Interview of Richard M Stone, MD

DR STONE: About 30% of patients with AML have a mutation in the FLT3 gene. And that was recognized about 20 years ago. Mutations come in 2 flavors: the internal tandem duplication mutation, which accounts for about three quarters of the mutations, and one quarter have a point mutation in the tyrosine kinase domain. It was recognized fairly rapidly after the determination that there were mutations that those who had FLT3 ITD mutation had a high relapse rate and a poor overall survival. That was put in context with the fact that FLT3 mutations are a gain of function mutation, just like BCR-ABL in CML. Therefore, if one could inhibit that gain of function, one might be able to kill the enzyme and, in so far as the leukemic pathophysiology might be dependent on that mutated enzyme, fix the problem.

DR LOVE: One of the terms oncologists are used to hearing, for example, in lung cancer, is driver mutation. Do you visualize this as a driver or driver mutations?

DR STONE: Yes. Absolutely. It’s a driver mutation. However, critically it may not be a founder mutation. The difference is, the founder mutation would be found in the original cells in the tumor and then would be present throughout the tumor’s life history. FLT3 mutations are probably a late hit, which perhaps explains the issue that came up when FLT3 inhibitors were used as single agents. Though they’re active, they’re not nearly as active as imatinib or nilotinib is in CML, for example. So there was a lot of disappointment originally when we didn’t see a high remission rate with some of the early FLT3 inhibitors in AML, including midostaurin, which I’ll talk about in a second.

So then people said, “It does something good to the patients with advanced FLT3-mutant disease who get these FLT3 inhibitors. It does something good. It lowers the blast count. There are a few remissions here and there. So maybe we should combine an FLT3 inhibitor with another active agent in AML, ie, chemotherapy.” So that’s what we did.

We’ve been involved with the FLT3 inhibitor midostaurin, which is an interesting drug because it was originally developed as a protein kinase C inhibitor, nothing to do with tyrosine kinase, nothing to do with hematologic malignancies. Rather, it was first tested in patients with solid tumors because protein kinase C was thought to be important. So we knew about a Phase I trial with midostaurin in solid tumors published 10 years ago or more. We knew about a safe and effective dose. My boss, Jim Griffin, showed that midostaurin, which was then called PKC412, was a very effective FLT3 inhibitor as well. So Griffin and then Gilliland, also in Boston, began to show that midostaurin could kill cell lines transformed by the mutant FLT3 and could improve the survival of mice that had leukemias engendered by mutant FLT3.

So we did a series of Phase I and II trials with single-agent midostaurin. And we said, “The results weren’t great. They were okay, but we’re not going to license this as an FLT3 inhibitor as a single agent.” Then I did a trial in which FLT3, this FLT3 inhibitor, midostaurin, was combined with chemotherapy, and indeed, we developed a safe and effective regimen that looked like in the Phase II trial with pretty good results.

So that was the background to this large Phase III trial that took a lot of time and a lot of resources. It was simply a trial in which we give standard chemotherapy with a placebo or with midostaurin during induction chemotherapy, during postremission chemotherapy, and for a year of maintenance afterwards. So that was the trial. It was chemotherapy alone plus placebo versus chemotherapy plus midostaurin. And we’ll see where the chips fall with the primary endpoint being overall survival. So that was the study design. And that was the background.

So the trial was designed to show an improvement in overall survival in those who got midostaurin compared to those who got placebo plus chemotherapy. And lo and behold, the trial met its primary endpoint. Seven hundred and fourteen patients were enrolled. To get those 714 patients, we had to screen 3,300 patients because we only would take patients on the study who were documented to have an FLT3 mutation. And we had labs in 7 countries or 7 labs in about 5 countries, which would rapidly assess the presence or absence of an FLT3 mutation in our leukemic patients. If they had a mutation, they could go on the study. Then, they were randomized to placebo or midostaurin. And those who were randomized to midostaurin had a 23% reduction in the risk of dying overall, which was highly statistically significant.

What was interesting in the study was, okay, it was great. It met its overall endpoint in all 3 subgroups of FLT3-mutant patients. There were some patients who only had a point mutation, TKD mutation, and there were some patients who had a high level of FLT3 mutant allele compared to FLT3 wild-type allele. And in all 3 groups, high allelic burden ITD, low allelic burden ITD and point mutation TKD, all 3 groups benefitted by the addition of midostaurin.

Secondly, because the standard of care changed while the study was ongoing — and it was open between 2007 and 2011 — during that time, the standard of care changed such that it was thought to be a good idea to do allogeneic stem cell transplant in first remission for patients with FLT3 mutations.

So we predicted when we started the study that we would see a transplant rate of about 16%. But, in fact, we saw a transplant rate of 57% overall. About half the transplants were done in first remission. So we then said, “Maybe this is because of the transplant we saw a good result.” Even when you censor the data at the time of transplant, you still saw a survival benefit for midostaurin — and the midostaurin was not given after transplant. Once you went on transplant you were off the treatment part of the study, but people were involved for survival. So it was exciting to note that even with a relatively brief exposure to midostaurin — because people often got transplanted a few months after they were diagnosed, even with a relatively brief exposure to midostaurin — it still benefitted you. And I really think this represents a sea change in the management of AML.

I do think midostaurin should be approved, will be approved for the treatment of patients between 18 and 60 who have mutant FLT3 AML. And it needs to be explored in other contexts as well. But that was the important finding from the so-called CALGB 10603 or RATIFY study.

DR LOVE: I know the study only restricted to 18 to 60, but do you think that’s the way it ought to be applied and approved?

DR STONE: Yes. Because patients who are older are a separate disease biology, separate type of intrinsic host situation, vis-à-vis comorbid diseases. I do think one needs to study potential FLT3 inhibitors in older adults with mutant FLT3 AML. And I further think that people should be studied with midostaurin even if they don’t have the FLT3 mutation. What I sort of alluded to was that there was a benefit in people who had a low allelic burden of FLT3 ITD. And such patients might not have that much FLT3-ness to their leukemia. So especially in so far as midostaurin is a multitargeted kinase inhibitor sometimes referred to as a “dirty” drug, it doesn’t specifically inhibit just FLT3. There’s reason to suspect it might have a benefit in other types of leukemia. In fact, in the early single-agent trials, which I mentioned, there were some responses even in patients who did not have an FLT3 mutation.

So there’s a lot to be studied. A lot of potential benefit. But right now we can only use the data from the trial I just mentioned, to argue that it should be routinely given to patients who are under age 60 with AML who have an FLT3 mutation.

No. It certainly should be studied in the other groups I mention, though.

DR LOVE: So there was another FLT3 paper presented on another agent, ASP2215, gilteritinib. And I remember seeing a paper presented at ASCO last year on this agent that looked pretty interesting. Can you talk about what was presented at ASH and what you think about this agent compared to, for example, midostaurin?

DR STONE: Sure. So this agent, gilteritinib, is one of the class I would say, of second-generation FLT3 inhibitors. I would put quizartinib, gilteritinib and crenolanib in that class. Now, the different FLT3 inhibitors are separated by how specific they are against FLT3 versus other enzymes — and I’ve already mentioned sorafenib and midostaurin are not very specific — gilteritinib, crenolanib and quizartinib are all more specific.

So one scientific question is, is it good to be specific and just really potently inhibit FLT3? Or are these other enzymes that are inhibited by drugs like sorafenib and midostaurin beneficial in reducing the leukemia burden? And that’s very much of an open question.

Number 2, are the drugs bioavailable? Midostaurin, and to a certain degree sorafenib, are heavily protein bound, which makes the free drug somewhat problematic. Whereas quizartinib and gilteritinib aren’t so protein bound.

Finally, each FLT3 inhibitor has to be evaluated in terms of whether it just “hits” the FLT3 ITD, whether it also hits the point mutation. Obviously, inhibiting both is sort of an advantage, so you can give the drug to more patients. Midostaurin inhibits both the FLT3 ITD and the TKD. Crenolanib inhibits both the FLT3 ITD and the TKD. And gilteritinib inhibits both. And Dr Altman presented results of the Phase I/II study with gilteritinib. And the results with that drug were, to me, similar to what we have seen with single-agent quizartinib. There was an appreciable response rate, both in terms of the complete remissions and some partial remissions in these advanced FLT3-mutant patients with both TKDs and ITD mutations.

So it’s another drug that’s in the mix. Therefore, being an FLT3 inhibitor, it’s a fairly specific one. So it needs to be studied further in patients with FLT3 mutations, both probably earlier in the course of the disease along with chemotherapy. My understanding is that there is an ongoing trial in which gilteritinib is being combined with chemotherapy, just as we did a trial years ago with midostaurin combined with chemotherapy before we did the RATIFY trial that I presented at the plenary session.

DR LOVE: So continuing on in terms of papers in AML, I also wanted to ask you about AG-221, a potent inhibitor of mutant IDH2.

DR STONE: Yes. We’ve been involved with that trial, and we’re very excited about it as well. It was presented by Dr Stein of Memorial Sloan Kettering, as an update of previously presented data with this drug, in patients with mutant FLT3 IDH2 AML. A similar trial, by the way, was presented by Dr DiNardo of MD Anderson, describing a similar trial in patients with mutant IDH1 AML with a drug called AG-120.

Anyway, Stein’s presentation was AG-221 in mutant IDH2 AML. And a large number of patients have been treated to date. Most of the patients who were presented had relapsed/refractory AML and an IDH2 mutation.

The drug was well tolerated. And there were responses in about 40% or more of patients. Some of the responses were complete. Some of the responses were partial. But clearly, there was a benefit in many of the patients who got this single-agent drug. The drug was well tolerated.

One more thing that’s interesting about this. Some of the responses occurred via differentiation. Which means that patients, rather than seeing cytotoxicity like you would with regular old chemotherapy where the blood counts go down before they go up, there was kind of a gradual improvement in the blood counts. And there were even clinical features compatible with the differentiation syndrome, much the same as you’d get with retinoic acid therapy of APL.

So it just shows it’s a very interesting mechanism of action in some cases.

Some of the patients had a more traditional cytotoxic-type response. But some had this differentiation response before they went into remission.

DR LOVE: Where do you think this is heading?

DR STONE: I think it’s heading to the major leagues in the sense that, to see responses — many of these patients were very advanced patients — with a single-agent pill, very exciting. There were real responses. I’ve seen my own patients go into remission with this drug.

So the question is how it’s going to get approved. I don’t know the answer to that question. One strategy will be clearly to combine it with chemotherapy, just like it was done with midostaurin. A shorter-term strategy will be to compare it to dealer’s choice chemotherapy in the relapsed/refractory IDH2-mutant population and show that you can improve survival. I think that’s where it’s going to go. I do think that it’s headed for an approval, perhaps in the single-agent setting in the relapsed/refractory patient.

DR LOVE: What do you consider a minimum in terms of assays that need to be done up front in AML, assuming the patient’s in a community-based setting?

DR STONE: So right now, there are 4 genes ideally that could be tested in the up-front setting, and they would be FLT3, because you want to know if they have an ITD, and NPM1. Those are the 2 most important ones because you can determine whether a patient should have a transplant by knowing the answer to whether, yes or no, those 2 genes are mutated. And then, if you have a little bit more capability, the next 2 genes would be c-KIT and C/EBP-alpha. C/EBP-alpha is mutated in only about 5% of patients with AML. But if you have a biallelic mutation, in other words both copies mutated in AML, you have a very good prognosis. So it’s worth knowing about. C-KIT is worth knowing about in this subset of patients who have a so-called CBF chromosomal abnormality, either t(8;21) or inv(16). Having a c-KIT mutation seems to be a negative prognostic factor in those patients and maybe — maybe ­should be met with an allogeneic transplant, though that’s not clear.

So the top 2 are FLT3 and NPM1. The next 2 are c-KIT and the subset and C/EBP-alpha. And the next one would be IDH1 and IDH2, in case they need to go on a clinical trial. The next one would be p53, because if you have that mutation the prognosis is terrible and you might want to consider alternative therapy. There’s a host of other ones that can add prognostic information, but I think I’ll leave it right there.

Right now, FLT3, NPM1 at least.

DR LOVE: So I want to ask you about a paper looking at oral azacitidine in patients with AML.

DR STONE:  Sure. That was presented by Dr Savona. Since many older adults are treated with hypomethylating agents, either decitabine or azacitidine, right now the decitabine or azacitidine have to be given by intravenous or subQ shots, which means that the patient has to come to clinic. Wouldn’t it be great if we had an oral agent that was bioavailable and could be taken at home by these older adults with AML? And if it were equally efficacious, that would be a boon for these patients.

Savona’s study showed that oral azacitidine is safe and effective. I can’t tell from this Phase II study whether it’s better than standard subQ or IV azacitidine. I think we’ll have to do more work with this compound to see. The response rate was relatively modest, but then again, the response rate with azacitidine, normal azacitidine, is relatively modest in AML. Although you should be aware of the paper by Dombret et al, which was a report of the AZA-001 study, which was a comparison of azacitidine to dealer’s choice chemotherapy in older adults with white counts less than 15,000 with AML. That was published in Blood in 2015. It suggests that azacitidine was a pretty good alternative to low-dose Ara C, supportive care or standard induction chemotherapy.

So oral azacitidine, need more. Exciting to think we might be able to supplant IV or subQ aza with oral azacitidine. Too soon to know whether it’s better. We need more work to determine whether that’s going to make it to prime time.

DR LOVE: So let’s move on and talk about some of the papers presented in CML. It seems like every year at ASH we see some papers on stopping TKIs. There are a lot of studies out there looking at this. And one I was curious for your thoughts on was Abstract 345, the French 1 Stop Imatinib study, STIM1.

DR STONE: Right. The French have presented this STIM trial several times. And the advantage of re-presentation of these data is that you get more follow-up each time it’s re-presented. And it still looks like stopping imatinib in people who have prolonged negative PCR times is a viable option. Interestingly, it’s not yet become the standard of care in America to stop imatinib in such patients. Yet the results from France suggest that a little over half of the patients will relapse molecularly after they stop imatinib for a year or so. But you can render almost all of them back into remission with restarting the imatinib.

I guess the real question is whether “almost all” is good enough for us conservative Americans. You don’t want to lose anybody to disease resistance if you stop the imatinib.

We actually have a trial called the LAST trial, Life After Stopping Tyrosine Kinase Inhibitors, ongoing now. It’s where we are, at Dana-Farber, and it’s across the country. It’s amazing how many people are reticent to stop the imatinib. Why stop a good thing? They’re tolerating it well. Yes it’s expensive, but they don’t pay for it out of pocket really. So I think it’s feasible to stop the imatinib in the vast majority of patients. Either they’ll stay PCR-negative or they’ll be able to be rendered back into PCR negativity with restarting it should they relapse.

So we have a lot of data. We haven't reached a clinical conclusion yet about it in America.

DR LOVE: What is your own practice, outside a trial setting, in terms of allowing patients who are discussing the possibility of stopping? And how do you approach the woman who wants to become pregnant?

DR STONE: Yes. Those are 2 vastly different issues. For a middle-aged patient who’s doing well on imatinib, if they have no side effects, I don’t encourage them to stop. If they tell me, “My joints hurt. My life’s miserable. My PCR is negative for 2 years,” of course I would stop it in those patients. But I don’t recommend it otherwise.

Now, only because we don’t have long-term data and I don’t harm people and first do no harm, interestingly imatinib is now generic. It’s a little bit cheaper. Although patients still often have large copays.

Anyway, to answer your question about imatinib in pregnancy or TKIs in pregnancy, yes I think you cannot get pregnant while you’re on imatinib. You can get pregnant. You shouldn’t, because it is potentially teratogenic. So if you’re going to father a child or be the mother of a child, we strongly advise that you stop the tyrosine kinase inhibitor while you’re trying to get pregnant. And, obviously, if you’re in the patient category where you have a prolonged PCR-negative state, you could probably just stop it and just be watched closely.

If you’re young and don’t have a PCR-negative state for a long period of time, you want to have a baby, then I usually switch people to interferon, which is not teratogenic.

DR LOVE: We still see follow-up papers coming out of some of the major Phase III studies of the second-generation agents. And this year, we saw a couple of papers coming out of the ENESTnd study with nilotinib. One, the dose-optimized nilotinib again. And another, looking at the impact of age on efficacy and toxicity. Anything noteworthy there?

DR STONE: I didn’t really think so. I mean, the ENESTnd study obviously showed that nilotinib caused a more rapid reduction in the BCR-ABL transcript and probably a more rapid reduction and elimination of the Philadelphia-positive metaphases with very little impact on survival, conversion to blast crisis.

So I think it’s still an open question. There was another paper about whether to start people on nilotinib — that’s one of most commonly asked questions. A patient walks in the door, do I give imatinib, nilotinib or dasatinib? What do I do? And my practice right now is to use nilotinib or dasatinib in the very young patient, because they are more potent and potentially more effective. And imatinib in patients over 40, 45, just because it’s well tolerated and it’s effective.

There was a paper in which they switched people to nilotinib with sort of an early look at whether they were responding or not. That seemed to be a good idea too. I suspect that’s where we're going with this whole thing. We’re going to start people on imatinib because it’ll be cheaper. And then if they don’t have a perfect response, we’ll switch them early to a second-generation TKI. But that’s just a personal guess.

DR LOVE: I’ve got to say that I’m not sure I’ve heard anybody come up with this sort of algorithm you just mentioned of the second generations in younger patients versus older. I’ve heard the idea of imatinib in better-risk patients. But do you think there are a lot of people out there right now who have this age approach to it?

DR STONE: I don’t think so. That’s my own personal approach based on the fact that you’ve got many years ahead of you if you’re young, and you want to give them the best drug available. I mean, it’s worth the extra side effects. I mean, dasatinib causes pleural effusions. Nilotinib is difficult to take twice a day without food or milk. So I try to restrict it to people who are really in for the long haul.

DR LOVE: So let’s talk a little bit about ALL, beginning with Abstract 80, coming out of your place, and we’ve seen a number of papers on it in the last few years about dose-intensified pediatric regimens in adults, this one of a Phase II study of a peg asparaginase pediatric regimen.

DR STONE: Sure. This is very near and dear to my heart. The background, briefly, is that about 15 years ago, Wendy Stock from the University of Chicago and people around the world recognized that if you were adolescent or young adult, defined roughly between age 16 and 24, and you walked into a pediatrician’s office and you got treated for your ALL, you did much better than if you walked into an adult oncologist’s office and got treated for ALL. Why was that? Are adult oncologists bad compared to pediatric oncologists? Were the patients different who would go to a kiddy doctor versus adult doctor? Maybe. Or were the regimens different?

All those possibilities could have explained those findings. But what we and others have done is just adopted the successful pediatric regimens lock, stock and barrel, more or less, in our young adult population. And Dan DeAngelo, my wonderful colleague at Dana-Farber, spearheaded these efforts of using the DFCI Pediatric Consortium trial that’s been so effective in kids with ALL and has applied it to people up to age 40 or 50 with ALL. And our results, presented again by DeAngelo at ASH, suggested a 2-year disease-free survival of about 65%, which is quite good compared to the so-called legacy regimens used in ALL and other adult programs, such as the CALGB regimen, hyper-CVAD or some other ones.

You still get arguments from Dr Kantarjian. I think they’re viable arguments. That if you look at hyper-CVAD, which is the most commonly used ALL regimen in America for adults and you compare that to our results or other results in the same age-match population, you get about the same. I think we need to do a prospective trial if we really want to understand this answer better.

I’m convinced, though, that this pediatric regimen is the way to go for people who have Philadelphia-negative ALL under age 45.

DR LOVE: Any comments about the use of asparaginase in these younger people, so to speak?

DR STONE: Yes. I mean, the older you are, the harder it is to tolerate L-asparaginase. The good news, the older you are that probably the less benefit you get from L-asparaginase. 

In people up to age 40, we’ve been able to give it fairly safely, as noted. It was thought to be tolerable.

DR LOVE: Let’s talk a little bit about MDS. And there were a couple of papers focusing on patients with low- and intermediate disease that I was curious for your thoughts on, Abstract 91, 92, one, Eltrombopag for the treatment of thrombocytopenia and luspatercept treatment for patients with a hemoglobin reduction.

DR STONE: The treatment of lower-risk MDS, lower risk meaning low and intermediate 1 by the International Prognostic Scoring System, has been a bugaboo. I mean, there are approved drugs in this condition, so lenalidomide is approved for 5q minus low-risk MDS. But there are not that many patients with that. Lenalidomide does have a response in lower-risk MDS, about a 25% rate of reducing your transfusional burden. The hypomethylating agents, azacitidine and decitabine, are both approved in low-risk MDS. Again, the transfusional reduction rate is about 25%. So they’re not great drugs for lower-risk MDS.

But there were actually 3 papers presented at ASH that dealt with the lower-risk patient. One is the trial you mentioned with eltrombopag, which is a thrombopoietin agonist that’s orally bioavailable. There are some patients with MDS who have low platelets, and that’s their biggest problem. So how about giving them a thrombopoietin agonist? It should stimulate their platelet formation.

There was concern about using the thrombopoietin agonist in MDS because of some earlier work in which another drug, romiplostim, and eltrombopag, which romiplostim is given subQ, eltrombopag is given orally, but they’re both thrombopoietin agonists. If you give it to higher-risk patients with MDS, you may be simulating leukemia, which is not a good thing. Controversial, but probably worth staying away from.

In lower-risk MDS, using romiplostim and eltrombopag should not be that risky because there are no blasts. And, in fact, this trial to which you referred showed that many patients who got oral eltrombopag had a nice increase in their platelet count.

So I do think this is a very important trial because I do think there are some patients who have lower-risk MDS who have — thrombocytopenia is a big clinical problem, and it’s nice to have something that’s safe and effective for these patients.

So eltrombopag is only approved for ITP right now. But it’s certainly worth looking into for patients in this condition.

I have an 85-year-old rabbi Holocaust survivor who has lower-risk MDS, tried every drug in the world. When I finally gave him romiplostim, his platelet count went from 10,000 to 300,000, and he’s doing fine except he’s got dementia. But, I mean, it does work. So I’m encouraged about that abstract.

The other one you mentioned for lower-risk MDS is luspatercept – that’s an activin trap. What the hell does that mean? The idea why there might be anemia in lower-risk MDS is perhaps due to negative cytokines that are secreted by the bad stem cell in MDS. And if you could somehow eliminate those negative cytokines somehow, you might be able to improve the anemia or fix the anemia. And luspatercept, along with another drug called sotatercept, which wasn’t talked about ASH this year but was last year, can bind to some of these cytokines, remove them from the circulation and, perhaps, make hematopoiesis or, specifically, erythropoiesis, a happier thing.

Indeed, particularly in people with not so high transfusional burdens, giving luspatercept caused a reduction in transfusions.

So I think, and I’m sure the company will want to do a Phase III trial comparing luspatercept to standard of care, whatever that is discerned to be, either supportive care alone or possibly hypomethylating agents.

And the third abstract that dealt with hypomethylating agents in lower-risk MDS was a paper presented by Short on behalf of the MDS Consortium, which looked at briefer courses of hypomethylating agents in lower-risk MDS. It seemed like it could get a pretty good response rate from a 3-day or a 5-day course of azacitidine or decitabine compared to the usually used 5-day decitabine or 7-day azacitidine courses. And, in fact, right now there’s a randomized Phase III trial comparing, I think, 5-day azacitidine to 3-day azacitidine to 3-day decitabine in these lower-risk patients to see if you can get an improvement in the transfusional burden.

So it’s good to see a little bit of movement in lower-risk MDS.

DR LOVE: So another paper, the second time that the North American Intergroup Study, SWOG S1117, was presented by Mikael Sekeres. Can you talk a little bit about that trial and what you thought about this update?

DR STONE: The update was looking at survival. And again, it was a negative study, sadly. So there were data from Sekeres himself that looked at combining lenalidomide with azacitidine in a Phase II setting in higher-risk MDS. It looked like there was a very high response rate.

Silverman, at Mt Sinai, had data combing the HDAC inhibitor vorinostat with azacitidine. It looked that there was a high response rate. So there was a Phase III trial led by SWOG, conducted in the US Intergroup, comparing aza alone to aza plus vorinostat to aza plus lenalidomide in higher-risk MDS patients. And lo and behold, the response rate was really no different. And the update this year was of survival. Maybe it was hope that even though the responses weren’t really higher with the doublets, and maybe the survival would be better because of response and survival aren’t that well correlated. The survival was no better in the doublets than in the singles.

So we haven’t really made any progress, in my mind, in higher-risk MDS at this point.

DR LOVE: Anything out there in MDS that’s encouraging? Is there a trial out there with checkpoint inhibitors? I’m not sure that’s been reported.

DR STONE: There is. There are a number of trials with checkpoint inhibitors. I think at this point in time, we can’t get too excited about that other than to say let’s do the trials and see what happens. Garcia Manero has data that if you gave azacitidine you increase antigen expression, which might make you a more fertile ground to respond to a checkpoint inhibitor. We’ll have to wait and see on these. I remain skeptical but hopeful.

I think an interesting molecule in MDS might turn out to be venetoclax or ABT-199. It hasn’t yet been tested in MDS but has been tested in AML. We didn’t talk about that abstract that was presented by DiNardo in poor-risk AML patients who weren’t going to get chemotherapy, older adults. They gave azacitidine plus venetoclax or ABT-199. The response rate was very high. It’s myelosuppressive, so it’ll have to be used with care. But I’m optimistic that some day we’ll be doing aza plus ABT-199 in MDS and maybe see better results than with aza alone. But that’s just a pipedream at this point.

DR LOVE: Any issues in terms of tumor lysis syndrome in that study you were talking about?

DR STONE: No. There were tumor lysis or there has been tumor lysis, as you are alluding too, in CLL patients getting ABT-199. Not true in MDS or AML to date.

DR LOVE: I’m trying to remember, is venetoclax — I know it’s fast tracked for CLL, but is it also for AML?

DR STONE: Just about a month ago there was a fast-track designation, a breakthrough designation for ABT-199 in AML, thanks to that study I just mentioned, with ABT-199 plus azacitidine in AML.

DR LOVE: So let’s talk a little bit about myeloproliferative syndromes. And I’m curious what your thoughts were about Abstract 56. We’ve heard about this agent, PRM-151, in myelofibrosis. Can you talk a little bit about what it is and what we learned this year?

DR STONE: It’s an agent that is involved in wound healing. And of course when we heal our wounds, we have to get rid of the scar tissue. We all know those little scabs we have on our skin — they’ve got to go away. And this PRM agent seems to be able to lyse fibrous things. And let’s face it, myelofibrosis is scar tissue in the bone marrow. So let’s try to use it in myelofibrosis. And the initial results in this early trial were very encouraging. People actually had a reduction in their fibrosis in this short-term study. And you don’t get that with JAK2 inhibitors, which is the only approved drug in myelofibrosis right now, which, of course, is ruxolitinib.

So this is being tested now in a national trial. And I’m cautiously optimistic about the ability of this agent to reverse the fibrosis and, therefore, improve the outcome for patients with this difficult-to-treat disease.

DR LOVE: Any tolerability/toxicity issues?

DR STONE: There weren’t any major ones in this paper.

DR LOVE: We also saw some data presented by Dr Claire Harrison from the COMFORT-II trial, one of the big Phase III studies that originally reported on ruxolitinib. This was the 5-year study result. Anything exciting come out of that?

DR STONE: Nothing really new. I mean, retrospectively there was a survival benefit to those who were randomized to ruxolitinib compared to best available therapy. Maybe a slight decrease in the fibrosis levels, although that’s a little tricky to say for sure. But again, the notion that ruxolitinib is a good agent in myelofibrosis has not been dispelled whatsoever by this paper. In fact, it’s been enhanced.

Ruxolitinib does have activity in myelofibrosis. It’s not because it’s a JAK2 inhibitor, because it works in people who don’t have JAK mutations. It works because it’s an anticytokine drug. So, of course, people are going to combine ruxolitinib with other agents, eventually PRM, maybe imetelstat. And there are a whole bunch of papers, which we may talk about in a second, in which other drugs were combined with ruxolitinib.

To my mind, each of them — I think there was one with a hedgehog inhibitor, one with azacitidine, one with an mTOR inhibitor and one with pomalidomide — did I get them all? — that will combine with ruxolitinib. That’s a natural thing to do. Ruxolitinib has activity as a single agent. Let’s combine it with other stuff that might be active.

None of these papers were home runs. It’s hard to know in a Phase II setting what’s really going on. There was activity. I think we’re obviously going to need to do Phase III trials in this group of patients. Ruxolitinib plus or minus new drug x or y. Which of the four drugs — aza, pomalidomide, hedgehog inhibitor, mTOR inhibitor — should be combined? It looks like aza made some sense, maybe pomalidomide. Not too excited about the other ones. But we’ll have to wait and see.

DR LOVE: What about JAK inhibition in polycythemia vera? Ruxolitinib is now approved there. Where do you see that heading in terms of research?

DR STONE: Ruxolitinib clearly is active in polycythemia vera. I think the big question in everybody’s mind is, will we be using ruxolitinib early in the disease? Will it be worth causing immunosuppression? And using the expensive drug in diseases where people generally do well, with cheaper things like fludarabine and hydroxyurea? But hydroxyurea is chemotherapy. I think it’s going to take a bold step to do this up front, but somebody will do it eventually.

DR LOVE: Did you say “immunosuppression” with ruxolitinib?

DR STONE: Absolutely, because it’s an anticytokine drug. Almost anything that’s anticytokine, whether it’s the anti-TNF drugs for rheumatoid arthritis, can cause an increase in sepsis. We know that patients with latent hepatitis can get their hepatitis activated when they get a drug like ruxolitinib. I’ve actually seen a patient myself who had occult hepatitis who got pretty sick after I gave him ruxolitinib.

So these aren’t benign drugs to give for the long haul in people who are otherwise going to be well.

DR LOVE: You mentioned the hepatitis. Any other immune things you’ve seen with ruxolitinib?

DR STONE: No. That’s been the big one, really, hepatitis. There may be other viral infections, as you mentioned. So it’s not a dramatic problem, but it is still something if you’re going to be treating a disease where the natural history is very favorable, you’ve got to be very careful.

DR LOVE: That’s very interesting.

So we also saw some data, Abstract 58, on pacritinib. Can you talk about those data? And also, what’s going on with this drug, because it sounds like things are happening?

DR STONE: Pacritinib is another JAK2 inhibitor. Maybe less anemia associated with it than with ruxolitinib, which is a big problem. Is pacritinib going to be the first JAK2 inhibitor second generation that’s approved? It’s quite possible that it will be.

DR LOVE: To what extent do you think it does spare the marrow compared to ruxolitinib?

DR STONE: I think it’s slightly more marrow sparing. But again, we’ll have to see the true Phase III data to be sure.

DR LOVE: Any personal experiences with pacritinib, or any cases you’ve heard about that would suggest — I have heard cases. Again, one-off kind of things, of people who responded to it after progressing on ruxolitinib. Is that thought to be the case?

DR STONE: It’s definitely possible. I mean, other drugs in this category, there’s a whole host of JAK2 inhibitors that have been in development, some of them that have been no longer developed because they’ve had other side effects. But pacritinib and some of the other ones have been tested in the ruxolitinib failure setting and there have been responses.

So yes. And that doesn’t surprise me.

So, I mean, I think pacritinib definitely has legs in this disease. I suspect it will become approved at some point in the not-too-distant future.