Yale ASH 2022 Highlights: Myeloid Leukemia

Transcript

• 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.