Conversations with Cancer Experts Series
Myelofibrosis
Dr. Stephen Oh, MD PHD
Associate Professor of Medicine
Co-Chief Division of Hematology on Myelofibrosis
Washington University School of Medicine
Dr. Stephen Oh, MD PHD
Associate Professor of Medicine
Co-Chief Division of Hematology on Myelofibrosis
Washington University School of Medicine
SPEAKERS
Steven Oh, Ravi Vij
Ravi Vij 00:02
Hello, my name is Ravi Vij. I'm from MyCancerHaven and I'm here today with Dr. Steven Oh who's Co Division Chief and Associate Professor of Medicine. here at Washington University School of Medicine, one of the leading names in the myelofibrosis field. And someone who has done a lot in the way of clinical trials is also a brilliant scientist who does laboratory work. So he brings both the perspective of clinician and a laboratory scientist. We're glad to have him. Welcome, Steve.
Steven Oh 00:36
Thanks, Ravi. Pleasure to be here.
Ravi Vij 00:37
So, Steve, can you tell our audience as to what is myelofibrosis? It's, it's something that not too many people often probably have heard of till they have to deal with this issue.
Steven Oh 00:50
Absolutely. So yeah, this is a term or a disease that I think most people probably aren't familiar with. And unfortunately, they or a family member may be diagnosed with myelofibrosis, but the name as as you can see, with fibrosis, in the name is really characterized in large part by this abnormal scarring of the bone marrow, this fibrosis that occurs and it is part of a umbrella of diseases called myeloproliferative neoplasms or MPNS.
So myelofibrosis is one subtype of NPN. And then MPN is, of course, a group of clonal blood diseases or blood cancers that are, you know, again, within that broader round of blood cancers or hematologic malignancies, but the the the primary characteristic feature of this disease, again, is the scarring and the bone marrow that relates to abnormal blood cell production that is characteristic of this disease.
Ravi Vij 01:56
So is all myelofibrosis something that happens all of a sudden, or is it something that you can look out for?
Steven Oh 02:05
Yeah, they are kind of two common paths to a diagnosis of myelofibrosis as shown on this slide. So, you have primary myelofibrosis, which means that there was no prior history of a blood disorder, that it not necessarily just came out of nowhere or came suddenly, but that there again, there was no preceding history of unknown blood disorder that then led to myelofibrosis that can occur in many cases with myelofibrosis.
But then in other situations, patients may have a prior history of a blood disorder, such as polycythemia Vera or Essential thrombocytopenia. And then over time, that disease then progresses and developed into myelofibrosis. So what we call secondary myelofibrosis, or post Poylcythemia Vera, or post Essential Thrombocythemia myelofibrosis. In those cases, for instance, with Polycythemia Vera, or Essential Thrombocythemia, at that stage, the blood counts are usually elevated.
In the case of polycythemia, very high hemoglobin, too many red blood cells, or in the case of Essential Thrombocythemia high platelet count. And then over time, typically over the course of a number of years, the counts may begin to drop. And then oftentimes anemia will develop and then that's when the secondary myelofibrosis occurs.
Ravi Vij 03:27
So how much of it is primary and how much secondary?
Steven Oh 03:31
So I think it's roughly roughly equal. There there, you know, it's very common to see either either scenario, we think of the post Polycyhemia Vera or post Essential Thrombocythemia, myelofibrosis. Again, it's something that occurs after having one of those blood disorders for many years. So it takes time for that to develop. But if given enough time, the risk of that is not insignificant. But again, in many, many cases, primary myelofibrosis, without a history of a prior blood disorder can occur.
Ravi Vij 04:07
How common is it?
Steven Oh 04:09
That's relatively rare. You know, as the slide indicates, it sometimes can be a little challenging to pinpoint the exact incidence because getting to the diagnosis can sometimes be a little bit of a process. But, you know, through the course of various studies, the incidence is roughly estimated at about one to two out of 100,000 people. So it's not super common.
It is nonetheless something that in particular, as we have fortunately been able to develop newer therapies, it has become increasingly recognized. So if you go back, say 15 or 20 years ago, I think it would be considered even more unusual or unfamiliar to most hematologist nncologist. These days, although it's still it's relatively uncommon, I think there's an increasing recognition of this specific disease entity, again, in part because we have newer therapies available
Ravi Vij 05:01
And so what causes it?
Steven Oh 05:04
So at its root, like most blood cancers, we think that myelofibrosis is largely driven by mutation. So changes in the DNA that we think usually arise in a primitive stem or progenitor, so that again, start the disease process off. And in the case of myelofifibrosis, the most common mutation is in this JAK-2 gene JAK V617F, that occurs in about 50 to 60% of patients with myelofibrosis, and in the remainder of the 40, or 50% of patients who do not carry the JAK-2 mutation, either mutations or in MPL, or CAL-R, are present in roughly 30 ish percent of patients with this disease, so the majority of patients will have either JAK-2, MPL or CAL-R, that that contributes to these, say, 80 to 85% of patients with myelofibrosis. And then the remaining 15 ish percent are what we refer to as triple negative. Again, JAK-2, MPL and CAL-R are negative, and they have some other genetic alteration that we think is responsible for causing the disease.
Ravi Vij 06:10
So when you say genetic, a lot of patients ask, is this something that runs in families is that what do you mean?
Steven Oh 06:16
So this can be a little bit confusing. So on the one hand, we know that these mutations JAK-2 MPL, and CAL-R, they're not the kinds of mutations that that are passed down, say, from parent to child, unlike and some other diseases where that certainly is the case, we think that the mutations are acquired at some point in the individual's lifetime. So that's, it's an important distinction. A parent who has one of these mutations and has this disease, they're not necessarily going to transmit that mutation to their children.
That said, we do know that there is an increased risk in family members. That said it's not, super uncommon to see a patient where another family member may be affected with either the same disease or a similar disease. And so we do know that there is an increased risk, but we have to understand that that increased risk is on the order of maybe two to four fold higher, than a non relative. And so that is an increased risk. But when we come back to that incidence being about one to two out of 100,000, if you multiply that by two or four, now you're talking about, you know, say a three to five fold increase, or three to five out of 100,000, the risk of developing myelofibrosis.
So, yes, the risk is higher amongst family members, but it's still overall is quite low. And for that reason, when we talk about this particular question, with patients and their families, we do not recommend any particular special screening tests for family members, because the risk is still relatively low.
Ravi Vij 07:57
So what are the symptoms that you commonly encounter in your patients with myelofibrosis?
Steven Oh 08:03
So patients with myelofibrosis can experience a variety of symptoms. You can see the most common symptoms on this slide, I want to also just explain that some patients with an initial diagnosis, they actually have relatively mild symptoms, they may feel well overall, maybe have a little bit of fatigue, in particular related to anemia. But some patients, they overall feel pretty good.
Unfortunately, some patients are on the other end of the spectrum, and they have many of the symptoms listed on here and some cases to the point which they become debilitating. So fatigue, and that can be fatigue related to the disease, and it can be fatigue related to anemia. So both of those things are factors that contribute to fatigue. In patients with myelofibrosis, we know that it’s very common to have an enlarged spleen, typically at least mildly enlarged, in some cases quite substantially enlarged.
And because of the enlarged spleen that can cause symptoms, including abdominal pain, and it can affect the appetite. So what we see commonly is when the spleen is particularly enlarged, patients describe that they feel like they fill up very quickly when they eat a meal. So they take a few bites, all of a sudden, they feel full, and they really cannot eat more at any given time. So that's what we call early satiety, which is directly related to an enlarged spleen.
The patients may have bruising, or bleeding, in part related to low platelets, that's that may occur in the course of this disease. They also may have night sweats. So in some cases, patients have night sweats that cause them to wake up and their shirt is soaked and they often will have some degree of weight loss. So it's not uncommon to have a patient who comes to see us for evaluation and they've lost maybe 20 or 30 pounds because of this disease. So they can have a lot of symptoms. Again, not every patient has severe symptoms, that initial diagnosis, but certainly some unfortunately do.
Ravi Vij 09:58
How do you diagnose it?
Steven Oh 10:01
So really to make a diagnosis of myelofibrosis, this does require a bone marrow biopsy. So this is a standard part of the workup. Now the initial tip-off is usually based on the patient's symptoms, and their bloodwork, typically showing anemia and other abnormalities in the blood counts. But again, to make the diagnosis, you really have to do a bone marrow biopsy. And then you look at the bone marrow, and you're looking to see if, if that characteristic fibrosis or scarring in the bone marrow is present, that really distinguishes myelofibrosis, from most other types of blood cancers. There are certain situations where you can see a little bit of fibrosis in the setting of other types of blood cancers, but really, that is the characteristic finding of this disease.
Ravi Vij 10:44
And I know we talked a little bit about genetic testing a few minutes ago. So you also look for certain genetic mutations.
Steven Oh 10:52
Yes, absolutely. So testing for the three mutations that I mentioned earlier, JAK-2, MPL and CAL-R. That's more or less standard testing for this disease. So that testing can be sent on a bone marrow biopsy sample, it can also be sent from peripheral blood. But that is considered in this era, pretty much standard workup for this disease.
Beyond that there are there's a long list of other mutations that can be tested for. Some more extensive genetic profiling can be considered. It's not necessarily mandatory. But we do find that it adds additional information not so much about the diagnosis, but it does provide information about prognosis. So there are certain mutations where if they're present, we know that they're what we consider what we call high risk mutations, meaning that they increase the likelihood that the disease may eventually transform into acute leukemia, and they also have some impact on overall survival or lifespan after diagnosis so that that kind of testing can be done again, it's not necessarily mandatory, but JAK-2, MPL, CAL-R, for sure, plus or minus other mutations.
Now, we also look at the chromosomes as part of the standard workup of the bone marrow biopsy. This gives us an idea there are big changes in the structure of chromosomes. This can be identified by standard, what we call carrier typing. And then also FISH testing, where you have probes that bind to specific regions of the chromosomes to help identify if there are big abnormalities in the chromosomes. There are certainly known chromosomal changes or alterations that can occur with this disease, most commonly though their chromosomes are normal. It's really the genetic mutations that define this disease.
Ravi Vij 12:38
So like any cancer, I guess, we have to stage it or risk stratify it. So how do you do so? In the case of myelofibrosis, how do you know who's likely to do better? who's likely to do a little worse?
Steven Oh 12:53
Yeah, absolutely. So the first thing that I think is important for patients is, if they're more familiar with, say, other types of cancer, like breast cancer, or colon cancer, or lung cancer, typically you think about staging as a 1,2,3,4 kind of staging. That's the common staging terminology that's used for solid tumors. In the case of myelofibrosis and most of the heme malignancies, it's a little bit different.
So you know, we think, of course, this disease originating in the bone marrow. The abnormal blood cells are trafficking throughout the body. So it's not necessarily relevant to think about staging in terms of where in the body the disease might be. Nonetheless, we do certainly look at different factors that give us the ability to create different staging groups are based on prognosis.
And this is based on a variety of different features, and also utilizing a variety of different prognostic scoring schemes that have been developed over the years. So typically, these systems will take into account symptoms, enlarged spleen , presence of anemia or thrombocytopenia. We know that low blood counts, anemia and thrombocytopenia, in particular, impact the overall risk status and the prognosis.
And more recently, these risk stratification schemes are taking into account the mutations. So I mentioned earlier that there are specific mutations that we know are associated with higher risk. And so some of the more recently developed prognostic scoring schemes take into account presence or absence of these so called high risk mutations and the all that information is used to give us an understanding of what is the overall outlook in terms of overall survival, meaning, how long would we expect the patient to live after the diagnosis? And then also the other potential concern being: Is there a chance that disease would progress to acute leukemia at some point and the relative risk of that occurring over time?
Ravi Vij 14:59
How do you treat myelofibrosis?
Steven Oh 15:02
So as the slide indicates, first and foremost, there are supportive care measures that can be helpful. So for patients who are severely anemic blood transfusions may be necessary and appropriate. So this is something that can be arranged through most, you know, cancer treatment centers. And some patients will need to come in for transfusions every once in a few months or as often as every three or four weeks. So that can be arranged if needed.
And of course, you could, you could ask: well, are there ways to ameliorate the anemia to improve it so you don't need transfusions? And absolutely, that's something that we would be hoping to achieve, and there are various strategies can be explored to attempt to achieve that, including giving agents that stimulate red blood cell production. So what we call ESA, erythropoietin stimulating agents such as darbapoetin, or other forms of erythropoietin. So that hormone that stimulates red blood cell production, you still give a little bit extra, and try to stimulate the bone marrow to produce more red blood cells. Now, that can be effective to a certain extent, but the reality is that because of this abnormal scarring, and the abnormal function of the bone marrow, it's not really producing blood cells normally, so there is a limit to how effective that can be.
Now, the biggest advances in terms of treatment options for patients with myelofibrosis in the past decade or so have been the development of JAK inhibitors. So these are drugs that have specific activity against JAK-2. I mentioned earlier, this JAK-2 mutation that's common in this diseases. And in those patients that have other mutations, we know that the JAK-2 kinase is over activated. So the these drugs will target that JAK-2 what we call a targeted therapy specific to JAK-2. They are called JAK inhibitors because they often will hit other JAKs as well JAk-1 or JAK-2, to different extents.
So, the first JAK inhibitor that was approved which was in 2011, for myelofibrosis was ruxolitenib as listed here. And now that you know, this agent has been in use for for many years, and we know from experience and from the literature that Ruxolitinib tends to be very effective in terms of ameliorating symptoms and reducing the enlarged spleen. So it's it's quite common for patients who are having night sweats and poor appetite, weight loss, poor energy that these things will improve with treatment with ruxolitenib. And so for many patients, this is very, very beneficial, Ruxolitinib will not necessarily sort of fix the abnormal blood counts. So if patients are anemic, it's not going to fix that, not going to put the disease into remission, but nonetheless, it can be very, very effective, in particular, in terms of improving symptoms.
Now, more recently, in the past several years, now three otherJAK inhibitors have been FDA approved. So fedretinib, pacritinib, and very recently momelotinib. These are all similar to a certain extent in terms of being Jak inhibitors, but they also had some distinctions that make their use, perhaps relevant and specific scenarios. So for instance, pacritinib in particular, is thought to be useful in patients very low platelets were ruxolitinib, which can lower the platelet count maybe is not considered safe. But pacritinib can be utilized, even in patients with very, very low platelet counts. So that has a particular use, and also may provide some ability to improve anemia.
Now, momelotinib was just approved, less than a month ago. And this is also a JAK inhibitor that has the capacity to improve anemia, and also can be used in patients with lower platelet counts. So this is a particularly attractive option for patients who, for whom those are particular issues, in particular anemia. Whereas ruxolitnib and in particular, for patients who have very enlarged spleens and a lot of symptoms, maybe that's where in particular it would have its preferred use.
There are other agents that can be used and haven't used historically, including lenalidomide danazol particularly for anemia. In some cases, chemotherapy, in particular for patients who may be moving towards acute leukemia or be officially there. Some of the types of chemotherapy approaches that might be used for acute myeloid leukemia, and its there's where those might be considered. But by and large, most patients these days with myelofibrosis are treated with some form of JAK inhibitor. And this also continues to be a field in which there is very active investigation in terms of clinical trials, and new agents are in various stages. development that may soon become available.
And then the last category, stem cell transplants. So stem cell transplant remains the really the only modality currently available that has the potential prospect of curing the disease or putting patients into a sustained disease free remission. And so for patients who are considered good candidates for transplantation, typically patients who are otherwise pretty healthy, or relatively young to have this disease, and for them, other treatments either have been utilized already or not appropriate, there is where a stem cell transplant may be considered. But the reality is that the majority of patients have myelofibrosis tend to be older and stem cell transplant is not necessarily an option.
Ravi Vij 20:51
The one thing is that you do try to, you know, shrink the spleen with drugs. Do you ever radiate or take the spleen out if it is very big?
Steven Oh 21:01
Yes, there are certainly situations in which we will consider either or radiation or splenectomy. We have found over the years in particular, since ruxolitinib became available that because it's so effective at reducing the spleen that in many patients, that's not necessarily an option that needs to be considered. But nonetheless, there are certainly patients who have very enlarged planes, they do not respond optimally to Ruxolitinib or another JAK inhibitor or maybe they've been on treatments with one or more of these JAK inhibitors and eventually their their spleen does begin to regrow and become this big problem.
In that case, we will consider splenectomy. In some ways, it seems sort of logical, remove the problem, remove the spleen, sure. But we have to consider that the this is a pretty relatively high risk surgery in terms of potential complications. And so typically would not be done unless it's at a place where there is a surgeon who has a particular experience with performing splenectomies in patients with these very large planes.
For patients who are not candidates for surgery, because of the risk, radiation could be considered in some cases, and embolization procedures as well. But for the most part, we tend to focus on medical therapies to try to address the enlarged spleen.
Ravi Vij 22:22
And what is the outcome for patients these days with myelofibrosis?
Steven Oh 22:28
So, you know, I would say that it is variable. So when we use these resk allocation schemes, patients are typically put into either four or five different categories based on the risk factors. And on the one hand, in patients that have the best profile, the predicted survival for patients in that group may be over 10 years. So if your typical patient is diagnosed in their 60s or 70s, you know, that's pretty good compared to what would otherwise be their expected lifespan.
On the other end of the spectrum, in the highest risk categories, we are talking about expected survival of maybe one to two years. So it's very different, depending on which category you're in. And if you take all comers with a myelofibrosis you're talking about maybe a five year, four or five year average, survival. So it is variable, it certainly can be significantly impaired by the diagnosis. And of course, we're trying to develop newer therapies that can have a substantial impact as far as that's concerned.
Ravi Vij 23:29
I really appreciate your taking the time today to talk to our audience about myelofibrosis. It clearly it appears that there's a lot of new drugs coming out and a lot of advances being made in this stage. And I think that a lot of the stuff that is coming out is due to efforts that scientists like you are putting in the lab that can lead to new discoveries. So I hope that I can call on you in the future to come back and give us a little more update in the times to come.
Steven Oh 24:07
Absolutely. Thank you for having me.
Ravi Vij 24:08
Thank you
Steven Oh, Ravi Vij
Ravi Vij 00:02
Hello, my name is Ravi Vij. I'm from MyCancerHaven and I'm here today with Dr. Steven Oh who's Co Division Chief and Associate Professor of Medicine. here at Washington University School of Medicine, one of the leading names in the myelofibrosis field. And someone who has done a lot in the way of clinical trials is also a brilliant scientist who does laboratory work. So he brings both the perspective of clinician and a laboratory scientist. We're glad to have him. Welcome, Steve.
Steven Oh 00:36
Thanks, Ravi. Pleasure to be here.
Ravi Vij 00:37
So, Steve, can you tell our audience as to what is myelofibrosis? It's, it's something that not too many people often probably have heard of till they have to deal with this issue.
Steven Oh 00:50
Absolutely. So yeah, this is a term or a disease that I think most people probably aren't familiar with. And unfortunately, they or a family member may be diagnosed with myelofibrosis, but the name as as you can see, with fibrosis, in the name is really characterized in large part by this abnormal scarring of the bone marrow, this fibrosis that occurs and it is part of a umbrella of diseases called myeloproliferative neoplasms or MPNS.
So myelofibrosis is one subtype of NPN. And then MPN is, of course, a group of clonal blood diseases or blood cancers that are, you know, again, within that broader round of blood cancers or hematologic malignancies, but the the the primary characteristic feature of this disease, again, is the scarring and the bone marrow that relates to abnormal blood cell production that is characteristic of this disease.
Ravi Vij 01:56
So is all myelofibrosis something that happens all of a sudden, or is it something that you can look out for?
Steven Oh 02:05
Yeah, they are kind of two common paths to a diagnosis of myelofibrosis as shown on this slide. So, you have primary myelofibrosis, which means that there was no prior history of a blood disorder, that it not necessarily just came out of nowhere or came suddenly, but that there again, there was no preceding history of unknown blood disorder that then led to myelofibrosis that can occur in many cases with myelofibrosis.
But then in other situations, patients may have a prior history of a blood disorder, such as polycythemia Vera or Essential thrombocytopenia. And then over time, that disease then progresses and developed into myelofibrosis. So what we call secondary myelofibrosis, or post Poylcythemia Vera, or post Essential Thrombocythemia myelofibrosis. In those cases, for instance, with Polycythemia Vera, or Essential Thrombocythemia, at that stage, the blood counts are usually elevated.
In the case of polycythemia, very high hemoglobin, too many red blood cells, or in the case of Essential Thrombocythemia high platelet count. And then over time, typically over the course of a number of years, the counts may begin to drop. And then oftentimes anemia will develop and then that's when the secondary myelofibrosis occurs.
Ravi Vij 03:27
So how much of it is primary and how much secondary?
Steven Oh 03:31
So I think it's roughly roughly equal. There there, you know, it's very common to see either either scenario, we think of the post Polycyhemia Vera or post Essential Thrombocythemia, myelofibrosis. Again, it's something that occurs after having one of those blood disorders for many years. So it takes time for that to develop. But if given enough time, the risk of that is not insignificant. But again, in many, many cases, primary myelofibrosis, without a history of a prior blood disorder can occur.
Ravi Vij 04:07
How common is it?
Steven Oh 04:09
That's relatively rare. You know, as the slide indicates, it sometimes can be a little challenging to pinpoint the exact incidence because getting to the diagnosis can sometimes be a little bit of a process. But, you know, through the course of various studies, the incidence is roughly estimated at about one to two out of 100,000 people. So it's not super common.
It is nonetheless something that in particular, as we have fortunately been able to develop newer therapies, it has become increasingly recognized. So if you go back, say 15 or 20 years ago, I think it would be considered even more unusual or unfamiliar to most hematologist nncologist. These days, although it's still it's relatively uncommon, I think there's an increasing recognition of this specific disease entity, again, in part because we have newer therapies available
Ravi Vij 05:01
And so what causes it?
Steven Oh 05:04
So at its root, like most blood cancers, we think that myelofibrosis is largely driven by mutation. So changes in the DNA that we think usually arise in a primitive stem or progenitor, so that again, start the disease process off. And in the case of myelofifibrosis, the most common mutation is in this JAK-2 gene JAK V617F, that occurs in about 50 to 60% of patients with myelofibrosis, and in the remainder of the 40, or 50% of patients who do not carry the JAK-2 mutation, either mutations or in MPL, or CAL-R, are present in roughly 30 ish percent of patients with this disease, so the majority of patients will have either JAK-2, MPL or CAL-R, that that contributes to these, say, 80 to 85% of patients with myelofibrosis. And then the remaining 15 ish percent are what we refer to as triple negative. Again, JAK-2, MPL and CAL-R are negative, and they have some other genetic alteration that we think is responsible for causing the disease.
Ravi Vij 06:10
So when you say genetic, a lot of patients ask, is this something that runs in families is that what do you mean?
Steven Oh 06:16
So this can be a little bit confusing. So on the one hand, we know that these mutations JAK-2 MPL, and CAL-R, they're not the kinds of mutations that that are passed down, say, from parent to child, unlike and some other diseases where that certainly is the case, we think that the mutations are acquired at some point in the individual's lifetime. So that's, it's an important distinction. A parent who has one of these mutations and has this disease, they're not necessarily going to transmit that mutation to their children.
That said, we do know that there is an increased risk in family members. That said it's not, super uncommon to see a patient where another family member may be affected with either the same disease or a similar disease. And so we do know that there is an increased risk, but we have to understand that that increased risk is on the order of maybe two to four fold higher, than a non relative. And so that is an increased risk. But when we come back to that incidence being about one to two out of 100,000, if you multiply that by two or four, now you're talking about, you know, say a three to five fold increase, or three to five out of 100,000, the risk of developing myelofibrosis.
So, yes, the risk is higher amongst family members, but it's still overall is quite low. And for that reason, when we talk about this particular question, with patients and their families, we do not recommend any particular special screening tests for family members, because the risk is still relatively low.
Ravi Vij 07:57
So what are the symptoms that you commonly encounter in your patients with myelofibrosis?
Steven Oh 08:03
So patients with myelofibrosis can experience a variety of symptoms. You can see the most common symptoms on this slide, I want to also just explain that some patients with an initial diagnosis, they actually have relatively mild symptoms, they may feel well overall, maybe have a little bit of fatigue, in particular related to anemia. But some patients, they overall feel pretty good.
Unfortunately, some patients are on the other end of the spectrum, and they have many of the symptoms listed on here and some cases to the point which they become debilitating. So fatigue, and that can be fatigue related to the disease, and it can be fatigue related to anemia. So both of those things are factors that contribute to fatigue. In patients with myelofibrosis, we know that it’s very common to have an enlarged spleen, typically at least mildly enlarged, in some cases quite substantially enlarged.
And because of the enlarged spleen that can cause symptoms, including abdominal pain, and it can affect the appetite. So what we see commonly is when the spleen is particularly enlarged, patients describe that they feel like they fill up very quickly when they eat a meal. So they take a few bites, all of a sudden, they feel full, and they really cannot eat more at any given time. So that's what we call early satiety, which is directly related to an enlarged spleen.
The patients may have bruising, or bleeding, in part related to low platelets, that's that may occur in the course of this disease. They also may have night sweats. So in some cases, patients have night sweats that cause them to wake up and their shirt is soaked and they often will have some degree of weight loss. So it's not uncommon to have a patient who comes to see us for evaluation and they've lost maybe 20 or 30 pounds because of this disease. So they can have a lot of symptoms. Again, not every patient has severe symptoms, that initial diagnosis, but certainly some unfortunately do.
Ravi Vij 09:58
How do you diagnose it?
Steven Oh 10:01
So really to make a diagnosis of myelofibrosis, this does require a bone marrow biopsy. So this is a standard part of the workup. Now the initial tip-off is usually based on the patient's symptoms, and their bloodwork, typically showing anemia and other abnormalities in the blood counts. But again, to make the diagnosis, you really have to do a bone marrow biopsy. And then you look at the bone marrow, and you're looking to see if, if that characteristic fibrosis or scarring in the bone marrow is present, that really distinguishes myelofibrosis, from most other types of blood cancers. There are certain situations where you can see a little bit of fibrosis in the setting of other types of blood cancers, but really, that is the characteristic finding of this disease.
Ravi Vij 10:44
And I know we talked a little bit about genetic testing a few minutes ago. So you also look for certain genetic mutations.
Steven Oh 10:52
Yes, absolutely. So testing for the three mutations that I mentioned earlier, JAK-2, MPL and CAL-R. That's more or less standard testing for this disease. So that testing can be sent on a bone marrow biopsy sample, it can also be sent from peripheral blood. But that is considered in this era, pretty much standard workup for this disease.
Beyond that there are there's a long list of other mutations that can be tested for. Some more extensive genetic profiling can be considered. It's not necessarily mandatory. But we do find that it adds additional information not so much about the diagnosis, but it does provide information about prognosis. So there are certain mutations where if they're present, we know that they're what we consider what we call high risk mutations, meaning that they increase the likelihood that the disease may eventually transform into acute leukemia, and they also have some impact on overall survival or lifespan after diagnosis so that that kind of testing can be done again, it's not necessarily mandatory, but JAK-2, MPL, CAL-R, for sure, plus or minus other mutations.
Now, we also look at the chromosomes as part of the standard workup of the bone marrow biopsy. This gives us an idea there are big changes in the structure of chromosomes. This can be identified by standard, what we call carrier typing. And then also FISH testing, where you have probes that bind to specific regions of the chromosomes to help identify if there are big abnormalities in the chromosomes. There are certainly known chromosomal changes or alterations that can occur with this disease, most commonly though their chromosomes are normal. It's really the genetic mutations that define this disease.
Ravi Vij 12:38
So like any cancer, I guess, we have to stage it or risk stratify it. So how do you do so? In the case of myelofibrosis, how do you know who's likely to do better? who's likely to do a little worse?
Steven Oh 12:53
Yeah, absolutely. So the first thing that I think is important for patients is, if they're more familiar with, say, other types of cancer, like breast cancer, or colon cancer, or lung cancer, typically you think about staging as a 1,2,3,4 kind of staging. That's the common staging terminology that's used for solid tumors. In the case of myelofibrosis and most of the heme malignancies, it's a little bit different.
So you know, we think, of course, this disease originating in the bone marrow. The abnormal blood cells are trafficking throughout the body. So it's not necessarily relevant to think about staging in terms of where in the body the disease might be. Nonetheless, we do certainly look at different factors that give us the ability to create different staging groups are based on prognosis.
And this is based on a variety of different features, and also utilizing a variety of different prognostic scoring schemes that have been developed over the years. So typically, these systems will take into account symptoms, enlarged spleen , presence of anemia or thrombocytopenia. We know that low blood counts, anemia and thrombocytopenia, in particular, impact the overall risk status and the prognosis.
And more recently, these risk stratification schemes are taking into account the mutations. So I mentioned earlier that there are specific mutations that we know are associated with higher risk. And so some of the more recently developed prognostic scoring schemes take into account presence or absence of these so called high risk mutations and the all that information is used to give us an understanding of what is the overall outlook in terms of overall survival, meaning, how long would we expect the patient to live after the diagnosis? And then also the other potential concern being: Is there a chance that disease would progress to acute leukemia at some point and the relative risk of that occurring over time?
Ravi Vij 14:59
How do you treat myelofibrosis?
Steven Oh 15:02
So as the slide indicates, first and foremost, there are supportive care measures that can be helpful. So for patients who are severely anemic blood transfusions may be necessary and appropriate. So this is something that can be arranged through most, you know, cancer treatment centers. And some patients will need to come in for transfusions every once in a few months or as often as every three or four weeks. So that can be arranged if needed.
And of course, you could, you could ask: well, are there ways to ameliorate the anemia to improve it so you don't need transfusions? And absolutely, that's something that we would be hoping to achieve, and there are various strategies can be explored to attempt to achieve that, including giving agents that stimulate red blood cell production. So what we call ESA, erythropoietin stimulating agents such as darbapoetin, or other forms of erythropoietin. So that hormone that stimulates red blood cell production, you still give a little bit extra, and try to stimulate the bone marrow to produce more red blood cells. Now, that can be effective to a certain extent, but the reality is that because of this abnormal scarring, and the abnormal function of the bone marrow, it's not really producing blood cells normally, so there is a limit to how effective that can be.
Now, the biggest advances in terms of treatment options for patients with myelofibrosis in the past decade or so have been the development of JAK inhibitors. So these are drugs that have specific activity against JAK-2. I mentioned earlier, this JAK-2 mutation that's common in this diseases. And in those patients that have other mutations, we know that the JAK-2 kinase is over activated. So the these drugs will target that JAK-2 what we call a targeted therapy specific to JAK-2. They are called JAK inhibitors because they often will hit other JAKs as well JAk-1 or JAK-2, to different extents.
So, the first JAK inhibitor that was approved which was in 2011, for myelofibrosis was ruxolitenib as listed here. And now that you know, this agent has been in use for for many years, and we know from experience and from the literature that Ruxolitinib tends to be very effective in terms of ameliorating symptoms and reducing the enlarged spleen. So it's it's quite common for patients who are having night sweats and poor appetite, weight loss, poor energy that these things will improve with treatment with ruxolitenib. And so for many patients, this is very, very beneficial, Ruxolitinib will not necessarily sort of fix the abnormal blood counts. So if patients are anemic, it's not going to fix that, not going to put the disease into remission, but nonetheless, it can be very, very effective, in particular, in terms of improving symptoms.
Now, more recently, in the past several years, now three otherJAK inhibitors have been FDA approved. So fedretinib, pacritinib, and very recently momelotinib. These are all similar to a certain extent in terms of being Jak inhibitors, but they also had some distinctions that make their use, perhaps relevant and specific scenarios. So for instance, pacritinib in particular, is thought to be useful in patients very low platelets were ruxolitinib, which can lower the platelet count maybe is not considered safe. But pacritinib can be utilized, even in patients with very, very low platelet counts. So that has a particular use, and also may provide some ability to improve anemia.
Now, momelotinib was just approved, less than a month ago. And this is also a JAK inhibitor that has the capacity to improve anemia, and also can be used in patients with lower platelet counts. So this is a particularly attractive option for patients who, for whom those are particular issues, in particular anemia. Whereas ruxolitnib and in particular, for patients who have very enlarged spleens and a lot of symptoms, maybe that's where in particular it would have its preferred use.
There are other agents that can be used and haven't used historically, including lenalidomide danazol particularly for anemia. In some cases, chemotherapy, in particular for patients who may be moving towards acute leukemia or be officially there. Some of the types of chemotherapy approaches that might be used for acute myeloid leukemia, and its there's where those might be considered. But by and large, most patients these days with myelofibrosis are treated with some form of JAK inhibitor. And this also continues to be a field in which there is very active investigation in terms of clinical trials, and new agents are in various stages. development that may soon become available.
And then the last category, stem cell transplants. So stem cell transplant remains the really the only modality currently available that has the potential prospect of curing the disease or putting patients into a sustained disease free remission. And so for patients who are considered good candidates for transplantation, typically patients who are otherwise pretty healthy, or relatively young to have this disease, and for them, other treatments either have been utilized already or not appropriate, there is where a stem cell transplant may be considered. But the reality is that the majority of patients have myelofibrosis tend to be older and stem cell transplant is not necessarily an option.
Ravi Vij 20:51
The one thing is that you do try to, you know, shrink the spleen with drugs. Do you ever radiate or take the spleen out if it is very big?
Steven Oh 21:01
Yes, there are certainly situations in which we will consider either or radiation or splenectomy. We have found over the years in particular, since ruxolitinib became available that because it's so effective at reducing the spleen that in many patients, that's not necessarily an option that needs to be considered. But nonetheless, there are certainly patients who have very enlarged planes, they do not respond optimally to Ruxolitinib or another JAK inhibitor or maybe they've been on treatments with one or more of these JAK inhibitors and eventually their their spleen does begin to regrow and become this big problem.
In that case, we will consider splenectomy. In some ways, it seems sort of logical, remove the problem, remove the spleen, sure. But we have to consider that the this is a pretty relatively high risk surgery in terms of potential complications. And so typically would not be done unless it's at a place where there is a surgeon who has a particular experience with performing splenectomies in patients with these very large planes.
For patients who are not candidates for surgery, because of the risk, radiation could be considered in some cases, and embolization procedures as well. But for the most part, we tend to focus on medical therapies to try to address the enlarged spleen.
Ravi Vij 22:22
And what is the outcome for patients these days with myelofibrosis?
Steven Oh 22:28
So, you know, I would say that it is variable. So when we use these resk allocation schemes, patients are typically put into either four or five different categories based on the risk factors. And on the one hand, in patients that have the best profile, the predicted survival for patients in that group may be over 10 years. So if your typical patient is diagnosed in their 60s or 70s, you know, that's pretty good compared to what would otherwise be their expected lifespan.
On the other end of the spectrum, in the highest risk categories, we are talking about expected survival of maybe one to two years. So it's very different, depending on which category you're in. And if you take all comers with a myelofibrosis you're talking about maybe a five year, four or five year average, survival. So it is variable, it certainly can be significantly impaired by the diagnosis. And of course, we're trying to develop newer therapies that can have a substantial impact as far as that's concerned.
Ravi Vij 23:29
I really appreciate your taking the time today to talk to our audience about myelofibrosis. It clearly it appears that there's a lot of new drugs coming out and a lot of advances being made in this stage. And I think that a lot of the stuff that is coming out is due to efforts that scientists like you are putting in the lab that can lead to new discoveries. So I hope that I can call on you in the future to come back and give us a little more update in the times to come.
Steven Oh 24:07
Absolutely. Thank you for having me.
Ravi Vij 24:08
Thank you
