think, an exciting way, there really are only two therapies that are approved by the FDA in the treatment of myelofibrosis, and those both affect one class of agents. These are JAK2 inhibitors, and those can be ruxolitinib (Jakafi) and fedratinib(Inrebic) are the two drugs that are approved.
Now, we have a number of therapies that have been used off-label, meaning without FDA approval, so often and for so long that they’re considered alternative standards of therapy. These can be growth factors; these can be biological agents in certain situations. And then, clinical trials is really increasingly a common therapeutic option for patients.
And then, on the most aggressive side, is hematopoietic stem cell transplant and allogeneic transplant getting blood-forming cells from another person and replacing the entire blood system through transplant.
So, who is right for a stem cell transplant?
I would say, first and foremost, an informed patient about the risks of transplant and a patient for whom a donor exists, and a good quality donor. Transplant is not an option for some people or if a donor can’t be identified, obviously.
And it’s a patient for whom the risk balance, the risk/benefit balance is tipped so that the potential toxicity, frankly, of transplant is warranted. Transplant is our most aggressive therapy. Virtually every patient will have significant side effects from transplant. Some of them are short-lived, some of them can be chronic. People die from the consequences of transplant. And so, it’s not something that is considered in patients who are necessarily doing well or are frail. The risk of transplant versus the benefit may not be in favor of transplant at that time.
My approach for transplant is to get advice from transplant physicians. I’m not a transplant physician, but I have colleagues who I refer to.
And I refer in myelofibrosis fairly universally fairly early, with the rationale being that this is information. It is not a plan; it is to speak to a transplant, what kind of donor exists. If no donor exists, then transplant is not on the table. If we have a very good, high-quality donor, then this is something that wouldn’t make the decision in itself, but it’s kind of something we can keep in our hip pocket in case we need it. And I think it’s important for patients to understand and have a full and complete discussion with a transplant physician so they understand what that means. You know, it is a significant commitment of time and morbidity, and it comes with risks.
It is also our only curative therapy. And so, it’s a double-edged sword, and I think informed patients and understanding what the options are are the gateway to any consideration of transplant.
https://powerfulpatients.org/pen/wp-content/uploads/What-Are-the-Considerations-When-Choosing-Myelofibrosis-Therapy_-1.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:40:052021-03-26 13:28:13What Are the Considerations When Choosing Myelofibrosis Therapy?
Dr. Scandura, would you start by introducing yourself?
Sure. My name’sJoeScandura. I’m an assistant professor at Weill Cornell Medicine in New York City. I’m a physician scientist. My laboratory studies blood formation, normal and malignant, and clinically I treat people with myeloid neoplasms, particularly, and myeloproliferative neoplasms.
Would you define myelofibrosis for us, and also provide an explanation of primary versus secondary myelofibrosis?
Sure. Myelofibrosis is in the class of diseases called myeloproliferative neoplasms. And, really, its sort of marker feature is scarring in the bone marrow.
Clinically, this comes along most commonly and fairly universally with anemia, and there can be abnormalities of both the white blood cell count and the platelet count, sometimes, often in the beginning, being too high. And then they can also become too low.
It tends to be a progressive disease, or on the face on which it progresses is different in different people and there are a variety of different features that can go along with risk. But every individual, of course, is individual.
A primary myelofibrosis is what we refer to when the diagnosis is made and there’s no antecedent, there’s no precursor malignancy. And so, you come in and the diagnosis is myelofibrosis, and we can’t find anything that came before it.
Secondary myelofibrosis is what we refer to when somebody has another blood disorder, usually essential thrombocythemia or polycythemia vera, and in a small subset of these patients, the disease can change, what we call evolve or progress into a fibrotic phenotype or associated with the marrow scarring, and a lot of the features of myelofibrosis. Although there are some subtle differences between primary and secondary, they’re more similar than different in terms of their clinical features and how we treat them.
https://powerfulpatients.org/pen/wp-content/uploads/Primary-vs.-Secondary-Myelofibrosis_-Whats-the-Difference_-1.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:26:412021-03-26 13:28:05Primary vs. Secondary Myelofibrosis: What’s the Difference?
How does inhibitor therapy work to treat myelofibrosis?
So, the therapies that we have now that are approved therapies that are in this class are ruxolitinib (Jakafi) and fedratinib (Inrebic).
Both of these agents act to block signaling through a protein called JAK2. You can think of JAK2 as being part of the antennae system that a cell uses to communicate with the rest of the body. And so, our blood-forming cells have a lot of input from the body saying, “Okay, we need some of these kinds of cells, we need some of those kinds of cells,” and it’s a very adaptive system. And JAK2 is involved in a lot of the signaling in this as part of the antennae system.
And what happens in the myeloproliferative neoplasms is that signaling is a bit excessive.
And so, it’s like the volume is turned up too loud and the signaling is causing the cells to do things, make too many cells, make the wrong kinds of cells, and JAK2 is part of that signaling system. So, these inhibitors kind of help turn down the volume of the signaling in these blood-forming cells. They are drugs that have good activity in improving symptoms, they have great success in reducing the size of the spleen, they can be useful for a few years to many years. They are not curative therapies. We don’t think of them as therapies that change the course of disease, but they certainly have an important role in helping people feel better. There are other inhibitor therapies that are in clinical development.
So, clinical trials of some of these drugs have really impressive activity, but none is approved yet by the FDA.
I hope and expect we’ll have a couple more drugs available in the coming years. And there’s a lot of excitement in clinical trials in terms of some of the activities that are being seen, and really quite tolerable therapies, so not a lot of side effects for patients. And so, I think it’s kind of an exciting time for physicians and for patients and a lot more options now and, I think, a lot more options coming down the line.
https://powerfulpatients.org/pen/wp-content/uploads/How-Does-Inhibitor-Therapy-Work-to-Treat-Myelofibrosis_.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:22:242021-03-26 13:28:33How Does Inhibitor Therapy Work to Treat Myelofibrosis?
Are there specific mutations that may affect myelofibrosis treatment choices? Dr. Joseph Scandura explains the factors that are considered when deciding a myelofibrosis therapy, including a discussion of high-risk and low-risk disease.
Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.
Are there gene mutations that affect myelofibrosis treatment choices?
Yeah. So, you know, the primary mutations in JAK2 or CALR or MPL in myelofibrosis aren’t that helpful in guiding therapy.
And we look at the other genes for co-ocurrent mutations and those, as I was mentioning before, can come into one of two categories. So, there are a number of genes that we know tend to confer a higher risk, and so we call those high molecular risk mutations. And people who have higher molecular risk tend to have a more aggressive disease.
Now, I want to add a word of caution because when we talk about patients and risk, we’re talking about groups of patients. For any individual, everything kind of boils down to it happens, or it doesn’t happen. And so, there’s nobody is 50 percent dead in five years, right. You either are or you’re not. And so, when we talk about risk, then we’re talking about risk of bad things happening like death or other complications of the disease, we’re trying to guide treatment decision-making and guided discussion based on a chance.
But all of those things, for any individual, there are people who have high risk who do quite well for a long period of time, and people who don’t have high risk who don’t do as well as you think they should. And so, it’s a part of a conversation, it helps guide discussion, but it is not something carved into stone, and nobody has a perfect ability to predict anybody’s future.
And all of these things are our best tools to estimate, but they are not a future; they are a possibility. And so, people who have higher molecular risk, we might think about more aggressive treatments than people who have lower molecular risk.
What are the essential tests that should follow a myelofibrosis diagnosis? Dr. Joseph Scandura reviews the necessary laboratory testing, along with a discussion of next generation sequencing, and explains how often bone marrow biopsies should take place.
Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.
What testing should take place following a myelofibrosis diagnosis?
So, a diagnosis of myelofibrosis always comes after a bone marrow exam and a physical examination. Often, patients have an enlarged spleen and blood count testing and a variety of other laboratory tests. So, after that and a diagnosis is made of myelofibrosis and, sort of, coincident with the diagnosis, we often look for molecular markers of myelofibrosis. So, these are malignancies of the bone marrow, cancers, if you will, on the bone marrow, although the term is scarier than or is different than what we think of for many malignancies in how it acts. But the myelofibrosis, this is a disease that’s characterized by, really, mutations in the malignant cells, the abnormal cells.
They’re reallyjust one of three genes. And so, JAK2 being one of the genes, calreticulin or CALR being another one, and MPL one.
And more than 90 percent are people having mutation in just one of those three genes. And so, often at the time of diagnosis, tests for those mutations are done, and they help eliminate the possibilities of other causes of myelofibrosis – infections, rheumatological diseases. Sometimes, you can have marrow fibrosis but they don’t go along with mutations and the same clinical situation. And so, at the time of diagnosis, we usually know something about a mutation in JAK2, CALR, or MPL.
More commonly now, and it’s increasingly common over the past 10 years in, I would say, in New York City and many places across the country, we also look more broadly for other common mutations in the MPN cells. And these are what we refer in the batch as next generation sequencing or NGS panels, and we use the term panels because we’re looking at from a few tens to even 100 or a couple hundred genes for mutations that occur far less frequently than in JAK2 or MPL or CALR.
But they occur often enough that some of them we use to help guide treatment decision-making or approach to therapy. The reality of it is that that the technology to sequence and identify mutations has really outstripped our knowledge of what to do with all of that information.
And, for the vast majority of people, it comes down to do you have a marker, a genetic marker that tends to go along with higher risk, meaning a higher likelihood of something that we don’t want to have happen. And in that instance, although it may be looking at a hundred or so genes, it comes down to a binary thing – either you have or you don’t have.
Is there any other testing that you usually want to do?
Laboratory testing, for sure and, as I mentioned before, a bone marrow exam. But physical examination, some people might do imaging of the spleen size. Honestly, I don’t routinely do that outside of the setting of the clinical trial. I don’t really think it dictates therapy very often.
And if the spleen is so small that you can’t feel it on physical exam, it probably isn’t clinically meaningful anyway in terms of something to treat. It might be there, but it doesn’t really change things too much.
How often should patients have a bone marrow biopsy?
So, I’ll answer there is no standard in terms of monitoring for myelofibrosis with the marrow or otherwise. My personal approach is I do a marrow when I think it’s going to help medical decision-making. And so, for a patient who’s got early myelofibrosis, who’s been very stable, responding well to therapy, that could be three, five years between marrow exams.
For somebody who’s being considered for a clinical trial, oftentimes, a marrow exam is required before they start on the clinical trial and at various intervals afterwards. If there’s somebody who had been stable and something is changing, like the blood counts are changing or his symptoms are changing, or any of a number of clinical features, then I might look in the marrow to see what’s happening there, to see if explains and can help guide a treatment approach to help people feel better. So, there is no single standard, but my personal approach is to do a bone marrow exam when I think it’s going to help make a decision.
https://powerfulpatients.org/pen/wp-content/uploads/Have-You-Had-These-Essential-Myelofibrosis-Tests_.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2021-03-23 18:22:142021-03-26 13:28:40Have You Had These Essential Myelofibrosis Tests?
CLL specialist Dr. Richard Furman, Director of the CLL Research Center at Weill Cornell Medicine, answered patients burning questions live in this installment of Ask The Expert.
And hello. Greetings. I’m Andrew Schorr in southern California, San Diego area, and I’ve been living with CLL for 22 years, so I’m vitally interested in today’s Ask the Expert session, this Patient Empowerment Network program. We want to thank PEN, as we call it, and also the financial supporters of this program, AbbVie Incorporated and Pharmacyclics, although reminding you that they have no editorial control. You’ll be hearing from our leading expert in CLL in just a minute.
Over the next 30 minutes or so we’ll get to as many questions as we can. Remember not to make it too personal. Let it help everybody in the community. And also discuss what you learn with your own CLL provider so you get the treatment that’s right for you. Okay.
Let’s meet our expert joining us from New York City and Weill Cornell medicine, and that’s Dr. Richard Furman, who is the director of the CLL research center in New York City at Weill Cornell. Dr. Furman, welcome back. Thanks for being with us.
Thank you. It’s my pleasure. Thank you for having me.
Okay. We have lots of questions. One of them that somebody wants to know about is, first of all, if they’ve been‑‑maybe this is an easy one. If they’ve been diagnosed with SLL, small lymphocytic lymphoma, is that the same as CLL and what we’re talking about with CLL applies to them?
So that’s a very important question, and this is one that I actually think is very indicative of how little we used to know. So in 1993 we actually had a diagnosis of CLL, chronic lymphocytic leukemia, and a diagnosis of small lymphocytic lymphoma. And we had patients that were diagnosed with SLL if they had a lymph node sent to the pathologist, or they were diagnosed with CLL if they had a bone marrow biopsy sent to the pathologist.
Clearly, we knew that patients could only have one diagnosis and not two, so in 1994 with the new lymphoma classification system the term was actually changed to be CLL/SLL. So they really are exactly the same entity. We don’t actually refer to differences anymore, and the whole, the whole individual‑‑the whole disease should be called CLL/SLL.
Now, an important thing is sometimes people require having a lymphocytosis to meet the definition of CLL, but the truth is both conditions are exactly the same. Both should be treated exactly the same, and there should be no difference based upon having a lymphocytosis.
Why this is most important, let me just add, is that there are sometimes people will be diagnosed with stage IV SLL and it’s very important to recognize that these stage IV SLL patients unless they have thrombocytopenia below 100,000 like the Rai stage would indicate really are not stage IV. So the lymphoma staging system would automatically make them stage IV, and that’s certainly not correct.
Okay. Good point. All right. Here’s a question we got in from Julia and Betty and Shelly and Mark. They all asked a similar question. They’ve been on Imbruvica for five years now with success.
Is it working for most people, and what are some reasons why it doesn’t work for everyone? And then what treatment options do you recommend if they relapse on Imbruvica?
So right now I think the most important, there are a lot of prognostic markers available for CLL. At last count we’re probably up to 115. What’s most important is in 2018 what are those prognostic markers that really are relevant to the patient, and really as long as you stay as CLL you’re going to be able to have your disease very nicely controlled with our current agents and our novel agents.
So there are certain things that do indicate patients are likely to progress on ibrutinib, not likely progress must but who may progress, and people who might need something more, and that’s where a lot of our current clinical are research is focused. So patients who have a risk of developing a Richter’s transformation or patients who have a likelihood of developing a BTK mutation that might generate resistance to ibrutinib are the two groups of people that we worry about most.
17p deletion is probably the most important predictor for predicting those patient outcomes. There are other things that are predictive as well like having a NOTCH mutation. Those are all readily obtainable prognostic markers that allow us to determine who’s at risk and who’s not at risk for progressing on ibrutinib. If you don’t have 17p deletion or NOTCH1 mutation you have almost a 99 percent chance of being free from progression at five years on ibrutinib. And it looks like most of the people who are going to progress will progress within five years. So I think making it to that five‑year mark is really very‑‑is the most important thing.
Okay. So if you do progress, what then?
So fortunately we have a lot of great agents.
Venetoclax works very effectively in patients who progress on ibrutinib, generates some very, very deep responses and very long‑lasting responses. So that’s certainly one option. Another option is to be treated with a PI3‑kinase inhibitor. So we have idelalisib and duvelisib now approved. We will shortly have umbralisib approved as well as a novel agent. We also have a whole array of other agents coming down the pipeline looking specifically at means for progression on venetoclax. So we have an MCL1 inhibitor which targets the protein that’s likely responsible for resistance to venetoclax. So all these things are actually currently in clinical trials and certainly will hold a great deal of promise.
Okay. Here’s a question we got in from Jeff. He says, for young and fit patients with relapsed disease what are the best combos now and coming. And I suspect maybe Jeff had received FCR, so if he relapses after FCR, what about that?
So my belief is that these novel agents should always be used up front, or if you’ve gotten chemotherapy up front they should be used immediately at relapse. A lot of patients and physicians have the idea that there’s a benefit to holding back until you really need something, but I believe putting our best foot forward first is always the best approach. So I always recommend going forward first with BTK inhibitor therapy, followed by venetoclax or venetoclax followed by BTK inhibitor therapy. And I think so in a patient who has relapsed after FCR it will be ibrutinib or acalabrutinib. In a patient who has relapsed after acalabrutinib and ibrutinib would then move on to venetoclax.
Now, what I’m really very excited about is the possibility of the combination of either BTK inhibitor therapy plus venetoclax or PI3 kinase inhibitor therapy with venetoclax.
You know, both of these combinations really take advantage of the synergy that happens when you take a BCR antagonist like ibrutinib, acalabrutinib or idelalisib and duvelisib and combine it with a Bcl‑2 inhibitor. And it really sort of enables us to get very, very deep remissions with actually as short as just 12 months of treatment. And so those are what we’re currently testing in patients right now and what I hope will be the frontline treatment for patients in the not‑too‑distant future.
Now, one of the things people wonder about is if you take these big guns and put them together could you, like you’ve been able to do with FCR, stop treatment or take a break from treatment at some time.
So I’m a big believer in that if something’s working and you’re tolerating it well that we shouldn’t mess with it, but we are currently studying two different processes with relationship to the ibrutinib plus venetoclax combination. So we’re taking patients who become MRD negative on the combination after 12 months and randomizing them to either just get ibrutinib or to get placebo. And so that’s going to give us information as to whether or not it’s safe to stop patients on the combination and treat them with nothing long term. We’ll see, one, how many patients relapse, and hopefully none, and, two, if they do relapse whether or not we can then restart ibrutinib and control their disease. So this will provide us that important question as to whether or not we’re giving up something by discontinuing the therapy.
We’ll have as our comparative those patients who got ibrutinib plus venetoclax for 12 months and then just remained on the ibrutinib.
And so that will sort of be the patients who will continue on with their therapy, and then the other half will be patients who have discontinued all their therapy.
My belief for going to venetoclax is that you’re going to get almost all of the bang for your buck out of the first 12 to 24 months, so continuing it is unlikely to yield an additional benefit, so I think stopping it is safe. But, once again, these are the studies that will provide us with those data.
Okay. Now Maureen sent in a question where they responded to venetoclax and rituximab and they wondered what about testing for minimal residual disease? They don’t have any lymph nodes or anything, but is that then appropriate to do a MRD test to see how deep the remission is?
So the real important question should be whether or not that’s going to impact upon clinical management.
So MRD testing is easy, it’s noninvasive, it’s a peripheral blood test or a bone marrow biopsy, which I guess is only relatively noninvasive, and the information though is really not going to be of use. So if you’re taking a patient who’s on ibrutinib and you’re going to continue the ibrutinib knowing the MRD status won’t change anything. Likewise, if you have a patient who’s on venetoclax, who’s going to get a year of venetoclax on trial and then stop, knowing the MRD status won’t change anything as well. So currently there’s no real reason for doing MRD assessments in patients except for just the ability to know.
Now, one day there’s some modeling that suggests that the time it takes you to reach MRD negativity is half the time you need to be on a substance, an agent, before you can actually claim to have a deep enough remission that you won’t relapse. So we may one day say if you’ve been on ibrutinib for five years and became MRD negative, then 10 years of ibrutinib is enough and you can stop. But that’s currently just theoretical and based on mathematical models.
Theresa wrote in, she said, my husband is being treated with acalabrutinib for five months. He’s doing well, but should he have some sort of testing to know whether he will develop some sort of resistance in the future?
So that’s a very important question, and the answer really is, you know, testing for it now isn’t going to be able to change anything. Right now we would still continue the acalabrutinib until we see signs of clinical progression. There’s some early data emerging from Ohio State where they’re doing PCR testing on all the peripheral blood of patients, on the peripheral blood of all patients to see whether or not they can detect any of these mutations that lead to resistance. The problem is you’re still going to continue the treatment until you see the clinical relapse.
And, two, is you really‑‑you know, in essence when you look at the data that suggests that 92 percent of patients who get ibrutinib as a first‑line therapy will remain in remission at five years you’re talking about treating‑‑or testing a lot of people for very, very few people that will likely benefit.
Okay. So if you have a question now, send it in, email@example.com, and we’ll do our best to pose it to Dr. Furman. Okay.
So Beth with wrote in and wanted to know is there work going on on a CLL vaccine?
So we’ve been playing with CLL vaccines for at least the past 25 years, and a lot of these vaccines were originally designed to be what we call antiidiotype, meaning they were directed against the antibody made by the cell itself. Unfortunately, a lot of those vaccines have not proven effective, and we’ve gone through a lot of different iterations. We’re still trying, and hopefully one day we will have better success.
Right now a lot of our current research is focused on not so much the target that the vaccine should be against but ways to make the vaccine more effective. Things like using PD‑1 inhibitors, which can actually make the tumors more apparent to the immune system. Or using things that can actually enhance the presentation of the actual vaccine to the immune system, and that includes everything from idelalisib and ibrutinib to other different molecules that may actually make it more readily apparent.
Now, we do also have some new targets like ROR1, which may prove to be very exciting and interesting, but this is still all very far away from anything that will be approvable.
Okay. Now, here’s a question we got in from Cerisa, said, my understanding is that most drugs aim at destroying the CD20 protein like rituximab or obinutuzumab, etc.
Well, what about, CD9, CD15, CD23? Are they not as bad as CD20 in CLL?
So the thing that’s really important to keep in mind is only our monoclonal antibodies attack one protein in particular, and so we have obinutuzumab, rituximab, and ofatumumab all of which address or target CD20. CD20 was the first protein targeted for two reasons. One is it’s ubiquitously expressed on all B‑cell lymphomas, and so it’s a way to identify a target that we can actually generate one treatment for that will work in a large number of people.
The second is it’s a protein that doesn’t seem to actually get endocytosed or down modulated so that it remains positive in the cases most of the time. One of the problems with some of the other proteins you mentioned is that they’re not expressed on the CLL cell.
So CD3, CD15, those are not present on CLL cells, but they’re also present on a lot of other cells as well. The key about CD19 and 20 is that they’re only on B‑cells, and we really can actually do okay without our B‑cells. And so that way the down side to knocking an out all our B‑cells is actually relatively minor. And the CAR‑T cells, which are T‑cells taken out and reprogrammed, they’re reprogrammed to be directed against CD19 and 20, so in a way they work like the monoclonal antibodies.
Okay. Lynn wrote in and asked about transplant in CLL, and I’ve met people who have had transplant, so where does transplant fit in now, and does CAR‑T cell experimental therapy maybe supersede that?
One well, one of the things that’s important to keep in mind is that CAR‑T cells are still very novel, and the long‑term efficacy is not yet there, so we still need to do a lot of work to help that.
My belief is allogeneic transplants are very effective but they’re also very toxic and dangerous, and I do believe that they should be avoided if at all possible. So I am very, very selective in who I refer for allogeneic transplant.
With our novel agents like ibrutinib, idelalisib, duvelisib, umbralisib, acalabrutinib, vecabrutinib, zenabrutinib, the list is just rapidly growing, I almost believe that the patient who really needs an allogeneic transplant will only be those patients who have developed or are at high risk of developing Richter’s transformations. So I really do believe there’s a very limited role for allogeneic transplant at this point in time.
Okay. And CAR‑T, you’re watching it.
Okay. Here’s a question that came in from Mike, and this is the bottom line for a lot of people when they’re diagnosed, and he says, what is the current state of treating CLL for those of us watch‑‑he says wait and see patients or watch and wait. In other words, is it curable?
So right now CLL is not curable. The way that I would love everyone to start approaching CLL is very analogous to high blood pressure. So we don’t cure high blood pressure, but if you take a pill a day it’s not going to have an impact on your longevity. And I believe we’re there for about 75 to 80 percent of CLL patients, where they will be able to get a BTK inhibitor or a Bcl‑2 inhibitor or a combination and they will be able to not have to worry about their CLL for the rest of their lives.
There’s still the 20 percent who are going to develop either a Richter’s transformation or a progression on ibrutinib, and those are people we’ve got to figure out what to do differently for. But all the others, even though it’s not curable, we can definitely I think keep it from having an impact on longevity.
People on watch and wait who are high risk of progressing and developing a Richter’s or progressing onto developing resistance to ibrutinib, we do have a couple of trials that are very interesting right now where we’re treating people at diagnosis with BTK inhibitors with the hope, because they’re so well tolerated and because they’re so effective, we might be able to have an impact and prevent those patients from developing resistance or developing a Richter’s transformation.
Wait a minute. So are we looking at what has been the traditional watch and wait period differently now and some people will be treated much earlier?
Well, we’re just starting to look at that right now in clinical trials. So this is very early. It’s for a very select group of people.
We know from the data‑‑so we have seven‑year data coming out at ASH this year where we’re going to have a group of people who were watched and waited and only when they had evidence of disease progression and needed treatment and got ibrutinib, 92 percent of them were still doing well and free from progression at seven years. So for those 92 percent of patients we couldn’t do any better. So it’s really just a very small group of patients who need something extra.
So, yes, we’ve proven I think in a large number of patients that BTK inhibitor therapy might be all that’s necessary, but in everyone else, in those 8 percent we do have studies going on to try to answer how to treat them differently.
Okay. So we got a question early on about somebody who was asking about should he be taking a statin along with his oral therapy for CLL. So people have other conditions. So what about that?
So if you have hyperlipidemia you should definitely be on a statin, otherwise, no, you don’t need a statin. I think it’s important to keep in mind that there was a lot of data generated at one point about statins perhaps changing the CD20 expression on the surface of the CLL cells or making rituximab or other anti‑CD20 antibody therapy more efficacious. I’m not aware of any data that suggests there’s an impact to statins on non‑anti‑CD20 therapy efficacy, and I think the impact on anti‑CD20 antibody efficacy is actually really quite small and unlikely to generate a significant difference. So I really don’t believe there’s a need to do anything outside of just treating your lipids.
I promised our audience weeks ago that I’d ask you about this. So should we have flu shots? Should we have the shingles vaccine?
So, absolutely. Everyone should definitely get a flu shot each year. And it’s important to get the flu shot each year because the immunity doesn’t persist. So I actually recommend people get vaccinated either October or early November. All right? So any earlier than that I worry that you’re going to have your immunity peak before the height of the season, and later than that you may not actually have sufficient time to respond.
Regarding the shingles vaccine, so there’s a new shingles vaccine called Shingrix which is a recombinant vaccine, so it’s not a live vaccine, and that’s how it’s different than the previous shingles vaccine. The previous shingles vaccine was an attenuated or live virus vaccine, and CLL patients really shouldn’t have taken it because it really theoretically could have caused shingles.
Now, the old shingles vaccine was also not very effective, so even though the risk was low with low efficacy there’s really no risk/benefit assessment that puts it in favor of doing.
But the new shingles vaccine actually has been tested in patients post autologous bone marrow transplants, so it’s very effective in patients who are very immunosuppressed, and because it’s not a live vaccine it is safe. So I do recommend it for everyone.
Okay. Dr. Furman, so you mentioned it earlier and we’ve heard about a lot of programs, the 17p deletion and I almost think of it as the dreaded 17p deletion, but is that necessarily true? Pam wrote in, she said, I have the 17p deletion. What are my options? So first of all, are all 17ps alike, and then what are the options?
So the thing that’s most important to keep in mind when we talk about prognostic markers is they’re really just surrogates for clinical behavior. And so the answer always is going to be if you have historical data that’s always going to trump the prognostic marker.
So someone who is 17p deleted and their disease has remained stable for the last five years, their disease is stable, and the 17p deletion is not going to be what drives the prognosis. I think that’s very important because when you look at a curve you’re going to see some people doing well and coming off the curve late and some people doing poorly coming off the curve early. You know, where they are on the curve we have no idea how to predict. All we know is that they’re on a particular curve. So prognostic markers tell us about the population, never about the individual.
Now, with that being said, we do know 17p deletion a lot of it, the percentage of the deletion if you’re above 20 or below 20 does have an impact on how you do overall. So 20 percent and below, they‑‑patients seem to have a better prognostic outcome than the patients who have 20 percent and above.
With that being said, I do have patients who have 17p deletion in 70 percent of their cells and they’re just hanging out doing quite nicely. So clinical behavior does trump everything else.
Okay. So, obviously, most CLL patients are older. I’m 68 now, but I was diagnosed at 45, which is pretty young, but here’s Matthew who writes in he was diagnosed at age 31 and he wonders, he knows a lot of the statistics but he knows it’s mostly older people. He’s trying to figure out, well, what’s his life going to be like. So what do you say to younger patients with CLL today?
So, remember, we’ve only had these novel agents since 2010, and so what I really do believe is that we really don’t know how good things are going to be yet. I think things are going to be a lot better than we ever envisioned, so I am quite optimistic about the future.
We don’t know whether or not a 31‑year‑old could enjoy a normal long life expectancy but if they don’t have evidence of or suggestions that they’re going to have particularly aggressive disease and develop resistance to a BTK or a Richter’s transformation, they could theoretically have 40 years on a BTK inhibitor. And so that’s certainly what my hope is for the future.
You know, all the survival curves that people talk about and all the survival curves that people show really don’t take into account any of the novel agents, and that’s always very important to keep in mind. So we do some have data. As I mentioned, the seven‑year data is coming out from‑‑will be out at ASH, and the seven‑year ibrutinib data really suggests almost a nearly flat curve for patients with CLL who get ibrutinib as a front‑line treatment.
So you mentioned over the years the Rai staging system, and Dr. Rai, the grand old man of CLL.
So how does that apply now? You know, somebody’s diagnosed with CLL, they come across this Rai staging system, but is that meaningful for them today, or are there new ways of looking at it?
So the Rai stage really still drives when we’re going to treat patients. So patients are still treated based on meeting, you know, the classic indications for initiation of therapy. So Rai stage 3 and 4, namely hemoglobin less than 11 or a platelet count less than 100,000, really are the two primary reasons why people initiate therapy. We know that if you watch and wait someone until they meet classic criteria and they have disease that doesn’t harbor one of these high‑risk changes we know that they’re going to do extremely well. So that’s good news. Whether or not patients who have these other markers should be treated before they have aggressive disease is on open question.
Now, what I really do think that’s also important to keep in mind is, you know, the watch and wait ideology really came about when we had therapies that were not very effective and also were quite toxic. Now that we have these novel therapies that are far less toxic and highly effective, maybe the bar should move towards initiation of therapy sooner, but that’s still on open research question and not one that we know the answer to yet.
Okay. And Bob has had the same treatment I’ve had. He had Gazyva or obinutuzumab with high‑dose methylprednisolone, and now that was, gee, about two years ago, and now his CLL has started to show up in his spleen and his lymph nodes. He said, well, can he be treated with the same combination again, or might he move to something else?
Well, that’s going to depend on a lot of factors. Most importantly is whether or not there was, you know, he had received the full dose in which case the likelihood is that with just a two‑year remission I would expect that retreatment would generate a shorter remission this time, and the risks associated with high‑dose methyl prednisolone plus obinutuzumab probably don’t outweigh, or aren’t going to be‑‑the risks are going to outweigh the benefits that would be gained if we’re talking about a response that’s going to last less than two years. So it would probably be better to move on to additional agents. And, fortunately, we have so many others that I think it would be a way to avoid resistance and also develop‑‑avoid, actually, the toxicities associated with high‑ dose methylprednisolone.
Okay. We’ll take just a few more questions, and thank you, Dr. Furman, for sticking with us. And I relate to this one. So I did have the obinutuzumab and rituximab years ago, and I developed sort of a history of sinus infections for a while and even some chest congestion and I’ve seen other people write in about it.
Do we have the sinus or the respiratory issues from the CD20 antibody or is it something else?
So it’s important to recognize that CLL patients, 75 percent of CLL patients will develop hypogammaglobulinemia, and that hypogammaglobulinemia is probably most of the cause of the chronic sinusitis, chronic bronchitis, sort of that‑‑those issues with having the constant drainage. So I do believe that CLL in and of itself is certainly the first factor that impacts upon that.
The anti‑CD20 by itself will also cause a lot of those problems as well, so the two together are just a double hit. But we do know that CLL patients, totally regardless of their prior‑‑regardless of their prior treatments will run into those issues.
Now, with that being said, what people often forget is the most common cause of a chronic sinusitis in anyone, even a CLL patient who’s gotten obinutuzumab, is still going to be a deviated septum, or it’s going to be a blocked sinus channel, so I always recommend and I always insist on all my patients being evaluated by an ear, nose and throat doctor first just to make sure there isn’t something anatomical that could be fixed.
I went to an ENT the other day, and also I’ve been doing‑‑and I know my Dr. Kipps here is urging me, I’m doing the nasal wash and all that stuff, just trying to have sinus hygiene, if you will, working on that.
Okay. Couple more questions. Aukie wanted to know, and we’ve talked about this in the CLL world forever, should he be taking a green tea extract? Is there any validity for that? What do we know?
So my belief is no. I think it’s important that we have a lot of alternative medicines, medicines that have been studied, and until they show evidence clinically I do believe that it’s important to actually stay clear of them, and there are a couple of reasons why.
So a lot of things work in the laboratory, but that doesn’t mean they’re going to translate into working clinically. And a lot of the medications that are sold as alternative medications or homeopathic medicines are unregulated and can make claims that aren’t substantiated, but they also don’t have their products necessarily vetted. So we’ve had a number of examples of people who have been taking a root or have been taking some leaf that’s turned out to be laced with amphetamines. So a leaf that claims to enhance your energy output, absolutely, if it’s laced with amphetamine will certainly be able to accomplish that.
So it’s important to keep in mind that anything that’s made naturally or that occurs naturally doesn’t actually get regulated the same way as pharmaceuticals. There was also a change in the laws in the 1990s where anything that was natural didn’t have to be tested and approved by the FDA, so the claims that they make‑‑like Tony the Tiger can say that Frosted Flakes are great without proving that in a randomized controlled clinical trial. Because it’s a naturally occurring substance it can make claims that aren’t necessarily substantiated. I do worry about that. And there are some definite cases of patients coming to harm from taking medication‑‑from taking supplements that weren’t well regulated.
So, as you know, so many of us complain about fatigue with CLL. What can we do about that? Is there any medication or something you feel comfortable about as a supplement that could help with that? Certainly, we’ve been telling people exercise is a good thing and can give you more energy, but what do you tell your patients when they talk about fatigue?
So this is actually a very common question, and I really do believe it’s very important to remember that having CLL doesn’t protect you from the things that befuddle the rest of us. So the most common cause of fatigue in a CLL patient is not going to be the CLL but it’s going to be the same thing that befuddles the rest of us. So it’s poor sleep hygiene. It’s not sleeping long enough. It’s all those things that really should be addressed first and foremost. So we see a lot of sleep apnea that’s undiagnosed. We see a lot of people who are just not sleeping long enough.
If we’ve ruled out everything else and a patient seems to have progressive disease, yes, there are definitely patients with CLL whose fatigue is related to the CLL, but I’m a big believer that fatigue related to CLL should only be present in a patient who really has active signs of CLL. So if someone is on watch and wait and their lymphocyte count is not changing and their lymph nodes are not enlarged, their fatigue is not going to be related to their CLL.
But if someone’s lymphocyte count’s climbing and their lymph nodes are growing then certainly their fatigue might in part be related to their CLL.
Okay. This has been like being on a game show. I keep throwing things at you. I want to thank you for all your time.
Folks, we’re going to let Dr. Furman go, but we will be doing other Ask the Expert sessions and doing some live broadcasts in from ASH. ASH, you alluded to, Dr. Furman, always has more coming out, more longer range studies, combination information. So just to wrap up with, for those of us living with CLL, and, thank god, so many of us long term, me, 22 years, are you very hopeful that you have more options for us now no matter what our CLL situation is?
I really do. I think we have some amazing options now. We have also the data that our current crop of novel agents really can be safe and effective long term, and that’s what I really think is so important to be cheerful about.
And in those patients who do progress we have a whole crop of other agents that will prove to be hopefully effective in those situations. But I think it’s going to be the‑‑you know, the home run though is going to be the combination of BTK and Bcl‑2 inhibitor therapy or PI3 kinase and Bcl‑2 inhibitor therapy because in those situations I really do see patients getting very, very deep remissions that I hope will be extremely long lasting.
Think about it, folks. I mean, I got FCR, a three‑drug combination, in 2000, 18 years ago, and it worked for a long time. So the idea of combination therapy has worked well in cancer therapy hitting those cancer cells in multiple ways. Dr. Furman, thank you so much for being with us today.
Okay. From Weill Cornell.
And I just want to mention for our audience, remember we’ve got a lot coming up. On Wednesday, November 28, we’re going to understand the ins and outs of watch and wait for those of you who are in that situation. From the big ASH meeting in San Diego‑‑yay, I don’t have to get on a plane to go anywhere‑‑we’ll be also doing live broadcasting so be sure to be signed up for that.
And then on December 5th we’re going to talk about the financial issues because, as Dr. Furman talks about, combining these oral therapies, these are expensive, and so what support is there for you so you get the combination should you need it and it’s affordable. So keep an eye on that. Go to the Patient Empowerment Network’s website, powerfulpatients.org, and take a look at what we have on Patient Power as well. Thank you so much, Dr. Furman. Thanks to our audience and stay tuned for what comes out of the ASH meeting. I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.
Please remember the opinions expressed on Patient Empowerment Network (PEN) are not necessarily the views of our sponsors, contributors, partners or PEN. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.
https://powerfulpatients.org/pen/wp-content/uploads/Dr.-Furman.png600600Kara Rayburnhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngKara Rayburn2018-12-11 20:25:362019-09-02 12:28:38Ask the CLL Expert – Dr. Richard Furman
MPN specialist Dr. Joseph Scandura from Weill Cornell Medicine answers patients’ burning questions.
Greetings from southern California. I’m Andrew Schorr from Patient Power. Welcome to this Patient Empowerment Network program where you can ask an MPN expert your question. I’ve been living with an MPN, a myeloproliferative neoplasm myelofibrosis, since 2011. So, believe me, I have questions and I want answers just like you. I want to thank the Incyte Corporation for its financial support, but tell you, of course, that all the editorial control is our expert and our producers and me. Nobody tells us what to ask or what to say.
Okay, let’s meet today’s MPN expert. Joining us from New York City is Dr. Joseph Scandura. He is with Weill Cornell Medicine in New York City and he is also the scientific director of the Richard T. Silver Myeloproliferative Neoplasm Center at Weill Cornell Medicine. Dr. Scandura, welcome and welcome back to Patient Power. We’ve had you before. Thanks for being with us.
Thanks for having me, Andrew.
Okay, and I should mention that Dr. Scandura is a physician-scientist, so you can see that whiteboard behind him. He spends time in the lab, as well as seeing patients, in-patients, and in clinic. So, he is meeting us, but also working on a cure and we’re gonna talk more about that and hopefully, we can get there. Okay, are you ready for our first question Dr. Scandura?
Okay. So, this one comes from Philip who writes and he says, “I’m a 63-year-old male with PV, polycythemia vera. What does it mean that my blood is too thick?”
What it’s probably referring to, the term too thick is a little bit – can be generalized in a lot of different directions. It’s a colloquial term, not really a medical term, but what people often are referring to there in the context of polycythemia vera is too many red blood cells. If you think of the blood vessels in your body as being highways, they can only accommodate a certain amount of traffic. And you being in southern California are probably aware of this, that sometimes there’s too many people trying to get on the highway at the same time and that slows everything down. You could consider the highways too thick in that situation and that’s what’s really happening in polycythemia vera.
There’s too many red blood cells. There’s about 1,000 red blood cells for every of the white blood cells there, so the most common blood cell type and they occupy about half of the whole blood volume. And when you have too many being produced, they end up causing traffic jams in the blood vessels and that is what people are trying to describe when they’re saying the blood is too thick.
And you’re at risk for stroke and blood clots?
Yeah. So, it has a lot of both short-term and long-term consequences. Short-term certainly it provides a risk of having abnormal blood clots. That can be in an artery, so that could be a stroke, an artery in your brain, or an artery in your heart, a myocardial infarction or heart attack. It can also be a clot in a vein and so these, I’m sure you’ve seen them on TV, the advertisements for DVT or deep venous thrombosis or pulmonary embolism which is usually a clot in a vein that then has broken off and traveled through the circulation and landed in the lung where it can cause symptoms there. And so, the short-term risks of a clot are certainly elevated in people with polycythemia vera when the blood counts aren’t controlled.
Okay. Just one follow up question. Philip was wondering about this too. So, we see ads on TV whether it’s the DVT medicine ads or the blood thinner ads. Does that apply to people with PV?
It can. We treat people with PV to reduce the risk of a clot, but some people are diagnosed with a clot at the same time they’re diagnosed with PV and some people, even with the best of treatment, end up developing a clot. If it’s a clot in the vein, then one of the things that is a standard of care is to administer drugs that colloquially again are referred to as blood thinners. In this context, it has a different meaning and this is a group of drugs that interfere with the blood clotting system. So, these are proteins, not cells, and it’s what – if you ever have cut yourself and you feel just with your fingers, it gets a little sticky between the fingers. That’s actually clotting.
It’s a little bit like Jell-O. It starts out liquid and then it solidifies and that’s what your body does to help prevent bleeding. It forms this sort of polymer fiber that ends up being part of the plug. And what the blood thinning medications, the so-called blood thinning medications, do is they interfere with that process. Either given by injection or given by pill, the ultimate goal is to reduce the formation of that sort of sticky acellular clot. And that’s more of a treatment and can be a preventative for future clots as well, but it’s a little different than what we were talking about before in terms of too thick blood from too many red blood cells.
Too many cells versus the quality of the cells.
Yeah, but not even the cells. A lot of the blood clotting factors are produced by your liver. They’re not from the cells themselves that are floating around in the blood.
Andrew: I’ve never understood that before. So, thanks for explaining. I should also just say one thing about Philip. He shared with us that he has AFib. So, when somebody, and that’s not uncommon atrial fibrillation, does that complicate all the treatment for somebody with PV?
Well, one of the risks with AFib, some of them can be just related to the heart, it can disturb a little bit in how the heart functions and if people have some mild symptoms, AFib can make symptoms worse just from a heart function standpoint. But one of the things that’s related to, again some of the commercials you see on TV and the rationale for blood thinners, is the heart – the atrium, the left atrium which is really what fibrillates, which is just – normally the heart is pumping like this, all together coordinated. And what fibrillation means is it’s sort of not doing that. It’s going like this and what happens is the blood and the surface of the heart ends up not being pushed out normally.
And sometimes actually clots can form on the surface of that fibrillating heart and then when they get pushed out, they can travel. And because it’s usually the left atrium where this happens, when they travel they go into the arteries and then they can form clots and that can be stroke is the big thing people worry about. So, you can have atrial fibrillation that puts you at risk for stroke and that’s why people think about anti-coagulation medications to prevent that risk. And so, again, that’s another rationale for blood thinner, although it has nothing to do with the blood being too thick. It has to do with atrial fibrillation itself.
Okay. So, two things going on. Here’s a question we got in from Julie. Julie says, “What is the significance of a very low allele burden in a JAK2 positive patient?” And may you could define allele for us too.
Sure. So, as you know, we have some of our genes from mom and some of our genes from dad and the genes that we get are always in these two copies. And so, one copy from mom, one copy from dad, and they’re mixed and matched while we’re being sort of grown up from the embryo. But what happens in MPN is sometimes one of those copies, always starts with one of them, becomes mutated and that can be for instance, in the most common mutation, in the JAK2 gene, JAK2 V617F, a particular mutation that’s associated with abnormal function of the JAK2 gene product. And so, if we have just one copy in a cell, then one copy’s normal and one copy is mutant.
So, if we are talking about that one cell, that variant allele frequency, so that’s the abnormal gene. The proportion of all the genes that are abnormal would be 50%. Right? One abnormal, one normal. But now we think about all of the blood cells, trillions upon trillions of blood cells and then we have to take sort of an average of all of those cells. Some of them will be normal, some of them will be MPN cells, some of them will have one copy normal, one abnormal, some two abnormal, and some both normal. And so, when we look in a composite from a blood draw which is generally what people are sending, it’s a representation of how many abnormal alleles are present among all of the alleles of all of the DNA from the blood cells that’s been selected.
So, what a low variant allele frequency means that the proportion of mutant alleles in that sample of your blood is low. So, low would be maybe 10% or 5% or something like that and what is the significance of that? It’s an area a little bit of some debate, but there’s certainly a number of studies that have shown a correlation between the variant allele frequency in blood and the disease type itself. So, for instance, essential thrombocythemia, or ET, generally has a lower bearing allele frequency than myelofibrosis for the same mutation. And polycythemia vera is often in between.
While we’re talking about genes, I just wanted to bring in this question from Jocelyn because we’ve been learning are we JAK2 positive, are we CALR positive, these others that you’ve been discovering. So, Jocelyn said, “In 2006 I tested positive for JAK2 V617F. In 2018 I was told that I’m not JAK2V617F positive, but that I’m CALR positive. So, is it common for mutations to change and what does it mean?”
So, it’s not common for the mutations to change in terms of going away if they’re present, although there are certainly examples of this happening. It’s not common. What is probably a little bit more common is sometimes people have one mutation or a couple mutations and then sometimes more mutations are found later. And that often, not always, is linked to the disease changing its character itself. So, somebody with polycythemia vera having more of a fibrotic phase of the disease. In this situation, it’s a little hard to know exactly what happened, but there is a fair amount of variability from one laboratory or one test type to another in terms of sensitivity and the specificity of what is being detected.
So, JAK2 may have been at a very, very low level, could have been an erroneous measure, or it could have been at a relatively low level and the calreticulin mutation wasn’t tested for. And then later somebody retested with a different test that wasn’t sensitive enough to pick up the JAK2 mutation and they looked for a CALR and now that’s coming up positive.
So, the testing modality, the type of test that’s being done, and its individual sensitivity is an important part of this story and it’s a little hard, I think even for many physicians, to sort of get their heads around because it’s not like a blood count where you have international standards and basically a half-dozen equipment makers everybody uses across the world. There’s a lot of different technologies, each of which have little wrinkles to them that can limit somewhat exactly what’s being reported.
Okay. Here’s another one we got. This was actually asked by several people. Nick, Maggie, and Philip all want to know related to phlebotomy. What are the goals of phlebotomy as a treatment and how does it work and when do you know when it’s time to switch from phlebotomy to medication?
Right. So, I just came from a conference the end of the week and this is a topic of debate among physicians. When, whether to do phlebotomy? Whether phlebotomy therapy by itself is sufficient? What are the alternatives and when to make those decisions? I would say, I can tell you what my own feeling is. I feel that there is good support to justify that, but to be totally honest, there are physicians who feel differently than I do and I don’t know if any of us can claim to be absolutely correct. But I think we can all agree that the goal of phlebotomy in the short term is basically to take cars off the highway.
If you go back to the analogy of having too many cars on the highway causing thickened blood or this sludging from the red blood cells, this is a therapy specific to polycythemia vera, is that phlebotomy is just a very simple way of taking blood out of the system, taking cars off the highway. So, if you were to imagine and I frequently imagine this in New York City, is all of the sudden a third of the cars disappeared, it’d be a lot easier to get around. And so, that’s really what the goal of phlebotomy is, is to make it a little easier on your body to pump the blood around because there’s less resistance to having all that traffic in the vessels. How much? Go ahead, you had a question.
I was just gonna say, but debate about when to leave phlebotomy behind and have medication try to do the job when you prove one or others that may be coming.
So, I think the first goal is to get people under what would be considered control. So, an adequate level of traffic. And the numbers that are generally accepted by people in the field is having a hematocrit, that’s the portion of blood occupied by red blood cells, in males it’s below 45% and in females below 42%. Although we can all argue about that a little bit. I think people settle down around those numbers.
When is too much? My personal feeling and this is where there isn’t great data, so you’re left with opinion, but my personal feeling is it depends a little bit on the patient, the convenience, and I find that people who are getting phlebotomy more than four or five times a year, it ends up being a real burden on them in terms of the amount of time that they’re having, poor control of their polycythemia vera, and the amount of time required for phlebotomy, and the amount of risk of things like iron deficiency which can cause symptoms.
And then there’s some suggestion, I wouldn’t say great data, that maybe iron deficiency or repeated phlebotomy may be a risk in the long term, although I think that data is not very clear. My biggest determinant is patients, in my experience, just get a little fed up with getting phlebotomy when it gets above four, five, six times a year.
Okay. Thank you for that. I should mention to our audience again if you want to send in a question, whether we can use it on this program or a whole bunch we’ll be doing coming up, send it to firstname.lastname@example.org. Okay, so here’s a question we got from Nick and all of us wonder about it. How often or do we need bone marrow biopsies so that you, as our doctor, and we are well informed about what’s going on?
So, another area where there isn’t – you know, in medicine we look for the perfect data. We’ve controlled – we treated one group of very similar patients one way, we’ve treated another group of people another way, and we compare and see who does better. What’s the better approach? This hasn’t been done for how often to check bone marrow. I think bone marrow evaluation is very important. Personally, I generally follow how the patient is doing as the primary determinant and if there are any signs that something is changing. And those signs can be how the patient is feeling, new symptoms that are arising, but oftentimes it can be just in how the blood counts are responding.
You’re on a stable dose of a medication for several years and all of a sudden it stops working or all of sudden it starts working too well. You have very low blood counts whereas before you were okay. That suggests to me something’s changing. The bone marrow is the factory for all the blood cells. So, if you wanna know what’s happening with the production in the factory you really have to look into the factory and see what’s going on. And so, that’s my personal threshold for doing a bone marrow, when I’m seeing something that’s suggesting that the factory is not functioning the way it was the last time I looked.
Okay. And for those of us who’ve had many bone marrow biopsies, and I have, hopefully where it’s done is someone who does it frequently. Usually, the anxiety we have is worse than the exam itself. It takes 15, 20 minutes, whatever and someday I’ll tell you the story of the lady down at MD Anderson who believed in voodoo and talked to the bone marrow as she was pulling it out. And it was so weird, that I was so distracted, I didn’t feel a thing, but anyway I understand it’s important.
Here’s a question that will help our friends with ET. This is from Michelle. She says – well actually now she has post-ET myelofibrosis. She says she has ASXL1 and TP53 gene mutations. Does the mere existence of these predict aggression and poor outcome? That’s what she worries about that those have been found.
Well, obviously every individual has their own history that they’re developing and so exactly what this means for you, for an individual, is different than what it would mean for a population of people with similar mutations. That’s really what we know in medicine. We look at people in a cross section and we say people who we can put into this bin tend to behave in that way, but within that bin, there are individuals who don’t act that way, the way that the others do. So, I would in myelofibrosis, in MDS, in polycythemia vera, P53 mutations are an area of some concern, as is ASXL1 mutations are also an area of some concern.
In ET it’s less well established and so I think because, if this was just ET and you had those mutations, I think many people, myself included, would say well, maybe we don’t know perfectly, but it is an area of some concern. I’m gonna keep a closer eye on you. Now that it has already evolved into myelofibrosis, I would say this is probably more like myelofibrosis where we know that P53 mutations, TP53 mutations, and ASXL1 mutations, can sometimes be some of the harder ones for us to treat. It’s something that, if an allogenic transplant is something that is possible, should at least be considered and discussed.
It doesn’t – speaking with a transplanter, getting typed doesn’t mean you have to get a transplant, but it gives you information and so I think that that would be a reasonable thing to do. Again, the decision at the end, it may not be the right decision for you, but it is something that is information for you to use in making informed decisions.
Right. I did have a consultation with Dr. Castro, who was at the time here in San Diego, exactly about that. Not to take action, but just to have the relationship and be typed, et cetera. Here’s a question we got from Paul. He says, “I was diagnosed in 2009. I take a weekly dose of 90 mg of interferon. How long can a patient continue to take interferon and what indicates a move to change treatment?”
So, we have people who have been treated for 20 plus years with interferon. So, I don’t know if there is a known duration which is too much. For many patients it’s a very well tolerated therapy, can be quite effective, and I think that it is one of the few medications that seems to have some disease-modifying activity. However, when to change? If it looks like it’s not working, it’s time to think about changing and that can be adjusting the dose, but I think if somebody has been on it for a long while, that’s when I think thinking about additional therapy, either adding another medication to the interferon or changing completely to a different medication.
Clinical trials, there’s a lot of activity in MPNs in clinical trials. Thankfully, over the past five years or so, it’s really been increasing. There’s a lot of options. There’s some drugs that we’re really pretty excited about right now in terms of thinking they might have some nice activity and talking to somebody about what might be a suitable treatment for you if the interferon was not working anymore.
Okay. Here’s a – again we’re getting similar questions from a number of people. So, Ragita, Nankin, Raven if I’m saying the name right, and Jacquelin sent in basically this question. How common is it in patients with MPNs to have bone pain? What causes it? Is there anything that can help with the pain?
So, bone pain is always on the list of symptoms reported by patients with myeloproliferative neoplasms. I wouldn’t say, in my experience, it’s one of the more common ones. It might be a little bit more common early in disease. Sometimes things like phlebotomy that you can actually have a rebound where the bone marrow is a little bit revved up to try to replace all those cells that were taken out, that can cause some bone pain. It can be seen in myelofibrosis occasionally and sometimes when the disease is becoming more aggressive or is having a – changing its pace. But the cause of bone pain, we think of as being related to sort of expansile pain.
So, the bone marrow, the factory for all the blood cells, sometimes is just working so hard that it causes, it irritates the bone fibers that are around the surface of the bone. There’s very little in the way of pain fibers inside the bone, but on the surface of the bone you have a lot and that expansile pain, that gives that sort of vague, achiness people often describe as bone pain. The treatment for bone pain in some ways is determined by what the cause is. If it’s just, for instance, a rebound after phlebotomy, it can last a day or two and then go away. And so, short-term symptomatic treatment with non-steroidal anti-inflammatories, NSAIDs like Motrin, can be helpful or Tylenol even.
But occasionally patients report a real benefit from things like histamine blockers which the mechanism for that is entirely unknown, but there’s certainly a population of patients who feel like the bone pain has gone away with medications like Claritin you can get over the counter. It’s worth a try. They are very well tolerated medications and not all patients have any symptomatic benefit, but a subset of people do. If the bone pain is related to the cells being too active, a very proliferative feature of the disease, sometimes it dictates treatment.
So, if you were on phlebotomy alone, well maybe it’s time to change to a more cytoreductive therapy and see if that can help with the pain. Sometimes it prompts additional evaluation. If you’ve never had bone pain, all of a sudden the blood counts are a little different, you have bone pain, it might be something somebody would think about doing a bone marrow evaluation for. Again, looking in the factory which is probably where the cause is coming from.
I have a couple more topics I want to cover just before we close. We’ll go just a little bit longer if that’s okay. So, Robert wrote in and said, “How does a stem cell transplant cure myelofibrosis?”
So, I’ll go back to that factory analogy. If you think of the bone marrow as being sort of corrupted by these MPN cells. You have, normally this is a very orderly factory. It’s producing a number of different lines if you think of it as a car factory. You can be producing red blood cells maybe your sports cars, and your white blood cells, your infection-fighting cells, as sedans, and platelets as SUVs, but it’s all very orderly and it should be proceeding in a regular way. And you get MPNs and somebody has just turned up the volume and are just cranking out a lot of cells. And sometimes that production starts becoming abnormal too and that’s more like in a myelofibrotic setting.
And so, what is the point of a stem cell transplant is really to clear out that factory, get rid of all the workers in there, and replace them with completely different workers to come in, set up shop, clean up the factory, and start normal blood cell production. There’s another part of it is, it’s not just the blood cells, it’s actually the immune system. And so, you’re giving the recipient an entirely new immune system. You have to wipe out the old immune system to allow the new donor cells to get a hold in the bone marrow and then they have to be educated to sort of relearn how to fight off infections and to figure out who is who.
So, graft versus host is one of the complications where those cells from another person come into the recipient and say, “Ah, I don’t know you. I’m going to attack.” And so, that can be a problem. It can be a short-term problem. It can be a long-term problem. It can be mild and it can be severe, but there’s another edge of that sword which is what we think of as graft versus leukemia effect, or in this case it would be graft versus MPN effect where some of those donor cells recognize the little differences between them and the MPN cells and wipe them out. And so, that’s really what you’re trying to do is allow that new immune system to find the bad actors and wipe them out.
Okay. You touched on something I think we’ve got to ask about and that is people are hearing in the blood cancers now the experimental and in some cases an approved approach called CAR-T, chimeric antigen receptor T-cell therapy, but again immunotherapy to train the T-cells to fight your ailment. What do you think about that in MPNs? Does it have promise?
I mean, it definitely has promise. It’s been a challenge in myeloid disease as a whole, so AML, MDS, MPNs have not been the first diseases where this has been shown to be successful, more lymphomas where it has had a lot of traction and some nice responses. What it really is it’s a living drug and this can be done in a couple different ways. They can be cells from yourself that then are treated in the laboratory so that they start recognizing these immune cells. You start tricking them into saying, “I’m going to attack this particular thing.” Even though they weren’t really trained to do that, they are now being tricked into doing that.
And so, in a disease like a B-cell lymphoma, most of them express a particular protein that’s on B-cells, CD19. So, if you take these CAR-T cells and you say, “Well, go out and kill everything you see that has CD19 on it”, it will wipe out a lot of those lymphoma cells. In myeloid diseases like MPNs, it’s a little harder. The targets are not so clear-cut and they’re shared with normal cells. There’s one area where I think it has the most promise is calreticulin because the mutation in calreticulin isn’t a tiny little mutation. It’s a mutation that causes a whole new end of the protein that doesn’t exist in the body otherwise.
And some of the calreticulin actually gets onto the surface of the cells so it’s displayed to the immune system, and so this is an area where I think there’s some promise for CAR-T cells to target those calreticulin mutant cells. There may be other targets as well and I think we’ll learn as time goes along. People are trying to target molecule CD123 which is expressed on certain abnormal stem cells. The problem is it’s expressed at relatively low levels on those cells. It’s also expressed on normal cells and it’s expressed at higher levels on much more common cells. So, it makes it a somewhat imperfect target, and also difficult from a drug standpoint because there’s a lot of people wearing the same mask, only some of them you want to kill. So, it can be a problem.
Okay. You have quite the analogies. But, I’m just gonna ask you about two more questions and then we’re gonna have to go. This came in from Linda who says, “I am CALR positive and I have many symptoms. What causes vision symptoms for me and migraines? Can that be tracked to the CALR somehow?”
It’s common in a subset of people with MPNs. Sometimes it’s linked to the platelets themselves, to the white blood cell count, so I would certainly unless there’s a reason not to try aspirin, that’s something that can help with patients. It may also be an indication for cytoreductive therapy, so actually trying to lower the blood counts. I don’t know exactly what disease that Linda has, but it’s one that I would think is a symptom that would warrant therapy because it can be quite bothersome.
The vision changes is something that may be related to the migraines, but it’s also something that might prompt a visit to an ophthalmologist so they can actually look at the blood vessels in the back of the eye and sometimes what happens is you can have a little irritation of the blood vessels or even clots in those blood vessels and that’s something that would definitely trigger a change or new therapy.
Dr. Scandura, our audience is saying, “Please, one more question, one more question.” So, if I can a couple more. Philip said, “Is iron deficiency a new normal if you have PV and you’ll, therefore, have weakness, fatigue, maybe even some cognitive issues because of anemia as well?”
Yeah, so I sort of fall in the camp, as I mentioned before, there’s some debate in the field and I sort of fall in the camp that if you’re getting symptoms from iron deficiency, it might suggest that something other that phlebotomy could be beneficial or could relieve that symptom. Everybody, if you take enough blood out of them, is going to become iron deficient and, in fact, most people diagnosed with polycythemia vera, if tested, actually meet the criteria for iron deficiency, not because they actually don’t have enough iron in their body, but because all of the available iron is soaked up in making red blood cells. Red blood cells are red because of iron.
So, if you think about all of the iron in your body and all of the places it’s used for metabolism and everything else, there’s a lot of enzymes that actually use iron as part of their catalytic site. A large proportion of all of the iron in our body goes to making red blood cells. In polycythemia vera, that regulation is completely abnormal and you end up just making a lot of red blood cells that aren’t needed and it soaks up all the iron. Then when you start doing phlebotomy, you’re taking all of that extra iron and you’re taking it out, but the bone marrow still wants to try to make red blood cells. So, it continues to scavenge as much of the iron as it can.
So, iron deficiency is pretty common and if you need a lot of phlebotomies it’s universal. Some patients, in my experience, meet all the criteria for severe iron deficiency have very little in the way of symptoms. Others meet criteria for mild iron deficiency, but they’re quite symptomatic. And so, in those instances, you need to individualize a little bit. At least give a try to a different therapy and allow the iron stores to normalize and see if that improves the symptoms.
Okay. You used the word individualize and that’s where I wanted to wrap up. So, you alluded to earlier, that you were encouraged by new medicines coming for MPNs and you have your whiteboard behind you where you’re charting things and I hope, Joe, coming up with a cure of tomorrow for all of us. How encouraged are you in the near term and the longer term for beating back or even curing these diseases?
I think we’re gonna cure these diseases, I do. I don’t know if it’s gonna be this year, but I think that the number of tools we have to understand how these diseases work and the number of new drugs that are being developed that have real promise, like real mechanistic reasons why they should work, I think is going to yield, reap rewards over time. People have heard this for a long time. The war on cancer has been going on for a long time, but I think we didn’t have the tools that we have now for that entire duration. Right now, we can sequence a genome in a week of a person. Now, do you need to do that? No, but it allows you to get a level of information that was in the past, really just fantasy world, science fiction, and now it can be done on a routine basis.
There are, virtually all of our patients, have sequencing for 40 plus genes. It allows us to know a little bit more about what their risks are, and also gives us a spectrum of targets to start hitting. There’s models that are better than what we’ve had in the past for many of the cancers that have been targeted. Breast cancer models, you know, there’s some decent breast cancer models, but they’re very complex tumors. MPNs, for better or for worse, if you look at the spectrum of genetic complexity, they’re really pretty simple meaning that they have one to half a dozen mutations.
Now mutations aren’t the whole story, but it’s a good starting point and if you only have maybe 10, 15 genes that are currently mutated in a disease, it’s trackable. You can figure this out. You can figure out what they’re doing to allow them to win and once you know that, you start figuring out how to beat them back. And so, I think that their time is gonna come. I don’t know if it’s this year as I said, but I think it’s definitely doable.
You know, CML, when I was a kid, when I was in medical school my parents had a good friend with CML who died with CML. Now, it just wouldn’t have happened. He would have been fine, but he was on, for a long time, ineffective therapy, transformed to an acute leukemia as they all did, and then it becomes really untreatable. And now we have these magical drugs, semi-magical drugs, that for the vast majority of people just – it’s a pill a day. It’s amazing.
Well, you’ve got that work on your whiteboard and in the lab and your colleagues around the world and you had told me before the program started that you all are collaborating better now than ever before. So, Dr. Joseph Scandura from Weill Cornell in New York City, thanks for what you do as a physician-scientist and thanks for spending time with us today.
It was my pleasure and thanks for helping patients through what is a difficult ordeal I think in terms of adjusting to a diagnosis and getting information.
Well, thank you for joining us and Weill Cornell folks have been great and send our best to Dr. Silver too. He’s in his 90s and still going strong.
Yeah, he’s traveling today.
Thank you so much for being with us for this Patient Empower Network program. Thanks to Incyte for helping fund our series. We appreciate their commitment to the MPN community and as always, I just sign off by saying I’m Andrew Schorr and remember, knowledge can be the best medicine of all.
https://powerfulpatients.org/pen/wp-content/uploads/scandura-1.png600600PEN Editorial Staffhttps://www.powerfulpatients.org/pen/wp-content/uploads/New-Logo-300x126.pngPEN Editorial Staff2018-11-16 19:27:082019-09-02 12:28:34Ask the MPN Expert – Dr. Joseph Scandura
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