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Your MPN Questions Answered: Gene Mutations, Inhibitors and More

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Published on December 13, 2019

Key Takeaways

  • Researchers are learning more about gene mutations and how that impacts treatment decisions. 
  • Jamieson recommends getting the completely killed flu vaccine, Pneumovax or a Group A strep pneumonia targeting vaccine. She says people can make their own decision regarding the shingles or chickenpox vaccine. 
  • Talk to your doctor about clinical trials for new inhibitors.

This “Ask the Expert” program features myeloproliferative neoplasm (MPN) specialist Dr. Catriona Jamieson from UC San Diego Moores Cancer Center at the 2019 American Society of Hematology (ASH) annual meeting in Orlando answering questions from MPN patients and care partners on molecular testing, prognostic factors, patient-specific treatment plans and more. What does mutational status indicate about risk? Where is research on vaccine therapy for MPNs? Why do doctors recommend higher or lower doses of interferon for individual patients? Watch now to find out from a myeloproliferative neoplasms expert.  

This is an MPN Research Foundation program produced by Patient Power. We thank Celgene for their financial support through grants to the MPN Research Foundation. These organizations have no editorial control, and Patient Power is solely responsible for program content.

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Transcript | Your MPN Questions Answered: Gene Mutations, Inhibitors and More

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. 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.

Andrew Schorr:

Greetings, I'm Andrew Schorr. We're in Orlando, Florida and this is our live MPN Ask the Expert program. And I've been living with an MPN about eight years now, so I am vitally interested. And we have lots to talk about. Now if you have a question and you haven't already, send it to mpn@patientpower.info. mpn@patientpower.info. I want to take a second to remind you though, you're going to meet my doctor actually in just a second, but whatever we say here, talk to your own practitioner.

Someone you trust for your treatment of MPNs, or your loved one's, to see what is right for you. That is always important. Now, I want to tell you where we are. We are in Orlando, Florida. Right behind me is the Orlando Convention Center, 25,000 or more blood experts from all around the world. A lot about blood cancer, and increasingly a good bit of discussion about MPNs.

Where there wasn't much to say years ago. Now there's a good bit to say. All right? So, really a crowd and we're going to hear some headlines about that, but now let's take your questions as well. So, joining us is my doctor, Dr. Catriona Jamieson. Thank you so much for being with us. 

Dr. Jamieson: 

Oh, it's really my pleasure, Andrew.

Andrew Schorr:          

Thanks. And your title at the Moores Cancer Center at UC San Diego is what now?

Dr. Jamieson: 

So, I'm the Deputy Director of the Moores Cancer Center at UC San Diego. I'm also the Director of the Sanford Stem Cell Clinical Center and the Chief of the Division of Regenerative Medicine.

Andrew Schorr:          

Okay, one other point is there are guidelines for the treatment of MPNs. 

Dr. Jamieson: 

Right.

Andrew Schorr:          

And there are the NCCN guidelines. You've been one of the leaders in the discussion about what those guidelines should be.

Dr. Jamieson: 

Yeah, that's exactly right. So, the National Conference of Cancer Network has a group of physicians that used to be a fairly small group. It would get together annually starting a few years ago to decide what the guidelines should be for MPN treatment and actually diagnosis. And so, we got together.

It was Robin Mesa’s idea and he always has great ideas, so the rest of us came along. He was the original Chair. I was the Vice Chair. And then it expanded to be a much bigger panel with diverse opinions. It's a very effective panel and we discuss the different treatments and the evidence for those treatments, including now molecular diagnostics.

So, we're looking at actual mutation panels for people. And I think that it's become a really great source of knowledge for patients, because they can look up the panel recommendations. So, it's not so capricious anymore. You can say, "Okay. This is the level of evidence that supports that recommendation." So, when you ask your doctor, "Why do you think that's the best treatment?" Then they can say, "Aha. It's because I read it in the guidelines and here is a copy of the guidelines for you. You can read it."

It's that—it's fairly simple. And I think in this community it's such an educated community because of Patient Power and the MPN Advocacy Group, MPN Research Foundation, The Leukemia & Lymphoma Society. But the thing with Patient Power is this reaches people in real time. So, they can ask their questions in real time. So, I'm a little nervous.

Andrew Schorr:          

All right. We're going to do like a lightening round along here, but here are the questions. So, first of all, I think many of us have learned that not all MPN is alike and that there are cancer genes that drive your MPN or mine. Mine is JAK2 V617F, because Dr. Jamieson did the testing for that. It can change to what's your gene, what's your driver gene on your—so, here's a question we got from Jerry, who said, "Why is CALR Type 1 considered low risk, despite high symptoms at the time?" So, CALR is another gene.

Dr. Jamieson: 

Right.

Andrew Schorr:          

So, he's saying is it considered low risk?

Dr. Jamieson: 

Yeah, I think it's the kind of risk that we're talking about. Usually when we ascribe risk to a gene mutation, like the JAK2 mutation, we're really talking about the risk of progression of scarring in the bone marrow. So, myelofibrosis. "myelo" means bone marrow. "Fibrosis" means scarring. Can progress from grade zero, which is a little bit, all the way up to grade three, which is a lot of reticulin. And then collagen fibrosis, which is stained with trichrome stain. So, it's really the risk of progressing with regard to myelofibrosis and then also transforming to acute leukemia. It doesn't really take into account so much the risk of clotting, stroke, heart attack, clotted into the hepatic vein or deep venous thrombosis. And so, for the calreticulin mutation, we think there's a slightly lower risk of myelofibrosis progression and a slightly lower risk of acute myeloid leukemia, but there's a slightly lower chance of responding to JAK2 inhibitors.

So, even though people with a JAK2 mutation maybe have a slightly higher risk of progressing, they're more likely to respond to a JAK2 inhibitor, because they've got more target. So, with the calreticulin mutation, you can still activate the JAK-STAT signaling, but it's not as robust as with the JAK 2V617F mutation.

Andrew Schorr:          

So, is there a CALR medication?

Dr. Jamieson: 

There isn't. Whether—the thing with the CALR mutation is that you can—and there are two different types of mutations, but both can activate JAK-STAT's signaling, so they should be sensitive to JAK-STAT inhibitors. They just won't be as sensitive as somebody with a JAK2 mutation. So, the people with a JAK2 mutation tend to respond really nicely.

Andrew Schorr:          

And I should mention I've been on the JAK2 inhibitor for seven years, and I'm going scuba diving after this conference. So, really there's a—you know, you want to have as full of life, and if there's a medication that can work, and you get the right dosage, that's your discussion with your doctor. 

Dr. Jamieson: 

Well, there is one more thing we're interested in for CALR mutated disease, and that's can we focus on this survival set of genes called Bcl-2 and Bcl-XL? And those look like very interesting targets. So, as you remember in the field of chronic lymphocytic leukemia…

Andrew Schorr:          

…I do.

Dr. Jamieson: 

There was a drug that was made for that called navitoclax. And venetoclax (Venclexta) is already used in CLL. Navitoclax stopped being used, because it targets both Bcl-2 and Bcl-XL. Well, it turns out that's exactly what you want in essential thrombocythemia. And it's actually what you want in certain people with myelofibrosis, who tend to have higher platelet counts. And that's more like what we see with the Calreticulin mutation. So, that might be a very good opportunity for people with the CALR type 1 mutation who haven't responded to JAK2 inhibition. So, they may want to get on to navitoclax at some point in the near future.

Andrew Schorr:          

Well, we'll talk about medications along the way, because that's a lot of what they talk about here, is are there studies that show some utility for a medicine that has been around, or is new, or is in clinical trials. And we'll talk about clinical trials as well. Okay, so Linda wrote it, "What are the indicators to you of the need to raise or lower interferon dosage?" Because we have a lot of people who are on interferons. So, how do you know what dose is right?

Dr. Jamieson: 

You know, I think that's such a great question, and actually at the last NCCN panel meeting, we debated interferon really rigorously, because there are different types of interferon now. Most people are on Pegasys and actually tolerate it very well. And I think that the main indicators for raising or lowering the dose really have to do with symptoms of progression. So, if people are having their spleens grow, they're getting itchy skin, having their night sweats come back, having their lactate dehydrogenase or LDH levels in other words go up.

That's usually an indicator that we want to adjust the dose upwards, so we're going to want to go up on the peginterferon alfa-1a (Pegasys) dose. And that's just a weekly dose. The range is all the way from 45 up to 180 micrograms under the skin weekly. And it's really a patient specific dose, and 45 is the absolutely lowest - not normally therapeutic. Usually people range in dosing from 90 to 180 micrograms, and it's symptomatic.

It's also normalizations of counts, and now we're getting a bit greedier. We're starting to look for molecular responses in addition to a reduction in actual fibrosis in the marrow. So, there's a suggestion that if we start early enough in low to intermediate risk myelofibrosis, we may be able to make incursions on that scarring in the bone marrow and actually reduce it.

And then the question is can we also reduce the variant allele fraction, or JAK2 mutation burden, or calreticulin mutation burden. Why couldn't we look at that before? Well, because we didn't have next-generation sequencing panels that could be done on the blood. And now in many centers, we have those panels of 150 some odd genes, but we can actually measure the level of the mutation. And that has changed everything, because we can do the peripheral blood test and say, "Oh, okay. Your JAK2 mutilation fraction or variant allele fraction, VAF, is 60 percent. If you go on Pegasys, can we lower that?

Andrew Schorr:          

So, you see why this woman is a scientist and getting in a lab. And many of the doctors we feature who are MPN experts spend time in the lab, and then maybe it's one day a week, two days a week. And they travel a lot. They see you in clinic. And you want that bridge between science and what you're getting, or through these NCCN guidelines to inform your local doctor if you're not near one of these research centers. 

Dr. Jamieson: 

I did want to mention one more thing about interferon, and that's this insidious depression that some people get that appears to be dose dependent.

Andrew Schorr:          

You mean just feeling sad?

Dr. Jamieson: 

Just plain sad, sadness, depression, all the symptoms of depression. It's a known side effect of interferon, and we have to remember that, because it's dose dependent. So, what I do is sometimes I have to lower the dose, because of this incipient depression. And we lower the dose, and then after a few weeks people feel better. 

Andrew Schorr:          

But not going on antidepressants. 

Dr. Jamieson: 

They can just for the shorter period of time to get over that, but generally they get better with just lowering the dose. And they—usually it's people that have had a preexisting history of depression in the past. But I have had that happen, where it was quite profound. And we've had to lower the dose and then see if they get better, and they generally do.

Andrew Schorr:          

You guys are really smart, and you have some tough questions. And she did not want to see these beforehand, so here we go. So, I think it's—I think Brenda asked this question, "Are there still MPNs that are unclassified?" So, we have ET, PV, MPN. She says, "Is there something that's not wild type," And you can tell us what that is, "as you have with next generation sequencing?" Is there something we've never given a name to? 

Dr. Jamieson: 

Absolutely. So, myelo—it's hard to even say the word. "Myelo" means bone marrow. "Proliferative" means you have cells in the bone marrow that are making more of themselves. Neoplasm suggests it is a cancer, because it can progress to acute myeloid leukemia, AML for short. That was something that we didn't even have a mutation for until 2005 when four groups said there's a JAK2 mutation in part of the gene where it can't turn itself off. And that's a V617F mutation.

So, then we said, "Okay. That's 97.5 percent of people with polycythemia vera. About 30 percent of people with essential thrombocythemia. About 50 percent of people with myelofibrosis." But we didn't know about any other mutations. And then a few years later the CALR mutation was found. "Okay, now we've got about 20 percent of ET, another 30 percent of myelofibrosis."

But there's still a proportion of patients where we can't find a mutation—or the bona fide mutations that we know as driver mutations. Where we think they're responsible for initiating the fibrosis and driving it, and making it get worse. And so, that is a proportion of patients that we're still trying to understand. But I think we're starting to make inroads based on next generation sequencing, where we can see some mutational patterns that weren't previously reported. 

And I think what's happening are two things. One, people can inherit an inability for their immune system to see these clones as foreign. And number two, they get a mutation in a gene, that's what's called an epigenetic modifier. Like TET2 that you've heard about, DNMA2, but they may not have that JAK2 mutation, or the calreticulin mutation, or the MPL mutation. Those are the three known mutations that drive this disease, but, you know, we've got 20—up to 20 percent of patients who are triple negative. They don't have any of those mutations.

Andrew Schorr:          

So, how do you treat it?

Dr. Jamieson: 

So, then we look at what is their clonal driver? Or what is the clone in the background? And we looked for the very same things. Do they have scarring in the bone marrow? Do they have a bigger spleen? And so, we start with the same recommendations for that group, but we tend to be a little bit more discerning about signs of progression, because it tends to be a more aggressive group.

They tend to progress more quickly. So, what we're looking at is a mutation and has international prognostic scoring system maps 70. For people under 70 to say, "Is there a subgroup of patients we should think of transplanting earlier?" So, people with the ASXL1 mutation, IDH1 or IDH2 mutation, TET2. Is that a group we should start to look at more carefully? 

Andrew Schorr:          

And that would be the treatment.

Dr. Jamieson: 

And that could be the treatment, or we may start to get a little bit clever about the type of cellular therapy we give people, recognizing the immune system is not recognizing these pre-malignant or malignant clones as foreign, and giving people NK cells, natural killer cells, or targeted T cells that recognize these new proteins on the surface of these cells. And those clinical trials are going on. 

Andrew Schorr:          

Well, okay. So, in some of the other conditions, and this is heavy-duty science, but we'll try to decipher it. In chronic lymphocytic leukemia, which I also have, but some other conditions. Even multiple myeloma, another blood-related cancer, and they've been doing lymphomas. They've been doing CAR T, chimeric antigen receptor T-cell therapy. So, you mentioned T cells a minute ago.

Dr. Jamieson: 

Yeah, that's right. 

Andrew Schorr:          

So, would CAR T possibly have an application for this group of patients you're talking about?

Dr. Jamieson: 

I think it's more likely to be a neoepitope, a new protein expressed on the surface of the stem cells in this disease. And that's something we're doing in myelodysplastic syndrome with our company called PersImmune that makes those for each person with a disease. So, they'll take the stem cells, they'll sequence them, and then they raise T cells that recognize those as foreign, and then they give the T cells back.

So, I think that would be more likely to work than a CAR T-cell approach, because CAR-T cells have to be directed against one cell surface protein. We don't have one cell surface protein that isn't actually pretty important in myeloid disorders. So, targeted and CD123, which is a cell surface protein, is needed for other cells that make our immune cells. So, that's two…

Andrew Schorr:          

…we want to have like a target that just says, "I'm a bad guy."

Dr. Jamieson: 

Yeah. There's no "I'm a bad guy" target yet. It doesn't mean that we won't find it, but not so much in myelofibrosis.

Andrew Schorr:          

Okay. Here's a question from John. "I'm a PV patient, and I've tried to research the possibility of a new therapeutic vaccine." He calls is ImMucin. It's being developed in Israel with little results. "Would you happen to know anything about it?" So, vaccine therapy. Anything about that?

Dr. Jamieson: 

Yeah, so sometimes what happens—and I'm not sure what kind of vaccine that is, but sometimes what happens is people get a peptide vaccine. So, it's a similar sort of thing to get in those T cells with the peptide that recognizes their myelofibrosis, or their PV in this case, in to culture together and trying to amplify the T-cell population. Get them to divide.

Instead, you give the peptide directly to the person you just injected, and then their own T cells are supposed to respond to that peptide that's made from the polycythemia vera cells themselves. So, your immune system's now supposed to say, "Hey, wait a minute. That's foreign." And make an immune response against it.

As I was alluding to earlier, I think part of the problem with myeloproliferative disorders or neoplasms is the immune system doesn't work that well. So, even if you try to boost it in the person, it just doesn't really do it. And the question is, is that because of an inherited inability to respond? So, I think one of the issues in MPNs, PV, ET and myelofibrosis is an immune tolerance issue where those cells aren't seen as foreign. So, trying to give a peptide is probably not going to be enough. 

You'd have to boost that immune response with IL-2 or come in with IL-15, which will boost the NK cells. There is a super agonist or mimetic for IL-15, meaning something that boosts that particular survival factor for natural killer cells. And that's going into clinical trials for solid tumors already. So, the question is, "Can we use that in PV?" When is it too early to start thinking about something? So, I can imagine that strategy, together with the peptide, potentially working.

Andrew Schorr:          

Okay.

Dr. Jamieson: 

And so, I think we can get creative when people ask very good questions like that.

Andrew Schorr:          

All right. I have some really basic ones for you. So, this is the lightening round. Is there any reason why we shouldn't get flu shots? You talked about the immune system, flu shots, pneumonia vaccines, shingles vaccines?

Dr. Jamieson: 

Yeah, everyone should have the killed, completely inactivated flu shot. It's really important. So, I think that's important. In terms of pneumococcal vaccine polyvalent (Pneumovax), you know Group A Strep is a problem for people with myelofibrosis, not so much PV or ET. For people with advanced myelofibrosis, it may be a good thing to get Pneumovax or protection against Group A Strep. And, of course, if you've had your spleen out, then you need the three vaccines. So, everybody who's had their spleen out knows that that's not standard of care anymore to take a spleen out.

Andrew Schorr:          

Shingles?

Dr. Jamieson:  

Shingles, that's sort of not as big a deal in myelofibrosis. It's really not in polycythemia vera or essential thrombocythemia. I know there's a big push on now for everybody to get zoster vaccine (Shingrix) and get this varicella vaccine. I rarely see shingles in our patients. I do see…

Andrew Schorr:                

Yay.

Dr. Jamieson: 

Yeah. Rarely. It's really not common, because we're not really devoid of B- and T-cell immunity to the extent that you see it in CLL and other lymphoid diseases. In myeloid diseases, your T and B cells aren't too bad. It's the neutrophil, so good cells that fight infection that don't work as well. 

So, I think people can make their own decision about that. I'm not a huge advocate of getting additional vaccines. I think that the flu vaccine, absolutely, provided it's completely killed. I think that having Pneumovax or Group A Strep targeting—or strep and pneumonia targeting vaccine makes sense. Shingrix or the varicella vaccines, I think people can make their own decisions.

Andrew Schorr:          

Okay. Karen sent this question in. She said, "My husband was diagnosed with myelofibrosis and is losing weight, because he cannot eat very much. He's on Jakafi, or ruxolitinib. Is there another medication he can take that will increase his appetite?"

So, I just want to say, I've been on Jakafi seven years. I think I eat too much. I hope that happens to him. Does that have to do with the size of his spleen or is it other things?

Dr. Jamieson: 

Yeah, usually that's a sign of progression. So, you have to see your doctor—have your husband see his doctor, and make sure that the spleen going up isn't coinciding with advance of the fibrosis in the bone marrow. So, when I see that, it usually correlates with a higher LDH, so people start to lose weight, because they have more of these inflammatory growth factors. Like tumor necrosis factor, another inflammatory cytokines, and it usually represents a loss of response to Jakafi.

So, then you have to look at the dose. Is it the appropriate dose? Fairly frequently people lose their response, so we have to increase the dose of Jakafi, and I've done that many times. Where someone was on 10 milligrams twice a day and we went up to 15 or 20 milligrams twice a day. And then they were fine. Their spleen shrunk. Usually you’re right, Andrew—that's exactly what it is. People don't feel hungry because their spleen has grown, and they feel full early.

And there are other medications. There's one in particular that was recently approved. So, if his doctor finds that he still having symptoms with an enlarged spleen, and that's an easy ultrasound to do, then he can switch to the newer medication to see if that's a more effective option. And then, if that doesn't work, go back to Jakafi or combine something with Jakafi.

Andrew Schorr:          

Okay. Those are—that's great. Okay. So, here is a question from Kathy. "Can you address risks or infeasibility of stem cell transplant when you have another problem? Like, diminished kidney function." And she says, "Due to PV, which arrived before the MF." So, reduced kidney function, is she a candidate for transplant? 

Dr. Jamieson: 

So, PV to MF. Yeah, I think this is a constant quandary for—in the myeloproliferative neoplasm field. Generally, people have reduced kidney function in myelofibrosis as the disease progresses, because the fluid tends to go into the tissues as opposed to staying in the bloodstream. Our kidneys take 25 percent of our cardiac output, and so, they're just not seeing enough blood flow.

So, that's very common. So, when we access risk for transplant, it's not just getting somebody else's stem cells. It's actually the immunosuppressant drugs that you need to take later to protect you from graft-versus-host disease. So, those stem cells from recognizing your skin, gut and liver as foreign. And that cyclosporine in other drugs that are pretty hard on the kidneys.

So, that's what we look for in our transplant workup. We say, "How likely is this person not only in terms of their risk for having a transplant-related complication, how likely is that to happen? But also, how likely is a post-transplant related complication going to be a problem?"  And because there's so many other therapies now, it's a risk versus benefit. You know, when's the right time to transplant?

Andrew Schorr:          

So, you're talking in a way about exclusion for a…

Dr. Jamieson: 

…absolutely.

Andrew Schorr:          

I want to ask you about that for a second. And that is, you're doing clinical trials?

Dr. Jamieson: 

Mm-hmm.

Andrew Schorr:          

As your peers are. I wonder, though, sometimes if—let's say the medicine I'm on is the bridge to what next. Will taking that medicine now because I need it preclude me from being in an exciting trial?

Dr. Jamieson: 

I really sincerely hope not. I think that the power of Patient Power is to make sure that doesn't happen. I think that we used to do clinical trials that included a placebo arm for myelofibrosis. That wasn't fair. Instead of best available therapy. So, I think as patients advocate for themselves and their families, I think that we can say, "No, actually. It should be okay to have had a previous JAK2 inhibitor, three previous JAK2 inhibitors."

And we did that in chronic myeloid leukemia. We didn't preclude people from getting the next best, greatest, able kinase inhibitor, tyrosine kinase inhibitor, TKI for short. We said, "Oh, okay. They didn't respond to imatinib (Gleevec) or dasatinib (Sprycel). Let's try nilotinib (Tasigna).” So, the way we do clinical trials is dictated in part by patients. 

And provided that we work with the FDA to say patients come first always, I think that we can change the treatment paradigm, including when it comes to clinical trials. What I would really like to take off the table for clinical trials is the idea that people with another malignancy can't be on a clinical trial.

Andrew Schorr:          

Right. 

Dr. Jamieson: 

Because that's far too many of our patients.

Andrew Schorr:          

Oh, that's me.

Dr. Jamieson: 

But that's…

Andrew Schorr:          

…CLL and myelofibrosis.

Dr. Jamieson: 

But that's more common than I originally thought. So, I'm picking this up more because now we're able to. Our molecular diagnostics tell us, "Wait a minute. It's not just myelofibrosis. There's also CLL or maybe follicular lymphoma or Waldenstrom macroglobulinemia." 

Andrew Schorr:          

Or breast cancer.

Dr. Jamieson: 

Breast cancer, absolutely. So, I think people should be allowed to be on umbrella protocols where we're trying to treat the driver mutation and do that instead.

Andrew Schorr:          

Okay. We have to work with leaders such as this, so that that voice is heard. Here's a question we got from Ron. He said very simply, "Can MPN patients donate blood or be organ donors?"

Dr. Jamieson: 

Generally, not. Not on either count. We used to have people—well, a little bit before my time. But before I started practicing, people with polycythemia vera would be told to go to the blood bank instead of having a phlebotomy, because they could just donate that excess blood that they made. And then the blood banks started to say, "No, there are mutations in the blood. We don't want to give that blood to other people."

Similarly, for organ donation, we don't know to what extent these MPN stem cells have infiltrated other tissue. So, generally people with MPNs are not organ donors. And sometimes I'm called by our transplant team to do a bone marrow biopsy to rule out a myeloproliferative neoplasm.

Andrew Schorr:          

Okay. Jerry sent this question, "What's the danger of having a high iron count?"

Dr. Jamieson: 

Well, iron is a problem for the bone marrow overall. So, it just depends on what kind of irons. So, we have iron in our blood that circulates, bound to a protein called transferrin, and that's fine. As long as it's bound to that, you don't run into trouble. But as soon as it's transferrin free, as soon as it breaks free of that protein, it can deposit in the heart, in the pituitary gland, in the pancreas, and in the skin and cause damage in all of those organs.

So, we don't like to have high iron levels, but more importantly for this disease that can lead to bone marrow failure, it can have a toxic effect on the bone marrow. So, if your iron levels get too high, ironically, and we measure that by ferritin, you can't make bone marrow. So, as we start to chelate off the iron, and that's a good news story, we can chelate off that excess iron. We actually start to see bone marrow recovery and people starting to make—not just more red blood cells, but more platelets and more white blood cells.

So, I think generally when it comes to chelation of iron, we're starting a little late. So, not only do we have to have more effective treatments for myelofibrosis that don't lead to a huge need for transfusions, we have to start with chelation earlier. And I think more people are pushing for that now.

Andrew Schorr:          

Okay, so Dr. Jamieson, just some headlines. We're here where you and your peers from around the world meet. And you have other meetings, but this is the big boy.

Dr. Jamieson: 

Right. 

Andrew Schorr:          

What are some headlines from what you're hearing or participating in that we want to tell the community that gives us hope?

Dr. Jamieson: 

Well, I think the great news is we have another approved drug. So, that's good this year.

Andrew Schorr:          

Fedratinib (Inrebic).

Dr. Jamieson: 

Inrebic. So, this is a JAK2 FLT3 inhibitor. It was in clinical trials for over five years. Went on clinical hold because of a concern of possible neurologic toxicity related to thymine deficiency, which goes back to the previous question about not wanting to eat because your spleen is too big.

So, I think what we learned there is people with myelofibrosis who have big spleens don't eat that much and they can become thymine deficient. And that's sort of a headline, because it's a quality of life issue, but it's also—it restricts what you can take. So, now we know to measure thymine levels. We know that people who take Inrebic tend to do well. It's not a happy pill. It doesn't make people's inflammatory cytokines go away right away, so they don't feel better immediately, but as the spleen starts to shrink, their counts start to normalize, and they start to feel better.

Andrew Schorr:          

So, we've got two JAK2 inhibitors.

Dr. Jamieson: 

Right.

Andrew Schorr:          

Others that are still remaining in trials.

Dr. Jamieson: 

Right. So, we've got two JAK2 inhibitors that are NCCN panel recommended standard of care. Jakafi and now Inrebic. They're different. JAK2 inhibition with Jakafi, a test to make people a little bit better from a symptom standpoint. And then Inrebic tends to make people feel a little better after a few months when it really starts working on the spleen. But both effective options.

In terms of clinical trials, momelotinib They're still moving through the clinical trials. It's maybe less of a problem for anemia. That's a suggestion. And maybe a little bit better in some ways or some tabetic improvement but may not be as affective for reducing the actual disease burden in the spleen and in the bone marrow.

There's another drug from a company called NS Pharma, called NS-108. It's a very selective JAK2 inhibitor. Extremely well tolerated. Takes a long time to work, but in some people, it really works to reduce the spleen by 50 percent to get the bone marrow scarring down by a little bit. It's just not as potent as the other JAK2 inhibitors, but still a well-tolerated option.

Andrew Schorr:          

Okay. And then for our friends with ET and PV, new thinking there?

Dr. Jamieson: 

I think there is new thinking. I think for ET—let's just start with PV. I think there is a role for Pegasys in some people with PV who are symptomatic, as the idea is to get back to that and know we've got a good drug there. There is a role for JAK2 inhibition in PV, where 97.5 percent of people have a JAK2 mutation. Whether that be with ruxolitinib or fedratinib. So, in other words, Jakafi and Inrebic.

I think we'll have to do the trials. We did trials for both drugs. They looked pretty effective, but I think we mixed up PV and ET, and they're really different. So, I think if we just did a purely PV study, I think we'll see benefit. We already have approval for Jakafi in people with polycythemia vera who have bigger spleens, but I think when you start to see those bigger spleens, they really have probably transitioned to myelofibrosis. So, I think we're too reluctant to do bone marrow biopsies in this disease where bone marrow fibrosis can only be diagnosed really by looking at the level of scarring in the bone marrow. 

Andrew Schorr:          

Have a bone marrow biopsy if you can with sedation. I did it. She asked—she ordered it. I just took a snooze. So, it wasn't so bad. And ET. Any news there? 

Dr. Jamieson: 

ET is very interesting. So, essential thrombocythemia, as I mentioned earlier, we see the CALR mutation a little bit more frequently there. But also, I think that that may respond to Bcl-2 and Bcl-X inhibition, because you make a lot of platelets. And that was the problem where we did the navitoclax studies in CLL. Their platelet counts plummeted.

Well, when we did the navitoclax study, and that will be presented here at this ASH meeting, with Jakafi plus navitoclax, there was a decline in the platelet count. But if you start earlier in ET, it might be all you need. So, I think it would be fantastic to do a single agent study with navitoclax and essential thrombocythemia.

I think it could be very useful. And then the question is, back to the immune system, can we start looking at the immune system's ability to gobble up these cells when they're not normal by using an anti-CD47 strategy. So, CD47 is the "don't eat me signal." It's upregulated by some cells that say to their macros, "Just don't eat me." Anyway, we can—there's now an antibody.

Andrew Schorr:          

So, we need a Pac-Man.

Dr. Jamieson: 

We need a Pac-Man. So, this antibody induces that Pac-Man effect. And that's made by a company called Forty Seven, Inc. They're using it in other diseases, other tumors right now, AML and some solid tumors, but it would be fantastic if they go into this disease.

Andrew Schorr:          

Okay. Thank you so much for being with us today.

Dr. Jamieson: 

Thank you. It's really my pleasure.

Andrew Schorr:          

I'm Andrew Schorr in Orlando right by the ASH Convention Center with Catriona Jamieson from UC San Diego. Thank you for watching. Remember, knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. 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.

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