Managing myelofibrosis (MF) before the availability of ruxolitinib

DR LOVE: Welcome to Oncology Today: Novel Agents and Strategies in the Management of Myelofibrosis; this is medical oncologist Dr Neil Love. For this program, I met with Dr Ruben Mesa from the Mays Cancer Center in San Antonio. In addition to this interview, there is also a corresponding program featuring Dr Mesa’s slide presentation. To begin, I asked him to discuss what it was like to treat myelofibrosis before the approval of JAK inhibitors.

DR MESA: It really was transformational. So just setting the stage, before we had started the Phase I trial with the JAK inhibitors, so (1) there was tremendous hope without question. We now had a target. We had the first targeted agents. So there was a real hope that they would be — make a big impact. But up to that point I had been involved with over 30 different clinical trials for patients with myelofibrosis along with my mentor and colleague, Dr Ayalew Tefferi from Mayo Clinic and many others around the country and globally.

And largely these trials had had limited benefit. Maybe it could improve anemia. Rarely improved splenomegaly. Typically didn’t improve how people felt, and clearly didn’t seem to have an impact on the natural history of the disease.

And transplant had become an option. Even transplant itself was initially thought that it may not be safe to do. When I had a conversation with E. Donald Thomas, who developed the transplant and won the Nobel Prize on that basis, they initially felt that myelofibrosis transplant wouldn’t work. The bone marrow was all fibrotic. Would there be a niche for the stem cells to even go? And fortunately there was, and there was a lot of discussion as even that got launched.

But when we treated the first few people on the Phase I trial it was clear this was dramatically different. Patients felt dramatically better, and the spleen shrank significantly, even by the first time we assessed them 2 weeks into the study. This was a dramatic change over where we had been before.

So before we had never really needed a great way to measure the spleen because nothing ever really tended to improve it. The main benefit we ever saw was really improving hemoglobin. And as it related to symptoms we had done preliminary work that objectified that patients had a lot of symptoms, but we did not have a patient-reported outcome form. We developed that only after we started the JAK inhibitor trials because we needed it.

So I went to our statisticians involved with PROs at Mayo Clinic and said, “Boy, I need a validated questionnaire.” And they said what do patients experience? So I went through the symptoms, and they said well there really is no PRO that really meets all those different needs. I’m like well should we develop one? And they said absolutely not. They’re like don’t do that. You develop a PRO, no one thinks they’re valid enough, they’ll drive you crazy.

But in the end that’s exactly what we needed to do because there really was no other option. So we created the PROs, we validated them, and it’s been rewarding in now that symptoms have 1) become a key part of drug approval for these diseases. The PROs we’ve developed have really become the global standard in all of the trials that go on globally, and we’ve translated them in over 30 different languages, and we have data in thousands of trials.

But the difference is really enormous. So the post-JAK inhibitor world is a very different world. It also includes in a very significant way people die less from myelofibrosis. And as someone who lost a lot of patients over the years the difference is really quite striking. I saw a patient earlier this year that had been put on the COMFORT study in 2010, who was still on ruxolitinib, and only now was progressing, and we moved him onto a trial. But that was 12 years.

Now I went back and calculated his risk score and saw that if we had estimated his risk of survival back in 2010 that individual had an expected life expectancy of under 3 years, so was alive 12 years as opposed to 3. So a huge improvement. We clearly have a ways to go, but there really have been some just dramatic changes.

DR LOVE: And of course nowadays oncologists who start people on first-line JAK inhibitors see that. But I’m curious what it was like for you when you saw those first few patients. To me it’s — some of the most dramatic stories I’ve ever heard in oncology have been in myelofibrosis. Anybody in particular that you remember treating early on?

DR MESA: I remember early on in the Phase I there was a surgeon from — actually from your neck of the woods. He was from South Florida. He was a surgeon. He was no longer operating. And I remember seeing him at 2 weeks and then 4 weeks. He’s like “I haven’t felt this good in a long time. I’m back to operating.” He’s like “I’m making love to my wife.” And another issue which patients don’t discuss. He’s like “I have not felt this good in a long time, and it gave me the energy to be myself again”, which was incredibly rewarding.

So we were starting to see patients really from all over the world as it became clear that this was really something dramatic.

It was also really quantifying well what is that benefit as it relates to — for the FDA. Because when we started the discussions with the FDA they said well, the only endpoint we really care about is survival. And we’re like well, it’s a really complicated endpoint in a disease where people average a survival of 3 to 5 years. Survival is a helpful endpoint when you have a short survival because then you can see a difference in a reasonable amount of time, if you’ve got advanced GBM or pancreatic cancer or something of that nature. But in myelofibrosis it was just not a practical endpoint.

So again, as we even evolved the thinking, how do you quantify clinical benefit for patients, and I’ve seen important evolution. As we think about many of the cancers that we treat, and patients have much longer survival, how do we quantify the benefit that they’re experiencing in a range of ways.

Pathobiology and mutational profile of MF

DR LOVE: So maybe you can also provide a little bit of a basic update in terms of what we’ve learned about the biology of the disease and particularly in terms of the mutational profiles you see.

DR MESA: We’ve learned quite a bit. Before 2005 the myeloproliferative neoplasms were even called the myeloproliferative disorders. There was again a lot of discussion are these really a neoplasm or not. And without question they are. There had been evidence on clonality studies that really confirmed that they were neoplasms, but the discovery of the mutations really helped nail that down.

These are very much chronic leukemias just as much as a chronic lymphocytic leukemia or a chronic myeloid leukemia. They were not called leukemias largely just because of the way that they were identified and named historically before there was clear pathobiology behind it. But they are chronic leukemias without question.

What we have learned is clearly there’s first a set of clear driver mutations that are necessary for the disease. The JAK2 V617F, calreticulin, or MPL. These are mutually exclusive, and they range from being present in almost all patients with polycythemia vera to the majority with myelofibrosis NET. It is important that all 3 of those mutations are activating — lead to constitutive activation of the JAK-STAT pathway. So they’re all hidden in the pathway in a different spot but any one of those can be necessary for that piece.

Now the second wave of discoveries have been around additional somatic mutations that we think might also impact that pathway that also can adjust the prognosis. Now these are additional somatic mutations that can also be relevant in MDS, in AML, or other myeloid neoplasia, and they can overlap with clonal hematopoiesis, so in particular like ASXL1, EZH1 and 2, IDH1 and 2, DNMT3A, TET2. There is — again, if one looks at a myeloid panel there’s about 40 of these possible ones, of which there’s 5 to 10 that are kind of the bad actors. They both have an implication in terms of biology, but they also have an implication in terms of prognosis.

So when we visit with these patients, and we try to get an estimation of risk, we both look at the MPN panel, are they JAK2 mutated or CALR or MPL, as part of the diagnostic process, and then we look at the additional somatic mutations as part of the prognostic process. So in many patients, particularly with MF, I will obtain a myeloid panel. There’s many variations out there, whatever the lab or your choice, but where you can both get your diagnostic mutations, as well as kind of those prognostic mutations, and then we typically then combine that along with clinical information such as cytopenias, blasts, bone marrow features, and then symptoms, and we can plug those into a range of different prognostic scores that give us a sense of the disease prognosis.

DR LOVE: So yeah, I was surprised when I saw IDH2 in one of your slides there. Of course we first started talking about that from a therapeutic point of view with AML and then more recently with cholangiocarcinoma. Really interesting biology, too, in terms of the — I guess the metabolism involved. Do you see responses to IDH2 inhibitors in myelofibrosis or MPNs?

DR MESA: Yes. So clearly it’s an ongoing study, but I can share with you we have seen some real responses. I had a patient who has had her — the blast features of her disease well controlled now well over a year with the IDH2 inhibitor, from blasts of 18, 20% down to under 5% over a year in that combination of therapy along with ruxolitinib. So it seems to have a real targeted piece.

Now when we think about the biology of accelerating blast phase myelofibrosis there’s kind of a base of how myelofibrosis is affecting them, and then there is this second biological step where they are moving towards acute leukemia with an increase in blasts, worsening cytopenias, and it seems that the IDH2 is really fitting into that piece. So I think, again, even though these are not a common set of diseases we’ll be able to tailor more and more therapy really based on the individual biology that the patient has in front of us.

DR LOVE: Do you see differentiation syndrome incidentally?

DR MESA: We have not in that situation, no. So in any of these targeted therapies we have not yet seen kind of a differentiation syndrome.

Matching treatments to individual patients with MF

DR LOVE: And you went over a bunch of new agents that I want to ask you more about, but when you look at the approved and also the agents in clinical trials how do you separate them out in terms of I guess affecting the phenotype or the symptoms? I mean you talked about the JAK pathway, to me it seems like that’s the symptomatic pathway not necessarily the biologic pathway in terms of the disease. I don’t know if that’s too simplified of understanding of it. But there have been other agents that seem like they’re trying to attack more the clone, the biology. How do you separate those out?

DR MESA: So certainly the drugs with the other mechanisms of action we certainly are hoping to kind of double down on what’s going on with the biology. I would say that the JAK inhibitors, they were criticized at first for saying boy, you’re just treating symptoms, this is just supportive or palliative care, and I’d say the evidence over time would say that that’s really probably unfair. Patients are living quite a bit longer. There is an impact on really that issue of progression-free survival. That’s probably a less hostile bone marrow environment, less pressure toward additional mutations, other more subtle things, but without question still room for biology. Because let’s say we use that individual that was on for 12 years, if one looks at what those 12 years looked like, the patient was stable, they were feeling pretty well, but they were anemic, they had fibrosis in the bone marrow, the spleen was not normal in size. So there was still some real room for further improvement that, again, how do we really double down on that.

So I think that’s really the hope, how do we further modify the biology of the disease. There may be, again, some need to individualize that. The biology may not be exactly the same between all these patients. We still do not fully know why do people progress. So one of the challenges we’ve had is we have not had a good surrogate marker for progression-free survival. There’s been great interest over time to see whether the JAK2 allele burden was a marker of progression-free survival. We think it probably is not. I think as much as we have wanted it to be let’s say the equivalent of BCR/ABL and how that has been as predictive in chronic myeloid leukemia it probably is not the marker for progression-free survival. So we still have had a little bit of a biology gap, but without question I think what we’re seeing with these other agents is the potential of greater disease modification.

I think the large Phase III trials are going to be really quite important, not only in terms of response rate but also seeing 1) are there subsets of patients that are a real homerun with BET inhibition, with Bcl-xL inhibition, with PI3-kinase inhibition. Yes, is there an overall higher response rate, but is there a subset that really looks like they go into remission or something of that nature, normal bone marrow architecture, normal blood counts, I think all things for us to see. So what is kind of the aggregate benefit, but again are there subsets that we really see further evidence of disease modification that may help us further refine our understanding of how do we further modify the course of the disease.

Case: A man in his early 70s with MF and worsening anemia

DR LOVE: All right. Let’s talk about your cases. So 72-year-old man. You first saw him in 2018?

DR MESA: Correct, correct. So I picked 3 cases to just kind of show 3 different scenarios of options, of challenges patients are facing, and how — kind of the decision making in terms of what do we do next, as well as I show kind of what we did for that individual.

So here’s an individual, again, comes in, 72, myelofibrosis. He’s got primary myelofibrosis. He’s got higher-risk disease, so by DIPSS intermediate 2 risk, and symptomatic. So an MPN10 of 25 out of 100, that’s a fairly typical symptomatic patient with myelofibrosis.

Now for 4 years they’re on ruxolitinib, but they start, as many do, on 15 twice a day but needed to dose reduce due to anemia to avoid transfusions. Had some reduction in the spleen, became more anemic. And unfortunately this patient is really kind of a microcosm of some of the challenge we face. They have benefit, but they have difficulty tolerating the dose of ruxolitinib that we most associate with improvement in survival based on challenges with anemia.

So now comes in, 4 years in. The spleen is pretty good size, 10 cm below the costal margin, a lot of symptoms, anemic, platelets are low at 110, and they’re only on 5 twice a day. So I’m sitting with this patient, what are my options? 1) I could go up on the dose of ruxolitinib. If I do, am I going to gain anything more? Probably not at this point in time, but it probably would worsen the anemia.

My off-study options are fedratinib. Fedratinib good in the second-line setting but not if anemia is your limiter. So if they’re anemic on ruxolitinib they’re going to be anemic probably on fedratinib. Pacritinib, I discussed this with the patient, and again that could be a consideration. Anemia might help to be improved with this individual. Or if momelotinib were approved this would be a very nice choice for this individual. Anemic, second line this patient very much would fit very much to MOMENTUM study. Now we’re kind of in between. The MOMENTUM, obviously, had been accrued, and we don’t yet have the approval. Or combinations studies where we add on an additional strategy.

So this individual we opted for a combination approach on a clinical trial along with luspatercept. They qualified for that study where you add luspatercept onto ruxolitinib to try to improve anemia. But my preference, had it been available, probably would have been momelotinib for this individual. If the platelets were a little lower it would be a bit more clear in terms of a pacritinib option, but that certainly could be a consideration as well.

Other options people could consider, so this one, he’s on a trial, people could add danazol to this setting to try and improve the anemia. If the anemia’s a little better maybe you try to increase the ruxolitinib. But this is kind of a classic trap patients can kind of fall into, where they’re too anemic to really tolerate enough JAK inhibition to get a benefit in terms of their spleen and symptoms.

DR LOVE: Can you say what combination the patient was put on and what happened?

DR MESA: Yup. So the patient’s currently on a study with rux and luspatercept, and there has been a little bit of improvement in the anemia, but it has not been dramatic. So we’ll wait and see, but it’s not been overwhelming, but it’s something.

DR LOVE: What is the utility of luspatercept in these patients?

DR MESA: So luspatercept can help to improve anemia. We’ve shown it alone or in combination with ruxolitinib. I think this patient probably has a very mature experience with rux, probably earlier on may have had more benefit. Certainly as clinical trials he kind of narrows the options. I think if luspatercept becomes approved in myelofibrosis we’ll probably be able to refine its use earlier on, as well as there’s some molecular markers, SRSF2, from that if they have that could be predictive of even kind of greater response. So there have been probably about a third of patients that can have a nice response with that combination, this patient probably a little less at this point, but again anemia probably one of the biggest unmet needs, which is where I think if momelotinib is approved I think there will be quite a bit of an uptake, particularly as it relates to this issue of anemia.

DR LOVE: So a final question about this case. I’m curious like how the patient appeared when you first saw him, kind of going back to what we were talking about before. What kind of symptoms did he have and what happened over the first couple months?

DR MESA: So this patient had some cachexia, had had some weight loss, had fatigue, felt quite a bit better over the first couple months but with a decrease clearly in the hemoglobin. And then over time as the hemoglobin decreased further we had to lower the dose. So we follow a little bit of that pattern where you can kind of come in strong, the beginning is strong, but then kind of maintaining it can be a bit of the challenge.

DR LOVE: Okay, let’s go to your next case.

Case: A man in his late 60s initially diagnosed with polycythemia vera now with MF requiring therapy

DR MESA: So next, here is an individual, much more recent patient I saw, 68 and had PV 4 years, good-sized spleen, symptoms, higher risk with mutations, a little bit anemic, some blasts, high white count, platelets, marrow 2-3+ fibrosis, karyotype deletion 13q. So this was a patient originally here from Texas, because the counts had been okay had been kind of watched, had not had — the patient had been offered but had opted not to go on a JAK inhibitor yet.

So I went through with this patient options. 1) We could start this patient straightaway on rux, hemoglobin at 10.2, again higher risk, might have a good response, probably will run into issues with anemia. We could use fedratinib, it clearly would meet the definition of the approval for fedratinib. This was a patient I registered onto the MANIFEST II study, so this was rux plus pelabresib. Would have qualified for the other front-line studies, as well, but kind of a perfect example, big spleen, lots of symptoms, JAK inhibitor naïve. Based on what we’ve seen in the Phase II studies anticipate a nice response in spleen in symptoms, as well as there’s evidence from the earlier studies that there may be more biology modification with the combination.

So there’s early data. Again, it’s Phase II data. Decrease in fibrosis, potential improvement in anemia. There may be even impact in terms of molecular phenotype.

So I think — so this patient has started on there relatively early on, but they’re having a nice response both in terms of spleen and symptoms. It will clearly take longer to see kind of the aggregate benefit, but I certainly have been encouraging all our JAK inhibitor-naïve patients to consider any of these combination up-front studies that — many of which are still accruing. There’s not a big downside we’ve seen from the Phase II data to any of these trials going on for the combination, so I’m encouraging everyone to consider these for JAK inhibitor-naïve patients, as well as people watching this video afterwards. If you have patients that have MF but have been JAK inhibitor naïve, know that there’s this whole cascade of studies available.

It's important because in the more recent past the studies were all about JAK inhibitor failure. So I would have patients sent to me, we’ll put the patient on ruxolitinib, and the patient can then get a second opinion with Dr Mesa to see if there’s an appropriate study. But know that there’s up-front studies so the moment you start them on a JAK inhibitor we’re pretty much obligated to kind of ride that out unless they fail.

DR LOVE: I’m assuming these are placebo-controlled trials.

DR MESA: So the MANIFEST study is rux plus pelabresib versus rux plus placebo, blinded. So everyone’s getting rux, then plus or minus the other drug. And all the other drugs are — all the other drugs are basically designed the same way. So at a minimum everyone is going to get the standard of care, and then it’s very straightforward, either plus or minus the investigational agent.

And then it’s blinded, but of course the other drugs, since they do tend to have more GI side effects, and rux typically does not, it’s not the best blinding in that it’s fairly easy to tell who’s getting both.

DR LOVE: Yeah. I was going to ask you about that because you mentioned the fact that you’re really not adding that much toxicity on. I don’t know anything about BET inhibition. I’m not sure where else it might be used, but of course PI3-kinase, I know there are different agents, but you have them in breast cancer, you have it in lymphoma. You were mentioning about venetoclax in CLL, AML. I was going to ask you like what’s the difference between venetoclax and navitoclax, and like does navitoclax not work in AML? Does venetoclax not work in MF? Or is it just a vagary of how they’ve been studied?

DR MESA: It’s a little less intense in terms of the toxicities. Venetoclax has been used along with rux in patients with more accelerated-phase disease, and the data have been mixed, although the prognosis in that group is pretty rough.

The other PI3-kinase inhibitors in CLL have not been looked at to kind of the same degree. There have been some other PI3-kinase inhibitors that have been tested that were negative in MF, so parsaclisib is the one kind of furthest alone.

DR LOVE: And what do you see? You mentioned GI issues. I think I’ve heard about GI issues with venetoclax. Do you see, for example, GI issues with navitoclax, parsaclisib?

DR MESA: We see about, with each of these agents, maybe kind of 20, 30% GI issues. And none of them is it overwhelming but also something that we need to kind of monitor. That is — one issue as we look combinations in terms of the JAK inhibitor base ruxolitinib typically does not have much in the way of GI toxicities. Ruxolitinib can, and has the maturest data set, but can increase the risk of nonmelanoma skin cancers, so that’s a big one, particularly in our neck of the woods, both in Florida where you are, as well as here in South Texas, it can be a limiter for some folks. It rarely has been associated with some atypical infections, surely increased risk of herpes zoster, probably in part because of its JAK1 inhibitory type issues that it has. Now pacritinib, fedratinib both have GI toxicities, momelotinib to some degree as well, all manageable but all a little different than rux. So that is the 1 kind of caveat.

As I look at one of the alternative JAK inhibitors plus pelabresib or parsaclisib or navitoclax we will need to see, again, what the toxicity is of the combination just whether the GI toxicity adds in between them.

Case: A woman in her mid 60s with MF that has a suboptimal response to first-line JAKinhibitor therapy

DR LOVE: Okay. Let’s take a look at the last case.

DR MESA: So the last case I think, again, represents a lot of the folks that are being seen out there in the community. So here’s someone post PV MF in 2021, baseline big spleen, 15 cm below the costal margin, lots of symptoms. The blood counts are pretty well preserved, as is the case with post PV. They still have a lot of that intrinsic myeloproliferation. They’re on rux 20 twice a day. But now, about a year in, the spleen is a little smaller but still enlarged, still lots of symptoms. They have — blood counts are okay, but they’re still not fully responding, and they’re pretty much on maximum dose rux.

So what are the options we have? We could switch him to fedratinib. We can do an add-on strategy. So again, this is a perfect example of somebody who would be great to add on a second drug such as navitoclax. So this individual, we went through the options, and they opted — they were going to have to drive for a distance, they didn’t want to participate in a trial, so we’ve gone with fedratinib. And we have seen some additional reduction in the size of the spleen but have as a backup considering the addition of a second drug like navitoclax for the suboptimal responder.

So if navitoclax becomes approved, or pelabresib, I would envision — again, we’ll probably be evaluating for response and expect response earlier. So 4 months in if you’re not having a good response do we add on kind of the second drug?

But this on, again, went to full-dose fedratinib 400 mg once a day. I do have them on thiamin. Again, thiamin is relatively straightforward for these patients to be able to have that added on for them. I give them a prescription for ondansetron and have them take it for the first couple days just to be sure they don’t have a bad experience, and then try to wean them off. I certainly have them consider loperamide at kind of their first signs of diarrhea, but in this patient it’s not been a big factor.

DR LOVE: Can you review the symptoms of thiamin deficiency and or Wernicke’s?

DR MESA: So Wernicke’s, again, they can have both kind of a cognitive encephalopathy piece, as well as kind of a bit of a motor piece. It’s not a common toxicity that us as oncologists are used to having. So when the trials were being done there was really a delay in identifying the cause of encephalopathy in large part because it was a toxicity we’re not used to seeing, whereas, again, as oncologists we’re used to cytopenias, we’re used to infection, we’re used to GI. So it was a bit of a learning experience as a field that, again, if a toxicity’s a little bit out of your wheelhouse then it may be delayed.

So that was an agent, it was on the cusp of being approved, and then it was identified that there were these cases, and they created this question. The FDA put the drug on hold because of this question. It kind of got shelved by pharma even though there was a path that could be followed, and then the drug was resurrected, saying boy there was clinical benefit there, there was an unmet need, and they were able to work through it, the black box and these other pieces. And then we have done additional studies in Phase III, both for additional safety data and efficacy data after approval of fedratinib, called the FREEDOM studies, that again have validated the approach to monitoring thiamin and replacing it is perfectly adequate for trying to mitigate any issues of Wernicke’s. So we clinically and in the trials really have not seen any issues with Wernicke’s after the — after taking those steps.

DR LOVE: What is the thought about the pathophysiology of why it causes thiamin deficiency?

DR MESA: I think it interferes a little bit with I think thiamin uptake, which kind of decreases the levels, and then the levels in the serum, which is a little bit different than some of the other JAK inhibitors. So it is a bit more specific to fedratinib than the other JAK inhibitors. It’s not been seen with the others.

Efficacy and safety of novel agents and strategies for MF

DR LOVE: Getting back to navitoclax, of course, again, in these other cancers, particularly CLL, you have the issue of potential TLS. I assume that’s not an issue here.

DR MESA: It’s not been seen. It’s certainly being monitored for, but we’ve not seen those sorts of issues.

DR LOVE: And is it thought that the drug causes additional cytopenias?

DR MESA: It can. Certainly one of the limiters are around thrombocytopenia. That certainly has been kind of a dosing issue that certainly are being looked at. There’s additional drugs in this class, DT2216 is being developed actually by a company led by the Dean of UT Health San Antonio, Rob Hromas that may have a little bit less of that piece, so there may be some other drugs kind of coming down the pike that may have less issues with thrombocytopenia.

That by — is one of the reasons we’re — again, it hasn’t been tested yet, but interesting combinations. If you have a drug that causes thrombocytopenia, but if you used it with let’s say pacritinib, would it be a good fit because you would not be lowering it kind of from both sides.

DR LOVE: Any comments on the use of any of these agents, but particularly ruxolitinib, in PV and ET?

DR MESA: So ruxolitinib approved in polycythemia vera in the second-line setting. It’s a good drug, helps make people independent of the need for phlebotomy, improve symptoms. In ET it is not approved, but it clearly can be helpful. In the NCCN Guidelines we have it as a third-line therapy, particularly if they have symptoms and splenomegaly it definitely can be helpful.

The other drugs have not had significant testing yet in P vera or ET, and since they each have different characteristics (1) it seems fedratinib might be the most logical for PV or ET because it has the impact on the red cells and the platelets more similar to ruxolitinib. Momelotinib you might imagine again in PV probably is not a natural fit because it may not decrease the red cells to the same degree or the platelets, and likewise pacritinib.

So there may be some difference between them, but again as we learn more about those diseases it is always possible that combinations may have a slightly different profile.

DR LOVE: Anything you want to add to what we’ve chatted about today? Anything that you often will bring up when you give talks that we haven’t talked about?

DR MESA: I think some of the things that are notable that are absent are (1) checkpoint inhibition. So checkpoint inhibition has been looked at, and at least kind of our current slate of checkpoint inhibitors along with JAK inhibition has unfortunately not been very beneficial. We still hope that again some immune-based response may be helpful, and people are studying the biology further.

There is great interest in calreticulin as being a little different than the other mutations as being present on the cell surface. And the first of the vaccine studies was presented at EHA earlier this year and was solidly negative. Now again, it may be many issues. Is it the right vaccine, the epitope, all these different sorts of things. But there is hope that calreticulin-mutated disease may be more accessible to an immune-based approach, a CAR T-type approach, a vaccine-type approach. So there are many things, they have not really hit the clinic yet, but are kind of looking at that kind of in the future.

Finally, long term there is great interest, of course, in gene editing. Gene editing obviously is really — it’s in its first iteration looking at gene editing in benign hem disease, sickle cell and hemophilias. People often thought boy if you can just edit JAK2 V617F would it cure the disease. No one knows yet for certain. So I can kind of — intermediate and longer term, but more in the intermediate term I think we’ll go from this kind of targeted molecular approaches to perhaps something that is really more immunologic or targeting calreticulin as a first step. Longer-term gene editing and other parts are at least of interest, but again will be complex. Many of these diseases have more than 1 genetic abnormality, so again is it — will it be applicable kind of across a broad group, I think to be determined.

But without question at a high level I would leave people with the sense of there’s been tremendous progress. Before 2005 we had nothing, nothing that really made any dent at all. I mean we’re clearly in a situation where having MF in 2022 has a much longer life expectancy, better quality of life, and many more options than we had before, and also many more biological clues in understanding of pathophysiology that may lead to further advances.