EDUCATED PATIENT® Acute Myeloid Leukemia Webinar: December 17, 2020

Topics for discussion included:

• Recent research data presented during the 2020 American Society of Hematology (ASH) conference
• Relevance of data for patients currently in treatment
• Updates on clinical trials and key approvals on the horizon

Transcription:

KRISTIE KAHL:Hi everyone.Welcome to today’s live broadcast, a CURE Educated Patient Webinar in Acute Myeloid Leukemia.

I’m Kristie Kahl, Editorial Director of CURE Magazine.We are pleased to bring you this webcast presented by CURE and in partnership with Abbvie and Genentech.We have a few important announcements before we begin.We encourage you to ask questions during the event, which you get to admit by typing them in Q and A box.You will be receiving a survey via email tomorrow.As a thank you for watching the full webinar and completing the survey you will be entered to win one of three Visa gift cards.

We are pleased to be joined today by our moderator, Dr. Harry Erba, Director of the Leukemia Program at Duke University, Dr. Naval Daver, Director of Leukemia Research Alliance Program and Associate Professor at M.D. Anderson Cancer Center, and Dr. Rami Komrokji, Vice Chair of the Malignant Hematology Department, Section Head Leukemia & MDS, and Professor of Oncologic Sciences at the University of South Florida and Moffitt Cancer Center.Thank you for joining us today and I will now pass it off to our moderator to begin the discussion.

HARRY ERBA, MD, PhD:Thank you and welcome all of you this evening.My name is Harry Erba and I’m joined, as you heard, by Naval Daver from M.D. Anderson and Rami Komrokji from the Moffitt Cancer Institute.We would like to spend at least the next 45 minutes discussing some of the information that we all learned at the 2020 American Society of Hematology meeting.It was supposed to be in San Diego but we did it virtually and actually a lot of us liked it done virtually because we actually got to spend more time and listening to the data and various different areas.It was a very well done meeting, although, it wasn’t sunny Southern California but maybe next year we will be there.My colleagues, Rami and Naval, being down in Houston and Tampa have it sunny all the time, except when those hurricanes come through, I guess.

But let’s get started and I am going to start by turning to Naval and then to Rami to just start our discussion with what was the most exciting information that you learned about AML research at this year’s meeting, Naval?

NAVAL DAVER, MD:Thanks, Harry.I agree.I actually liked the ASH setup this year to listen to things that were not in the presentation because you were at home and not running everywhere so it was actually really nice.For me, there were many things that were exciting but to start off with magrolimab and this is for the p53 in very high-risk cytogenetic patients where we were very hopeful three or four years ago looking at the response rates with aza/ven of 55% or so that this will improve outcomes in all older - - AML and it has been a major, major breakthrough but, unfortunately, the TP53 mutated in high risk cytogenetic patients continue to do poorly, even with aza/ven.And there were two abstracts at this year’s ASH showing although the remission rates are about 50, 55% the median survival is only 5 to 6 months with aza/ven in TP53’s.So this kind of put light on the emerging exciting data with magrolimab, which is a very interesting, unique mode of action.It is a CD47 inhibitor so it is kind of the checkpoint on the surface of macrophages that blocks macrophage from working.Normally, the macrophages are some that should eat up leukemia cells or cancer but the cancer is able to shut them down so this antibody by preventing the cancer from approaching and shutting down macrophages likely leads them to start working again and they start fighting against the leukemia.

So that is the science.It is a very unique drug.The first kind of in class for the CD47 inhibition.The data that was shown in frontline overall was very encouraging with response rate of about 60, 65%, which is a little lower but in the ballpark of what you see with aza/venetoclax, but especially in the high-risk TP53 AML we are seeing 70% CR, CRI, and median survival of almost 13 months, which is much better than what we have seen with aza/ven, where the median survival in three different study sets has been between 5 to 7 months.So again, it is an early study, phase 1, single arm, and we know all the caveats with that, but looks very encouraging.We also saw good molecular and deep remissions so I think this is, hopefully, an important drug to combine in the future for high-risk AML.

DR. ERBA:Thank you, Naval.I had muted myself because I was hearing some feedback so I apologize for that.In any case, I agree with that.I think a lot of people are excited about CD47 as a target and partly because not just active in myeloid malignancies, MDS and AML, potentially, but CD47 provides a don’t eat me signal, as we call it, for all of our normal cells in our body so that the innate immune system, as we call it, those cells that are ready to gobble up on defective cells, viral-infected cells, called macrophage they are blocked from doing that.But by blocking the signal you can overcome that effect, which means that this class of drugs may not only be effective for our patients that we treat with AML or myeloid neoplasm like MDS but we may be seeing a lot more work with these drugs in other cancers, as well, which is wonderful for the entire cancer community.You know, a lot of patients often say to me why can't we find something that is just good for all cancer?I go about explaining the heterogeneity of the disease and the mutations, as you talked about TP53, but activating the immune system, in some way, may be the best way to do that.Now, I am going to come back to you, Naval, because you have been a leader here in doing just that in myeloid neoplasms.

Let me turn to Rami, though.Rami, what did you take away as important research?

RAMI KOMROKJI, MD:So I think it is a very important time and I think what is exciting is really the changing landscape and the several potential drugs to be approved.What is frustrating for me is, like, we need to get those approved quickly so like you know many of those are heading to phase 3 trials but they are not approved as we can use them in practice now.

I think if we stay in the line of the p53 APR246 is another drug that has finished phase 3 so that is hopefully here to read out on in the coming month or so.As Dr. Daver said, the p53 mutant AML historically and the MDS, unfortunately, do very poorly.P53 we can think of it always the way I explain it is it is almost like p53 is like a protein like a brake and when we say p53 it a mutant the brakes are off and things are completely under hectic, uncontrolled proliferation.So one approach promising is the magrolimab that Naval talked about and then the APR-246 is actually a drug that binds to the p53 and restores the function so puts the brakes back.We have been testing this in a phase 1 and phase 2 in combination with hypomethylating agents and we have seen doubling or tripling of the responses, more than 50%, and that now had finished a phase 3 randomization where patients were either getting azacitidine or azacitidine plus APR-246 and I am hopeful that the results of that study would be positive because that will translate to first approval of a drug particularly for that group of patients with the p53.

There are many other exciting drugs in development.Some of them are early on.I was excited a little bit about the class of drugs called the menin inhibitors.Those work for a group of patients that have a chromosome abnormality called 11q23 or MLL gene that typically happens in patients that have acute myeloid leukemia from prior treatment, we call it treatment related, but that can happen, also, without a prior history of treatment.Historically, unfortunately, there is a poor outcome.They respond to treatment but then they relapse.This class of drugs act binding the menins and interfering with their interaction with the MLL.This is very early phase so there are two drugs that can target those menins and we heard about the first few patients that go on the study but it is a very early promising result that those drugs could work so a small subset of patients we saw some activity.A couple of patients achieved complete responses so I think that is going to moving into phase 2 or 3.

The excitement for me, there, again, this is a targeted therapy for an unmet-need population.

DR. ERBA:All very good points.Iagree with you.I like how you focused on those menin inhibitors and the data that was presented by our colleague Eunice Wang from up in Roswell Park for the investigators.You know what strikes me as making the following point for our patients who are listening and that is all the exciting drugs that are coming.Well, I shouldn’t say exciting.It is not exciting to have leukemia, right?But all of the hope that we can now have for our patients and we have already seen in the recent years developed so along those lines we are going to talk a little bit more detailed about the standard initial treatments for AML, either intensive chemo or a regimen with a drug called venetoclax.So I definitely want to get to some data from ASH about those agents.But unfortunately for our patients, whether they have had an allogeneic transplant or not, relapse remains quite common.I think what is really important for our patients to understand is if their physician hasn’t talked to them about specific targets in that relapse of leukemia then they haven’t had a complete evaluation.I think with the drugs we have it is important to do that evaluation.It is a genetic analysis looking for mutations, genetic changes in genes like FLT3, IDH1, IDH2, and now Rami you just mentioned MLL gene rearrangements and where the menin inhibitors may turn out to be very important.Also, nucleophosmin menin inhibitors may be very important.But you have to look for those genetic changes in order to see if a patient is eligible for a commercially-available drug or one that is in development.

So with that, I am going to tag team back to Naval because one of those targets is FLT3 that is found mutated in about a third of our patients with AML and there are a number of drugs that are being developed that for relapsed/refractory AML and in other situations.Why don’t you give us a little summary of that, Naval, plus an update from ASH?

DR. DAVEL:Yeah, sure, absolutely, I completely echo what Harry is saying.I think the key for relapsed patients, you know, for the patients out there or caregivers, is to really check for mutations.Just yesterday I had a patient and I’m very excited when I find a mutation because we know we really have now a chance of targeting this and getting the patient to transplant and potentially trying to get to a cure.It is much harder when we don’t have a mutation so absolutely the big mutations we look for in AML relapse are FLT3, very common, one third of the patients, IDH1 and 2, about 20% of the patients.Now, MLL we are even NPM1, another 5 to 10% and then maybe TP53, based on some of the data around Ian and Harry’s book about APR and magrolimab so maybe 60, 70% we are hoping could have a mutation even in 2021.

Specifically with FLT3, which was the first mutation to be targeted in acute myeloid leukemia almost 15 years ago in the first generation FLT3 inhibitors, I think this one is really critical.Front line the addition of FLT3 inhibitors like drug midostaurin, which is actually FDA approved in the U.S. and many countries, has shown improvement in survival and improvement in response rates and is absolutely critical standard of care.So I think it is very important to have the FLT3 check diagnosis in our patients in whatever setting they are being treated and get the FLT3 inhibitor added.

Also, with FLT3 mutated transplant really is the goal for the majority, 90% of these patients.There are few exceptions but I would say for the majority we want to take a FLT3 mutated, give a FLT3 inhibitor, take them to transplant, and now even there is data showing that after transplant continuing oral maintenance with the FLT3 inhibitor can even further improve the outcome.Just to summarize, 20 years ago when we first saw data with FLT3 the 5 year survival published by one of the larger cooperative groups was 20% and today in some of the recent data sets with the addition of FLT3 inhibitor, transplant, post-transplant FLT3 inhibitor, we are seeing 60, 65% survival.I think this will be improved further because at ASH this year there was a lot of data on what we call the second generation FLT3 inhibitors so we have been using midostaurin when now there are drugs, gilteritinib is the one approved, quizartinib is another one, which is very, very active and also completely a phase 3 that we hope to hear about soon.So there was data now showing that if you use these drugs, even in the relapsed AML, as a single agent you can get about 50% of the patients, 50 to 55%, in remission, giving them a hope for transplant and then maybe after transplant continue the FLT3 inhibitor.But more importantly, when you combine active drug, so you are taking your FLT3 inhibitor and combine it with venetoclax or with aza/venetoclax, you can get really high remission rates, 85% remission rates are showing with some of these combinations, even in relapsed patients who have two or three prior treatments.So I think this is the same thing we will see with the menin inhibitors that Rami mentioned that will be combined with other drugs, with IDH inhibitors, but the key is absolutely we need to keep checking for a mutation.Sometimes these mutations can be dynamic.The patient I had yesterday, for example, she didn’t have a FLT3 for a year and she was on different treatments and now we see a FLT3 at a high rate level so I was very excited because I will try a combination like venetoclax/gilteritinib and this has opened a path for her for potential remission and transplant.So it is really practical.

DR. ERBA:I think that last point you brought up is so important to do this mutational analysis that is commercially available to our pathology labs around the country and for the most part not much pushback from insurers about payers about doing a molecular analysis at specific times.And those specific times are when you are thinking about treatment, when the patient has active disease, either at diagnosis or when you are worried about relapsed or refractory disease, because we have agents, now, that are FDA approved for FLT3 mutated, IDH mutated, and so it translates into a therapeutic algorithm or approach for the patient.

And then the importance of maybe seeking, if time permits, second opinions is that we all have studies that are looking at these other targets, TP53, only found in about 5 to 10% of AML patients but we know it confers a poor prognosis and now we have two different approaches that appear to be effective, not FDA approved yet but clinical trials are there.The menin inhibitors, as well.

But probably one of the biggest advances that we have seen, I will say I focus on taking care of older AML patients.I am not a transplant physician.The median age of AML in the United States is 68 and until recently a minority of older patients hadn’t gotten any therapy for their disease because it was such an aggressive disease, the therapies had very low response rates, took a long time to work and, quite frankly, our clinical trials didn’t quite show an improvement in survival by impacting with this treatment.But Rami, that is completely changed, now, right?We now have therapies that our older patients can tolerate with significant response rates and specifically I am talking about the agent BCL-2 inhibitor venetoclax that we have been talking about.Do you want to give our audience a little update on venetoclax-based regimens for older patients and anything that might have come out of ASH about that?

DR. KOMROKJI:Absolutely.I want to echo all what you said in terms of also how to think of this and approach this.Just to start with a frame for where to put the venetoclax in I always teach my Fellows and Residents it is like in those diseases you have to go through three steps.One, make sure that the diagnosis is right because we still see cases where sometimes there is misdiagnosis.Get all the information for what we call a risk stratification, which is our staging, which is all based on molecular and cytogenetic.And then tailor the treatment according to that risk.And that is true whether you are talking about younger or older patients.

Now, in older patients, as you mentioned, like the intensive chemotherapy is not always the answer or physically and doesn’t derive benefit.I think one of the important points for the patients to know that treatment is always better than no treatment, no matter the age is, and there is several data that has established that in terms of quality of life, short and long-term survival.But the question always has been what type of treatment?With intensive chemotherapy in patients that have - - problems, you know, bad cytogenetics, the mortality could be very high.So we have used for many what we call the hypomethylating agents, azacitidine or decitabine, as the backbone with the improvement in survival, improved quality of life.But the reality is almost only 20% of the patients or less go into what we call a complete remission, where the counts are normal and disappearance of the blasts, and the median survival used to be less than a year.

So venetoclax is an anti-apoptotic drug that had been in combination with hypomethylating agents and now I think it is becoming the new standard of care.So the combination had been tested in a phase 3 clinical trial where the patients either got the hypomethylating agent azacitidine alone or azacitidine/venetoclax, which is a pill that the patients will take on a daily basis.And the study had showed almost doubling or tripling of the response rates and almost doubling of the overall survival.And certain patients with certain molecular features actually have even longer benefits from that.So I think that is where the standard of care is shifting to the combination.

Now, the study was focused, obviously, on patients that were not fit or eligible for intensive chemotherapy, either by disease risk or by age or by certain other comorbidities so this is for patients that cannot get intensive chemotherapy.The treatment, I think, obviously, has to be monitored carefully.The combination, really the major issue with it is the cytopenia or low blood counts, especially at the beginning.So I think, as we said, the devil is in the details.With close monitoring, doctors that are experienced, have used those regimens, to know when to repeat the assessment for the disease, back off the dosing with the treatment.But there is no doubt that this is emerging as the new standard of care for patients with rapid responses, complete remissions.We know that, in general, most of the patients will derive good benefit from this treatment.At ASH, for example, this year, also, we heard subsets, like the patients that have IDH1 or IDH2 mutation, actually, derive even more benefit from this treatment with almost median overall survival increased, higher response rates, and durable responses.We know that there are subsets that may not do as well, like the p53, maybe higher responses at the beginning but they relapse, and we know that there are subsets that may be resistant but in majority of patients this combination is evolving and becoming almost the standard of care for our patients.

And as Naval alluded, this is going to become the backbone for even adding other of the newer drugs that we are testing in combination to see even if we improve the outcome.So that is probably a long answer, I’m sorry, but it’s really exciting to see that the newer standard of care and we are finally moving the bar for the outcomes in our patients.

DR. ERBA:I agree.I mean this has improved the survival of our older patients with acute myeloid leukemia and it provides an option for a treatment that does have high response rates.There are some nuances, some tricks, to dosing these drugs appropriately for effect but also safety and so one thing I would stress to our patients is that this needs to be given by somebody who has experience giving it or has access to somebody who has experience giving it.I know that is a lot to say but there are nuances to how long you continue the venetoclax and once the leukemia is gone and how you adjust the doses and do you need to be admitted for that for a cycle or can you do it as an outpatient if you live close and have a caregiver?So all very important issues to consider but definitely something that our patients should think about.

Now, the interesting thing about this BCL-2 inhibitor is that, and our audience may know, this was first approved in a chronic leukemia, CLL, so it has activity other places and I think this really illustrates the fact that BCL-2 is a protein that is in our cells that prevents the cells from dying.It is a pro-survival signal, which is good in the sense that you don’t want your cells all just going to mush, you know, and we all become zombies or something.We don’t want that to happen.But if the cells is defected or you give chemotherapy to damage the DNA you want the cell to be able to die and what we have learned in many cancers, lymphomas and AML, that these often have higher expressions of BCL-2 so it makes sense to add venetoclax to the therapy.Something that blocks that, allows the cell to die, and this is major advance for our patients.

But I am going to come back, now, to Naval and first Naval knows that he is Chairing a faculty position with Courtney DiNardo, there, who is part of an international team that has led to the approval of these drugs, hypomethylating agents they are called, with venetoclax for our patients.One of the youngest I have ever seen honored with a lecture-ship at the ASH meeting.Quite impressive.As my sister institutions there, M.D. Anderson and Moffitt are and pushing the field forward and M.D. Anderson doesn’t sit on its laurels.Neither does Moffitt.I am not leaving you out, Rami, and always want to move forward.

So Naval, so you have taken this idea at M.D. Anderson of combining venetoclax with one regimen but at ASH we heard maybe there is an opportunity to combine venetoclax with less intensive regimens or intensive regimens.Do you want to tell us about some of that work that your group has presented?

DR. DAVER:Yeah, absolutely, I mean I want to echo, I think, you know, not think, I believe venetoclax is the most important breakthrough in AML and very, very effective, has really been a game changer and what started with the low-dose venetoclax that Rami talked about and covered so nicely is now leading to many other combinations.

So there are many of them but I think the two or three that are most close to hopefully moving to some kind of registration or approvals in the future there is some very nice data looking at combining high-dose chemotherapy, so ida intensive chemotherapy we use very frequently in relapsed AML and unfortunately doesn’t give us very great activity, about 30% or so response rate, which is something.We try to take those patients for transplant.But what we saw is when we combined venetoclax with ida the remission, true CR, CRR rate, went up to 75% in relapsed AML, which is really dramatic.We have never seen that kind of response in previously treated relapsed AML.We were able to take those patients to transplant.We were actually looking at long-term survival, one-year survival rates, of more than 70% and two-year survival rates of close to 60%.

So this really does seem like a real improvement, again, showing the venetoclax, as you had mentioned, Harry, is a great potentiator of anything that causes cell death, whether it is hypomethylating agents, like azacitidine, whether it is low-dose cytarabine, or now whether it is high-dose chemotherapy and so of course this is not in the frontline setting and the trials are going to see if we can really get very high, deeper remissions, clearance of disease, in the frontline-treatment patients getting venetoclax with the initial induction and we would see we need more followup to know.

The second combination is combining venetoclax with a targeted therapy.So this is something that eventually we all knew was going to happen.We are doing a number of these combos here, many of them at the center, you and others are collaborating with us on this.So one is with the FLT-3 inhibitor so when we combine venetoclax with the second generation FLT-3 inhibitor, so kind of the best of both worlds, very good FLT-3 inhibitor, very good BCL-2 inhibitor, we saw in relapsed AML we could get 85% marrow clearance rates, giving us great opportunity to get a lot of these patients who just 5 or 6 years ago we would consider no options or trial or it was hospice if you had relapsed with AML and today we are talking about 85% remission and transplant.Again, we have to wait and see the followup survival but very hopeful data.

And then the third was combining venetoclax with a drug that Rami’s group, actually, has dealt with a lot, which is CPX-351, Vyxeos, which is a novel, safer formulation chemo and it is effective on its own but we want to try and see if we can make that even better and so that led to a combination of CPX/venetoclax, which showed encouraging responses but the thing we are seeing with a lot of these venetoclax combinations is something that you mentioned, Harry, is that they are not easy.This is something that requires a lot of experience with the drug, a lot of close monitoring, ability to start and stop treatment, use growth factors, manage infections.Yes, it looks like it is paying off with the responses and early signals of survival but I do think that this is something that will require more fine tuning and may be something, eventually, that should be done only in the academic centers.There may be a role for that in the future of AML treatments as we get more effective outcomes.

DR. ERBA:Thank you.I agree.I think we will be seeing this is much like rituximab, the antibody was in lymphoma, venetoclax will be added to a number of different regimens.We have to learn how to manage the toxicities but we do think that there is great promise to show that that kind of approach is going to improve outcomes for patients.

You know, as you were talking you mentioned CPX-351 and then said Vyxeos.It is the first time we have said a trade name here and that is because the three of us are trained never to say brand names or trade names but our audience has probably only heard brand names so venetoclax is Venclexta, I will tell you.We talked about gilteritinib, that is Xospata, and I think everything else has been mostly investigational.

But I want to come back to Rami because Rami’s institution and his colleague there, Jeff Lancet, have really taken a lead on the development of a novel way of giving chemotherapy that we have had for 40 years and here we are 40 years after chemotherapy was developed in AML learning how to give it better.So tell us a little bit about Vyxeos and where it might be still useful to have intensive chemotherapy regimen?

DR. KOMROKJI:So as you mentioned, Vyxeos is really a different way of delivering the standard chemo that we have used for many years so the backbone for patients that can get intensive chemotherapy has been a regimen called 3 plus 7, based on the number of days that the drugs are given.One is cytarabine and the other one is anthracycline.What Vyxeos is is really like a packaging of those drugs to be delivered in a certain ratio that in the lab we saw if you have that ratio of between those two drugs that you maximize the killing of the leukemia cells and allows more delivery to the bone marrow.

So when we did the phase 1/phase 2 studies there was a signal that maybe the best outcomes are seen in patients what we call secondary AML.So this is AML coming from prior treatment for other types of malignancies or cancers or for patients that had prior history of myelodysplastic syndrome.So that led to a phase 3 trial and comparing it to the standard 3 plus 7 we have used and that did show a survival advantage for patients getting CPX-351 and led to the approval.

So nowadays we use this treatment for patients first if they are fit and they are able to get intensive chemotherapy that they probably either had AML secondary coming from MDS or had what we call therapy-related AML.At ASH Dr. Lancet presented the update at the five years showing that the data confirming that survival advantage at five years, historically in patients older with intensive chemotherapy the five-year survival, unfortunately, appears to be less than 10% and with this treatment we are seeing probably still around 20% so there is definitely improvement.Again, we need to do much better, no doubt about that.

Also, what is interesting with the CPX-351 or the Vyxeos is that patients that got Vyxeos and proceeded to allogeneic transplant seems to have much better outcome with the transplant.Mostly, people think that what is behind this is that we obtain deeper responses with the Vyxeos treatment.

So this is an improvement.It is something available for patients.Again, it is not for all the patients, it is for that subset of patients with secondary AML that are eligible for intensive chemotherapy.In terms of side effects and toxicity it is similar to what we expect with intensive chemotherapy but, you know, we do see a little bit more prolonged time to have the counts recover a little bit with this treatment compared to the standard 3 plus 7.

As Naval just alluded to, it has been looked at to be done in combination with other new treatments.As he alluded to, there was some presentation about combinations with venetoclax.We are looking at it in patients with relapsed, FLT3, to add some FLT3 inhibitors, gilteritinib.There are some other trials looking at it so it will be, probably, a backbone for those patients with secondary AML to be used.

DR. ERBA:Thank you.it is a wonderful summary about Vyxeos and how we can still learn how to give chemotherapy better and most of the investigators felt it was somewhat less toxic.That didn’t really come out in the study results but, basically, the drug targets the leukemia cell in the bone marrow more specifically than the chemo with the same two drugs given in a different formulation.So definitely a benefit for patients.

So one thing to remember, though, and you focused on it, is the only, for patients with really high-risk AML, where we can tell by their history or this mutational data or chromosome data that we gather at the beginning, or even the presence of persistent disease using some very high sensitivity test, like flow cytometry or genetic tests, in all of those situations, unfortunately, we know that relapse rates with chemotherapy are quite high and stem cell transplant, bone marrow transplant, provides maybe the best option for, you know, preventing a relapse at a cost of more toxicity.But that would, hopefully, prevent the relapse.

I think you very nicely summarized the data with Vyxeos showing that those patients went on to transplant, really had a better outcome than patients who went on to transplant after 7 and 3.But I think the other point is when we look at the patients who actually are still surviving five years later many of them did get a stem cell transplant after achieving a response.

However, keep in mind that even older patients with AML in remission after what we call a less intensive therapy, like azacitidine or Vydaza or Venclexta can also benefit from stem cell transplant.

I guess at this point what I’d like to do is just give one shout out to a study that was done by our transplant colleagues in MDS patients.So patients who had high-grade, high-risk MDS, basically, you think of this is one step away from AML, you know, that is a pre-leukemic condition but very close to presenting with AML, in a study that has been done here in the United States we have shown that the survival of patients with high-grade MDS who get a transplant was better than patients who got the standard of care for MDS, even in patients between the ages of 55 and 75, even in Medicare recipients 65 and older.So don’t let your doctor tell you you are not a candidate for a transplant because of your age.None of us will admit to an age cutoff for transplant.You could be in your 70s and if you are otherwise healthy, good performance status, you know, strong, white bull, have a caregiver and want to think about curative approaches stem cell transplant remains one.

DR. DAVER:- - most of the time, like, I am going to - - so Harry - - Southwest Oncology Group taking many of those treatments in leukemia at MDS to phase 3 and - - so I think one thing we haven’t talked about and I think is important is that now we also have a role for maintenance in AML so can you tell us when - - so tell us about the maintenance and that treatment because I think that is also a new standard of care for our patients with AML.

DR. ERBA:I agree and I think it is and as we are getting close to the end of the program I am going to come back to the two of you for what you think might be close to showing promise, I should say, and maybe FDA approval for our patients.

So I’ll start with history and then you can go to the future.The history is the approval of an oral form of Vydaza.It is an oral form, it is called Onureg.It is the same drug azacitidine given by mouth for 14 days, consecutive days, out of the 28-day cycle.This was approved by the FDA on September 1, 2020 so just two to three months ago, based on the following study.In the study, they took patients over the age of 55 who got intensive chemotherapy, so our standard chemotherapy, got a remission, many of them got post-remission treatment, and at that point they were facing a decision should they undergo stem cell transplant or not?And many of the patients were not eligible, many, all of our patients aren’t eligible for stem cell transplant because of comorbidities, because in the old days, maybe not now, they didn’t have a donor or, quite frankly, we gave them intensive chemotherapy and they were pretty sick and weak after the intensive chemotherapy.You need a caregiver to go through a stem cell transplant.Many of our audience probably already knows that if they have had a stem cell transplant.You actually need somebody who is going to take care of you for at least three months afterward.You need to live close to a transplant center.So a lot of our older patients said, no, that’s okay.I’ll see how long this remission lasts.

Well, that is where oral azacitidine comes into play.In the study that was an international trial patients who got oral azacitidine after they finished their standard intensive chemotherapy every month until disease progression or some toxicity compared to placebo lived longer.So at one year and two years more people were still alive and the median survival so that is like the average survival of our patients, not exactly the same but that is how we think of it, was improved by a full ten months.It didn’t cure patients that weren’t already cured by the chemo but it extended their life.So now there is an option for a maintenance therapy.

At this year’s ASH our colleague up at Cornell, Gail Roboz, showed that even people where we could still see some low evidence of leukemia at the end of that intensive chemotherapy even they benefitted from this oral azacitidine and it could clear that minimal residual disease.You need to keep track of the blood counts, you may need to take antiemetics or anti-diarrheal agents along with it because it is an oral chemotherapy but it does appear to be a benefit to our patients.

Okay, so that is history, right?That is last year’s ASH leading to this year’s approval.Naval, what do you think is the next thing that our patients will have access to?

DR. DAVER:Yeah, so I think, you know, the FLT3 story unfolded in probably the last ten years there.There are two, actually, FLT3 compound studies with second generation FLT3 inhibitors that are completely, hopefully, in 2021.One is with the drug I mentioned previously, Xospata or gilteritinib, a very potent second generation FLT3 inhibitor and there is a study using azacitidine with Xospata versus azacitidine alone for FLT3-mutated AML.It is called the LACEWING study.It is a lot newer because in the U.S. they, of course, have aza and venetoclax and triplets, also, of aza, venetoclax and FLT3 in trial so we still haven’t seen the results because that may bring gilteritinib to the frontline and then we have all three drugs, aza/veno and aza/gilt and we have to find the best way to sequencing them or combining them.But I think we could really get good, long-term cure rates.So we are thinking that data may be available by next ASH.The study is about 70% enrolled.

And the second is a drug that Harry has worked a lot with and is one of the Co-Chairs for the frontline study of quizartinib so there is a study of 3 plus 7, which is induction therapy for AML, with quizartinib versus just induction 3 plus 7.It is called the QuANTUM-First study and we are very excited to see the data because our belief is, based on phase 2 single-arm studies with the second generation FLT3 inhibitors, quizartinib and gilteritinib, are way more potent than midostaurin and sorafenib and single agent they give you almost five to ten times higher response rates so the hope would be when you moved them up front they would get very good activity.And that one, also, they are hoping some time in late 2021 we may see data and further change the FLT3 landscape.

So really more stuff to keep looking forward to in spite of all the nice data that has already come out, which is great.

DR. ERBA:Yeah, great, Naval, I completely agree with that.It is funny, here I sit on the Senior Scientific Council or steering committee for that QuANTUM-First study and as we were thinking about what we were going to talk about I forgot about it but you’re right.The readout is going to be in 2021 so what we are hoping is that the first generation FLT3 inhibitor, midostaurin, which added to chemotherapy showed some improvement in survival, we are hoping that with the second generation drugs that are much more potent whether we can even push that needle even further to improve survival of our patients with FLT3-mutated AML.That is as an initial therapy.

Quizartinib is not approved in the United States but it is approved in Japan so the drug is tolerable and can be taken by AML patients, just like Xospata or gilteritinib.So we definitely have room for more than one FLT3 inhibitor in our patients, more choices for our patients.

Rami, what do you think?

DR. KOMROKJI:We covered some of the drugs that are going to be in phase 3 and maybe will have readout on them so I think Naval nicely covered the magrolimab.That is going in phase 3 now.We are entrusting that in MDS and AML there is also going to be randomization for patients with p53.APR-246, as we mentioned, so those drugs are in phase 3.There are other drugs that we didn’t discuss.There is a drug called sabatolimab, a TIM-3 inhibitor that targets both leukemia stem cells and immune system.That is going in phase 3.So I think by 2021, 2022 we start getting readout on those randomized phase 3 trials.But all those drugs are going in phase 3.Another drug called pevonedistat, which is an - - inhibitor, several trials, actually, and they are phase 3, which, obviously, hopefully, will lead to approval if we confirm the activity seen previously.

So the landscape is going to continue to change and hopefully with all of this we will have more options to offer our patients.

DR. ERBA:Naval, for our patients that are listening here, the audience, they may have friends and they are probably listening because of AML and wanting to hear what we have to say from ASH, but they may have friends with other cancers, like lung cancer and melanoma and renal cell, where checkpoint inhibitors have improved the outcomes.Naval, you are a leader in this area in terms of clinical investigations, as far as checkpoint inhibitors in myeloid malignancies.Now, one of the things that our audience may hear from their colleagues, from their friends, is the toxicity of checkpoint inhibitors, these autoimmune diseases.Have we seen anything like that in with sabatolimab, with magrolimab, which are also checkpoint inhibitors?

DR. DAVER:Yeah, interesting, yes, absolutely, checkpoint inhibitors, for anybody who has had any kind of solid tumor, lung cancer, bladder, friends, colleagues, are very familiar.It is kind of become the cornerstone of therapy for many of these cancers.In myeloid malignancies, unfortunately, we have not seen that degree of success with the traditional checkpoints like PD1, PDL-1, CTLA-4, nivolumab and pembrolizumab kind of drugs.We have done a lot of trials and there may be some small…

DR. ERBA:I think we lost him.We lost Dr. Daver.Can you pick up his thought there, Rami?Where was he going?

DR. KOMROKJI:I don’t know.We will wait for him, I guess.

DR. ERBA:You have used magrolimab and we both use sabatolimab.It seems like by inhibiting this checkpoint in the innate immune system maybe we are not going to see the same kind of toxicities.

DR. KOMROKJI:- - magrolimab - - is different so with magrolimab we don’t see any of those classical immune mediation so with checkpoint inhibitor we have seen colitis, pneumonitis, like Dr. Daver was discussing, we don’t see that with magrolimab.The most we have seen with magrolimab is what we call on target - - because there are blood cells doing - - CD47 so when we give the drug at the beginning we do see destruction of red blood cells but we have not seen any immune mediating - - patients that were not, you know, the classic immune mediated.Naval I had to cover for you.I don’t have the good looks like you but I tried to make it up.

DR. ERBA:Naval, it was amazing.As soon as you lost connection Rami was right there with the next word of your next sentence.

DR. DAVER:He was right there and went right into it.basically, as Rami said, with the new drugs, magrolimab, sabatolimab, we are not seeing the immune checkpoint toxicity that we did with PD1, PDL-1.I think in a general statement I think in the next five years we are going to see a lot of immune therapy done with AML and MDS.It may be CAR T cells, eventually, CAR and K cells, but I think this is the next wave after targeted therapy and it is going to be exciting.

DR. ERBA:So there was a question from our listeners regarding pediatric cancers at ASH.I don’t remember any, well, first of all, I don’t think any of us probably went to many of those because we don’t treat kids and we have enough to do but I will say that there is one abstract that I think, one presentation, that is important that I heard at the ASH meeting last year and then it was updated this year.Basically, it is about the treatment of a type of acute leukemia called acute lymphoblastic leukemia or ALL B cell type.

What is interesting here is that we have developed an immunotherapeutic approach for those patients with a drug called a biospecific T cell engager.This is a novel form of therapy where an antibody is basically created that can stick to a protein on the outside of the B cell, the cancer cell, called CD19, and also stick to a protein on the outside of the T cell, called CD3.And what this drug does, called blinatumomab or Blincyto, is it brings the T cell, your immune system right next to leukemia cell in such a way that miraculously it activates the T cell so you kill the leukemia cell.So it is an FDA-approved drug.It had been FDA approved in adults with a relapse of B cell ALL.It has now been approved even if the patient is in remission but we could still see a little bit of the disease.

Well, the study that was done by the Children’s Oncology Group showed what, I guess, adult oncologists wouldn’t be surprised at because we did a similar study.In fact, Dr. Kantarjian published that study.That is Naval’s boss at M.D. Anderson.He published it for a group of international investigators but let me tell you about the study in pediatrics.

They took these patients, kids with a relapse of ALL, and gave them either chemo or this antibody therapy and the outcomes in terms of responses and survival were better with this antibody therapy called Blincyto.Now, it comes at a cost of something called cytokine release syndrome, where a patient can get fevers and chills and low oxygen level in their blood or low blood pressure.But it is a transient effect.We know how to treat it.patients can get encephalopathy, some confusion, sedation, sometimes seizures but, again, these are temporary effects that can be managed and, of course, don’t happen in all the patients.

So again, getting to the point where I think one of the exciting things we saw at ASH in AML is we are hitting the cancer from multiple different angles, right?the mutations that drive it but also the immune system to control it and I think it is through these combinations that we will be able to actually advance the outcome, improve the outcomes, of our patients with cancer.

Let me look at some other questions.There was a question about - - causing AML.Rami, would you like to take a crack at treatment-related AML?

DR. KOMROKJI:Sure.Definitely.So treatment-related AML - - of the cases this is like a sequela of the treatments we do that they can cause damage to the stem cells.However, nowadays, we know that patients may have some predisposition to that and have that acquired - - mutation as we get older and we get another - - of the disease.We think of them of a couple times, one happens early on within a couple of years of the treatment.That is - - we call it - - and we discuss - - abnormality we can see it there.And another type we see - -hypomethylating agents so things like Cytoxan - - transplant for lymphoma and those can happen years later.In general, we do think of - - or MDS as having a poor outcome but - - by the chromosome makeup of the cells - - so it appears to be we see more p53 in therapy related, normal cytogenetic.But there is such a patient that will not have those and we - - better than those that have the mutations.So it - - we treat more solid tumors successfully we do it more and more therapy-related AML and MDS but - - for patients having what we call - - potential to develop - - in that population.None of the newer drugs - - with magrolimab include a lot of patients with therapy-related - - point of timeline, as I mentioned, some of them happen early but some could happen years later.I saw a patient today 10, 12 years later after exposure to treatment had developed therapy-related AML.

DR. ERBA:The Adriamycin-induced leukemias, as you mentioned, can often occur quicker with a monocytic phenotype and they often have genetic changes where this gene on chromosome 11 called MOL is fused, well, actually, now it is called KMT-2A, I believe.I always think of it as MLL.You think you guys in the audience have it bad that you have to remember all these different drugs that we talk about, they keep changing the names of genes on us and so it is really hard for us to keep up, too.

But in any case, this gene called MLL can be fused with other genes and causes the leukemia.It is part of the pathogenesis, we call it, of the leukemia while the menin inhibitors that Rami introduced earlier would be, hopefully, an effective agent in that group of patients.So besides chemotherapy like Vyxeos, besides magrolimab and some of magrolimab, all of these different CD47-targeting agents, we have other agents that may actually really pinpoint and get at the biology of the disease and help improve outcomes for patients.Naval, one of the questions that our patients are asking me in clinic is this COVID vaccine, should I get it?what is it?so I know none of us our infectious disease experts but I think this year I think some of us have become junior virologists.If you listen to Tony Fauci enough I think you can't help it.so any updates for our audience about the COVID vaccine?

DR. DAVER:So what I would say is that I am getting my vaccine tomorrow so I would see how that goes but I think it is critical.It has done a 30,000 patient so I know there is a lot of politicization of COVID, which is very unfortunate, and a lot of decisions being made not on science but when you use these drugs that we are giving you for leukemia, IDH, you have to remember the trials report to 500 at the most.So here you have a 30,000 patient study that showed safety.I am pretty comfortable to get it.it showed 97% seroconversion and protection.It shows zero COVID cases compared to 30 in the control arm so my recommendation because almost every patient is asking me is I would get the vaccine.It is not a viral component.It is an mRNA that makes a particular protein so there is zero risk of viral activation, unlike some of the other vaccines.

What we don’t know is how effective it will be in producing antibodies in some of our AML transplant patients but we will learn that doing the research on it the next six to nine months.But I think it will afford some protection, the 97% conversion, but some protection is better than no protection for COVID so my recommendation has been to get it.

Now, you do want your platelets a little bit above 30, 40 and the neutrophils probably a little bit high so you don’t get - - and that is something you talk with your local hematologist, oncologist, whoever is seeing you.but otherwise, yeah, I recommend getting it.

DR. ERBA:So one of the most interesting sessions I attended at ASH was when our ASH President, Dr. Stephanie Lee, who I actually trained.She was a Fellow at the Brigham and Women’s Hospital and has now become an international expert in myeloid and lymphoid malignancies in especially transplantation and outcomes with transplantation.Well, she is our President and she had a fireside chat with Tony Fauci by Zoom call, of course, and actually there was no fireside there.There was no fireplace.But the question that was posed to him was exactly that one that you brought up, Naval, so I want to say in more of a little bit, I want to emphasize it.Our patients who have leukemias that are causing immune deficiency or are getting drugs that cause immune deficiency may not have as robust a effect of the vaccine as somebody else but the specific words he said was we think some response, some effect is better than no effect and strongly recommended it.and as Naval said, this is not a live virus.It is a piece of RNA that encodes one unit, one protein, of the virus so it should be safe.Rami, did you want to add anything?

DR. KOMROKJI:Yeah, so I got mine today so so far I am doing good.I agree with everything that you said that there is no harm with the - - to get the vaccine - - take the chance of more patients contracting the infection so the households or people that live with them.So that is the other recommendation I have got for patients to make sure that close contacts get the vaccine.

DR. ERBA:So Rami, let me say to the audience just in case they were wondering Rami had no hair even before the vaccination, okay, so it is not a side effect of the vaccination.I agree with what he said.Some people have worried that we don’t have a lot of followup and, in fact, the commission on that was brought together to independently evaluate the data, independent from the FDA, independent from the manufacturer.That was probably the only cautionary note that they brought up, that we don’t have a lot of followup data.However, I agree with my colleagues.I wouldn’t wait for the followup data.I don’t mind telling this audience that back in November I actually contracted the SARS COVID-2 or COVID-19 virus and got sick enough to be seen in emergency room and get a monoclonal antibody and almost got admitted.It is real.I consider myself pretty healthy.I am not that old.I’m 63.You just never know who is going to get really sick from it and we worry most about our patients who have immune deficiencies who are getting chemo so please do not depend on herd immunity.You should go, you should get it, and I agree with Rami, your household contacts should get it.

I guess the last political statement I would make is look at what we have done in one year.Our government has underwritten the development of this vaccine with drug companies and it has been fast tracked.No corners have been cut.It is just all the regulatory baloney that we face every day in doing clinical trials was pushed out of the way to get this done.But safety was never compromised in the development of the drug, just the administrative regulatory things that got in the way of more rapid development and, basically, the money was put up.So that is my one political comment.If we could do this for cancer I think we would all be better.

So let me, I have taken three minutes longer than our hour but in the absence of any other questions I am going to close for us because, unfortunately, we are out of time.if you would like to watch this webinar again it will be available on the webinars on demand page of CUREtoday.com within the coming days.I want to thank our panelists, my friends and colleagues, Naval Daver and Rami Komrokji, and the audience for attending and participating in today’s event.I would also like to thank CURE and our partners, Abbvie and Genentech for making today’s educational webcast possible.Don’t forget to check your email tomorrow for the survey to be entered to win a gift card and thank to all for joining.We will see you next time.Goodbye.