Introduction: Myelofibrosis (MF) for Oncology “Newbies”

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to Year in Review, as today we focus on the management of myelofibrosis. We have a great faculty for this program, Dr Aaron Gerds from the Cleveland Clinic in Cleveland, Ohio.

As always, if you have any questions or cases you’d like to run by us, just type them into the chat room, and we’ll talk about as many of these as we have time.

We put a 1-minute survey in the chat room for you to take, and also at the end of the meeting. If you do that, you’ll get a lot more out of this exercise here today.

We know a lot of people end up listening to our webinars, particularly on replay. If you’re into podcasts check out our Oncology Today series, including a recent program on myelofibrosis with Dr Mesa.

We’re getting ready to head out to the Hilton Hotel, as we’ve done every year for the last 15 years, to the ASCO Meeting, the big ballroom there. This year we’ve got 9 programs, starting out on Friday, and these will all be available online. So Friday afternoon of ASCO, 11:45 AM, May 31st, we start out talking about HCC and biliary tract cancers, and we’re going to be covering a whole variety. We have a couple just live webcasts, but always a lot of fun there at ASCO.

But today we’re going to talk — some stuff going on in myelofibrosis there, too, as well. But today we’re going to talk about what’s happened over the past year in myelofibrosis. And as always we will be referring to non-FDA-approved agents and regimens. Check out the package inserts.

Here are some of the papers that we’re going to talk about here today as we focus on this.

I want to start out with kind of an introduction before we sort of dive into some of the clinical research issues and questions and clinical management questions.

You know, our group has been thinking a lot about the issue of education for fellows. We know a lot of fellows use our work, and we’ll be very interested in the chat room. If you have any thoughts about whether there’s other things that fellows might want in education beyond what we typically do in our program, you think they want to hear about, you know, some of the psychosocial issues, end-of-life care, supportive care, complementary care. Anything you think that a fellow might be interested in.

And in that regard I was really curious, Aaron, that you had this super-cool paper, I thought, you’re part of this group that this came up, “Consensus recommendations on how fellows should be able to read a peripheral blood smear as part of their fellowship.” And I thought that was a pretty cool idea. I also was curious how it relates to myelofibrosis. Can you kind of summarize what your group did there?

DR GERDS: Yeah. Well, thank you so much, and thanks everyone for joining this evening. It’s a pleasure to be with you all.

This project was kind of fun. It admittedly did not start out with anything related to myelofibrosis. In fact, Dr Chase approached me about joining the group. He said, “Do you know what? Fellows — it’s very unclear what fellows need to know by the time they’re at graduation, and maybe we should try to figure this out.” And so we spent a couple different focus group sessions focusing on like what a fellow should know when they graduate when looking at a blood smear.

And you can see here, there was a representation of different types of faculty. We have classical hematologists, red cell folks, white cell folks, benign and malignant both, and so there’s a big range of opinions on what we cover.

And this map here kind of shows how we organized the information. We talked about what a fellow should know technically of a smear, the different types of cells, abnormal — both normal/abnormal, and we kind of mapped these conversations out and really looked at not only the time spent on each topic but really where we kind of arrived at some consensus.

And so in the paper itself, there’s a consensus statement saying okay, every fellow should know X, Y and Z. But this is kind of, again, a graphical representation of the breadth of the conversation.

We spent most of the time talking about blasts and identification of various features of blasts on the malignant side. On the classical side we talked a lot about identifying thrombotic microangiopathies, which actually myelofibrosis is at the center of that. So as a graduating fellow recognizing blasts in a myelofibrosis patient is important, of course, in risk stratification, identifying progression to accelerated blast phase, as well as looking out for hemolysis and microangiopathies that can occur with increased frequency in these patients.

So while it didn’t start out as a myelofibrosis paper, everything comes back to MPNs at the end of the day, at least in my small world.

DR LOVE: So in addition to kind of wanting to pick people’s brains about fellows, I also have to say, I really love the colors on this chart here. I’m always looking for colorful things. And I was thinking if we ever do do a fellows initiative I wanted to use this, some variation of this as the symbol. And I tried it different ways. I turned it around. I want to know what you think about this as the symbol of our fellows program.

DR GERDS: I mean, this is very Sons of Anarchy, right? We can start our own hematology motorcycle gang. Beware of the nerds on bikes. That’s for sure.

Biology of MF

DR LOVE: Alright. So let’s get down to the nitty-gritty of myelofibrosis. And as we were chatting about it, our primary target audience is the community-based general medical oncologist. This is not like lung cancer or breast cancer for them, a much less common scenario. We here in the CME group are kind of seeing things from a macro perspective, and there’s obviously a lot of very interesting things going on biologically.

Now we put a bunch of slides in here, and I’m going to kind of flip through them, but you don’t need to talk about that. I just want you to talk like you’re on rounds. And what I’d like you to do is talk a little bit about your vision of the biology of myelofibrosis, the type of mutations you see, and the implications, the difference between the different JAK inhibitors in terms of their mechanism of action, and then it seems like a lot more is getting defined about the pathways of red blood cells. We’re seeing hepcidin. We’re seeing treatments for polycythemia, momelotinib, et cetera. So it kind of looks to me like — and particularly the biology’s kind of going farther with red blood cell developments. So I’m just kind of curious how you paint a picture on rounds to your fellows and everybody else about your vision of this disease.

DR GERDS: Yeah. That’s a fantastic question. I take a very kind of start at the center and work my way approach. At the center of the biology of this disease, it doesn’t matter if you have myelofibrosis, PV or ET, is activation of the JAK/STAT pathway. That’s kind of the central piece. And the JAK/STAT pathway is the pathway of your kind of cytokines that mediate growth of cells in the bone marrow. We’re thinking erythropoietin, thrombopoietin, G-CSF, these kind of classic molecules that drive red cell, white cell and platelet production. So it makes sense that we get a mutation in this pathway that leads to constitutive activation, and we see increased blood cells. It makes complete sense there.

And the other kind of key piece of this pathway is the dimerization that’s needed. So JAK molecules need to come together in order to affect a downstream target, and that’s the point of the JAK inhibitor. JAK inhibitors prevent that dimerization and the signaling downstream.

These mutations, we focus on them because they are central. Virtually every patient will have a mutation and typically within 1 of the 3 genes, JAK2, calreticulin or MPL. JAK2 really heavy — very prevalent in polycythemia vera, particularly JAK V617F, and roughly 60% of patients with ET and myelofibrosis will have the JAK2 mutation. Calreticulin is very common, 20-30% of patients with ET or myelofibrosis will have a calreticulin mutation. And there’s a decent chunk with MPL mutations.

They all do the same thing at the end of the day. They activate the cytokine pathway in the absence of a cytokine sitting on the receptor. So it’s like your thermostat turned off a long time ago, but the furnace is still making heat. And so we’ve got to bring down the heat by going in there and kind of smashing the electronics so the furnace will turn off.

DR LOVE: I love this kind of analogy.

DR GERDS: Yeah.

DR LOVE: Maybe before you go — before you go on — I love these kind of analogies, but before you go on, any difference in the way patients respond to JAK inhibitors based on the type of mutation they have? In the beginning when the COMFORT trial came out a lot of people thought you had to have a JAK mutation to respond to JAK inhibitors. What do we know at this point?

DR GERDS: Yeah, and I think that still applies. But equally across the board patients respond to JAK inhibitors similarly no matter what their driver mutation is. It doesn’t matter if it’s JAK2, calreticulin or MPL because the key thing that links all 4 approved JAK inhibitors together is inhibiting JAK2. That’s the commonality you’ll see here in this green horizontal bar.

So if we kind of work — if that’s our alignment, where we kind of line up all the JAK inhibitors. And then everything else kind of springs off of that of what each of them do. Some inhibit JAK1, some do not. Some inhibit mutant JAK2 and others do not. Some inhibit things like ACVR1 or IRAK1 and others do not. And so all these kind of extra effects help us select what JAK inhibitor to use in what situation, but there are kind of key pieces all hitting JAK2, wild-type JAK2.

DR LOVE: So for us out here in the real world, we kind of look for stuff that you are talking about, and I’ve been hearing more about ACVR1, more papers on it. It looks pretty cool. Can you try to explain it?

DR GERDS: Yeah. ACVR1 is also called ALK2, and it’s a regulator of the SMAD pathway, which regulates transcription of hepcidin. Nothing’s hotter in MPNs right now than hepcidin. It is like from — I don’t know if you remember the movie Zoolander, Hansel, he’s so hot right now.

DR LOVE: Right.

DR GERDS: But like Hansel — hepcidin’s our Hansel right now because of 2 reasons. One, by inhibiting ACVR1 we can decrease hepcidin in patients, and when hepcidin is high iron gets stuck in those iron stores and can’t get out for erythropoiesis. It’s anemia of inflammatory block. By blocking ACVR1 we can relieve the anemia of inflammatory block. So iron comes out of those iron stores, available for erythropoiesis. That part of the anemia pie is solved.

On the flipside, we’re using hepcidin memetics, or drugs that increase levels of hepcidin in the body to lower erythropoiesis or to treat polycythemia vera, like we can lower red cell counts by increasing hepcidin. So we’re lowering hepcidin to treat anemia. We’re increasing hepcidin to treat polycythemia vera. Same pathway, different drugs, related diseases. It’s so cool. It is so Hansel.

And here’s a nice slide showing the mechanism of action of momelotinib. Again, blocking ACVR1. We’re lowering those hepcidin levels, iron can come out of the iron stores and be made available for erythropoiesis.

Now, this is not the end-all be-all for iron. There’s lots of — for anemia in myelofibrosis. There’s lots of reasons patients are anemic with myelofibrosis. It’s multifactorial. But this is just something we haven’t hit before. We’ve hit early erythropoiesis with ESAs, late erythropoiesis with luspatercept. We understand that ruxolitinib can increase anemia through some cytokine signaling pathway, but this is kind of going about it in a very different way, and so it’s very, very exciting.

DR LOVE: So you mentioned polycythemia, and we have this agent rusfertide, a hepcidin memetic.

DR GERDS: Yeah.

DR LOVE: Any thoughts? Any comments?

DR GERDS: Yeah. It’s a pretty cool drug. Now there’s clearly an unmet need in polycythemia vera because a lot of patients will still need phlebotomies despite being on a medication or be on the lower end of risk and really burden with phlebotomies. Sorry, I mean phlebotomies not transfusions, the opposite.

I mean, I don’t know, phlebotomies, they’re a lot of work, right? You have to come into the clinic. You have to like get an IV. Yo have to sit there and wait for them to take the blood out. And it makes you iron deficient, and you can have a lot of symptoms related to the iron deficiency. And so the idea is that we can alleviate this from the patient burden and hopefully improve their quality of life.

And so this was a randomized trial pitting rusfertide versus placebo with a second double-blinded section there where every patient got to serve as their own control. So everyone got rusfertide, then half the patients went through rusfertide withdrawal on a placebo and then went back to open label. So we can really see — there are swimmers’ plots in this publication that are just really cool, where you can see patients getting tons of transfusions, going on drug, and then no longer needing — or phlebotomies. I keep saying transfusions, but I mean phlebotomies.

DR LOVE: So my aging brain can only take, like, 1 pathway at a time, but would you like to try to take a shot at where the mechanism of action of luspatercept fits and your vision of at least anemia?

DR GERDS: Yeah. So if you think about the ACVR1/SMAD/hepcidin pathway right here, right next door, probably actually in a duplex, I would say, in the same duplex, is what luspatercept is doing with the SMAD pathway. Little bit different SMAD signaling it interferes with, but it’s this activin ligand trap which sucks up all these TGFβ superfamily ligands and then actually can downregulate the SMAD pathway in a slightly different angle. And by doing so we really see a burst of late differentiation of erythroid cells.

When we give ESAs, a synthetic EPO, that is, it really works early on, on the top of this figure here on the left-hand side of that. Where luspatercept, by blocking this pathway, really works on later differentiation of erythroid precursors.

So obviously, if they’re very similar pathways you might say well, are these virtually the same thing? But they’re doing very different things, but, potentially, at least in preclinical models, might be synergistic. So there’s a lot of interest in combining luspatercept with ACVR1 inhibition.

DR LOVE: And we’re going to get into some of the clinical issues related to these pathways and anemia, but just as long as you’re on a roll here in terms of biology, I thought I’d give you a shot. We’ll talk later on about selinexor, which is an agent we talk about in other cancers, including uterine cancer.

DR GERDS: Yeah.

DR LOVE: But everybody takes their own approach to how they explain it. Would you like to take your shot?

DR GERDS: I profess that I’m a simple country doctor, and so sometimes these things are lost on me. But we always talk about in myelofibrosis and MPNs in general JAK-PAT — JAK-STAT is not the end of the story. This is not CML. It’s not like where we can throw the MF equivalent of imatinib at the disease and it melts away and is in remission. So there are clearly a lot of other pathways activated. NF-κB is so critical in the pathobiology, not only for the derangement of the megakaryocytes but the production of scar tissue and cytokine production, so it makes sense to try to target this.

And it turns out by blocking the export molecules within the nuclei of these cells that we can affect a difference. And certainly the preclinical data was suggestive that selinexor would be an active agent at lowering cytokine levels in patients with myelofibrosis. And it turns out in early trials that that’s the case, that we’re lowering cytokine levels leading to both symptom and spleen responses well beyond what I would — I personally was expecting with the agent. So very exciting for sure.

DR LOVE: That also leads into the other question, you mentioned cytokine levels, but the issues that’s always been out there of all of these treatments, the issue of how much of the benefit is symptoms and performance status and how much is it actually affecting the biology of the disease, the progression of the disease? Where are we today with that very basic concept, particularly just in terms of JAK inhibitors? You could certainly imagine when your spleen shrinks down, and you gain weight that you might live longer, but what about the underlying disease? Does that slow down?

DR GERDS: Yes. Definitely we see that. So patients are living better, so we think they live longer because they’re living better. There’s plenty of data with ruxolitinib and the other JAK inhibitors showing that patients who have significant spleen volume reductions do have a better survival repeated over and over and over again. But how much does it is truly killing off cells? It’s unclear. Yes, lowering cytokine levels, people have a better performance status, better quality of life, and are doing better for longer, but is it truly killing off myelofibrosis cells? It’s hard to say.

Now in PV, the MAJIC PV trial, which is a randomized trial of hydroxyurea verus ruxolitinib, we’re seeing more molecular responses in PV, with longer durations of therapy. And perhaps a less genomically complex disease that PV is we can see more effect there. But it’s largely thought that JAK inhibitors do not deeply modify disease, and that’s why we have all these strategies of adding other drugs, like selinexor to ruxolitinib to impact the disease more greatly.

DR LOVE: So I want to go back to this slide that we were talking about before —

DR GERDS: Yeah.

DR LOVE: — in terms of the — your vision of the approved agents that we have to deal with. In addition to these biologic variables can you talk a little bit more about your vision of these agents clinically? And then we’re going to get into the really important question I want to address that we’ve been hearing from oncologists for a while, particularly since the approval of momelotinib, which is how do you deal with a patient who develops anemia while on ruxolitinib. Do you dose reduce? Do you transfuse and keep them at the same dose? Do you switch to momelotinib?

I’m going to show you some of the scenarios we presented to try to see what people are going to do. But let’s just start with your vision of clinically how these agents differ and how they’re used, their tolerability profiles and their efficacy.

DR GERDS: Yeah. And I think this is a great slide to have that conversation with. So again, they’re all JAK2 inhibitors. They all inhibit wild-type JAK2. That’s how they work. The least important thing on this slide is inhibiting mutant JAK2, definitely the least important thing. I mean we’ve had very good pure JAK2 — mutant JAK2 inhibitors no better, no better than good old fashioned ruxolitinib. And then these other effects where we get into.

So IRAK1 kind of jumps out at you, because IRAK1 and then the NF-κB pathway again pops in, same as selinexor, as a key kind of pathobiology behind myelodysplastic syndrome. There are actually IRAK1 and IRAK2 inhibitors that are being developed for myelodysplastic syndrome right now and entering trials. So you start to develop this picture about well, maybe more cytopenic or myelodysplastic-y type of myelofibrosis. And then you add in ACVR1, I mentioned, a drug that could potentially treat anemia with inflammatory block. And so pacritinib emerges as kind of an optimal agent in those patients.

Ruxolitinib is still the champion in terms of spleen volume response and symptom response. I know we’re going to talk about novel therapies in a little bit, but to me the biggest story from those trials was the fact that rux is still really good at treating symptoms, owing largely to this — its effect on JAK1, I think, as well as JAK2, but we’re certainly seeing those improvements there.

But that’s kind of how we start to parse these things out. Momelotinib being very similar to ruxolitinib but having this ACVR1 effect, so you think about like ruxolitinib plus anemia benefit, pacritinib kind of more of this cytopenic myelofibrosis, and fedratinib kind of cementing itself in “the second-line setting.”

Management of Anemia in MF

DR LOVE: So here are some of the scenarios that we’ve presented in our meetings from the surveys we’ve done of patients who develop anemia while on ruxolitinib. Depending upon exactly how you present the scenario, people might do — in this scenario everybody switched to momelotinib. Depending, they might do other things. They might dose reduce depending upon exactly how you present the case.

And we’ve asked this question about this, and, of course, it was just approved now just in September. But then when I was going through your CV I saw this paper, a letter to the editor that really addressed this question. A whole bunch of really cool graphics in there that I really wanted you to walk through a little bit.

DR GERDS: Yeah.

DR LOVE: First, can you talk a little bit, though, about what are the clinical scenarios where you see anemia in patients on ruxolitinib, and how do you think it through based on the available data? And then how you all kind of thought through this issue for this paper.

DR GERDS: Yeah. So there are a lot of different situations where anemia can creep in, but I kind of see it as 3 major bends within the context of ruxolitinib treatment. There are those patients that are anemic before you even start, and therapy selection can be very important at that point. So patients who come out the gate, even before they get a JAK inhibitor who are anemic. Then there’s this group of patients who they go on ruxolitinib and immediately become anemic, first month to 2 months their hemoglobin just tanks. And then there’s this third group that did really well on — really well on ruxolitinib for a very long time and then slowly months, years later develop anemia.

So I think all of those are very different situations, and you can kind of think about different therapies in those situations. But either of those situations would be considered for momelotinib. Momelotinib has been used in the up-front setting for patients with myelofibrosis, as well as the second-line setting after ruxolitinib. In the SIMPLIFY-1, SIMPLIFY-2, and the MOMENTUM studies.

The question in my mind is, is someone on a JAK inhibitor, are they doing well? Do they have good control of their symptoms, do they have good control of their spleen, and is it just the anemia that kind of snuck in? Then you might think about adding an anemia supportive agent in those cases. But if they’re not hitting their goals in terms of spleen volume reduction and symptom burden improvement then it makes all the sense in the world to switch to another JAK inhibitor like momelotinib.

DR LOVE: Can you comment on some of the supportive graphics that were in the paper?

DR GERDS: Yeah. So this is data from the SIMPLIFY-1 trial. SIMPLIFY-1 was a prospective randomized trial pitting ruxolitinib versus momelotinib in the front-line setting. Its primary analysis was spleen volume reduction and symptom burden reduction at week 24, and it was not inferior to ruxolitinib in terms of spleen volume reduction but was inferior to ruxolitinib in terms of symptom burden response, which again kind of goes back to my earlier point, rux is a great drug for symptoms.

And so with this, though, what we saw, that patients who struggled on ruxolitinib in terms of anemia can benefit from switching over to momelotinib when they did so in the open-label extension of trial. And we saw this repeated actually in the MOMENTUM study, when patients transitioned from danazol over to momelotinib we saw these anemia benefits. And really kind of the take-home point for me here is that we have multiple drugs. We don’t have to keep stretching out rux over time and lowering the doses and adding other drugs in, we can simply just switch to another JAK inhibitor these days because if patients aren’t optimized on rux they don’t have those preferable outcomes.

There’s a paper called the RR6 model, where simply I remember it because it’s super simple, I’m a very simple person, but if you’re not hitting a 30% spleen volume reduction, if you’re not on ruxolitinib 20 twice daily, and if you are transfusion independent — sorry, if you’re not transfusion independent or transfusion dependent, the outcomes are not great and so again, kind of pushing you to change. And so if your patients aren’t doing optimally on ruxolitinib think about an alternative agent.

DR LOVE: So Priya Rudolph, an oncologist, is in the chat room, said she attempted to access momelotinib for a patient with a hemoglobin of 6, first-line treatment, but they would only approve ruxolitinib.

DR GERDS: Oh, boy. That’s awful. Yeah. Hemoglobin of 6 on ruxolitinib you’re going to run into a lot of trouble there. Yeah, insurance authorization is a challenge.

So in my appeal letters, in those instances, I cite the fact that the label for momelotinib is line agnostic. There’s no second line, first line, no line. Secondly, I do really point strongly to the SIMPLIFY-1 data. SIMPLIFY-1, again, being that front-line therapy study showing not only that we can shrink spleens with momelotinib on par with ruxolitinib, maybe symptom burden not so much, but the anemia benefit in SIMPLIFY-1.

So at week 24, roughly half there were — 50% fewer patients were transfusion dependent on momelotinib as compared with ruxolitinib. So to me that’s saying that yeah, we can deliver this therapy in anemic patients if not improve their anemia at least not make it worse.

DR LOVE: So anything else you want to say about the critical studies that led to the approval of momelotinib last September? You were talking about this trial where you saw the SIMPLIFY-2 comparison. We saw an update at ASH. Anything else you want to say about that study?

DR GERDS: Yeah. So SIMPLIFY-2 was a prospective randomized trial in the second-line setting, so patients were on rux and then went on to be randomized between best available therapy and momelotinib. And this trial was plagued by poor design. Patients did not have a washout period, and so their spleens could have been partially responding to ruxolitinib, and then they go on the study, and we didn’t see the spleen responses with momelotinib that we saw — that we saw with SIMPLIFY-1 or the subsequent momelotinib — MOMENTUM study, primarily because we just didn’t give it enough time for the spleens to go back to their baseline.

And so we’ve done a lot of subanalyses or ad hoc analyses on SIMPLIFY-2 to really try to tease out benefit in the second-line setting. And really there’s this kind of like holy grail of transfusion response, SVR35, meaning spleen volume reduction of 35%, and TSS50, a 50% reduction in symptom burden. And with this we were truly trying to show that patients were getting multiple benefits from all these different kind of key endpoints, and more patients were in that kind of middle of that Venn diagram compared to the best available therapy, which was mostly ruxolitinib on that trial.

DR LOVE: Hasan in the chat room wants to know why not just add EPO and luspatercept to the patient that Dr Rudolph has?

DR GERDS: Yeah. I think if a patient — to me with that patient if they are symptomatic, if they have a big spleen and have significant symptom burden, then you certainly want to give them JAK inhibition, right? If they’re otherwise asymptomatic then yeah, absolutely, jumping in with an ESA if their EPO is less than 500, or luspatercept would be a preferable option.

So if a patient just has anemia and doesn’t have significant spleen or symptom burden, then anemia-directed agents, ESAs, luspatercept, danazol being kind of your top 3 go-to there, make complete sense. But if a patient does have an enlarged spleen and significant symptom burden then considering a combination — a combination and 1 therapy, like momelotinib, makes a lot of sense.

DR LOVE: Anything you want to say more about the MOMENTUM study comparing momelotinib to danazol? Pretty impressive waterfall plots.

DR GERDS: Yeah. They are very nice waterfall plots. And so this was the trial that served the large basis for the approval for momelotinib, momelotinib versus danazol. Danazol was selected because it’s an active drug at treating anemia in myelofibrosis. Some may argue though that it’s kind of a chlorambucil of myelofibrosis, we picked it to beat up on it, but this is what the FDA wanted.

And the key take-home points, momelotinib was, of course, better at shrinking spleens and improving symptoms, as you would expect, because danazol’s not really too active at doing that, but it was not inferior to danazol at improving transfusion burden. So you’re getting the spleen volume responses, you’re getting the symptom burden responses, but you’re also getting transfusion improvement. So again, the whole concept of well, just stay on the rux and add danazol on top for example.

Well, this drug is doing that with 1 single pill. And early on there was a trend maybe to better survival in the patients randomized to momelotinib, but of course with the crossover that started to wash out. In this trial at week 24 patients were allowed to cross over to open-label momelotinib.

So there were some attempts later on to try to, like, do this fancy statistical analysis to pretend statistically as if patients never crossed over and showed that maybe the survival can — there might be a beginning of a survival advantage with this population.

Novel Strategies for MF

DR LOVE: So let’s talk about some of the newer approaches. We saw some interesting Phase III trials at the ASH Meeting beginning with this one, the TRANSFORM-1 study with navitoclax, which I guess people were somewhat disappointed with in that they didn’t see symptom improvement.

DR GERDS: Yeah. Wow.

DR LOVE: Right. Yeah.

DR GERDS: Wow. Was ASH exciting this year? I mean 2 prospective randomized Phase III trials in the front-line setting for myelofibrosis, of course presented at opposite abstract sessions, so that got everyone all excited. But yeah, you know, to me, when I first saw the results, I was super excited. Hey, we got a positive study. The primary endpoint, SVR35 at week 24, was positive. I was ecstatic. But everyone kind of tempered that with this whole like, well, symptoms didn’t hit. It’s a secondary endpoint. And on top of it, rux is a great drug at treating symptoms. And so to me looking at this, we’re not making patients worse. We’re doubling, almost doubling the spleen volume response but not making anybody worse in terms of symptoms. That’s fantastic.

I think really where a study like this will pan out is with more time, right? So this is only week 24. We want to see how durable are these responses. Is the combination more durable than single agent? Are we delaying progression or other kind of markers of deeply modifying disease? I worry, though, not being an investigator on the trial, that the patients with this is starting to wear thin. Our we going to be able to hang on long enough with this trial in order to see those long-term effects? I don’t know.

DR LOVE: What are the downsides of navitoclax in terms of toxicity/tolerability?

DR GERDS: Yeah. The 2 big things are cytopenias, and of course in myelofibrosis that’s always a challenge. We begin with cytopenias as a major issue from the time of diagnosis. So you do have to dose reduce and monitor early on very closely blood counts. The other is infection risk, right, worry about fungal infections or pneumonias kind of topping the list there akin to venetoclax, which we use for other hematologic malignancies.

DR LOVE: So surprise or disappointment number 2, MANIFEST-2 study.

DR GERDS: Well, yeah. I mean, again, another prospective randomized trial comparing ruxolitinib alone versus a ruxolitinib combination, this time pelabresib being a BET inhibitor, a BET inhibitor that doesn’t have as much GI toxicity as BET inhibitors in the past. But again, positive for SVR35 at week 24, which was the primary endpoint for this trial. So a positive randomized Phase III trial, but had a numeric improvement in symptom burden response, but didn’t quite hit that kind of metric.

I think both of these trials make an incredible — 2 incredibly important points. As I said before, rux is a great job — does a great job at treating symptoms. It lowers cytokine levels like a champ, makes people feel better. But 2, this has really reverberated through the halls of myelofibrosis investigators, that we need to push for different endpoints for these trials. We’ve been held to SVR35 and TSS50 for way too long. We see meaningful benefit in these patients beyond what these metrics can show us, and we really need to advocate as a community for better endpoints in clinical trials with regulatory authorities, as well as trial sponsors. And so really it’s kind of triggered this grassroots effort to better the trials for these patients.

DR LOVE: I guess we’re going to see a little more data also at the ASCO Meeting.

DR GERDS: Yup.

DR LOVE: And the other — the third one was selinexor, not exactly Phase III.

DR GERDS: Yeah.

DR LOVE: The Phase III’s still cooking, I guess.

DR GERDS: Yup.

DR LOVE: But where are we with selinexor?

DR GERDS: Yeah. So the Phase III for selinexor is ongoing, kind of in the early ramp up. It’s enrolling patients. And actually there’s a really nice complementary Phase II with selinexor for thrombocytopenic patients, where every patient starts on single-agent selinexor and then you add the rux on later, which is kind of a cool design.

But in terms of a single-agent drug in the Phase I and Phase II trials, Phase I/Phase II trials, I mean, impressive responses, more so than I would expect with — more so than I was expecting before seeing these results, I would say. And so I think it really warrants continued development. Again, major issues being cytopenias and GI toxicity, but that’s nothing new to us in the myelofibrosis world, and so I think it is manageable. These doses are a little bit less than what we use say for multiple myeloma, so a little bit more manageable there.

DR LOVE: Although the myeloma people say there is a way to give it comfortably.

DR GERDS: Yup.

DR LOVE: At least some people. Joe Mikhail thinks so.

A couple things from the chat room. So again, Dr Rudolph says, “I thought there was a high AML risk with pelabresib, and it’s not going forward.” I haven’t heard that one.

DR GERDS: Yeah. So the stat news leaked — or published in our news item a couple of weeks ago that the FDA issued a warning letter to investigators that there may be — that they saw a few more cases of AML — progression to blast phase disease in the combination arm versus the ruxolitinib arm alone. The numbers are incredibly tiny. It’s hard to say. Certainly not statistically significant. Certainly something worth monitoring.

And then also, along with that we don’t know what the baseline of those patients were. Were these kind of more of the high-risk molecular types? Did they have blasts that were already kind of like bubbling under the surface that were associated with this progression?

Thinking back to other clinical trials, we actually saw that in the luspatercept Phase II trial. There’s a cadre of patients who just blasted off, and it turns out that these patients were already progressing. One patient had a pain in their shoulder when they enrolled in the trial, and it turns out that it was a myeloid sarcoma. We didn’t find that until later.

DR LOVE: Wow.

DR GERDS: So really, I think we need to take those few cases, really look at them very closely to see is this the drug, is this the combination, or is it just these patients were randomly assigned to that group and were destined to do this no matter what?

DR LOVE: So getting back to anemia, Thoi in the chat room wants to know, “Do you use ESA and luspatercept concomitantly for transfusion-dependent myelofibrosis? I can’t seem to get response from ESA along despite maxing out on the dosing and EPO less than 500.”

DR GERDS: Yeah. I’ve yet to try the combination of ESA and luspatercept. Biologically they work on different parts of erythroid differentiation, so it could potentially work together. But you definitely want to max out that ESA. You’re talking about with things like erythropoietin analogs, 60-80,000 units every week or with something like a darbepoetin you’re talking 500 mcg every 2-3 weeks. So if you’re hitting those doses and not getting a response I think it’s — it makes sense to switch to luspatercept at that point.

I have, outside of a clinical trial, combined luspatercept with some of the newer JAK inhibitors that target ACVR1 to try to get more of an effect there, and I mentioned the SMAD pathway kind of parallels within the same duplex — not the same house, but at least the same duplex with each other, with some responses in patients. Those are patients who needed a JAK inhibitor. They had spleens and symptoms and I’m just happy to pick one with ACVR1 and add that with luspatercept. But I know that is the subject of ongoing clinical trials as well.

DR LOVE: So I was just flashing also, when we were talking about momelotinib, is the issue of pacritinib. And I think we’re seeing data there where it has a beneficial effect on anemia as well. Obviously –

DR GERDS: Yeah.

DR LOVE: — thrombocytopenia is the main issue, but also — so how do you factor in pacritinib in terms of its effect on anemia, for example, compared to momelotinib?

DR GERDS: Yeah. So if you look at the way it inhibits ACVR1 you would predict that actually pacritinib would be better at that than momelotinib. And certainly going back and reanalyzing PERSIST-2, a prospective randomized trial in the second-line setting in myelofibrosis, we definitely see a fair number of patients who gained transfusion independence on pacritinib, certainly compared to best available therapy. That was a paper just published in Blood Advances not too long ago.

And so it definitely does work. I think in terms of the more cytopenic patients you actually get this added benefit of IRAK1 inhibition. So if you kind of look at the curve of anemia improvements in patients treated with pacritinib you get this early bump, which is probably more ACVR1 related, and then if you follow these patients 6, 8, 9 months later you start to see a second bump in anemia improvements, like actually your patients will become transfusion independent.

Sometimes I joke that the P in pacritinib means patience. You have to have a little bit more patience to see the spleen volume responses, a little bit more patience to see the symptom burden improvements, and more patience to see the anemia improvements. It’s not immediate. We’re so trained with ruxolitinib to see this immediate response. It just takes a little longer with pacritinib. So I think that’s kind of a key lesson there. But it’s probably this — we’re seeing this dual action, almost, on anemia response with pacritinib, which is really interesting.

But again, in terms of spleen volume response and symptom burden improvement in more proliferative patients, patients with higher platelets, higher allele burdens of the driver mutations, momelotinib presumably would work — may work a little bit better in those patients, although not directly tested, against pacritinib.

DR LOVE: Any quality-of-life side effects that you see with JAK inhibitors other than cytopenias?

DR GERDS: Yeah. Cytopenias is at the top of the list. When we talk about pacritinib and fedratinib we talk about the — they’re also FLT3 inhibitors, and that’s associated with GI toxicity, nausea and diarrhea. So definitely we’re prophylaxing our patients when starting therapy there.

Other quality-of-life issues. Momelotinib, we do see some GI toxicity, although not as much as like say fedratinib, but I’m still prescribing patients an antiemetic just to have in their closet just in case, as well as advising them to have some loperamide on hand. That typically is worse in the first month and then gets better subsequently.

With ruxolitinib one of the quality-of-life things that kind of sticks out in my mind, especially here in Ohio, we don’t have a lot of sun, but a lot of my patients winter in Florida, your neck of the woods, and —

DR LOVE: Yup.

DR GERDS: — they’ll get all these precancerous skin lesions, actinic keratoses or even squamous cells and basal cells. And for some patients on ruxolitinib it’s a major issue, where we’re lopping these things off quite frequently. So to me that’s something that’s kind of come up as well.

DR LOVE: You don’t see that with the other JAK inhibitors?

DR GERDS: No. We don’t see it with momelotinib, pacritinib or fedratinib. And it’s unclear why. Maybe it has to do with the JAK1 inhibition, but we definitely don’t see the degree of nonmelanoma skin cancers and precancerous skin lesions.

DR LOVE: Any difference between the JAK inhibitors in terms of susceptibility to infection?

DR GERDS: Yeah. It’s unclear. The one thing that does seem to stick out, not so much the bacterial pneumonias or fungal pneumonias, but really the viral reactivations seem to be more frequent with ruxolitinib versus momelotinib, pacritinib and fedratinib, probably the same mechanism that’s leading to increased risk of nonmelanoma and precancerous skin lesions. And so we do see more shingles, most commonly, with ruxolitinib use versus the other JAK inhibitors.

DR LOVE: So I think our group knows there are certain trials and things that, just, I get obsessed with, and one of my current obsessions, you were mentioning the fact that these 2 trials, Phase III trials, didn’t improve symptoms. With this randomized study that Dr Mesa was involved with, which was a randomized study, I’m not saying it was like a Phase III, whatever, but was a randomized study on the Mediterranean diet.

DR GERDS: Yeah.

DR LOVE: This looks pretty much like low fat, low meat, a lot of vegetables type thing, and they did see a benefit in terms of symptoms. Any thoughts about that? Do you recommend this to your patients? Any idea about why? They looked at the gut microbiome. Any thoughts?

DR GERDS: Yeah. Inflammation and myelofibrosis are intricately related, right? So myelofibrosis, the cancer cells, the megakaryocytes, will produce cytokines leading to inflammation. Inflammation can make the symptoms worse, and then probably this feedback circle. And so any way we can kind of break that cycle I think can be of benefit. Dr Fleishman, who’s the senior author on that poster, also has published work looking at N-acetyl cysteine in terms of trying to break that inflammation.

So there is definitely something to it. We’ve just got to figure out how to best capitalize on this whole-body inflammation idea. I think, honestly, the Mediterranean diet, it’s an easy — it’s an easy hurdle to clear, right? I think that’s something that every patient could try to see if it helps them feel better, helps to improve their symptoms, and it makes a lot of sense to try it. The randomized data speaks for itself. Perhaps if we combine pelabresib plus ruxolitinib plus Mediterranean diet we’ll get a positive trial, fully positive trial. So certainly when patients ask me about this we talk about the data. We admit it’s a small study, but I think there’s little harm in this, and if it works for them, great.

There’s a pilot study looking at yoga that was also associated with improved symptoms. There’s some small data suggesting that strength training can also improve symptoms in myelofibrosis.

So we’ll have a conversation with the patient. We’ll talk about their diagnosis, their prognosis, the medical treatment. But then at the end I say, here are some things that — patients are all right, what can I do. Like here are the 2 things, right? Eat well, whether that’s the Mediterranean diet or for just some patients getting back to a more balanced diet, as well as exercise. Stretching exercises, strength conditioning exercises all can really help a patient out, how they feel today and how they will feel tomorrow.

DR LOVE: Any other comments? Again, oncologists don’t have anywhere near the number of patients that you all who specialize in this do, but any other comments about supportive care issues with myelofibrosis, particularly as it relates to the spleen. You see cases where patients have real — their main problem is the spleen. Do you ever do surgery? Radiation therapy? What are some of the end-of-life issues that are involved here?

DR GERDS: Yeah. And certainly this is a challenge at the end of life for patients who have cycled through JAK inhibitors who are still struggling with splenomegaly. I have tried radiation therapy in the past. I think the major challenges are (1) you need multiple therapies over time, and the spleen will grow back once you stop the radiation therapy, and then lastly it causes massive cytopenias, and so you can really worsen a patient’s platelet count or red cell count.

I have turned back to splenomegaly — splenectomy for splenomegaly in patients who are JAK inhibitor refractory. I’ve had some really positive outcomes. I have a surgical team here that I really trust and work closely with. I think that’s the key piece of it. I fully acknowledge that there are increased risks for … and various visceral thrombosis post splenectomy, but boy, have we seen some pretty remarkable outcomes.

For example, I can recall in the last year 2 patients that were definitely not going to go to transplant because they were so symptomatic, their spleens were so big, their performance status were so poor. We took their spleens out. They improved. Their counts actually got better, too, and they went to transplant and have done well post-transplant. So I’m actually kind of coming full circle on splenectomy in myelofibrosis, especially when JAK inhibitors, you’re not getting that optimal response in JAK inhibitors.

DR LOVE: Wow. I have not heard that, but I’ve heard questions about it a lot.

DR GERDS: Yeah.

DR LOVE: That is really fascinating.

Journal Club

DR LOVE: Let’s do a little Dr Gerds’ “Journal Club.” I have a bunch of papers that you were involved with I wanted to get your thoughts on. Anything that involves economics always catches my attention. You have this interesting title. What were you trying to do there?

DR GERDS: Yeah. Yeah. So ruxolitinib is expensive, right? The wholesale acquisition price over $10,000 a month. All the JAK inhibitors are expensive for that matter relative to like a pack of gum. So is this cost of the drug worth it in a larger medical sense?

And really what we tried to show in this study was, could you spend a little bit more money on a JAK inhibitor but save in other related healthcare costs? And that’s actually what we saw. We saw that patients who were treated with ruxolitinib had lower medical costs, largely — the biggest increase we saw, if we kind of break down those different medical costs, was in emergency room visits. So patients pound for pound who are on ruxolitinib spent more — less time in the emergency room, less dollars in the emergency room, if you will, than those who were not on ruxolitinib. That was the biggest jump we saw, oddly enough. A lot of those were for pain admissions and transfusions and symptom admissions to the emergency room.

Definitely there’s a more — there’s a larger up-front pharmacy cost for patients on ruxolitinib, but that was outweighed by all the other medical costs that incurred in patients who were not on ruxolitinib in this study.

DR LOVE: A couple quick questions from the chat room. Jhapati wants to know about mini-lap for splenectomy.

DR GERDS: Oh yeah. So usually our — it depends on what the spleen looks like under the CT scan, but our surgeons will attempt a laparoscopic removal of the spleen if they can. Sometimes the — it’s just technically too difficult. My surgeon that I work with estimates at least 50% of the time he’ll convert to an open splenectomy, but they do attempt laparoscopic first.

DR LOVE: Kind of like a C-section, huh?

DR GERDS: Yeah. Sometimes. It depends on how big the spleen is, but yeah.

DR LOVE: How big the baby is.

DR GERDS: Are we talking, like, chihuahua or rottweiler?

DR LOVE: So Jorge wants to know, how do you manage liver dysfunction after splenectomy?

DR GERDS: Oh, very carefully. The big worry, of course, is clot that’s leading to liver dysfunction. So definitely I have a heightened worry for that postoperatively. We’re checking ultrasounds. Even in patients with a heavy clot history prior to splenectomy I might even consider anticoagulation for a period of time. So you can definitely see that liver dysfunction.

A lot of times the liver dysfunction, if it’s due to extramedullary hematopoiesis, I’ll put a patient on ruxolitinib or other JAK inhibitor to try to lessen the effect of that. I’ve even used low-dose or even full-dose hypomethylating agent to try to reverse the EMH in the liver leading to liver leading to liver dysfunction.

DR LOVE: We’re getting a lot of interest in this. Sara wants to know what about splenic artery embolization.

DR GERDS: Oh. It turns out a good friend of mine, our kids play on a hockey team together, he’s an IR doc at a competing hospital, and so we actually had a conversation about this once. And he’s like, what’s going on? I feel like all I do is splenic embolizations anymore. And I think that the truth of the matter in myelofibrosis, it’s painful. You do splenic embolization, you’re killing a part of the — you’re causing a splenic infarct. And patients can have pain for months, 2, 3 months you’re dealing with opioids, which aren’t really effective, trying gabapentin, trying tricyclics until hopefully the pain just gets better. To me, if you can’t make it better with JAK inhibitors, you’re not getting an edge on that splenomegaly, splenectomy is the preferred option over splenic artery embolization. Yes, in the case of a bleeding spleen, where you’ve got to temporize things. Otherwise I would just go ahead and take the spleen out.

DR LOVE: So they just won’t stop. Hasan wants to know about radiotherapy to the spleen.

DR GERDS: Yeah. Radiotherapy, I use it in palliative situations where a patient’s at the end of life, I’m a little less concerned about blowing out their cellular production. Cytopenias through the abscopal effect is the major consequence of radiation to the spleen, and it’s very temporary. You can get a few months out of splenic radiation, typically, before it grows back and causes trouble again.

DR LOVE: So we were talking at the beginning here about fellows, and the last program we did, I think it was with Dr Mesa, that I was talking about before, we started out talking about what happened 10, 12 years ago, when the fellows were, I guess, in high school or something, but this is a paper — this is a paper this past year looking at ruxolitinib 10 years later. We were just talking about how stunned people at that ASCO Meeting when they saw the data and they heard the stories, et cetera. Any thoughts about this 10 years later?

DR GERDS: Yeah. I mean stunned is a great word. I still have seen, Serge’s slide, the picture of the guy’s belly with the spleen, like before and after.

DR LOVE: Right.

DR GERDS: His belly’s, like, sticking way out, and then he goes on rux, and it shrinks right down. Just an unbelievable image in my mind that’s still there to this day. But a watershed moment, right? So not only are we making people feel better, but through splenic volume reduction and cytokine reduction people are living longer. The pooled analysis showed that survival advantage. The pooled analysis of the COMFORT study showed that survival advantage.

What’s also in this paper that is a cool analysis that really speaks deeply to me is a Medicare analysis showing that — the survival of patients with myelofibrosis before the approval of ruxolitinib and after. So before ruxolitinib the median survival was poor. It almost doubled after the approval, even in patients who didn’t get ruxolitinib, which is kind of cool. It’s saying that not only did this immediately help individual patients, but it helped the field in whole. Like it drew more attention to myelofibrosis. It drew more dollars for research. Other therapeutics, other pharma said hey, Insight’s doing pretty well with this drug. Maybe we can do well in this space too. So it really opened up the world for basic translational and clinical research in the field.

And now we’re seeing the benefits. We have 3 other JAK inhibitors. We have these large prospective, randomized Phase III trials in the front-line setting, which is just unbelievable to me. And so it’s really kind of cool to see this all come together.

DR LOVE: Yeah, it really is. I can remember all the stories I remember hearing in the beginning, these miraculous clinical responses that people had.

DR GERDS: Yeah.

DR LOVE: But I guess you’re still seeing them now.

DR GERDS: Yeah.

DR LOVE: Alright. Well, I thought I’d give the audience a little treat here, because one of my field defects is CHIP, and I saw this great paper that you did, so I thought I’d give you a shot at going through what CHIP is and what it means in terms of taking care of patients.

DR GERDS: Yeah. Well, thanks for bringing this. This is a cool project. I mean, first of all, I’ll say you can’t have CHIPs without guacamole. No. The forever joke there. But no, CHIP is a pretty remarkable entity, not existing what, 10 years ago, and now kind of on the face of everything. And just the sheer prevalence of CHIP as we age is remarkable. And the fact that CHIP itself carries a 1% chance a year of turning into malignancy.

And then on top of it you think about all these patients who have other cancers, breast cancer, colon cancer, that we’re giving chemotherapy to, potentially clonally selecting out these bad clones that could come up as a secondary MDS or AML or other, or myelofibrosis even. If we think about it, the fifth most common CHIP mutation is JAK2 V617F. So certainly MPNs are within that kind of scope of practice.

And so this is our effort to —

DR LOVE: Before you go further, could you just pause for a second and talk a little bit more about what your vision of CHIP is? My understanding is these are somatic mutations. What characterizes them?

DR GERDS: Yeah. So as we all age, are alive in the world, we’re bombarded with stresses, space radiation, all of our cells constantly dividing, and that can lead to errors, and the errors are these mutations that occur in our hematopoietic systems.

And if we look at serial samples from, like, people in their 20s versus in their 50s versus their 80s, we see this kind of curve shoot up of acquisition of these mutations at a very low level. And these are patients who have no hematologic history at all. And to the point where if you get into people who are in their 80s upwards of 20% of people will have identifiable mutation.

CHIP typically is a variant allele frequency greater than 5%, so there is this kind of cutoff. So these are relatively large clones. Less than that we typically call that ARCH, or age-related clonal hematopoiesis. And then this is with normal blood counts. Once you start to see cytopenias or elevated blood counts, that’s more a clonal hematopoiesis with cytopenias, or CCUS if you will, a different acronym. So it’s kind of on the spectrum of normal bone marrow to acquiring a mutation to the clone getting bigger to starting to see abnormal blood counts as we go from normal to ARCH to CHIP to CCUS and then ultimately MDS and related myeloid disorders.

DR LOVE: Alright. So let’s talk about what was looked at here.

DR GERDS: Yeah. So the idea in this particular study, again, this is kind of an expose of our CHIP clinic under the guise of a prospective observational study, where we’re looking at patients who are diagnosed with CHIP and actually screening our solid tumor patients for that. So these are patients who are getting treatment for breast cancers, colon cancers and the like that — or head and neck, in this figure, who would then subsequently enroll in our CHIP clinic to look for CHIP. So it’s like what is the incidence of CHIP in these patients and what happens to them long term and what are the common mutations that we’re seeing and how do these clones change year over year to better understand, primarily because as we get better at cancer treatments we’re seeing more and more of these long-term consequences. If now our pancreatic cancer patients are living longer, our lung cancer patients are living longer, they have more time to develop these clonal hematopoietic problems. And so can we better understand these?

And really what we saw was a remarkably large number of CHIP patients within these populations, larger than what we would probably expect just in the normal population alone. And certainly some really high-risk mutations mixed in there. So like for example DMT3α was prevalent and is one that’s a little bit more worrisome for progression.

It also makes you wonder, too, is this somehow related to their original primary oncology problem? Is there some milieu that CHIP creates within the body that allows another solid tumor cancer to grow? We talk about inflammation from CHIP increasing heart risk disease. We talk about similar to like dental caries can increase your risk of heart disease. We also see this weird reverse effect with CHIP, where CHIP can actually lower — lowers the risk of Alzheimer’s, but I think that’s a little harder to explain.

But at the end of the day, we definitely saw through serial sampling a high prevalence of CHIP in our cancer patients with high-risk mutations and predilection to progression to myeloid cancers.

DR LOVE: What’s the pathophysiology connecting CHIP to cardiac disease?

DR GERDS: It’s thought to be an inflammatory state. So if you have CHIP you’re more inflamed. Getting back to inflammation, perhaps the Mediterranean diet would be a nice, randomized trial in CHIP, honestly. But a higher rate of inflammation that is leading to this increased cardiovascular disease, akin to the story about dental — poor dental hygiene and cardiovascular disease.

DR LOVE: So I saw this paper you had at ASH looking at MDS, and also I think you had another one with AML. Were you able to look at CHIP in these patients?

DR GERDS: So these were actually large databases that we analyzed, and so there wasn’t really — we couldn’t get that molecular data that we wanted.

DR LOVE: Right, right.

DR GERDS: Largely, it probably has to do — it’s related to CHIP in the fact that these patients treated with cancers with chemotherapy and radiation, we’re selecting out for these small CHIP clones that may exist well below our level to detect. And so I think it — as we get better at treating other solid tumor cancers we’ve got to be — have a heightened awareness that patients may develop myeloid malignancies subsequently because of the treatments that we’re giving them.

DR LOVE: So Aaron, thank you so much for working with us today. I think we all learned a lot. Audience, thank you for attending. We’re getting the team ready to head out to the big show out there at ASCO at the Hilton Hotel. We’re starting out Friday, May 31^st, 11:45 AM, and we’ll be finished sometime on Tuesday. Check it out online, or if you’re in Chicago stop on by. Have a great weekend. Have a great day. Aaron, thank you so much.

DR GERDS: Thank you.