Immune Checkpoint Inhibition and Novel Therapies for Myelodysplastic Syndromes/Neoplasms

Transcript

• 00:00Thank you so much for coming.
• 00:02You know, we are getting back to
• 00:04full in person and I know there are
• 00:06a lot of people on Zoom as well.
• 00:07So thank you so much for coming today.
• 00:09And I will be talking about immune
• 00:12checkpoint inhibition and Novant
• 00:13therapies for myelodysplastic syndromes.
• 00:16These are my disclosures
• 00:17and this is the outline.
• 00:18I'm going to cover 4 areas that have seen a
• 00:21lot of developments in the last few years.
• 00:23The first one is updates and classification
• 00:26as well as risk stratification
• 00:28and response assessment MD's,
• 00:31the evolving therapies for lower risk MD's,
• 00:33high risk MD's and then specifically
• 00:36about the immune checkpoint inhibition
• 00:37efforts that I have been trying to
• 00:40kind of doing in these disease areas.
• 00:43So what are myelodysplastic syndromes,
• 00:44neoplasm.
• 00:45You can see that we actually have
• 00:47formally added the name neoplasms finally
• 00:49because for a long time myelosplastic
• 00:52syndromes were thought of as syndrome
• 00:54or pre leukemia or a disorder,
• 00:57but they are actually cancers and this
• 00:59has been formally diagnosed by The Who.
• 01:01They are basically uncommon
• 01:03only four in 100,000 a year,
• 01:0620,000 cases of MD's in the US.
• 01:09However,
• 01:09the median ages in the early 70s
• 01:11and the number of patients with MD's
• 01:13has been increasing because we have
• 01:15more and more cancer survivors.
• 01:17I share many patients with many of you
• 01:19on the solid pumor side because those
• 01:22patients have secondary myelodysplastic
• 01:24syndromes and those can be among the
• 01:27most challenging patients to treat.
• 01:29And you can see here another fact that
• 01:31emphasizes the malignant nature of MD's.
• 01:33So this is the five year survival
• 01:35of patients with MD's in Violet
• 01:37and you can see it's 31%,
• 01:39very close to what you get with
• 01:41AML which is 25% but much worse
• 01:43than some of the more common solid
• 01:45tumors such as breast and lung when
• 01:47you take all the patients together.
• 01:49Again further emphasizing the
• 01:51malignant nature of these conditions.
• 01:54And more recently,
• 01:55we also understood that there is a
• 01:59large number of people who go through
• 02:01a process called clonal hematopoiesis
• 02:03of indeterminate potential or CHIP.
• 02:05And this is a condition that happens
• 02:08in up to 10% of people older than 70.
• 02:11And some of those progress to MD's
• 02:13and some don't,
• 02:14but they are also associated with
• 02:17inflammation and cardiovascular
• 02:18risk and many other syndromic
• 02:21dysfunction across the body.
• 02:23This is why multiple disciplines including
• 02:25cardiology have been interested in this.
• 02:27And for that more and more cancer
• 02:29centers have been interested in
• 02:30establishing clinics for chip and seekers.
• 02:33And here our newest recruit, Dr.
• 02:35Lourdes Mendez has taken over this
• 02:37aspect and I think this is going to
• 02:40become very important in the coming years.
• 02:43The management of MD's,
• 02:44as I'm going to show you in a little bit,
• 02:45has been difficult to get new therapies.
• 02:47And part of this is because of the
• 02:50large heterogeneity of the disease.
• 02:52This is a schema showing the
• 02:54genetic landscape of MD's.
• 02:55And you can see here that there are more
• 02:57than 40 recurrently abnormal somatic
• 02:59mutations that can happen in patients.
• 03:01However, less than six of those
• 03:03happen in more than 10% of patients.
• 03:06Therefore, there are many different driver
• 03:08genes and developing therapies that
• 03:10work across the spectrum for patients
• 03:13with MD's has been quite challenging.
• 03:15Another I think challenging feature
• 03:17has been the classification of MD's.
• 03:19And over the years,
• 03:20how do you separate MD's from
• 03:22AML has been a moving target.
• 03:24Historically A+ count of 30% was used
• 03:28and then this was changed to 20% most
• 03:31recently last year and this created a
• 03:34huge difficulty in the field is the
• 03:38target blast count has been moved to 10%.
• 03:40So now there is this new entity
• 03:43called MD's slash AML which is 10 to
• 03:4519% blast and this is causing a lot
• 03:47of confusion for patients especially
• 03:49that the PATH reports get released
• 03:51immediately to patient nowadays or
• 03:53they are being told that you have
• 03:55MD's by 1 classification and AML
• 03:59by another classification.
• 04:00And to address this issue,
• 04:02we actually have worked with a large
• 04:05number of international colleagues to
• 04:07establish international consortium of MD's.
• 04:10This is an effort that involves
• 04:12many experts across the world to
• 04:14try to come up with a unified way
• 04:17of classifying the disease.
• 04:19And indeed we have put together
• 04:21more than 70 more than 7000 cases,
• 04:23which by the numbers of MD's is
• 04:26quite actually quite large of highly
• 04:28annotated cases to try to come up
• 04:30with one unified classification.
• 04:32There's another update of this effort
• 04:34that will be presented in ASH in an
• 04:36oral fashion this year and hopefully
• 04:38the paper will be published soon so
• 04:39that we can have one common way in
• 04:42which we can talk to patients with MD's.
• 04:46After that.
• 04:47What is I think important is the risk
• 04:49stratification. Why is that important?
• 04:51Because patients with MD's
• 04:52have variable prognosis.
• 04:53Some patients can live for multiple
• 04:55years while other patients have
• 04:57prognosis that's almost akin to
• 04:58that of acute leukemia patients,
• 05:00meaning that the prognosis can
• 05:01be less than six to nine months
• 05:04and therefore having good risk
• 05:05stratification systems is very important.
• 05:08Historically,
• 05:08you can see in this table four of the
• 05:10most commonly used stratification systems.
• 05:13All of them rely on the number of
• 05:15the plast in the bone marrow as
• 05:16well as the karyotypic abnormalities
• 05:18and the blood counts.
• 05:20However,
• 05:20none of those were very good because
• 05:23for a long time we and others have
• 05:25shown that some of the patients that
• 05:28are called lower risk MD's die quickly
• 05:30die within two years of diagnosis.
• 05:32More than 1/4 of those lower risk
• 05:34MD's patients and it was clear that
• 05:37these prognostic risk scores are
• 05:38not capturing the whole spectrum
• 05:40of the disease severity.
• 05:42And we also have shown that among
• 05:44patients with therapy related MD's,
• 05:46which historically have been
• 05:48considered very high risk disease,
• 05:50some of them do OK,
• 05:52do better than some of the other patients.
• 05:54And that's again reflective of the
• 05:56variability on prognosis of those patients.
• 05:59And This is why it's important to
• 06:01apply good risk stratification
• 06:03process for every patient.
• 06:06After all of this basically the IPSSM,
• 06:08the molecular IPSS was finally published
• 06:10after a large international effort in
• 06:12the New England Journal of Evidence.
• 06:14You can see the Bernard ET al Citation.
• 06:17But the short of this is that it
• 06:20incorporated the molecular alterations
• 06:21in the calculation and that led to a more
• 06:25accurate risk stratification picture.
• 06:27And we have shown in a large
• 06:30analysis of two phase,
• 06:31phase two and phase three trials that
• 06:34were presented last year in ASH that this
• 06:36system does lead to upstaging of patients.
• 06:39You can see in red the high risk
• 06:41patients by the old scoring system,
• 06:43the Ipss, then the revised Ipss,
• 06:45then most recently the molecular IPSS.
• 06:47And you can see that the number of
• 06:49patients who are being diagnosed
• 06:51now as high risk disease because
• 06:52their prognosis is indeed poor,
• 06:54is becoming higher and therefore
• 06:56more of those patients are being
• 06:58directed for aggressive treatments.
• 07:02The last area I want to cover before we go
• 07:04to therapeutics is the response criteria.
• 07:06This is actually a very important
• 07:08area because response criteria have
• 07:11been quite problematic in MD's.
• 07:12And I can tell you that it's my
• 07:16belief and several of my colleagues
• 07:18at the same believe that it has
• 07:20impeded drug development in MD's.
• 07:22Why is that?
• 07:23Because some of the issues with
• 07:24the response criteria have led
• 07:26to certain medications moving
• 07:27from phase one to phase three.
• 07:29That probably should not have been the case.
• 07:31And This is why we have many
• 07:33Phase 3 failures in MD's.
• 07:35So again using a large international
• 07:38effort over the last two years
• 07:41that was coordinated through the
• 07:43international working group,
• 07:45we have revised these response
• 07:47criteria and this consensus proposal
• 07:50for revised international working
• 07:52group criteria has been now published
• 07:55and it started to be implemented
• 07:57in some clinical trials protocols.
• 07:58We have been in discussions with the
• 08:01FDA as well about implementing this in,
• 08:04in their assessment and I'm hopeful
• 08:07that this will become a more uniform
• 08:10way of looking at clinical trial
• 08:13to further like establish their
• 08:15the efficacy of therapeutics in a
• 08:18more consistent fashion.
• 08:19And we are validating this using
• 08:22WD database which will look both
• 08:24at the international working group
• 08:26criteria as well as the IPSSM.
• 08:28We actually have this database
• 08:30again with 15 different centers.
• 08:33Six of those presentations are
• 08:35going to be upcoming in in ASH,
• 08:37two of them are oral presentations
• 08:39by Doctor Tarek Iwan and by
• 08:41our newer newest recruit Dr.
• 08:43Ian Beversdorf.
• 08:44So I think this is going to
• 08:46further validate these response
• 08:49criteria as the way to establish,
• 08:53establish them as a way to
• 08:55approve medications in the future.
• 08:57So now moving from classification
• 08:59and response assessment to other
• 09:02therapies and you are looking here
• 09:04at the approved therapies in in the
• 09:06top line by the FDA and in the lower
• 09:08line by the EMA.
• 09:09And what you can quickly see compared
• 09:11to many solid tumours is that we
• 09:13don't have many approved therapies.
• 09:14This has been a very frustrating Rd.
• 09:16for drug development in MD's and
• 09:19in high risk MD's. For example,
• 09:21we did not have a drug approved in
• 09:24the last 20 years until the year 2020.
• 09:27So I'm going to show you the main
• 09:29therapies that we currently have
• 09:31available and how we are finally breaking
• 09:33through that deadlock of therapeutic
• 09:35evolution and we are starting I think
• 09:37to have better therapies come along.
• 09:40So the traditional approach of
• 09:42treating patients with lower risk MD's
• 09:44depends on symptom control because we
• 09:46cannot currently cure these patients.
• 09:48The only way to cure a patient with
• 09:50MD's with bone marrow transplant,
• 09:52but bone marrow transplants are
• 09:53usually reserved for patients
• 09:55who have higher risk disease,
• 09:56not lower risk disease.
• 09:58For patients with anaemia,
• 09:59the standard treatment would be ESA's
• 10:02erythropoiesis stimulating agents.
• 10:04However, those drugs are not active
• 10:06except in less than 1/2 of patients,
• 10:0940% and the response last less
• 10:11than 12 months.
• 10:12And I'm going to show you how this landscape
• 10:15has changed in the last couple of years.
• 10:17So the first I think major improvement
• 10:20was the introduction and final approval
• 10:22of this drug called luspetercept,
• 10:24what is luspetercept,
• 10:25the silicon trap.
• 10:26It works on a pathway called
• 10:28transforming growth factor pathway.
• 10:30These ligands suppress erythropoiesis,
• 10:32especially late erythropoiesis
• 10:34and using this ligand trap has
• 10:36led to restoration of effective
• 10:38erythropoiesis and ultimately
• 10:41improved transition independence.
• 10:43This led to transition independence in
• 10:45around 40% of patients in the in the
• 10:48phase three Middle East trial which
• 10:50was the landmark paper published in
• 10:51the New England Journal of Medicine.
• 10:54And based on this this drug was approved.
• 10:56And we have subsequently published
• 10:58additional follow up from this trial
• 11:00that showed that this drug not only
• 11:02lead to high rates of transfusion
• 11:05independence but it actually also
• 11:06leads to significant reduction in
• 11:08transfusions for patients who do not
• 11:11become transfusion dependent and
• 11:12lead to hematologic improvements.
• 11:14And this year the major development
• 11:16in lower risk MD's has been the final
• 11:19publication of the commands trial
• 11:20which looked at the activity of the
• 11:23specter sit in the frontline setting.
• 11:25So this is comparing it against
• 11:28erythropoiesis stimulating agents
• 11:29in patients with ringsidroplasts
• 11:32and without ringsidroplasts.
• 11:33So this was a primary analysis.
• 11:35This paper is now out in The Lancet
• 11:38journal showing that patients who
• 11:40received Los Pertoset achieved
• 11:4260% transition independence,
• 11:43almost double that what you expect
• 11:46with patients who receive ESA.
• 11:48So clearly a very active drug and it's
• 11:50moving to the frontline treatment of
• 11:52MD's which is a fundamental change in
• 11:54how we treat patients with lower risk MD's.
• 11:57We are trying to move this
• 11:59further through two other trials.
• 12:02One is the element trial,
• 12:03which is a large phase three trial
• 12:05that will be looking at patients
• 12:07who are not transfusion dependent.
• 12:09Here we are trying to move the
• 12:11bar higher and
• 12:11we are trying to prevent patients
• 12:13from even becoming transfusion
• 12:15dependent by treating them at a
• 12:16earlier stage of their anaemia.
• 12:18So this trial which will open at
• 12:20TLI think will be very important as
• 12:23a landmark trial in the management
• 12:25of MD's if it's positive because it
• 12:27would be the first time we get a drug
• 12:29potentially approved for patients who
• 12:31are not yet transfusion dependent.
• 12:33And another phase three trial that
• 12:35we are working on with the sponsor
• 12:37basically is looking at the use of
• 12:39the drug at maximal doses because we
• 12:41currently many of the patients are
• 12:43not being escalated to the right dose
• 12:45that leads to highest response rate.
• 12:48So I think starting with the higher
• 12:50response with the higher dose is going
• 12:52to increase the response rate and
• 12:53potentially open the door for more and
• 12:55more patients responding to this drug.
• 12:58And this trial is also up going to open ATL,
• 13:01another drug that I think generated
• 13:03a lot of interest is Amitelestad.
• 13:05This is a first in class telomerase
• 13:08inhibitor.
• 13:08So telomerase activity in patients
• 13:10with MD's has been associated with
• 13:13high risk disease and inhibition
• 13:15of the telomerase it has led to
• 13:17restoration of effective erythropoiesis
• 13:19in a large phase two trial.
• 13:21This is a drug that's given intravenously
• 13:24every four weeks and in a phase two trial
• 13:27lead to 40% transfusion independence.
• 13:29So this was taken to a phase three trial.
• 13:32We have presented the data of this
• 13:35paper in in Asch or sorry in ASCO
• 13:392023 and the paper is now in Lancet in
• 13:42press where patients were randomized to
• 13:45receive hematillostat versus placebo.
• 13:47Again those are patients who are
• 13:49heavily transfusion dependent with
• 13:51lower risk MD's and you can see here
• 13:53again that the rate of transfusion
• 13:55dependence was similar to phase two
• 13:57trial with 40% compared to 15%.
• 14:00And importantly,
• 14:02the degree of hemoglobin elevation
• 14:04is actually quite prominence.
• 14:05So the hemoglobin increase was almost
• 14:073 grams on average from a hemoglobin
• 14:10of eight to hemoglobin of 11.
• 14:12So quite active and the durability
• 14:13is very good, It's around 51 weeks,
• 14:16which fought by MD's criteria is
• 14:18actually pretty good.
• 14:20So this drug is currently in front
• 14:22of the FDA for consideration of
• 14:23approval and if it gets approved it
• 14:25will offer another I think very good
• 14:28opportunity for our patients with
• 14:29lower risk MD's to become transition free,
• 14:31which is very important moving
• 14:33to high risk MD's.
• 14:35This is where we have more of our
• 14:38recent failures I would say in
• 14:40in development of new therapies.
• 14:42This figure I'm showing you has not
• 14:44really changed in the last almost 20 years.
• 14:46So patients who are candidates
• 14:48for transplant go for transplant
• 14:50and those who are not the receive
• 14:53hypomythylating agents.
• 14:53However,
• 14:54we know that hypomuthilating agent
• 14:57treatment by itself is not great.
• 14:59The long term survival only if you
• 15:01use HMA without going to transplant
• 15:03is less than 4% and for that reason
• 15:06we strongly encourage patients
• 15:08to consider
• 15:09transplant whenever possible,
• 15:10but also try to build up on HMA
• 15:13therapy to improve outcomes.
• 15:15And this is kind of a summary of
• 15:17three different real life studies
• 15:19that we have done that show that the
• 15:21real life outcomes with Hmas are
• 15:23actually much worse than what you
• 15:25see in clinical trials with immediate
• 15:27survival of only one year on average
• 15:29for patients with high risk MD's.
• 15:30Again further emphasizing the point
• 15:33for new therapies for patients with
• 15:36high risk MD's and we have tried,
• 15:38we have tried for a very long
• 15:40time over the last 20 years.
• 15:42Unfortunately this graveyard of
• 15:43combinations of drugs that were added
• 15:46to hypomthilating agents keep expanding.
• 15:48The latest addition was this drug
• 15:51magrolimab which works on the CD 47 pathway.
• 15:53This is a very,
• 15:55this drug has generated a lot of
• 15:58excitement early on but unfortunately
• 16:00a recent press release couple of
• 16:02months ago showed that phase three
• 16:05trial of this drug was negative.
• 16:07We can talk I guess in a in another
• 16:09time once the data is publicly released
• 16:12about the reasons for for failure and
• 16:14how we can try to come up out of this system.
• 16:17The good news is that we have other
• 16:20drugs that are more exciting and
• 16:22potentially could lead to approval.
• 16:24One of them is venetoclax.
• 16:25So venetoclax is an oral PCL 2 inhibitor.
• 16:28This is already approved for patients with
• 16:31acute myeloid leukemia who are older.
• 16:33The frontline phase two trial should
• 16:36CR responses of around 35% and across
• 16:40the genetic spectrum of MD's we have
• 16:43published a phase 1P study that shows
• 16:45that adding venetoclax to HMA is
• 16:47actually active in the HMA failure setting,
• 16:50which is a very difficult
• 16:52setting to treat patients in.
• 16:53It leads to responses as well
• 16:56as transition independence.
• 16:57But the pivotal phase three trial is is
• 17:00fully accrued now it's called Verona.
• 17:02This trial might change the
• 17:04landscape of how high risk MD's is,
• 17:07is going to be treated.
• 17:09This is the scheme of the trial that
• 17:11we presented a couple of years ago.
• 17:12This trial is now fully accrued.
• 17:13It's the results are actually expected by
• 17:16early 2024 and if this trial is possible,
• 17:20it would lead to a new standard of care.
• 17:22Now moving to immune dysregulation
• 17:25myeloid malignancies and this is
• 17:28an area where I have personally
• 17:29invested quite a bit of time trying
• 17:32to develop new therapies for both
• 17:34MD's and acute myeloid leukemia.
• 17:37So we know that the most effective
• 17:39treatment for patients with MD's
• 17:40and AML is bone marrow transplant,
• 17:42which is effectively is an
• 17:44immune intervention.
• 17:45We know there is significant
• 17:47dysfunction in the immune system
• 17:49happens in patients with MD's and AML
• 17:51both at diagnosis but also during
• 17:53the progression of the disease.
• 17:55There is both quantitative and
• 17:57qualitative abnormalities that happen in
• 17:59the T cells including the regulatory T cells,
• 18:02but also in the macrophages
• 18:04and the ANKAE cells.
• 18:05And study after study have shown
• 18:08that these increase in frequency
• 18:10as the disease progresses.
• 18:12The question has been
• 18:14always are these pathogenic,
• 18:15are they basically mediating the
• 18:17progression and the resistance of AML and
• 18:20MD's or are they basically are adhering,
• 18:22they are just a phenomena that comes
• 18:25with the progression of the disease.
• 18:27And the first trial I think that generated
• 18:29a lot of interest of immune checkpoint
• 18:31inhibition which clearly in solid
• 18:33tumors have led to a major revolution,
• 18:34but in in in blood tumors has not
• 18:37led to the same impact so far.
• 18:40However, the Dana Farber group
• 18:43published this trial using Epilumab
• 18:45which is a CTL A4 inhibitor
• 18:47approved for multiple solar tumors.
• 18:49Now it was a small phase one study,
• 18:52but it was done in the post
• 18:54transplant setting where the drug
• 18:56was given for patients who relapse
• 18:58after transplant and what they have
• 19:00shown that the drug was tolerated.
• 19:01There were some GVHD but generally it
• 19:04was well tolerated for the most part and
• 19:07they were able to achieve 5 responses,
• 19:105 complete remissions out of 13 patients,
• 19:13which again was a proof of principle
• 19:15that immune checkpoint inhibition
• 19:17post transplant does actually work.
• 19:19And this generated a a number of trials
• 19:22looking at the drug in MD's and AML.
• 19:24This is one of the trials,
• 19:26one of the early trials that I have
• 19:28worked on actually when I was at
• 19:30Hopkins and later moved it to Yale.
• 19:32It was multicentre,
• 19:33it was in the post relapse setting
• 19:36for patients with MD's.
• 19:38So this was not after transplant,
• 19:40this was after HMA failure in
• 19:42patients with MD's.
• 19:44And while we have shown that
• 19:45the drug was well tolerated,
• 19:46we could manage the immune related
• 19:48adverse events effectively similar
• 19:50to what they do in solid tumors.
• 19:52The clinical responses were generally very
• 19:54low and the drug was not clinically active.
• 19:57We did achieve some disease stabilisation
• 20:00but stable disease always very tricky
• 20:02in MD's to figure out is it related
• 20:05to the biology of the disease being
• 20:07indolent in some patients or is it
• 20:09related to the activity of the drug.
• 20:11However,
• 20:12among those patients who had stable disease,
• 20:15we have conducted extensive correlative
• 20:17testing with Leo Loznick at Hopkins.
• 20:20And we have shown that there was an
• 20:22increase in the frequency of Icos
• 20:24which is costimulatory molecule,
• 20:26but this this was not basically
• 20:30associated with increase in the
• 20:32peripheral T cell receptor diversity in
• 20:35terms of association with the response.
• 20:37And I think trying to find biomarkers
• 20:40for patients has been one of the
• 20:43also challenging areas in immune
• 20:45checkpoint inhibition in MD's.
• 20:47Of course single arm trials
• 20:49as I mentioned are not very,
• 20:51are not very definitive in any
• 20:53kind of activity.
• 20:54Some of those phase one trials
• 20:56have shown positive signals,
• 20:58but the definitive way to achieve
• 20:59that would be with a randomized
• 21:01trial and we worked with the with
• 21:03the Celgene slash BMS to develop
• 21:06this trial of randomized trial.
• 21:09This was the only randomized published
• 21:11trial to date of immune checkpoint
• 21:13inhibition both in MD's and AML.
• 21:15So patients with MD's or AML
• 21:18in two separate cohorts,
• 21:19more than 210 patients were
• 21:21randomized to receive azacitidine
• 21:23or azacitidine with dorvalumab.
• 21:25Many of you are probably familiar
• 21:27with this PDL 1 inhibitor which is
• 21:29approved to multiple solid tumors
• 21:31and has shown overall survival
• 21:33prolongation in in several settings.
• 21:35However, again this was a negative trial.
• 21:38You can see here complete overlap in
• 21:40the overall survival and progression
• 21:41free survival cares and no difference
• 21:43in the primary endpoint which
• 21:45was the overall response rate.
• 21:47So this was disappointing.
• 21:48We try to understand better
• 21:50why is that the case,
• 21:52why did the drug not lead to improvement?
• 21:54So the first theory is that one common
• 21:57thing we see with MD's trials is that
• 21:59when you add a drug in top of MD's,
• 22:01you lead to less exposure of
• 22:03azacitidine which is the only
• 22:05drug shown to improve survival.
• 22:07And therefore maybe adding the volumab
• 22:09has led to reduced exposure of Aza and
• 22:12that's why we did not see benefit.
• 22:14But you can see in this analysis
• 22:16in the green bars that the number
• 22:18of cycles between the two arms was
• 22:21actually similar and most patients
• 22:22have received more than four cycles.
• 22:24So it doesn't seem like this
• 22:27underlines the lack of therapeutic
• 22:29efficacy to the right.
• 22:31You can see also that there was similar
• 22:33hypomethylation which how we think how
• 22:35those drugs hypomethylating agents work
• 22:37and no difference between the two arms.
• 22:40So doesn't seem like there
• 22:42was antagonism there.
• 22:43We also tried to see if there was
• 22:45an increased expression in PDL 2
• 22:47as a mechanism to bypass the PDL 1
• 22:49inhibition and that also was not the case.
• 22:52So none of those mechanisms seem to
• 22:55suggest why the drug did not work.
• 22:58What was actually quite surprising
• 23:00is that when we conducted serial
• 23:02flow cytometric analysis,
• 23:04we did not see T cell expansion in
• 23:08diversity or in quantity by flow cytometry,
• 23:12neither in the bone marrow or in the
• 23:14peripheral blood between the two arms.
• 23:16And this was particularly surprising
• 23:19because there has been a prevailing
• 23:21theory that the reason why immune
• 23:23checkpoint inhibition does not
• 23:24work in AML is that once you give
• 23:27it subsequent lines, third,
• 23:28fourth line,
• 23:29that the immune system has been beat
• 23:31up a lot by the chemotherapy.
• 23:33So here we were giving it in the
• 23:35frontline sitting and still it did
• 23:37not lead to immune stimulation.
• 23:38And the last thing we tried to
• 23:40do with this trial is to look at
• 23:42substance of patients because here
• 23:44you are putting all newcomers
• 23:46together and maybe certain subsets
• 23:48of patients benefit better.
• 23:50So we tried to look at 2 specific subsets,
• 23:52patients who have TP 53 mutations,
• 23:55which have been shown to have a micro
• 23:57environment in the bone marrow that
• 23:59is more immunosuppressive and might
• 24:00be more amenable to immune checkpoint
• 24:03inhibition based on multiple sources
• 24:04of data as well as patients who
• 24:07have splicing factor mutations,
• 24:08which Omar Abdullah have from
• 24:10Sloan Kettering and others have
• 24:11shown could be more susceptible
• 24:13to immune checkpoint inhibition.
• 24:15However, we also did not see any any
• 24:19activity in those patients who have TB 53.
• 24:23This analysis was presented by Yan in a
• 24:26couple of years at ASH and is currently
• 24:29under consideration for publication.
• 24:31So we tried to think further about how
• 24:34can we overcome this immune checkpoint
• 24:37resistance for patients and one theory was,
• 24:41is that myeloid derived suppressor
• 24:43cells could be a mediating resistance.
• 24:46This was based on solid tumours
• 24:48and we replicated the data.
• 24:50Doctor Tikkun Kim who's currently at
• 24:52Vanderbilt was here at TL did very nice
• 24:56preclinical trials that suggested that
• 24:58there could be the benefit of combining
• 25:00a drug that targets myeloid derived
• 25:02suppressor cells such as entenostat
• 25:04which is a Estonia acetylase inhibitor
• 25:07with with Pimpro or PD1 inhibitor.
• 25:10And based on these preclinical data,
• 25:12this was translated to a clinical trial,
• 25:15multi centre phase one trial that was
• 25:18conducted in collaboration with the UM
• 25:21one group under Pat Larosso with the
• 25:24theory again that adding Antinostat
• 25:26would suppress myeloid giraffe,
• 25:27suppress our cells and therefore
• 25:29allow pimprolismab to exert its
• 25:31immune chip point inhibition.
• 25:32So that the trial has been presented by Anne,
• 25:35I'm not going to go through the
• 25:37results because again unfortunately
• 25:38it was clinically negative.
• 25:39We are currently going through the
• 25:42correlative data to understand what led
• 25:44to the failure of the clinical data.
• 25:47However,
• 25:47I think there are more exciting agents.
• 25:50One of them is sabatolimab.
• 25:53So sabatolimab is a novel
• 25:55immune checkpoint inhibitor.
• 25:56Sabatolimab targets term 3.
• 25:57So term 3 is not only expressed on T cells
• 26:01and medias immune checkpoint inhibition,
• 26:03but it's also expressed in leukemia stem
• 26:06cells and leukemia plast and targeting.
• 26:08Term 3IN.
• 26:09Preclinical data has suggested a
• 26:11potential not only efficacy but a
• 26:13potential π functional mechanism
• 26:15in which it can lead to immune
• 26:18checkpoint inhibition but also direct
• 26:20targeting of the leukemia stem cells.
• 26:23So the stimulus MD's one trial was the
• 26:25first randomized trial with this drug.
• 26:27This trial randomized patients to
• 26:30receive HMA versus HMA with sabatolimab
• 26:32and the primary endpoint was complete
• 26:36response and progression free survival.
• 26:38We presented this data in ASH last year.
• 26:41Currently the manuscript is under
• 26:43review and while the the trial
• 26:45did not meet its end point,
• 26:47there was no significant statistically
• 26:49improvement in complete remission
• 26:51or progression free survival.
• 26:53You can see that there was a late
• 26:55separation in the curve of the
• 26:57progression free survival and some
• 26:59trend toward improvement with the PFS.
• 27:02So we also sub analyse these data
• 27:04and what we have found is that
• 27:06patients who have lower disease
• 27:08burden seem to benefit more.
• 27:10However, of course this is ad hoc analysis,
• 27:13exploratory analysis.
• 27:14But what was also exciting is
• 27:16among the patients who achieved
• 27:18response as you can see in the red,
• 27:21patients who achieved The Who
• 27:22got the combination seems to have
• 27:24doubled the duration of response
• 27:26compared to those who have HMA alone,
• 27:28which again suggests that the
• 27:30combination might deepen the response
• 27:33leading to longer duration of activity.
• 27:37So the stimulus MD's two is a large
• 27:40randomized phase three trial of Sabatolimab
• 27:43plus Aza versus Sabatolimab alone and
• 27:45this trial again is fully accrued more
• 27:48than 530 patients enrolled on this trial.
• 27:51This trial is also expected
• 27:53to report by early 2024.
• 27:55So between venetoclax and sabatolimab,
• 27:58hopefully one of those two at least will
• 28:00will be positive and change the landscape
• 28:02of how we treat patients with high risk MD's.
• 28:05So moving to the AML front where
• 28:08we have also tried to move
• 28:10some of those concepts forward.
• 28:12So the plus AML one is a randomized
• 28:14phase two trial an IAT that is also
• 28:18running through the UM 1 mechanism
• 28:21with Pat Larosso Rory has been doctor
• 28:24Shalis has been working on this with me
• 28:27and this trial is actively enrolling.
• 28:29We have more than 40 patients right
• 28:31now where patients are getting 7 +
• 28:343 versus 7 + 3 with pemprolizumab.
• 28:36The primary endpoint is MRD negative CR,
• 28:41another randomized phase two trial
• 28:43that we are working through the same
• 28:45mechanism as last ML2 and this trial
• 28:47looks at older patients where the
• 28:49combination is is a citedine with
• 28:51venetoclax plus minus Pemprolizumab.
• 28:54This trial is also through the UM 1
• 28:58mechanism and through both of those
• 29:00trials and in collaboration with CMAC,
• 29:02which is a cancer immunotherapy
• 29:05monitoring group.
• 29:05Within C Tib,
• 29:07we are conducting an extensive set
• 29:09of correlative studies who are also
• 29:11collaborating with Doctor Jerry
• 29:13Radic from the Hajj to look at MRD
• 29:16negativity through different more
• 29:19sensitive techniques including
• 29:21circulating tumor DNA and at the
• 29:23level of the stem cells and looking
• 29:26at as I mentioned that other leukaemia
• 29:29specific T cell activation and a
• 29:32number of other I think important studies.
• 29:36Finally on the same front we have
• 29:38the plasty ML3 trial which is a
• 29:40phase two trial looking at combining
• 29:43IDH inhibitors with pimprolism AB.
• 29:45This is based on preclinical data
• 29:47suggesting that patients who have IDH
• 29:50mutations also have immunosuppressed
• 29:52micro environment.
• 29:53So Doctor Lourdes Mendez and Dr.
• 29:56Max Stoll at Hutch who I forgot to
• 29:58put his picture sorry are working on
• 30:01this trial and hopefully this trial
• 30:04is approved by Merck and hopefully
• 30:06it's going to open next year.
• 30:07And lastly on that front,
• 30:09we also have another trial with
• 30:11the triplet is Evan Sabatolimab.
• 30:12This is a phase two trial which
• 30:15enrolled more than 80 patients.
• 30:17We presented the data lost ash and
• 30:20for the only for the safety cohort,
• 30:23the full set of data has not been
• 30:25presented and I think we have shown
• 30:28extensively that immune checkpoint
• 30:30inhibition while can be difficult in
• 30:33patients with leukaemia is difficult
• 30:36to administer for multiple reasons.
• 30:38For example,
• 30:39our patients are often have
• 30:41deep thrombocytopenia,
• 30:42so we cannot biopsy them.
• 30:43If the patient has
• 30:44inflammation in their lung,
• 30:46sometimes it's difficult to know
• 30:47is this a fungal infection or is
• 30:50this pneumonitis And in solid
• 30:51tumours it's easy or not
• 30:53at least easier to go and get a
• 30:55biopsy out of the of the lung.
• 30:57But in our patients it's very
• 30:58difficult to get biopsies.
• 31:00We're also hesitant to give steroids
• 31:01many times because of fungal infections
• 31:03that are common in our patients.
• 31:05So conducting immune checkpoint
• 31:08inhibition trials in patients
• 31:10with MD's is a bit challenging.
• 31:12However it is it can be done and this
• 31:15is retrospective analysis that was done
• 31:17by Doctor Shalas in you're looking at
• 31:20our own data showing that the number
• 31:22of immune related adverse events was
• 31:25somewhat similar to what is seen in
• 31:27patients with solid tumors when they
• 31:29get immune checkpoint inhibition.
• 31:31But also importantly that we are not seeing
• 31:34excess mortality when we use these agents.
• 31:37So I think it's certainly feasible.
• 31:39I think it's certainly has a
• 31:41way to kind of move forward and
• 31:44one of those agents I have deep
• 31:46confidence is going to be positive.
• 31:48But I think another important
• 31:50concept that we need to apply is
• 31:53biomarker selection of patients,
• 31:55because currently we are unrolling all
• 31:59newcomers regardless of their susceptibility
• 32:02to immune checkpoint inhibition.
• 32:05And I keep making the analogy of
• 32:07like trying to treat patients with
• 32:09IDH or all patients with an IDH
• 32:12inhibitor when you only should treat
• 32:13the ones with the IDH 1 mutation
• 32:15or the same thing with the EGFR.
• 32:17So we really should select patients
• 32:19who are more likely to respond
• 32:21to the specific pathway.
• 32:22This is an example of I think a
• 32:25nice effort looking at an immune
• 32:27effector signature to try to
• 32:29define subset of patients.
• 32:31This is clearly retrospective,
• 32:32but I think this is what should
• 32:34be applied in clinical trials
• 32:35in a prospective fashion,
• 32:37so we can select patients who
• 32:38are more likely to respond.
• 32:40So and I'd like to thank the
• 32:43our colleagues in the leukemia
• 32:45and myeloid malignancy program,
• 32:47including our wonderful MPs and the
• 32:52fellows and mentors and collaborators.
• 32:55All of them have been working with us,
• 32:56but also importantly our clinical
• 32:58research team who has been fundamental
• 33:00to all those clinical trials that
• 33:03I've just shown you and have been
• 33:06extremely productive even during
• 33:07COVID and all the staffing shortages
• 33:10that we had over the years.
• 33:12And at the end I'd like to thank all
• 33:14the organizations that helped fund my
• 33:16research and all the collaborators
• 33:18and happy to take any questions.
• 33:27Have a great time and let me apologize
• 33:30for not being here yesterday.
• 33:32I realized I was supposed to notice
• 33:35I heard you again well on your
• 33:38own It's it's a pretty impressive
• 33:41body of work that that that we've
• 33:45seen over these past few years.
• 33:49What do we know about and I thought this
• 33:52team eventually was when I was here,
• 33:54but is there any fundamental
• 33:57difference in MD's in younger
• 34:00individuals than those who are,
• 34:02you know, more typically,
• 34:03yes, age, you know,
• 34:06so the occasional 40 or 50 year old person,
• 34:09you see it because this heavy year,
• 34:1080 year old. Yeah,
• 34:12this is actually a very important question.
• 34:14So the majority of MD's
• 34:16patients are older than 65,
• 34:17around 85% of patients are older than 65.
• 34:21We do see MD's in younger patients,
• 34:23but generally tend to be two big areas.
• 34:26One of them is previous exposure
• 34:28to chemotherapy or radiation in
• 34:30the context of solid tumours,
• 34:32usually breast cancer actually
• 34:34is 1 common setting where we see
• 34:37patients who have received radiation
• 34:38or chemo and have secondary cancer.
• 34:40But the second big area is
• 34:43genomic predisposition.
• 34:43So there are a number of patients who
• 34:46have for example underlying Franconia's
• 34:48anemia or plastic anemia or some
• 34:50kind of hereditary predisposition.
• 34:52The number of those predisposition
• 34:56genes actually has been increasing
• 34:58or we are discovering more and more
• 35:01of them and it's quite fascinating.
• 35:03For example, there is one called DDX 4,
• 35:05one that we did not for know about
• 35:07until you know a few years ago and
• 35:09it turned out that 10% of patients
• 35:11with AML and MD's have that.
• 35:14And those are I think important
• 35:16because they underlie different,
• 35:18different clinical behaviour.
• 35:20Those patients for example tend
• 35:22to be more indolent.
• 35:24I have a 96 year old patient with
• 35:26AML who has DDX 41 germline and
• 35:29it's just just mind boggling to
• 35:31me that you think that someone
• 35:33carried this mutation until she was
• 35:3595 to develop finally AML.
• 35:37So those tend to happen in older patients.
• 35:39There are other ones that tend
• 35:41to happen at a younger age.
• 35:42But I think the biggest message usually,
• 35:44I,
• 35:45I usually say regarding younger
• 35:46patients the MD's is you have to
• 35:48look for other things because there
• 35:50are many things that mimic MD's
• 35:51and you want to make sure what
• 35:53you are dealing with is indeed
• 35:55MD's because the treatment is,
• 35:56is is different.
• 36:00Yes.
• 36:13Yeah, this is a very good question.
• 36:14And actually this has always come up
• 36:16in our discussions with you know,
• 36:18with IR, BS and regulators.
• 36:19And there's actually a large chunk
• 36:22of evidence based on as I mentioned,
• 36:24the problems that most of the
• 36:26trials that we have done in the
• 36:29field have been single arm trials.
• 36:30So most of what we have right
• 36:33now is anecdotal experience.
• 36:35We are not seeing overall,
• 36:36if you look at the entirety of data,
• 36:39we're not seeing an increased incidence
• 36:41of GVHD that is that is of high severity.
• 36:45However, we have never had a randomized
• 36:48trial that would look at this in both
• 36:51in both arms and This is why I think
• 36:53our tube last trials are going to be
• 36:55very important because we have two
• 36:57arms and patients from both arms are
• 36:59going to transplant and I think this
• 37:01is going to give us a good sense of of that.
• 37:04The, the other argument I always
• 37:06say is that while there could be a
• 37:09potential that you could increase GVHD,
• 37:11there's also a potential that
• 37:12you could actually increase GVL,
• 37:14right,
• 37:14because the way GVL is a graft
• 37:16versus leukemia effect and this is
• 37:18how we think transplant can work.
• 37:20So I think it's always a risk benefit
• 37:22and I don't think you can answer
• 37:25that without a randomized data.
• 37:27This is something we are certainly
• 37:29keeping a very close eye on in our
• 37:31different trials and the regulators
• 37:33have been also kind of keeping
• 37:34a close eye on this.
• 37:36And I have to say in in our practice
• 37:39we usually try to say stop the
• 37:43immune checkpoint inhibitor like you
• 37:44know in the last six weeks before
• 37:47transplant 6 to 8 weeks ideally just
• 37:49because of that theoretical concern.
• 37:51I would say at the end is that in
• 37:53immune checkpoint inhibitors are
• 37:55approved in in in some in substance
• 37:59of lymphoma and in in that setting
• 38:01like Hodgkin's disease and generally
• 38:03there has not they have not seen
• 38:05that that issue as much.
• 38:07So I guess we'll,
• 38:08you know,
• 38:08we'll have to wait and see for AML and MD's.
• 38:11Yes.
• 38:29Yeah, this is a great question And
• 38:31part of why I did not divulge and
• 38:33like go too much into this is that
• 38:35this methylation business has been
• 38:37I think one of the most challenging
• 38:39aspect of you know Steve Gorwin,
• 38:41he used to be like he used to hate
• 38:43calling these hypomethylating agents
• 38:45because we we are not even 100% sure
• 38:47that this is how they actually work.
• 38:49You know, we always like to
• 38:50call them DN MT3 inhibitors.
• 38:53I guess the big answer is that in those
• 38:56trials that I presented they did not
• 38:59do like site specific methylation.
• 39:01But we still don't fully understand
• 39:03what because you are seeing
• 39:05a mix of hyper methylation,
• 39:07hyper methylation depending on where
• 39:08you are looking within the genome and
• 39:10until now we don't fully understand the
• 39:12mechanism of action of these drugs.
• 39:14I did not go into this because of,
• 39:17of, you know,
• 39:18the nature of of the audience here.
• 39:19But I think one of the biggest
• 39:22challenges in my own view about why
• 39:24we could not go beyond HMAS is that
• 39:26we are stuck with this schedule
• 39:27that is at the approved seven days
• 39:29of azacitidine in every single
• 39:31trial that we have.
• 39:32And this is a myelosuppressive
• 39:34combination and trying to add things
• 39:36to it has been quite challenging.
• 39:38But currently it's not
• 39:40considered ethical to randomize,
• 39:42you know,
• 39:43without including the seven days of HMA
• 39:45because it's the only drug that has
• 39:47been want to improve our all survival.
• 39:50But you're right,
• 39:50I mean there could be trials,
• 39:51there could be agents that could
• 39:54antagonize that methylation or it could
• 39:56be the other way around where this
• 39:58methylation is negatively impacting it.
• 40:00So that has been a big,
• 40:03I think, problem, Nathaniel.
• 40:18Like those seven the therapy,
• 40:21we know that those therapies
• 40:24result in quite profound immune
• 40:27suppression and not only they,
• 40:29they're also quite lymphopenic when you have
• 40:330.1. So does it make sense to
• 40:37give them concurrently? I mean,
• 40:39you're trying to mount some different
• 40:44response at the same time,
• 40:45completely suppressing their chemo,
• 40:47so it doesn't make sense
• 40:49to get them concurrently.
• 40:50Or would you have a more clever way
• 40:53where you perhaps cumulate the marrow,
• 40:55allow them to recover,
• 40:56have some given or reconstitution and
• 41:01then, you know, yeah.
• 41:02So there are people working on
• 41:03concepts like this where they are
• 41:05giving it around the time of immune
• 41:06reconstitution as you mentioned.
• 41:08I think 2 points on this front is that they
• 41:10actually have combined and solid tumours.
• 41:12They have multiple and you know,
• 41:14Barbara and others know more about
• 41:15this like solid tumours where you
• 41:17are giving chemo with immune therapy
• 41:18and it seems like it has worked,
• 41:20but they're, yeah,
• 41:21their drugs are not as lymph,
• 41:22you know, lymphodepleting as ours.
• 41:25But the other thing we actually
• 41:26have tried to do on these trials,
• 41:27I did not go into this into detail is that
• 41:29we moved the initiation of the immune
• 41:31checkpoint inhibition to day eight.
• 41:33So rather than waiting until day 21 when
• 41:35you know all the cells have have died.
• 41:37So around the aid,
• 41:38the idea of doing it early is
• 41:40similar to that you have.
• 41:42This is when you have all the antigens being,
• 41:44you know,
• 41:45from the dying cells coming out
• 41:47and trying to activate lymphocytes
• 41:49at that at that point.
• 41:50But you're right,
• 41:51I mean this is another I think big
• 41:53challenge of when what is the exact
• 41:55time to to use these these drugs has
• 41:58been somewhat kind of frustrating
• 42:00I have to say with with both PD1,
• 42:03PDL 1 so far and because multiple
• 42:05trials have been negative.
• 42:07So it might be that none of those
• 42:09pathways are you know what really
• 42:11is important in the MLN MD's and
• 42:14maybe the Sabatoli map that I
• 42:15just showed or some other.
• 42:17You know there are other,
• 42:19I did not go on to this as well in detail,
• 42:21but they are lag three, they are Lil RP4.
• 42:23There are a number of other immune
• 42:25checkpoint pathways that are also
• 42:28being tested in MD's and AML.
• 42:30Yes,
• 42:30with
• 42:51the the actually TM3 without the PD one.
• 42:53Yeah, so I did not go through that the
• 42:55solid tumor literature with TM3 but
• 42:58they actually had a big trial combined
• 43:00TM3 and PD1 and that has not led to
• 43:04clinical improvement in solid tumours.
• 43:06So the development has been
• 43:08largely focused on the MD's space.
• 43:10They have a, the company has sponsored
• 43:13trials where they are combining different
• 43:16immune checkpoint inhibitors and
• 43:18actually sabatorimab with other drugs.
• 43:20So those I think could give you know an idea,
• 43:25but from a regulatory path,
• 43:27you know you're as I was saying a little
• 43:29bit earlier is you have to combine with
• 43:31HMA to kind of get your first approval
• 43:34and then I think you know contagion, hago.
• 43:37Contagion also said like the real
• 43:39research starts once a drug is approved
• 43:41like you really need to get like
• 43:43something like once it's approved,
• 43:44I think you can do all kinds of concepts
• 43:46but the initial focus is always on
• 43:48trying to kind of get the trial that
• 43:51leads to approval and then you can
• 43:52do all these kind of bigger concepts.
• 43:55You can do them now in a small phase
• 43:56one study, but not in a large setting.
• 43:59Yes, Sir.
• 44:17I
• 44:51Again, I think this is a very good question.
• 44:53Clearly the post transplant setting is a
• 44:56very important development area because
• 44:58most of our patients unfortunately
• 45:00despite transplant they they relapse.
• 45:02So I think with the epilogue map, the trial,
• 45:05the New England Journal paper I showed you,
• 45:08people have had a very tough
• 45:10time replicating these,
• 45:11I would say outside of, you know,
• 45:15occasional responses.
• 45:16So most people are not using Epilomab
• 45:19of kind of label to to give it.
• 45:21And most of those responses by the
• 45:23way happened in the extramedullary
• 45:25relapses like skin disease and
• 45:27probably that speaks to different
• 45:29microenvironment between the bone marrow,
• 45:30between the extramedullary
• 45:32versus the bone marrow relapse.
• 45:34In terms of your other questions
• 45:36specific about the TM3,
• 45:38there's actually a trial giving
• 45:40TM3 inhibitor post transplant.
• 45:41I didn't go into this one,
• 45:43but this one is ongoing and I
• 45:45believe there could be presentations
• 45:47in the near future about this.
• 45:49I'm. I'm not involved in it.
• 46:07Yeah. No. I I think again, like,
• 46:09you know, I think it's like
• 46:10we're getting out like that.
• 46:11Sit right. Sitting.
• 46:23Yes,
• 46:42sorry, Could you phrase your hand?
• 46:51Is there any evidence that that
• 46:55prevents basically the development
• 46:57of an MPs or weighted MPs or AFL?
• 47:02Just thinking of like ways to
• 47:04sort of look at that rather
• 47:06than a code reading with like
• 47:11yeah, I think inhibiting development of
• 47:14MD's. This is actually an area
• 47:18that is getting more attention now
• 47:19because of what I showed at the
• 47:22beginning like this chip slash seeker
• 47:23spectrum where clonal hematopoiesis.
• 47:25We are seeing some of this
• 47:27actually in solid tumors.
• 47:27For example a breast cancer patient
• 47:30under you know underlying more and
• 47:34more people are doing these next Gen.
• 47:36sequencing and then the patient turned
• 47:38out to have TP 53 mutation chip like
• 47:40the blood counts are completely
• 47:42normal but she has TP53 mutation.
• 47:43And one of the increasing questions
• 47:45that are being asked like you know
• 47:47the oncologists are afraid to give
• 47:49chemotherapy because that TP53 clone
• 47:51could expand and lead to MD's or or AML.
• 47:55So I would say this is an evolving area.
• 47:57Currently we don't think immune
• 47:58checkpoint inhibition would work.
• 48:00Most of the trials that are looking
• 48:02at agents are looking at things
• 48:03that are very
• 48:06non-toxic. Let me put it this way
• 48:08because those are patients with good
• 48:10counts generally and normal bone marrow.
• 48:12So they are like they are trials of
• 48:14vitamin C and you know inflammation,
• 48:16anti-inflammatory agents etcetera.
• 48:18However those drugs can be given together.
• 48:21One of the things actually we benefited
• 48:23from doing these trials is that I have
• 48:25a number of patients I share with
• 48:27our colleagues here that need some,
• 48:29you know that that need immune
• 48:30checkpoint inhibition.
• 48:31I have multiple patients including
• 48:33with Barbara where they are on some
• 48:35kind of immune checkpoint inhibitor
• 48:37and they have MD's now and I need to
• 48:39give them azacitidine because they
• 48:41have MD's and we have been doing
• 48:43this in a number of patients and
• 48:45for the most part is pretty safe.
• 48:47So this in the past used to
• 48:49be a horrendous situation.
• 48:50It's still a horrendous situation.
• 48:51You have two active tumours,
• 48:53MD's and solid tumour,
• 48:54but many of those patients used to get
• 48:57only supportive care and nothing else.
• 48:59But now we for the most part because
• 49:01immune checkpoint inhibitors generally
• 49:02will not lower your blood count.
• 49:04So they are able to give them even
• 49:07with patients with MD's and I'm
• 49:08able to treat the patient with
• 49:10azacitidine because it does not
• 49:12worsen their immunosuppression.
• 49:13You can give it safely.
• 49:14But again,
• 49:15this I think how to prevent
• 49:17clonal evolution is I think is
• 49:20an important area as well.
• 49:25OK. Thank you so much my e-mail
• 49:28if anybody has any questions then.