Yale ASH 2022 Highlights: Myeloid Leukemia

February 27, 2023

Information

February 24, 2023

Presentations by: Drs. Amer Zeidan, Nikolai Podoltsev, and Lourdes Mendez

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00:00Will. Occupy some time,
00:03which we don't have a lot of today.
00:06Uh, my name is Nicolai Podolski.
00:08If I'm associate Professor,
00:10Department of Medicine, Hematology section,
00:12and I'm joined by Doctor Amir
00:15Zadan and Doctor Lourdes Mendez.
00:18Today we will be talking about myeloid
00:20malignancies and acute leukemias.
00:21I will start by talking about ash
00:25presentations I have selected on the
00:27topic of myeloproliferative neoplasms.
00:29Amar will continue and we'll discuss. Mrs.
00:33Abstracts and finally Lordis will finish,
00:35uh this session, uh,
00:38by discussion of studies which
00:41were presented on the subject of
00:44acute myeloid leukemia and all.
00:47So without further ado,
00:48I will proceed with my presentations.
00:51Those who are joining late will be
00:53able to get benefit anyway because
00:55this presentation is structured
00:56and includes quite a few things.
00:58So hold on one second,
01:00let me just see here we go
01:02this off my disclosures.
01:05Uh, so I'm going to talk about UH-4,
01:08uh,
01:08different presentations on the
01:10subject of myelofibrosis and then uh
01:12I will finish with polycythemia Vera.
01:14It is interesting how many drugs
01:16are being developed in the area of
01:18myelofibrosis taking into consideration
01:20relatively low prevalence of the
01:21disease in the United States.
01:23At any given time,
01:24we have about 13,000 patients.
01:25Of course,
01:26PVR is much more prevalent because
01:28these patients survive a bit longer,
01:30so maybe 10 times more so,
01:32but of course development of
01:33this new drugs are benefiting.
01:35For patients and today I will
01:37be talking about four,
01:38four different medications and
01:39different stages of development.
01:41And I just wanna say that none
01:43of them are approved by FDA in
01:46myelofibrosis at this time.
01:47And you know some of them are in
01:49the pipeline closer to be approved
01:51to others is just at the beginning
01:53and phase one development.
01:54So this is the table which summarizes
01:58currently approved drugs which are
02:01Jack inhibitors as well as the drug which is.
02:05Uh in the pipeline for approval,
02:07new drug application was submitted by
02:09the company developing this drug to the FDA.
02:12This is monoethnic,
02:13the last and the table and the
02:15review is expected to end sometime
02:17at the beginning of summer.
02:19So very soon we'll know if this
02:20drug is going to be approved and
02:22it is expected to be so this
02:24drugs called Jack inhibitors,
02:26but they actually have slightly
02:27different mechanism of action and that's
02:29why they may have slightly different
02:31effectiveness as well as different
02:33side effects was approved in 2011.
02:34More than 10 years ago and it is Jack
02:37one Jack 2 inhibitor used in frontline
02:38treatment for high risk patients
02:40with myelofibrosis intermediate
02:41and high risk patients with main
02:44side effects related to cytopenias
02:46to drive them followed in 2019,
02:48eight years later.
02:49And this is the drug which can be
02:51used in frontline but most of us
02:52are using it in second line and it
02:54inhibits Jack 2 but also Jack one and
02:57some other tising kinase including
02:58fleet 3 enhanced GI side effects.
03:00Pacritinib approval was in
03:02February of 2022 for patients with.
03:05Myelofibrosis who have low platelet
03:07count less than 50 button second line
03:09NCC and recommends to use it uh for
03:11patients with any platelet count.
03:13Again GI side effects can be seen
03:15in patients using this drug.
03:17Finally momelotinib.
03:19Claims fame in the area of anemia which
03:21is one of the common manifestations
03:23of myelofibrosis and mostly it is
03:26expected to be beneficial for patients
03:28with myelofibrosis lavania because
03:30of its inhibition not only of Jack,
03:32not only Jack 2, Jack one, but acvr.
03:34In fact, inhibition of Jack two
03:36leads to anemia and acvr inhibition
03:38actually is beneficial for anemia.
03:40So this is the study momentum phase
03:43three study of MOMELOTINIB versus danazol
03:46in symptomatic patients with anemia.
03:49Who have uh intermediate or high
03:52risk myelofibrosis and previously
03:54treated with Jack inhibitor.
03:56So these are the patients mostly treated
03:58with ruxolitinib who then either were
04:00resistant or refractory to this drug
04:03and proceeded with the second line
04:05treatment which included monoethnic
04:06or danazol in this randomized study.
04:08So as I've mentioned inhibits Jack one,
04:11Jack two similar to ruxolitinib but
04:13also a CD R1 which is active in a
04:17receptor type one and signaling in ACR.
04:19One leads to increased production of
04:22hepcidin which limits access to iron
04:25for hematopoiesis and inhibition of C acvr.
04:27One actually decreases hepcidin and
04:30improves production of red blood cells.
04:32As the result it is expected
04:35that anemia can improve.
04:36So the phase three trial looked at
04:39patients who are Jack experienced
04:40and those who are symptomatic as
04:43well as an intermediate to high
04:45risk disease based on dips and have
04:48hemoglobin less than 10.
04:49So with all of this.
04:50Actions anemic to certain degree and
04:52platelet count should be more than 25,000.
04:54So the study randomized patients into to
05:00one fashion and the first group received
05:03more melatonin but 200 milligrams
05:05per day versus danazol placebo the.
05:08The group with Danazol received
05:10danazol 300 milligrams twice
05:13a day and monolithic placebo.
05:15So the key primary endpoint was told
05:19symptoms score response at Week 24,
05:21secondary endpoints transfusion
05:23independence at Week 24 and
05:25splenic response rate at week 24.
05:27This is the results which were
05:30presented AT-2022.
05:31So this the top line results at week 24.
05:36Also the results were published
05:38in Lancet climatology.
05:40This month, uh, so uh, as you can see,
05:43uh, I didn't start from primary endpoint,
05:45I started from transfusion independence
05:46here where you can see in the Red Square,
05:49the response rate for momelotinib group
05:51was higher than for danazol group,
05:5430% versus 20% of patients were
05:57transfusion independent at Week 24,
05:59it is actually impressive how well
06:00danazol did, 20%.
06:01So this drug certainly has role in
06:03management of anemia, myelofibrosis,
06:05but obviously one Molotov was better.
06:07So the other result, the primary endpoint,
06:09the symptoms.
06:10There are controlled in 25% of
06:14patients and splenic reduction by 35%
06:17was accomplished in 23% of patients.
06:20Certainly you wouldn't expect much
06:21of that happening
06:22in Danazol arm. So when the Lightning
06:25did reasonably well from the
06:26standpoint of symptoms and spleen size
06:28reduction in this group of patients
06:31previously treated with ruxolitinib.
06:33So the data was then looked at in
06:36different subgroups based on platelet
06:38count and it looks like it works as well.
06:40The patients got platelet count
06:42less than 50 uh hundred,
06:43less than 100 or less than 150
06:45with uh uh better results in
06:48MOMELOTINIB treated patients.
06:49So side effects, uh,
06:51there are not no surprises here uh.
06:54So the Grade 3 or higher adverse
06:57events happened with similar
06:58similarly in 49 and 46% of patients in
07:01Momelotinib Group and Danazol group,
07:04the rate of serious adverse
07:05events was very similar.
07:06So just want to highlight obviously you know
07:09cytopenia still a current myelofibrosis,
07:11there are some GI side effects which
07:13happened similarly in both groups
07:15of patients and peripheral sensory
07:17neuropathy is highlighted at the bottom.
07:19Was there was a signal in early phase
07:21studies that that may be an issue in
07:24more melodic treated patients but
07:25it didn't really seem to happen in
07:27this particular phase three trial?
07:29Moving on uh,
07:30so from Jack inhibitors to the drugs
07:33which uh have different mechanisms
07:35of action and still used and
07:37myelofibrosis and this particular
07:39drug is called navitoclax and in this
07:42study it was used together works with
07:44Jack inhibitor naive patients now.
07:46So it's a frontline treatment for
07:49patients with myelofibrosis who have
07:51intermediate to high risk disease.
07:53So and now the study highlights certain
07:56things which claim that the results are.
07:59Suggestive of disease modification.
08:01Let's look at uh,
08:03the navitoclax itself.
08:04So what does this drug so and why
08:06would we combine it with ruxolitinib?
08:09So rux lithium suppresses transcription
08:11through Jack inhibition of jackstadt pathway.
08:14You can see how it can suppress
08:17transcription of pro survival
08:18proteins MCL one and BCL Excel.
08:21So Navitoclax it's direct inhibitor of
08:24antiapoptotic activity of BCL XLS well
08:27as BCL two and in preclinical studies.
08:29Yeah,
08:30they showed this to drug showed
08:32synergistic synergism in inducing
08:34apoptosis in malignant cells that led
08:36to the development of this combination.
08:39And at ASH 2022 Cohort 3 of refined study
08:43phase two trial enrolling Jack Jack
08:46inhibitor naive patients was presented.
08:49So key criteria key endpoint was splenic
08:55volume reduction by 35% at week 24 measured.
08:59Grammarian cat scan and key secondary
09:02exploratory endpoints were changing
09:04bone marrow fibrosis grade from
09:06baseline reviewed locally as well
09:08as reduction variant frequency for
09:10driver mutations determined centrally.
09:12So as we are 35 was achieved in 80%
09:15of patients which is pretty good.
09:18So you can see that pretty much all
09:20of the patients had some splenic
09:22reduction and again among those who
09:24accomplish as CR35 response at 24
09:26weeks about third of patients had achieved.
09:29Reduction in marrow fibrosis by
09:31at least one grade.
09:32So the secondary endpoint
09:34looked at fibrosis itself.
09:36The reduction by one grade was
09:38observed in nine out of 32 patients
09:4028% and among nine patients,
09:42two had complete resolution of myelofibrosis.
09:44The mean time to resolution to reduction
09:47in bone marrow fibrosis was 12.3
09:50weeks and also there was reduction,
09:52significant reduction of Jack 2V617-F
09:54mutation very until frequency.
09:56So 36% of patients had 50% reduction or more.
10:00So this findings uh in improvement
10:02of fibrosis as well as reduction
10:05of varietal frequency objectives,
10:07617 mutations suggests disease modification
10:09with use of this medication combination.
10:12So next drug which also was tried
10:15in treatment naive patients.
10:18So together with ruxolitinib
10:20is called Palabra Zeb.
10:22So this is again a phase two
10:24study and first of all couple of
10:27words about collaborative itself.
10:29So it's better.
10:29Keep it and that is a family
10:31would be genetic proteins which
10:32are overexpressed in cancer.
10:34Collaborative is novel oral BET
10:36inhibitor which belongs to this class
10:38of drugs known as epigenetic modifiers.
10:40The lab razip selectively inhibits
10:42BD1 and D2 bromo domains of that
10:44proteins and you can see on the
10:46cartoon on the right that it can work
10:48concordantly with Jack inhibitors.
10:50So Jack inhibitors inhibitors jackstadt
10:53pathway that proteins are important in.
10:57Transcriptions which lead to
10:59production of TGF Beta NF, Kappa B,
11:02BCL two and cmic.
11:03Those are associated with aberrant
11:06mechanistic differentiation,
11:07increased cytokines,
11:08bone marrow fibrosis and cell survival.
11:11So if you inhibit Jack as well as
11:13better at the same time you decrease
11:15production of this site okines and
11:17this can lead to the improvement of
11:20symptoms and perhaps disease modification.
11:22So the study we're looking at is has
11:25four arms, but we're only looking at.
11:27Arm 3 which is a first line uh,
11:30uh treatment for patients not
11:32exposed to Jack inhibitors who have
11:34intermediate tool to high risk disease
11:36and there's all of these people
11:38were in this phase two trade study
11:40received collaborative and ruxolitinib.
11:42The primary endpoint was SVR 35,
11:45splenic volume reduction by 35% and total
11:48symptom score is actioned by 50% at week 24.
11:51So as you can see the SVR
11:5535 was at week 24 was 68.
11:57Some previous study actually 80% again
12:00we can't come cannot compare apples
12:02and oranges here and TSS 50 reduction
12:05was accomplished by 56% of patients.
12:07Interestingly at any given time as we
12:09are 35 was accomplished again by 80%
12:12of patients similar number to which
12:14was shown previous study I shared with you.
12:16So from the standpoint Ballmer of
12:19fibrosis again about 27% of patients
12:21here at had at least one great reduction
12:24in bone marrow fibrosis by Week 24.
12:27Clinical responses were connected
12:29to reduction of variable frequency
12:31inject 2V617-F mutations.
12:33Most adverse events here were low
12:35grade and 14% of patients had to
12:38discontinue the study participation
12:40due to adverse events.
12:41So uh,
12:42this is to me is one of the more
12:44exciting presentations plenary session.
12:46You can see this presentation #6 and
12:49it looks at completely different
12:51mechanism of action.
12:53This group of diseases and
12:55myeloproliferative neoplasms,
12:56so this is the presentation of
12:58preclinical data on monoclonal
13:00antibody against mutant calreticulin.
13:02So mutant calreticulin is so calreticulin
13:06as a protein is responsible for modification
13:10of thrombopoietin receptor before it moves
13:14to the surface of the cell and mutated
13:18calreticulin instead of just modifying
13:20it attaches itself to the TPO receptor.
13:23And moves together with the
13:25receptor to the surface uh,
13:26causing dimerization of the receptor
13:28and its activation uh,
13:30which doesn't require ligand.
13:32So what happens when antibody attacks
13:35and mutated color electrically and
13:38on the surface of the cell it?
13:40The reverses this dimerization and
13:43activation of jackstadt pathway.
13:45So this study used fully human
13:48FC silent IgG 1 antibody again
13:51against mutant calreticulin.
13:53The binding was selective to mutant
13:56calreticulin antagonized mutant
13:58calreticulin used signaling and congenic
14:01function inhibited cell proliferation.
14:03Start 5 phosphorylation in CD34
14:05mutant calreticulin cells.
14:07It caused apoptosis of those cells
14:09and didn't affect non mutant.
14:11Political in cells once again you
14:13know this is the uh preclinical data.
14:16The Phase One study is expected to
14:20be opened within next few months.
14:23So moving on to polycythemia Vera,
14:26much higher incidence and prevalence
14:28of this disease and the United States
14:31only one study and this is the study
14:34for patients with low risk disease.
14:36So low risk defined as age less
14:39than 60 and no history of.
14:41Thrombosis,
14:42so this patients historically
14:44treated with phlebotomies and aspirin
14:46and what this study looked at is
14:49addition of row peg interferon A2,
14:51B to this treatment.
14:54So the patients randomized in
14:55this phase two trial in one to one
14:57fashion standard of care is on the
14:59left phlebotomy plus aspirin and on
15:01the right is lobotomy plus aspirin
15:03as well as row peg interferon.
15:05It's at fixed dose of 100 micrograms
15:08every two weeks.
15:09Primary endpoint was response and.
15:11Response was defined as median
15:13chemical less than 45 in the absence
15:15of disease progression.
15:16Definition of disease progression
15:18for low risk HPV patients includes
15:20progressive symptoms and progressive
15:23symptomatic thrombocytosis,
15:24progressive Leukocytosis,
15:26vascular and major bleeding complications.
15:28So this is the primary endpoint.
15:29The study was published in 2021.
15:32So at that time the second interim
15:34analysis was presented at one
15:36year and this is a final results.
15:38So this is observation of patients
15:40over a period of two years.
15:41Study was stopped to accrual after
15:44uh second analysis uh because uh
15:47significantly better performance of
15:49patients who were treated with row
15:52peg interferon from the standoff
15:54composite primary endpoint.
15:55So you can see that this is
15:57schematically control lack of
15:59progression which was observed
16:01in much higher number of patients
16:03treated with row peg interferon.
16:05So the separate endpoints for hematocrit
16:07control and disease progression you
16:10can see that frequency of phlebotomies.
16:12Was less in experimental arm and uh,
16:16you can see that the disease
16:18progression was only observed in
16:20patients treated with phlebotomies
16:22plus aspirin without rollback.
16:24In six patients placed count
16:25increased to more than a million
16:27and baseline was lower than 602
16:31patients planning infarction and
16:33transient ischemic attack occurred.
16:35So the effect was reasonably durable as
16:38you can see and also there was improvement
16:41of symptoms as measured by MPN.
16:43Off TSS and P splenomegaly improved
16:45in ROBEC treated patients as well
16:49significantly when compared to
16:51patients treated without rollback.
16:53So Jack 2V617-F very until frequency
16:56decreased in ropek treated patients
16:58and slightly increased the 12 months in
17:01patients who didn't receive rollback.
17:02So I would like to also show
17:04the side effect table.
17:05Obviously people who are treated with row
17:08Peg had higher incidence of adverse events.
17:11This is included treatment.
17:13Related adverse events 55% versus 6%
17:15grade 3 or 4 adverse events were about
17:18the same and adverse events that caused
17:21treatment discontinuation were only
17:23revealed in rollback treated patients.
17:25In conclusion,
17:25I would like to summarize what
17:27I presented to you.
17:28Molotov may improve anemia in
17:30patients with myelofibrosis and
17:32acne due to acvr inhibition.
17:34Ruxolitinib and collaborative,
17:35the better inhibitor and light
17:37treatment associated with high
17:39SVR rates and TSS 50 reductions.
17:41Decrease fibrosis the clustering of
17:44megakaryocytes and decrease in Jack
17:462V617 affair and total frequency may
17:48be a sign of disease modification and
17:50phase three trial which used the same
17:53model of combining roots lithium and
17:55collaborative just completed accrual.
17:57So waiting for the results
17:59Rubidium and Navitoclax and another
18:00combination frontline treatment.
18:02This BCL two BCL Excel inhibitor also
18:05was associated with a significant
18:07reduction in spleen volume as well
18:10as decreasing fibrosis and Jack.
18:12Will be six months S there until
18:14frequency phase three transform
18:15one study is ongoing monoclonal
18:18antibody against mutant calreticulin
18:20is effective in preclinical models.
18:22We are looking forward to see how this
18:24drug will perform in clinical trials.
18:26Finally,
18:27row Peg interferon can be considered
18:29for selected patients with low
18:30risk polycythemia Vera based on
18:32the results of phase two study.
18:39Thank you, Nikolai. So I'm going
18:42to be talking about MD S right
18:45now and let me share my. Slides.
18:52OK.
19:05OK. Thanks everyone.
19:08So I decided actually talk a
19:10little bit more in general about
19:12some of the main updates and on
19:14the management of MSDS in 2022
19:17integrating some of the ASH abstracts.
19:19These are my disclosures.
19:20So I'm going to talk about updates
19:22in the diagnosis, classification,
19:24prognostication and response assessment
19:26and then management to flower.
19:28On higher risk MD S.
19:30So I think the first important thing to
19:32know is that the diagnostic criteria
19:35for MDS were updated by The Who.
19:37So right now rather than requiring
19:39a hemoglobin of less than 10 and a
19:42platelet count of less than 100,
19:43as you can see to the left,
19:45the thresholds were a little
19:46bit less restrictive.
19:47So any anemia which is hemoglobin
19:49less than 12 in women and 13 in men
19:52or thrombocytopenia platelet count
19:54less than 150 can diagnose MSDS
19:56once you exclude other things that
19:58can cause MSDS but importantly.
20:01Certain genetic alterations such
20:03as as after B1 and B53 one could
20:07potentially lead to diagnosis
20:09of MDS in the right context.
20:12So that will probably mean that you
20:14are going to see more diagnosis
20:16on the as among your patients.
20:18The second I think major change in 2022.
20:21Is the update of The Who classification.
20:24We have two different classifications
20:26right now for
20:29MDDS WHO 20222020 and ICC 2022 and
20:34this is important because you there
20:36are some differences between these two
20:39classifications and you are going to start
20:43seeing in your pathology reports some
20:46discrepancies between the two diagnosis.
20:48In some cases a patient could
20:50be diagnosed with.
20:51Animal by one category and MDS by the other.
20:55For the sake of time today I'm not going to
20:57be able to go through the details of this,
20:59but the main updates is that certain
21:02genetic alteration as I mentioned,
21:04such as 3B1 and TB53 mutated
21:08now can define genetically.
21:10And the and also the category of 10 to
21:1619% blast in the ICC classification
21:19is called M DS/AMD.
21:21So I think this is important to remember
21:24as you look at your path reports and
21:26one of the ASH abstracts actually
21:29compared the two classifications.
21:31This was a large effort on behalf
21:33of the International Consortium for
21:35MDS and I'm not going to go again
21:38through all these results, but what?
21:40Was found is that certain aspects of
21:42each classification seem to function
21:45well and therefore ideally this these
21:48two classification should be harmonized,
21:51which is an effort that is currently ongoing.
21:54But until that happens,
21:55feel free to reach out to us and to
21:58the pathologist to discuss any aspects
22:00of the path report that does confuse
22:03you a little bit because it's going
22:05to be a confusing gear in terms of
22:08the diagnosis and classification.
22:10Now going to prognostication
22:11where things a little bit easier.
22:13So we still think about MDS in two big
22:15groups, lower risk and higher risk.
22:17Lower risk quality of life is the main goal.
22:20Higher risk you generally would
22:21treat with the goal of changing
22:23the Natural History,
22:24often requiring bone marrow transplantation.
22:28So this is the classical scoring systems,
22:31IPS and revised ipss,
22:32the two most commonly used ones.
22:35And based on the adding of the blast count,
22:39cytogenetics and cytopenias you classify the
22:41patient into these lower and higher risk.
22:44And one of the main developments of
22:462022 was the publication of the ISM.
22:50So this finally and formally
22:53integrated molecular IPS into the
22:55prognostic picture you can see here.
22:58On this table a list of the genes.
22:59So there are 17 or sorry,
23:02there are 31 different genes that are
23:04part of the molecular classification
23:06and this is becoming the standard
23:08of care risk tool assessment.
23:10Again,
23:11why is that important for your practice
23:13is now it's having the molecular
23:16data affects both the diagnosis
23:18classification as well as prognostication
23:20of MD S and I still see many path
23:23reports or when the World Cup for Ms.
23:26is done in Community settings.
23:28Many times people are just sending
23:30karyotype and fish and they are
23:32not sending molecular assessment.
23:33So it's really important that
23:35an exigency sequencing,
23:36which is readily available in our impact
23:39department should be run on those
23:41patients because it can affect all of these.
23:45Assessments which subsequently
23:46can influence therapy.
23:48The ISM now uses 6 categories
23:51rather than five categories,
23:533 lower risk ones and three high risk ones.
23:56And the good news is that this good
23:58thread of the intermediate ISR,
24:00which used to be a problem because it
24:03it was never clear whether you treat
24:04it as lower risk or higher risk.
24:06There are different ways to do that,
24:08but in the molecular IPS the patient
24:11is either lower risk or high risk,
24:13and I think that makes it somewhat easier.
24:15Now this model is a bit complex and
24:18it's not easy to clearly remember
24:21all the different variables,
24:23but the good news is that you
24:25have this website.
24:26And the as riskmodel.com you can see to
24:30the left side and all what you need to
24:32do is just enter the variables plus count,
24:34age, hemoglobin,
24:35platelet count and what molecular
24:38alteration the patient has.
24:40And then you can see that the
24:42ISM score for example for this
24:44patient was .24 moderate high.
24:46Also, this gives you the revised ISS score,
24:49so you can get both the molecular and
24:52the revised IPS in the same in the
24:54same snapshot when you enter the data.
24:57So one of the important presentations
24:59from ASH 2022 was comparing the
25:01molecular IPS which was just published
25:04in 2022 again against the revised IPS.
25:08And what you can see here is that
25:09the C index,
25:10which is a measure of the prognostic
25:13utility or the model accuracy is
25:15better for the molecular IPS as
25:17in this large European cohort.
25:19There were a number several presentations
25:21looking at this from different cohorts
25:23and all of them showing the same thing
25:25is that the molecular IPS is better.
25:27And therefore I think we should really try
25:30to get it calculated on all of our patients,
25:33but of course that's going to require
25:35you to give them molecular data.
25:37So we talked about diagnosis classification
25:40prognosis and the response criteria.
25:42And response criteria have been
25:44somewhat problematic in MD S because
25:47they have contributed to some of
25:49the delayed drug development in
25:51my opinion by introducing data,
25:53molecular response responses that
25:55are sub optimal such as model.
25:58PR which has never been correlated with
26:00long term survival and at the same time
26:03used very high cutoff for hemoglobin,
26:05for example of 11 to denoise donate
26:07complete response which is very
26:09difficult to obtain in an Ms.
26:11patient.
26:11And there's this is beyond the scope of
26:14discussion today about all the issues
26:16that come with the response criteria.
26:18But finally an international panel,
26:20the IWG has revised the criteria so we
26:24have a new criteria for higher risk.
26:28Mrs.
26:28and I think this is going to address several
26:32of the shortcomings of the 2006 criteria.
26:37How about some of the clinical
26:40development abstracts?
26:41There were several important ones
26:42for both lower risk and higher risk.
26:44For lower risk MD as the treatment
26:47continues to be ESA erythropoiesis
26:49stimulating agents for most
26:51patients with lower risk MD S.
26:53How about for patients who have deletion?
26:555Q Lenalidomide is an important drug.
26:59Lenalidomide is currently approved
27:01for lower risk deletion 5Q DS patients
27:04who are transfusion dependent.
27:05So this important abstract,
27:07this is a randomized phase three
27:09trial looked at giving Lenalidomide
27:11in patients with Delphi Q lower risk
27:14who are not yet transfusion dependent.
27:16As you can see the criteria
27:18eligibility anemia of less than 12.
27:20So if you have a hemoglobin of
27:2110 or 11 and you are symptomatic.
27:23Even if you are not needing transfusions,
27:25you would be eligible for this trial.
27:27Patients were randomized to
27:29Lenalidomide in a time limited fashion,
27:31meaning that you are getting
27:32the drug only for two years,
27:33it's not continuous versus placebo.
27:36And then the patient who are monitored
27:38and this is the top line result of
27:41this study is that Lenalidomide has
27:43significantly lower the chance of
27:45needing regular transfusions as well
27:48as delayed the time to transition
27:50dependency significantly more than six years.
27:53For patients who are only related
27:55to mild compared to patients who are
27:57getting a placebo and also induced
27:59a lot of cytogenetic responses and
28:01their safety profile,
28:03both hematological and and non
28:05hematological was generally well tolerated.
28:08So I think this could potentially
28:10lead to a major change in practice in
28:12earlier initiation of Lenalidomide
28:13and this is one thing that I think
28:16is important to consider in patients
28:18with deletion 5Q who are anemic but
28:20not yet transfusion dependent.
28:23The Middle East trial which many of
28:25you have contributed to when it was ongoing.
28:29This trial led to the approval of
28:32Los Battleship the transforming
28:34growth factor pathway drug that is
28:37illegal trap that has been shown in
28:39patients with RingCentral Plast Mrs.
28:42with ring sideroblasts to improve
28:44transition independence.
28:45You can see this is the New
28:47England Journal of Medicine,
28:48a paper that led to the approval
28:5038% transfusion independence we.
28:52Published an update from that
28:55study in 2022 showing that the
28:57responses would lose better ship,
28:59were long lasting and not only
29:01limited to transfusion dependence,
29:02but there was a lot of improvement
29:05in hematologic parameters as well as
29:07significant reduction in the red blood
29:09cell transfusion among those who did
29:12not fully achieve transfusion independence.
29:15However,
29:15the approval was after SF failure
29:18for patients who have Ms.
29:20with ring sideroblasts,
29:21so the commands trial this is a phase three.
29:24Well,
29:24uh of less partnership versus ESA,
29:26so this is a frontline treatment
29:28where patients were randomized to
29:30receive either lose partnership or
29:32erythropoietin in the frontline
29:33setting first treatment and not only
29:35in patients with RingCentral Press,
29:37but also in patients without ring syndrome.
29:39Last and this trial was a large
29:42international trial,
29:43more than 350 patients were enrolled
29:46including here at TL and data were
29:48not presented from this trial in ASH,
29:51but there was a press release from
29:54the manufacturer.
29:54Uh,
29:55basically declaring positive
29:56results for the primary endpoint.
29:59So this is I think could be an
30:01important development in the
30:02management of lower risk MD S in 2023.
30:04We are hoping to see the data later this
30:07year describing the impact of Los
30:09leadership in the frontline setting.
30:11Another free trial that. Was open here.
30:14TL is the trial that looked at
30:16the imetelstat which is a first
30:18in class telomerase inhibitor.
30:20This is an IV drug that's given every
30:23four weeks and phase two data single arm.
30:26Phase two data previously published
30:28have shown that among patients who
30:31are heavily transfused without
30:33deletion 5Q but had lower risk.
30:36MD S 38 patients have higher
30:38rates of transfusion independence.
30:40With this drug 40% achieve
30:42transfusion independence.
30:43This was previously published.
30:45What was presented in ASH is an
30:47update on the patients who had
30:49transfusion independence on the drug,
30:51which lasted more than one year
30:53and there were eleven out of the
30:573829%. And you can see here that among
31:00those patients there was significant
31:03durability of the transition independence,
31:0692 weeks of transfusion independence,
31:07but also the mean change in the
31:09hemoglobin was quite impressive.
31:11The median increase was almost 3 grams.
31:14So those are not patients.
31:15Going from hemoglobin 8 to 9,
31:16this is someone going from 8 to 11.
31:19So that's certainly is a meaningful benefit.
31:22But importantly there was a press release
31:25also this was a year of press releases,
31:27all our risk and bias,
31:29the Imerge phase three trial,
31:32the top line results also confirmed
31:34that advantage of the phase two showing
31:37transition independence with the
31:39loss would initially start in 40% of
31:41patients who have received this drug
31:43and this drug is now in front of the.
31:46They are also in consideration for approval.
31:48We are hoping to see the data
31:50also later this year.
31:52But between these two drugs,
31:53I think there could be a significant
31:55change in the landscape of management of
31:57lower risk MD S about higher risk MD S.
32:01So at Jamies have been a significant.
32:05Basically in terms of helping patients with
32:08high risk MD S but real life data such as
32:11the one I'm showing you here showed that
32:13the benefit from HM is is suboptimal.
32:16The median survival is only 11 to 17 months.
32:18Once they stop working,
32:19the survival is 5 to six months.
32:22So we certainly need improvements.
32:24However, many of the drugs that were
32:26added to HMA's have not unfortunately
32:30shown any benefit.
32:31We have a big graveyard of drugs.
32:33You can see some of them listed here.
32:36That once combined with HM is initially
32:38they showed good data in single arm trials,
32:40but once you have the phase three trials
32:42or the randomized phase two trials,
32:44the results were negative.
32:46However, we have other drugs that
32:48are now in phase three trials and we
32:51are optimistic about some of those.
32:53You can see here 6 randomized phase
32:55three trials ongoing in the high risk
32:58MD S sitting in combination with HMS.
33:00The two trials that you see the
33:02drug listed in black people need
33:04to start and APR 246.
33:06Unfortunately,
33:06those two threads have read out as
33:08negative for the primary endpoint.
33:10But the other four trials with venetoclax,
33:12sabatelli map,
33:13negroli Mab and Tammy paroxetine,
33:15all of those are ongoing and I'm going
33:17to tell you a little bit about them.
33:19However,
33:19none of those four trials have yet reported.
33:22But I think those are trials
33:24that are important for the field
33:27because they potentially,
33:28if any of them are positive,
33:29it could change the landscape of
33:32treatment of high risk MD S so
33:35another important reminder is that.
33:37Patients with MDD should be
33:38considered for transplant when
33:39they have higher risk disease.
33:41If you just keep the patient on HMA alone
33:44the long term survival is very poor,
33:464% for higher risk Ms. patients.
33:48And now we have randomized data.
33:50This is biological assignment trial.
33:53If you have a donor versus no donor and
33:55that showed up to the age of 75 that
33:58your overall survival could be doubled.
34:00The three-year survival for patients
34:02who had a donor was 50% compared
34:04to 26% and again this is up.
34:06At the age of 75,
34:08many patients are being told they are
34:10not candidate for transplant because
34:12they are late 60s or early 70s.
34:14But if the patient is otherwise good shape,
34:17I would strongly recommend that you
34:19refer them to discuss transplant.
34:22Venetoclax is approved for all
34:24their unfit patients with AML.
34:25However,
34:26the data in frontline in high
34:28risk MD S has been promising.
34:30But this is single arm trial.
34:32We have previously published a trial
34:34that Yale participated in in the
34:36relapse refractory setting where
34:38venetoclax has been added after HMA
34:40failure and the Verona trial which
34:42also was open at TL randomized
34:44patients to receive Asia versus Asia
34:47when this trial has fully accrued.
34:49And we are waiting for the results
34:51of this trial to.
34:52Look at the role of venetoclax
34:54in high risk MD
34:55S. Another I think interesting
34:57molecule that we've been part
34:59of is sabatelli map and item 3.
35:01So tem three basically is an inhibitory
35:04receptor that is not only present on T
35:07cells like regular immune checkpoints,
35:10but this is also present on some of
35:12the leukemia stem cells and the blast.
35:14So Sabato Lima could basically be
35:17targeting both the immune system
35:19as an immune checkpoint inhibitor,
35:21but also directly attacking the
35:23plus and the leukemia stem cells.
35:26Early data have suggested activity
35:28in the clinical setting and based
35:30on this around the phase two trial
35:32which we had open here at TL,
35:34the stimulus MS1 randomized patients
35:37to receive Sabato Lima with HMA
35:41versus HMA alone and the primary
35:43endpoint was CR and PFS.
35:46We presented this data in in ASH.
35:48This was the only randomized phase
35:50two trial presented in ASH 2022.
35:52Unfortunately the primary endpoint
35:54on this randomized.
35:56This too was not reached.
35:57There was still no significant
35:59difference in CR and PFS.
36:01But what I attract your attention
36:02to is that there was late separation
36:04of the curves and the PFS was eleven
36:07months compared to 8.5 months,
36:09which would be potentially consistent
36:11with delayed onset of action seen
36:14with immune checkpoint inhibitors and
36:17importantly among patients who achieve CR.
36:19So the CR rate was not increased,
36:21but those who achieved CR,
36:23the duration of the CR was doubled
36:25for the combination compared to.
36:26I mean one of therapy again suggesting
36:29potentially that there could be a
36:31deeper response and more durable
36:33response with with the combination.
36:35But of course these are exploratory analysis.
36:39The phase three trial is already also
36:42fully accrued. It was open at Yale.
36:44Some of the care centers have
36:45contributed patients to this royal
36:48which randomized patients to receive
36:50Sabathia versus sorry Sabato Lima
36:52with HM versus is alone and this
36:54trial is fully accrued and we
36:56are waiting for the results.
36:58Negroli Mab is another drug that had
37:01attracted a lot of attention in AML
37:03and MD S This is this works on the on
37:06the CD 47 but don't Eat Me Signal CD
37:0947 is expressed in MDR cells and it.
37:13Can evade phagocytosis so inhibiting
37:15it with the anti CD 47 agent can
37:19lead to increased phagocytosis
37:21of blasts and clinical benefit.
37:24This is a phase two study of
37:27margaroli map with azacitidine
37:29showing promising responses,
37:30but this was a single arm trial.
37:33They are ongoing phase three trials
37:35with this drug margaroli map.
37:37And we also have a study coming ATL where
37:40oral HMA is being combined with Negroli map.
37:43This is a trial in progress abstract
37:46presented in ASH that discusses
37:48the design of this trial.
37:50And we have another anti CD 47
37:53agent that is being tested and for
37:58MSDS and AML after HMA failure.
38:03So a lot of drugs are being tested
38:05in MD S This is showing them of
38:08some of the trials that we had open
38:11or are in activation process that
38:13Tammy protein which is Arara agonist,
38:16super agonist.
38:18Aurora is basically over expressed in
38:20around half of the patients with MDS.
38:22So this is a phase three trial
38:25that randomizes patients to Asia
38:26Tami paroxetine versus Asia.
38:28This is an activation in addition
38:30to the single arm oral decitabine
38:32with macro for higher risk MD S
38:35and then for the lower risk we
38:37have an extension of the imetelstat
38:39sub study that I mentioned to you.
38:41So this is a single arm study that
38:44gives patients initially stat and
38:46this includes patients with HMA.
38:48Earlier or Lenalidomide failure.
38:50So I encourage you to refer patients
38:53who are transfusion dependent who
38:55have not responded or benefited
38:57from standard of care drugs.
38:59So this is my last slide and I'm
39:01happy to take any questions later.
39:03Thank you so much.
39:14OK, this will present now
39:17updates on acute leukemias.
39:20OK. So I'm going to start with
39:23AML and then move to a LL.
39:25I have no disclosures.
39:27So AML remains a disease
39:30with suboptimal outcomes.
39:32The five year relative survival is 30.5%
39:35and this is a disease of older adults.
39:39Median age at diagnosis
39:40is 68 and at death is 73.
39:44And so treatments that are
39:47efficacious either new agents or.
39:50New combinations,
39:51particularly that are tolerated
39:53by this age group are needed.
39:56The addition of an edit flex to
39:59hypomethylating agents improved CR
40:01rates to 65 to 70% in the frontline
40:05setting and older unfit AML.
40:08However.
40:09Longer term data from the Viale study
40:12has shown that only a minority of
40:15patients experience durable remission
40:17and survival such as it two years
40:20and in high risk groups such as TP53,
40:23mutant JML,
40:24but also flip three mutant AML.
40:27Particularly in older and unfit AML patients,
40:31they're continued to be very poor outcomes.
40:35As an example, in TP53 mutant AML,
40:38the median overall survival is 5 to 7 months.
40:42With our standard of care therapies,
40:44there's also a great need in
40:47relapsed refractory AML where the
40:49median overall survival and the
40:51unfit subgroup is 3 to 7 months.
40:57And so turning to the TP 53 mutated group,
41:01it is occurring this mutation in five
41:05to 10% of patients with the Novo AML
41:08and its enriched in therapy related
41:11AML and as noted before with standard
41:14of care the survival is poor less than
41:18one year including post transplant.
41:21And so doctor Zaiden discussed this
41:24agent Mike Roll Amab which targets
41:28CD-47 which has been called amyloid
41:31checkpoint and is a do not eat me signal
41:35and naval daver presented results from
41:39the phase one two study of the triplet
41:42of megola map on the venetta claxson,
41:45azacitidine backbone and
41:48newly diagnosed patients with.
41:50AML, a group of in in a group of
41:53patients that was heavily enriched
41:56for TP53 mutated AML and still
41:59what's being shown here and what was
42:03presented was a frontline cohort
42:06and separated into de Novo AML and
42:10secondary AML that was untreated
42:12secondary meaning having antecedent
42:17hematologic malignancy that could have been.
42:22Treated but not with hypomethylating
42:25agent and so you can see the age
42:29is older individuals and almost
42:32exclusively I'm heavily weighed in
42:35terms of being adverse risk group
42:38ELN 2017 classification system.
42:43And further separated into by the
42:45TP 53 status mutant versus wild type
42:49and as I mentioned heavily enriched
42:52for TP53 mutated patients given
42:55that there's hope for a grolla mab
42:59for the subtype of AML and.
43:02These are the response rates again
43:05separated into the de Novo group and
43:10the untreated secondary AML group and
43:14separated by the status of TP53 mutation.
43:18And so there is a CR CRI rate of
43:2563% with TP53 mutated patients in
43:31de Novo and untreated secondary.
43:33In a higher CRI CRI rate in in the wild
43:36type patients ranging from 80 to 90%.
43:41And on the left is the are the survival
43:45curves for the de Novo population alone.
43:48You can see a separation in the
43:51curves between TP53 wild type and
43:53TP53 mutant patients.
43:55The 12 month overall survival of
43:58the TP53 mutant patients was 53%
44:02which compared to historical data is
44:07encouraging because I'll remind you
44:10that the median overall survival.
44:12Is on the order of six months.
44:14On the right is the median overall
44:17survival in the combined frontline groups,
44:19which is less favorable because the
44:23secondary AML patients did not respond
44:26as well and had short responses as well.
44:31So moving on to a separate high risk group,
44:35the FLIP 3 mutated group.
44:40Nicholas Short reported updated
44:43results from a phase one two study
44:47of another triplet,
44:49gilteritinib added on to the backbone
44:51of venetoclax and azacitidine for
44:54patients with FLIP 3 mutated AML.
44:58And there were two groups of patients,
45:00those who were newly diagnosed
45:02with split three mutated AML and
45:04this could be ITD or TKD who were
45:06unfit for intensive chemotherapy.
45:08And then there was also a
45:11relapsed refractory group.
45:12And in the middle you see the schedule
45:15of treatment notably with triplets
45:17myelosuppression is a concern.
45:19And so built into the treatment schedule
45:22is a day 14 mayoral that informs
45:26the subsequent continuation or not.
45:29Of venetoclax,
45:30Gilteritinib was given at one of
45:32two doses and the recommended phase
45:35two dose was ultimately selected to
45:38be 80 milligrams of gilteritinib.
45:41And on the right you see the
45:44consolidation treatment plan.
45:48So these are the responses for the
45:51frontline and the relapse refractory group.
45:54You can see the composite
45:56CR rates are quite high,
45:58100% in the frontline group and 70%
46:00in the relapse refractory group and
46:02there were no early deaths and it
46:05was considered to be well tolerated.
46:07These are the overall the relapse rate
46:10survival on the on the left and the
46:13overall survival curves on the right and
46:16you can see that the one year overall.
46:18Survival rate is 85%,
46:21which is again very encouraging and.
46:26Umm, sorry, Umm compares favorably
46:31with historical results.
46:36So I just briefly want to touch
46:39on men and inhibitors and the
46:42concept behind these these drugs.
46:45There are several minute inhibitors
46:48under development and the men in KMT
46:512A previously known as ML interaction.
46:55Is it critical dependency in ML
46:58mutated rearranged leukemias as well
47:01as interestingly in NPM 1 mutated
47:03leukemias where it's responsible?
47:06Um for enacting an aberrant leukemia
47:09genic gene expression program so the
47:12inhibitors bind a well defined pocket
47:15and this disrupts the interaction between
47:18ML and MENNEN and causes an abnormal
47:22transcription complex to disassemble
47:25and through down regulation of Hawks,
47:30A and mice, mice,
47:33transcription and other targets.
47:37Allows differentiation of the
47:38leukemia cells as well as apoptosis.
47:44And so as I mentioned,
47:46there's more than one of these
47:49inhibitors that's being developed and.
47:51Doctor Isa reported results
47:56from the Phase one study of the
48:01men and inhibitor review Munib
48:04in patients with KM22KMT2A
48:06rearranged or MPM One mutant AML.
48:11And for the sake of time that trial
48:13is the AUGMENT 101 trial and what was
48:16notable in terms of adverse events were
48:19frequent QTC prolongations and there
48:21were two dose limiting toxicities because
48:24of QTC prolongation, but there was.
48:29Lesser rate of grade,
48:31three or more QTC prolongation and
48:34in a heavily pretreated group with a
48:37median of four prior lines of treatment,
48:40there was encouraging activity
48:42with 30% CRC RH meaning incomplete
48:45hematologic recovery rate.
48:47In these genetic subgroups and
48:50MLL rearranged and NPM 1 mutated
48:53leukemias and the response rates
48:56were different by each genotype.
48:59Doctor Harry Erba presented on
49:02another minute inhibitor Dominic
49:05in the same type of AML and also in
49:10the relapsed refractory setting,
49:12the comment 001 trial and.
49:17Here differentiation syndrome
49:18was observed as was and with the
49:22prior men and inhibitor,
49:24but there were no drug induced
49:28QT or QTC Prolongations reported.
49:31And again,
49:32particularly at the 600 milligrams dose,
49:35which was the recommended phase two dose,
49:39there was in heavily pretreated
49:42population evidence of encouraging
49:45activity with a 30% CR rate in
49:48the NPM 1 mutated group.
49:51The CR rate was much lower in the
49:53in the ML group and it remains to
49:56be seen whether in fact there's
49:58differential activity in different genotypes.
50:01With these agents.
50:03So in conclusion for the for this
50:06AML section,
50:06men and inhibitors are showing
50:08promising activities and relapsed NPM
50:11one and MLL rearranged or mutated patients.
50:13And the two triplets that I I touched
50:16on with gilteritinib on a backbone
50:19of azacitidine and venetoclax also
50:22showing promising safety and efficacy
50:24in the upfront but also relapse setting.
50:27Whereas Megola map added to azacitidine
50:30and venetoclax shows promising activity.
50:33And TP 53 mutated AML's and
50:37their randomized trials ongoing.
50:40For magala map.
50:43So turning to ALAL is evenly split in
50:47the in between the pediatric and the
50:50adult groups, roughly half and half.
50:53However,
50:54whereas the median age at diagnosis is 17,
50:56the median age at death is 58 and
50:59so the outcomes are far inferior
51:01in adults and this is a particular
51:04problem in older adults.
51:06And here you see a summary of overall
51:10survival at the three and five year marks.
51:13Which on average is about 20%.
51:15And if you consider individuals
51:16that are elderly 70 or above,
51:19they're really dismal rates and
51:22outcomes and just as a kind of
51:24a reminder of the importance of
51:28measurable residual disease.
51:30In L, the two two outcomes,
51:33event free survival and overall survival,
51:36you see, you know,
51:37dramatic split between those
51:39patients who have no measurable
51:41residual disease and those who do.
51:43But importantly,
51:44there's also relapse and mortality
51:47even in the situation of no
51:50measurable residual disease.
51:52And so one of the strategies that's
51:54been taken to try and improve outcomes,
51:57particularly in older adults,
51:59is the integration of novel agents
52:02into the frontline setting,
52:04focusing on blinatumomab and inotuzumab.
52:07Inotuzumab is an antibody drug
52:10conjugate against CD22 Lina.
52:12Tuma Mab is a bi functional T cell
52:15engaging antibody that directs
52:17cytotoxic T cells to CD19 expressing cells.
52:21And notably,
52:22the trials that led to the approval
52:27of Blinatumomab and Inotuzumab in
52:30relapse refractory Bal demonstrated
52:33that I Natuzzi Mob has activity
52:35across all levels
52:36of disease burden, suggesting that
52:38it could be suitable for induction,
52:40whereas blinatumomab has higher
52:42efficacy with lower burden of disease.
52:44I'm suggesting that its role may be
52:47primarily in a setting where there's
52:49already been side a reduction.
52:52So there's multiple trials that
52:55are studying the combinations
52:57of inotuzumab with chemotherapy.
53:00Particularly in older individuals and
53:03this is one that Gmall initial one trial.
53:08And in this trial it's the sequential
53:10strategy and the choose amab is
53:12given for three cycles followed
53:14by conventional chemotherapy and
53:15patients greater than 55 years of age.
53:18In this trial a primary event free,
53:20the primary endpoint was 12 month
53:22event free survival with a goal
53:24of seeing better than 60% and and
53:26you can see on the left that this
53:29was met at one year it was 88% and
53:31the two years it was 73%.
53:33But you'll also note though
53:34is the downward slope of this
53:36curve indicating that there are.
53:38Ongoing events after year one suggesting
53:40that there may be a need to improve
53:44on the consolidation strategy.
53:46There was a similar in terms of
53:51approach study that was presented by
53:55Chevalier the result of the Ewal Ino
53:57study and here I know choose Amab is
54:00intercalated with chemotherapy from
54:02the beginning and these are only two
54:04of a number of of such studies the the.
54:08Presentation that perhaps received
54:11the most notoriety at ASH 2022 was
54:14by in the space of L was by Mark
54:17Lizzo reporting the results of
54:20E1910A phase three randomized trial
54:23of BLINATUMOMAB for newly diagnosed
54:26pH negative Bal in adults.
54:28And these adults were age ages ranging
54:33from 30 to 70 and they received.
54:37Two cycles of induction intensification
54:40and were then randomized either to the
54:43experimental arm or to the standard
54:46consolidation chemotherapy arm.
54:48The experimental arm had four cycles
54:52of blood and blinatumomab intercalated
54:55with chemotherapy consolidation
54:57and MRD of course was it.
55:00It was actually the outcomes in
55:02MRD negative patients was the focus
55:05of the study and.
55:07MRD was defined as greater than
55:09or equal to 1 in 10,000 cells as
55:12assessed by 6 color flow cytometry.
55:15And so these are the the results.
55:19These are this is overall survival
55:22and MRD negative patients and you can
55:25see a very clear survival advantage
55:27with the addition of BLINATUMOMAB.
55:30The median overall survival is 71 months.
55:32It with chemotherapy alone and with the
55:34addition of Lena Tuma Mab is not reached.
55:37And so this was,
55:39this is a landmark study and.
55:42Showed for the first time a benefit of
55:46blinatumomab and MRD negative patients.
55:49Not I'm not showing here,
55:51but MRD positive patients.
55:52There's also a separation in the
55:55curves that did not reach statistical
55:57significance and it's unclear if this is
56:00due to smaller numbers or for other reasons.
56:04So very briefly for pH positive,
56:08AL.
56:10Nicholas Short presented for upfront
56:14treatment the combination of panic and
56:18blinatumomab and here the rationale
56:21is that with second generation
56:24tyrosine kinase inhibitors the
56:27majority of patients will relapse with
56:30T315I mutated BCR able which put
56:33that nib is active against and
56:37in pH positive AML chemotherapy.
56:40Free induction has been pioneered with
56:44publications on dissent and Prednisone,
56:46ponatinib and Prednisone and the Dealba
56:49trial reporting Dasatinib and BLINATUMOMAB.
56:52And just very briefly,
56:55they're very striking results
56:57in 40 patients in the frontline
57:00setting CR CRI rates of 96%,
57:04complete molecular response of 87% with an.
57:09Equally striking event free survival
57:12and overall survival curves with a
57:16medium follow-up of 18 months with the
57:21two year overall survival being 95%.
57:26So in summary,
57:27for the abstract shown for ALS into choose,
57:30the map is an effective induction
57:32agent with acceptable low toxicity and
57:36promising early survival outcomes.
57:38And in the late breaking abstract
57:41presented by Doctor Litzow,
57:43the addition of Blinatumomab to
57:46chemotherapy consolidation in adult
57:48patients with MRD negative Bal has
57:51shown for the first time in overall and
57:54relapse free survival in a randomized study.
57:57And so blinatumomab as a part of post
58:00remission therapy represents a new
58:02standard of care for this group of patients.
58:05And one of the challenges in the field
58:08will be how to incorporate this in
58:11regiments in addition to E 1910 since
58:15that is not too frequently used.
58:18And the combination of Panaginip
58:20and Blinatumomab is a promising
58:22chemotherapy free potentially transplant
58:24sparing regimen for pH positive AL.
58:32Alright, so we're open for questions.
58:35Um, uh, please go ahead. We will
58:38stay a few minutes late if necessary.
58:40I know it's end of the hour already.
58:50Any questions?
58:53I probably can ask question while we are
58:56waiting for people like to to poor Mendez,
58:59so for for ALS treatment,
59:02do you foresee moving away to
59:05chemo free regimens even in younger
59:09patients in the near future?
59:12Clearly the progress has been quite
59:14impressive with those novel novel agents.
59:18I think so, especially I mean one
59:21of the hesitancies in terms of
59:23bringing ponatinib to the front
59:25line is its toxicity profile,
59:28which I didn't have a chance to
59:30discuss and the concern for that
59:32would be less in younger patients.
59:34And the efficacy at least that we're
59:37seeing is so high that I think that
59:40that would be a reasonable approach,
59:42I think one of especially I mean in
59:45combination with BLINATUMOMAB so.
59:47One can envision a chemotherapy
59:49free approach there and I think the
59:52difficult question is the role of stem
59:54cell transplant and we need longer,
59:56more mature data to guide us on that.
01:00:11There is a question of the chat.
01:00:13Uh, I think it's uh.
01:00:15Uh, to you I'm almaas.
01:00:17No, it's it's to Lord us.
01:00:20To the.
01:00:23Mab drug substitute of
01:00:26chemotherapy and a LL or AML.
01:00:30So any, I guess you know any of those drugs,
01:00:33uh, which you know will lead to be 3 like.
01:00:38Going to have actually maps.
01:00:42Ohh so so it's a similar question about
01:00:47chemotherapy free treatment of ALS and AML.
01:00:51And AML, that's an interesting question.
01:00:55And I, I took notice of a comment by
01:00:58Naval Daver who was saying that there's
01:01:01going to be a trial exploring magrou,
01:01:05amab and a drug I didn't
01:01:06have a chance to touch on,
01:01:08which is I think now been given
01:01:11the name provoke evoke.
01:01:13You could correct me if either
01:01:15of you knows how to pronounce
01:01:17that antibody drug conjugate.
01:01:21I don't know,
01:01:22but for CD123 and so that's one
01:01:26that's going to be something
01:01:28that we're going to explore.
01:01:30I think chemotherapy free, you know,
01:01:35there's other possibilities, sorry.
01:01:39Umm. You know, if if we talk about TI's
01:01:43and and vanetta clacks, umm, you know,
01:01:45those are other possibilities as well,
01:01:47but I think there's a lot of hope
01:01:48in in the triplets and I don't
01:01:51know if anyone would comment more.
01:01:54On terms of, I actually
01:01:58actually have a question to Amir.
01:02:01So there was nothing mentioned about
01:02:03immunotherapy and this malignancy is you
01:02:05know so in myeloid malignancies today.
01:02:07So what do you think is the role of
01:02:09immunotherapy in this group of patients?
01:02:12Yeah, I mean I I talked a little bit
01:02:14about Sabato, Olimov and Margaroli maybe.
01:02:15I mean I I think as immune checkpoint
01:02:18inhibitors I would put them in that category.
01:02:21But I think the other drugs we did
01:02:24not mention or approaches were
01:02:26Karti cells as well as by specific.
01:02:29So the cortices are going to be
01:02:31covered by the cell therapy talk
01:02:33which I think is later in the series.
01:02:35However, in the myeloid space,
01:02:37both of those approaches have been quite.
01:02:39Challenging mostly because of cytokine
01:02:42release syndrome and prolonged cytopenias.
01:02:45B says you can apply it as much as
01:02:47you can without and you can live with
01:02:51no immunoglobulins generally, OK.
01:02:52But in myeloid space it's has been
01:02:55a very difficult development.
01:02:58So it it remains to be seen.
01:03:00There are some phase one trials that are
01:03:02going both with Carti sales and by specifics,
01:03:04but this particular area I think has
01:03:07struggled a lot the antibody drug conjugates.
01:03:10And you could debate whether
01:03:11this is immunotherapy or not.
01:03:13I tend to think of them more as targeted
01:03:16delivery of agents rather than immunotherapy.
01:03:19I think there is more progress.
01:03:20We clearly have gemtuzumab ozogamicin
01:03:22already approved and then the CD 123
01:03:25agent that took tremendous mentioned
01:03:27and in the transplant session which
01:03:30I encourage everybody to attend,
01:03:32there is this I map drug.
01:03:35There was a just a couple of
01:03:37days presentation in the tandem
01:03:38transplant meetings.
01:03:39This is a.
01:03:40Radio immuno conjugate,
01:03:41so it's radioactive iodine conjugated
01:03:44to CD45 and there was an improvement
01:03:46in overall survival when it's given as
01:03:49part of the conditioning for transplant.
01:03:51So there is some movement with the ADC,
01:03:53but bytes and drug cartels for myeloid
01:03:57malignancies have been a bit of a challenge.
01:04:02Yep. Thank you, Amir.
01:04:03So I think we're going to wrap it up.
01:04:06Uh, uh, hematology tumor board is coming up.
01:04:08So I have to say goodbye to everyone.
01:04:10And if you guys have any questions,
01:04:12you can certainly e-mail us and
01:04:14contact us after this meeting.
01:04:19Thank you, thank
01:04:20you. Thank you everyone.