Myeloid Malignancies

January 29, 2021

Information

January 29, 2021

Presentations by Drs. Nikolai Podoltsev, Rory Shallis, and Amer Zeidan

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00:00Typically this is a CME event
00:03composed of six sessions.
00:04We already had the first session for
00:07multiple myeloma on January 15th and the
00:10lymphoid malignancy session last week.
00:12Today will be updating you on the myeloid
00:16malignancy and next week we have an
00:19update on pediatric leukemia and also
00:21adult acute lymphoblastic leukemia.
00:24February 12th will be classical or
00:26non benign hematology and we will
00:29conclude on February 19th with cell
00:31therapy and transplantation updates.
00:39So as you can tell,
00:40there are many great abstracts that
00:42are being presented in ash this year,
00:45and it's very difficult to
00:46try to cover all of these,
00:48especially with the time limitation.
00:50So here the abstracts that have
00:52been selected in this session and
00:54in the other sessions basically are
00:56chosen for their highest impact,
00:58and the ones that are most
01:00relevant clinically,
01:01especially in areas of unmet clinical
01:03need with decided to group them
01:05basically by the disease area AML MD's.
01:07And my love I almyra preffective neoplasms.
01:10Of course, that doesn't mean that
01:12the other abstracts that are
01:14not presented are not as great.
01:16It just as time limitation,
01:18and also important to remember that a
01:19lot of the abstracts contain preliminary
01:22information and preliminary data,
01:23and they have not been peer
01:25reviewed or finalize or published.
01:27So these results always have to be
01:30taken with that consideration in mind.
01:32We also like to thank all the
01:34authors of those abstracts
01:36who have shared their slides.
01:38With us for this presentation at the
01:40end of the entire Series A recording
01:42of this session and the other sessions
01:44will be available on the subsequent week.
01:47An slice of each presentation that will
01:49also be available for your review and
01:52for people who cannot make the live event.
01:55At the end of the six session series,
01:57CME Credit will be provided
01:59for those who claim it.
02:01You will have to fill a quick form and.
02:05Supply some feedback to claim the
02:08CME credit at the end of the series.
02:11So today we'll be covering
02:13the myeloid neoplasms.
02:14As you can see here,
02:15I will be updating you for Milo
02:18dysplastic syndromes then,
02:19Doctor Orish Alice will update us on
02:21acute myeloid leukemia and finally doctor,
02:23but also full update us
02:24on myeloproliferative.
02:25Neoplasm's will try to stick to
02:27the times that you can see here so
02:30that we can allow some time for
02:32questions in the last 10 minutes.
02:34We can stay a few minutes beyond one.
02:37For those of you who can stay if
02:40there are many questions as well.
02:43So I'll start with the updates
02:45on my latest ostick syndromes.
02:47So these are my disclosures.
02:50So I'm just as many of you know,
02:53their management is really highly
02:55risk adaptive.
02:56It's somewhat unusual compared to
02:57other malignancy's in which the
02:59interventions vary significantly
03:00all the way from observation.
03:02For patients with lower risk,
03:04MD S All the way to recommending
03:06a very aggressive intervention,
03:08like allogenic bone marrow
03:09transplantation for patients who
03:10have very aggressive disease,
03:12which have a prognosis almost
03:14like acute myeloid leukemia.
03:15In the most aggressive forms of Andy's,
03:18this is actually a schema from 2013,
03:20and the reason I'm showing you this one.
03:23From seven or eight years ago is be cause.
03:27Not much really has changed in
03:29the schema in the management of
03:31Andy as until last year until 2020
03:34and in 2020 we have the first 2
03:37approvers basically since
03:382006 so we had 14 years without any
03:41approvals for Andy's until 2020 when we
03:44have two drugs that have been approved.
03:46One of them is last battleship which
03:49is a transforming growth factor beta,
03:51an inhibitor disinhibits. Elegant and.
03:54This is recommended for patients who
03:56have lower risk MD's who have any
03:59meandering senior class and other drug,
04:01was an oral decitabine.
04:02An oral version of this item,
04:04in that we will be talking about,
04:06but this was also approved in late
04:092024 patients with high risk MD's.
04:12So I think it's important to start the
04:15presentation by highlighting that high
04:16unmet need for patients with high risk MD S.
04:20So these are some real life analysis
04:22that showed that despite the
04:24introduction of hypomethylating agents
04:26in for treatment for high risk MD
04:28as the outcomes or me and pull the
04:31overall responses is around 40 to 50%.
04:33However,
04:34the complete response rate is only
04:36around 15% and most of those responses
04:38are limited and most patients die
04:41from the disease relatively quickly.
04:43You can see here previous real life
04:45analysis that we conducted for patients
04:48who receive is cited in or decide
04:51to be in and you can see the median
04:53overall survival for older patients.
04:55And this was a serious Medicare
04:57analysis was eleven months while for
05:00patients who were younger and were
05:02referred to tertiary big centers in
05:04the MD's Clinical Research Consortium.
05:06The median overall survival was 17 months.
05:08So basically it's much lower than what
05:11is generally described in the literature.
05:13On 24 months,
05:14and for patients who progress after
05:16receiving those hypomethylating agents,
05:18their survival is even worse.
05:20This is an important study that
05:21was published by our colleague,
05:23Doctor to my Propay,
05:25showing that the median survival
05:27was only five months.
05:28Basically after failure of hypomethylating
05:30agents and I think all of this data
05:33highlight the significant unmet need
05:34that we should not just routinely
05:36use hypomethylating agents.
05:38But we should try to improve
05:40the outcomes of patients.
05:42So going to some of the major
05:44highlights from the ash meeting,
05:46I will start with this one.
05:48This is a drug that I just mentioned.
05:51Oral deci TB in that has just
05:53been approved in August 2020,
05:54so decide to be in the reason why
05:57you cannot give this ITB in orally
05:59is because it's highly metabolised
06:01in the gut by this enzyme.
06:03Citadine dominates as well as in the liver,
06:06so you have significant first pass effect.
06:08So what was done here in to develop
06:10this drug which is called in covi.
06:13Is to combine decided being with an
06:16inhibitor of this city in Germany
06:18is called sisters OR and the
06:21combination in phase one.
06:23Phase two trials was shown to result in
06:26similar pharmacodynamic and pharmacodynamic.
06:30Activities to the Ivy decided mean,
06:32so this combination was taken to a phase
06:35three trial that looked at pharmacokinetic
06:38equivalence as a final end point,
06:41and this trial was presented in 2019
06:44and you can see A at the bottom.
06:47The final conclusion, which you have 99%
06:50equivalence pharmacokinetic equivalence
06:51between oral and Ivy decitabine.
06:53However, the follow up from this study was
06:57somewhat limited and an important update.
07:00Was presented in the American side of
07:02hematology meeting this year by Doctor
07:04Savona, and this trial is actually a trial.
07:07We participated in an many
07:08of you in the care centers,
07:10have refer patients for us,
07:12so we thank you for that.
07:14So the update from the certain study
07:16showed that the complete response
07:18rate was around 22% and the median
07:21overall survival after median follow
07:22up of 24 months has not yet been
07:25reached and the median duration
07:27of best response was 12 months.
07:29So I think well.
07:31The follow up still needs to be longer.
07:34It's important to know that for now it
07:37seems that oral version of Decitabine is
07:39very similar to how we decide to be in,
07:42and I think we have a lot of data
07:44now suggesting that it can be
07:46completely replacing the IBD side
07:48been as monotherapy for Andy's.
07:50And on this note also I like to
07:53highlight that many of you are aware
07:55that there is an oral version of is
07:58cited in the CC-486 or on your leg.
08:00That has been approved,
08:02but this is was only approved
08:04in AML on your egg Aurora.
08:06Laser sighted in is very different in
08:08pharmacokinetics. Ann for Neko Dynamics.
08:10Then I be decided in an.
08:12I'm sorry.
08:13Then Ivy is exciting in and therefore
08:16should not be used in MD as its only
08:19approved for AML and I think it should
08:21be used only in that sitting and
08:24AML only in the maintenance setting.
08:26After achieving remission with
08:27intensive chemotherapy and not as
08:29a replacement as monotherapy or.
08:31In combination with Venator class
08:32so this is important to note.
08:35I think another combination that's
08:36attracting a lot of attention as
08:38a combination of hypomethylating
08:40agents with Veneto class.
08:41So this is an update that was
08:43presented by Doctor Garcia and her
08:45colleagues in the frontline setting,
08:47so this is a phase One piece study
08:49that looked at combination of SSI tied
08:52in with Veneto class and this is a
08:54single arm study and they provided an
08:57update here in around 78 patients and
08:59what you can see is a very high CR rates.
09:02So the CR rate is around 40%.
09:05Remember that the CR rate would is cited in.
09:08Monotherapy is only around 15%
09:10to 20% at best and the overall
09:13response rate is around 80%.
09:15The responses,
09:16as you can see,
09:17sorry for that responses were durable
09:19around 13 months and the median follow up
09:22on the study was somewhat short 16 months,
09:25but the survival so far,
09:27especially for those patients
09:29who have complete responses,
09:30appear quite significant.
09:31However, I think these data are important
09:34to take into consideration still early.
09:37A single arm. We don't have randomized
09:39data and we have many drugs that
09:41shown excellent data as monotherapy,
09:43but when they went to randomized
09:45setting they did not basically show
09:48improvement in overall survival and
09:50I think This is why it's important
09:52to wait for the randomized data
09:54before this could be used as a,
09:57you know a setting in like in routine clinic.
10:01Practice.
10:03Another I think important study is the
10:06one we conducted here at at at Yale in
10:09collaboration with many other centers.
10:11And we also provided an update from this data
10:14in the American Society of Hematology here.
10:17The other side in and venetoclax were used
10:19in the relapsed or refractory setting,
10:22and as you can see,
10:23the response rate is around 40% total.
10:26Around 7% of those have complete responses,
10:29but many of those who have more
10:30complete responses also achieved
10:32significant hematologic improvement
10:33transfusion independence of.
10:35Latest on blood.
10:36As you can see.
10:37So there are significant clinical benefits.
10:39But also as you can see on the right side,
10:42the median overall survival
10:44of all patients was 12 months,
10:46which compares favorably than the four
10:48to six months that I showed you earlier
10:50in the typical refractory relapsed MD
10:53S setting and even patients who have
10:55more OCR have significant survival.
10:56As you can see with 15 months.
10:58Again,
10:59this is single ARM study,
11:00not randomized,
11:01and I think we need more data before this
11:04could be used in routine clinical practice.
11:07There are important differences
11:08in how financial classes used
11:10in real life setting or for Andy
11:12as compared to AML for example.
11:13And both of those studies,
11:15Veneto class was given only for 14 days,
11:17not the 28 days that are given in AML.
11:20And that's important because MTS
11:22patients might not tolerate the same
11:24degree of myelosuppression that their
11:26male patients who tend to be somewhat
11:28younger than on average and MD's patients.
11:30So we have now around a nice face retrial.
11:33The Verona trial,
11:34which is looking at,
11:35is cited in versus cases cited in with
11:37venetoclax in the frontline setting
11:39among patients with high risk MBS and
11:41this study is going to open at Yale.
11:43We are also opening at a number of
11:46daycare centers and I encourage you
11:47to enroll patients on it to see if
11:50this setup we actually will change the
11:52standard management of high risk MD's.
11:55Another update that was prevent presented
11:57in the American state of Mythology
11:59meeting was on this drug people,
12:01and it is that which is the 1st
12:03in class need it inhibitor.
12:05So this this is an upstream of the
12:08proteasome and it was shown in
12:10early phase trials in combination
12:11with their society into lead to
12:14improvement and responses.
12:15This trial randomized patients,
12:16but this was a randomized phase two
12:19trial in which not only patients with
12:21MD as but also patients with illegal plastic,
12:24AML and CML were randomized to receive.
12:26Cited in alone or as a sighted in with
12:29people needed stat and this trial also
12:32was actually open here at at year and what
12:35you can see here or the subgroup analysis
12:37of the patients who had higher risk and
12:40the S which were a total of 67 patients.
12:43This paper this this was just also
12:45published in Leukemia Journal.
12:46What you can see is that there was like a
12:49marginal improvement in event free survival,
12:52But the primary endpoint of the study
12:54the overall survival was not improved.
12:56And I think most notable here is
12:59that the overall response rate,
13:01but especially the CR rate,
13:03was significantly higher with
13:05the combination compared to the
13:08monotherapy and was more durable.
13:11There is a phase three trial of the same.
13:14Basically, design of P1 is a sighted
13:16in compared to azacitidine alone.
13:18This trial,
13:19actually called the Panther trial,
13:21has fully accrued and we expect
13:23results from the study soon.
13:24So I think this also could potentially
13:28be a practice changing if the
13:30if there is us are posted.
13:33How about immunotherapy?
13:34Many of you use like immune
13:35checkpoint inhibitors such as anti PD,
13:37One PD, L1,
13:38CLU for routinely for management
13:39of solid tumors,
13:40we've been trying to use these drugs
13:43for some time now in high risk MD ASAN
13:45myeloid malignancy really and so far
13:47a lot of the data has been single arm and.
13:51A single center data.
13:52This is what I'm showing you is a
13:55presentation from ASH 2019 in which
13:57we showed with colleagues from other
13:59centers in a randomized phase two
14:02study that the combination of is
14:03cited in with the anti PDL one door
14:06volume app which is approved for
14:08several solid tumors did not improve
14:10outcomes compared to other sighting.
14:12However I think this is probably
14:16just related to PD L1.
14:18And does not extend necessarily to other
14:20classes of immune checkpoint inhibitors.
14:23And on that note,
14:25another immune checkpoint inhibitor
14:27called sabatella mob or MPG 453.
14:30Is basically being studied in
14:32combination with hypomethylating agents,
14:33not only for high risk MD's,
14:35but also for AML patients and the
14:38data from what was presented in
14:40in ash this year showed this is a
14:43single arm again phase one study,
14:45but it showed the CR rate of 23%
14:48which is slightly higher than
14:50what you expect with monotherapy,
14:52but the overall response rate was 64%,
14:55and what you can see on the right hand
14:57is that there was encouraging durability.
15:01Of the combination,
15:02especially with patients who have
15:04long or very high risk disease,
15:06and I would note the side effect
15:08profile here it does not seem to add
15:11myelosuppression to the exercise again alone,
15:13and also importantly,
15:15the incidence of immune related
15:17effects seems to be low with this.
15:19With this particular agent,
15:21so appears on this data.
15:22There are ongoing several study.
15:24We just completed a cruel to a randomized
15:27phase two study in higher risk MD S of.
15:31Is there with the battle map versus
15:33is alone and this study is completed
15:35accrual and we expect the results
15:38in the next one to two years.
15:39There's another face retrial
15:41that will open here as well.
15:43Called the stimulus MD S2,
15:44which is a randomized phase three
15:47of the same combination is with
15:49the battle map versus Asia and we
15:51have our as well a frontline study
15:53with a 7 is events a battle map.
15:55All of those are open at at
15:58yet another interesting immune
15:59checkpoint inhibitor is the CD 47.
16:01Anti CD 47. They don't eat me.
16:04Signal inhibitor mag rolling up
16:06what was presented in ash this
16:08year was an update and what the
16:10authors shown the significant plus
16:12reduction among all patients.
16:14But the data was most impressive in
16:16patients who have TP 53 mutations
16:18in which the median overall survival
16:21among patients who had TP 50.
16:22Three was 12 months,
16:24which is higher than what we
16:26typically expect it to nine months.
16:28Generally in patients who have this mutation.
16:31So this drug now is being studied.
16:33In a randomized trial called
16:35the enhance in high risk MD's
16:37whether they have TP 53 or not,
16:39magherally map with laser versus is alone,
16:42but also there are efforts to study it in
16:44acute myeloid leukemia patients as well,
16:46especially those with TP 53.
16:49This is a transplant
16:51abstract and as I mentioned,
16:52there is a separate transplant
16:54presentation that will happen
16:55at the end of the series,
16:57but I just wanted to highlight
16:59this the conclusion from this
17:01because this is in my view,
17:02one of the most important abstracts
17:04from this ash becausw it showed
17:06in a randomized trial data,
17:08so here this was randomized.
17:09All the data that we have about MD's
17:12improving survival in high risk MD's
17:14patients compared to hypomethylating
17:15agents alone is based on Markov
17:17decision analysis and modeling,
17:18but this is the first randomized
17:20trial to actually show.
17:21An absolute improvement in overall
17:23survival and the three year survival
17:26for donor versus no donor arm.
17:28And I think what is very important is this
17:31study allowed patients after the age of 75.
17:35And this is important to get out there,
17:37that because we still see patients who
17:39are like 72 who come to us very later
17:42there and their scores and being told
17:44they were not candidates for transplant.
17:46So I think it's important to know
17:48that even patients up to the age of
17:5075 could be considered for curative
17:52therapy and they should be re ferd
17:54for big Centers for clinical trials
17:56as well as transplant consideration
17:57in the last couple of minutes.
17:59I will talk about lower risk MD's
18:01as I mentioned was partnership has
18:03been approved after ESA failure.
18:05For patients who have RingCentral
18:07plastic anemia from lower risk MD's now,
18:09this drug is being studied in the
18:12frontline setting in the commands trial,
18:14so this is it's being studied compared
18:16to low Earth roelle powerton and
18:18this or a potent procrit and this
18:21is in the frontline setting and regardless
18:23so whether you have ringstad or plus or not,
18:27you could be randomized to either a
18:29proton or low spatter set and this trial
18:32is open in the care centers as well.
18:35So many of you will be able to enroll in it.
18:39Another interesting drug is the emitted step,
18:41which is the 1st in class telomerase
18:43inhibitor which has been shown also
18:45to improve transfusion independence.
18:46Regardless of having RingCentral Plus or
18:48not and some of those responses which
18:50occur in 42% of patients were at durable.
18:53Now we have actually an open study here.
18:55The High Merge study the phase three
18:57so this is a randomized study after
19:00he has a failure so frontline we have
19:03the commands in lower risk and be as.
19:05Refractory, we have the Hymer study
19:08for patients after failure of PSA
19:10in which patients are randomized to
19:12him until a stat versus placebo.
19:14In the last minute I wanna show you
19:17another like non interventional study
19:19that we did in patients with MD S who
19:22have lower who have anemia and as you
19:25know one of the open questions in MDSS.
19:28When do you transfuse patients with
19:30MD S and many people use different
19:32cut off seven or eight of hemoglobin?
19:35Here we used verified quality of life
19:37instrument in a investigator initiated
19:39effort led by Doctor Go in Table.
19:42Go on Dana Farber.
19:43And we looked at the quality of life
19:46improvement before and after transfusion
19:48and what we have shown is that most
19:51patients 2/3 of patients did not
19:53experience an improvement in their
19:54quality of life after transfusion.
19:56So I think that puts into question
19:59our practice of Troy.
20:00Using patients based on hemoglobin
20:02cut offs of aid,
20:03and I think it's important to try
20:05to study this in more extensive
20:07sitting about what is the right cut
20:10off for transfusions in,
20:11especially in the outpatient setting.
20:13For patients with ambius rather than
20:15using random cut offs of hemoglobin.
20:17So this is my last slide and I will
20:19give the floor now to my colleague
20:22Doctor Rory Challis who will update
20:24us on acute myeloid leukemia.
20:26Updates from the ash.
20:27Thank you and we'll be happy all
20:30of us will be taking questions.
20:32At the end of that seminar at 12:50,
20:34thanks.
20:52OK, How are we looking?
20:54Every seeing a full slide who
20:56screens two screens again? Sorry.
21:00Standard technical difficulties.
21:07Yeah, I think you need to swap your
21:10screens. Let's try this again.
21:15Yep. How's that? That looks good,
21:18not yet ticket.
21:21Yes.
21:23Looks good.
21:25You're seeing one. Yes, one scream.
21:27You're good to go alright? Do this by then.
21:32Sorry bout that.
21:35OK.
21:38Alright one screen we're good to go so.
21:43Thanks for the introduction.
21:45I'll be specifically focusing on
21:48the highlights presented this past
21:50meeting as they pertain to AML.
21:53I have no disclosures, so.
21:57Again, you're still seeing one screen, right?
22:01OK, it's a bit hard to really focus
22:03in on really a select few updates
22:06from an entire years worth of.
22:08I would say progress in the field.
22:12So I'll try to really focus on agents
22:15with which we already have some
22:17familiar that Phillip familiarity,
22:19but also some new combinations or regiments,
22:21some of which you can guess we're
22:24going to include the BCL two
22:26inhibitor of medical acts.
22:27All of these are all the studies
22:30I'll be discussing are going to be
22:32interventional of only really try to
22:34give some minimal background so it's
22:37really focused on the updates themselves.
22:39So jump right in.
22:41As many of you are.
22:43Aware Gilteritinib is a
22:44flip through inhibitor,
22:46which in the Admiral trial was shown
22:49to improve survival when compared
22:51with classical salvage chemotherapy
22:54in their refractory setting.
22:56So its approval for such over
22:58the outcomes for these patients
23:00treated with guilt,
23:01or it never guilt are still quite poor.
23:04The preclinical data does support
23:06some synergy when Gilteritinib is
23:08combined with a BCL two inhibitor
23:10and those data prompted the launch of
23:12the trial that I'll be talking about.
23:15In brief, you can see here,
23:17so this was done in the context of
23:19the following trial schema patients,
23:21as you guessed it,
23:23had relapsed refractory disease,
23:24including wild type patients.
23:26In the dose escalation phase,
23:28without you know, a low white counts.
23:30They really had controlled proliferation.
23:32They received standard phonetic lacks
23:344 milligrams in combination with
23:36either guilt 80 or 120 milligrams,
23:38which the latter of which is the
23:40standard dose that was studied in Phase
23:433 testing, and this was later expanded,
23:45so the demographics were,
23:46for the most part, I would say,
23:49expected with regards to age,
23:51set of genetic risk given the inclusion
23:53criteria that I mentioned before,
23:55a majority of patients.
23:57Did have ITD mutations?
23:59Of note,
23:5965% of patients received prior
24:01therapy with the flip three inhibitor
24:04and a third enrolled after they
24:06had a relapse after allogeneic
24:08metaplastic stem cell transplantation.
24:11All patients experienced an adverse
24:12event in nearly all grade three,
24:15with unsurprisingly, was being cytopenias.
24:17You know,
24:17given the combination with medical access,
24:20you know a very well known Milo
24:22toxic amount suppressive agent,
24:24but perhaps some contribution of guilt.
24:26And as well,
24:27three patients were reported as having
24:29laboratory tumor lysis syndrome with
24:31only one of these having clinical TLS,
24:34only 60% of patients,
24:35at least as of last follow-up,
24:37discontinued the drug due to adverse events.
24:41Of note,
24:41no patients died within a month of dosing,
24:44but six died with up to 60 days out.
24:49Amongst 41 amongst 41 adult patients,
24:52only three achieved CR or 7% specifically.
24:55However,
24:5627% of patients achieved a
24:58less than CR remission,
25:00which here was inclusive of CR or CR P.
25:04Half of patients achieved MFS or
25:07morphologic leukemia Free State again,
25:08in the context of the Netflix
25:11related mileage suppression.
25:12Amongst responders,
25:13the median time to response was one month,
25:16but best responses were
25:17observed up to four months out.
25:19No more could differences in
25:21response or the types of response
25:23for that matter were apparent after
25:25accounting for prior flip three
25:27inhibitor exposure other than maybe
25:29a little less or chance of CR.
25:31As you can see here,
25:337.3 versus one quote versus 3.6%.
25:37The median overall survival for
25:39the overall cohort was 12.3 months
25:41and specifically not reached,
25:42including an unreached lower limit of
25:44the 95% confidence interval for ITD patients.
25:47Clear differences in survival were
25:49noted based on prior filter exposure,
25:51so I would say in some the addition of
25:53attacks appears to augment the efficacy
25:56of of guilt monotherapy in this situation,
25:59which based on the Admiral
26:00trial I had mentioned before,
26:02predicts a median survival
26:04around 9 nine and a half months.
26:07This is at the expense of near
26:09double hematologic toxicity,
26:10which I think we can all agree is
26:12attributable to the phonetic LAX,
26:14but of course.
26:15Just heating some caution and saying
26:17it appears to increase the efficacy
26:19outside of a randomized clinical trial,
26:21so this isn't of course need
26:23to at least confirm this.
26:25This likely benefit here.
26:28Jump into the next update.
26:29I have 40 or so older patients with AML.
26:34Have generally a poor outcomes,
26:36but there there is some variance
26:38noted to improve these outcomes.
26:39Ventures like the following are underway,
26:42so next I'd like to discuss the
26:44interim results of a striking study
26:46of cladribine and lodosa Terrapin,
26:48which is essentially a double
26:50nucleoside backbone and Aza,
26:51both with the addition of an ethics course.
26:54The double clad plus Ldac backbone
26:56has been previously studied this.
26:58This isn't showing here in this
27:00slide with alternating decide to be
27:02as treatment for newly diagnosed.
27:04Older patients with AML and this led to
27:07a composite CR of 68%, including CR 50%.
27:11Quite quite nice with a median
27:13OS of well over a year.
27:15It appears 14.8 months with quite low
27:18for an 8 week rates of mortality.
27:22So this is the actual trial.
27:24This scheme is a little complex,
27:26but essentially like I mentioned,
27:27older,
27:28newly diagnosed patients with AML
27:29received clad plus ldac with van with.
27:32As you can see here,
27:33the standard dose reductions for
27:35CYP 3A four inhibitor use receive
27:37this for cycle one,
27:38with cycle to being the same three
27:40drugs but less clad and a little bit
27:43less fanatical acts with cycle three
27:45switching the nucleoside backbone
27:46for Asia on the standard schedule,
27:49again with phonetic lacks for 14 days,
27:51similar to cycle two.
27:52So basically patients received.
27:54Part A,
27:55as you can see here and they can move.
27:57I don't.
27:58I don't know how to use a
27:59highlighter or whatever,
28:00but patients received a * 2 then
28:02B * 2 and then back and forth back
28:05and forth for up to 18 cycles.
28:08So here the patient characteristics
28:10as of the first day to cut of
28:13note 40% of patients for older.
28:16Sorry older than 70 years,
28:1825% were had disease characterized
28:20by porous I,
28:21genetics ANAN would be would be
28:23generally expected given this population,
28:25although nearly half were ellenor
28:28European leukemia net poor risk
28:30after accounting for the relevant
28:32molecular features on top of genetics.
28:35Amongst the 54 patients that
28:38today have been accrued and are
28:40in fact invaluable with a median
28:42one cycle or month to responses,
28:45striking 78% achieved CR and basically all
28:48except three achieved MFC MRD negativity.
28:50Basically,
28:51MRD negativity negativity by flow
28:53centric analysis including CRIA
28:55composite CR rate of 93% was
28:57rendered which is simply amazing and
29:00perhaps I really should have saved
29:03this safest route for the end so.
29:05One of the more striking updates from
29:08ASH with regards to the response rates.
29:10However,
29:11it's not all about response rates
29:13for the patient not proceeding
29:15to cure to therapy,
29:16really care bout event based outcomes
29:18like survival in evaluating survival
29:20and a medium median of 14.2 months.
29:23The OS and RFS curves were
29:25essentially the same,
29:26meaning OS was reached was not reached.
29:28Sorry,
29:29and 60% of patients were still alive at
29:31two years after starting therapy again.
29:34Quite amazing considering the
29:35fact that half of patients were.
29:37Yellen adverse risk. Sorry
29:39hadelin adverse risk disease.
29:43However, this is just some.
29:45You know, some smaller kind
29:46of subpopulation analysis.
29:48You can see that when accounting for
29:50set of genetic risk and Dylan risk,
29:53not surprising differences
29:54are in fact observed.
29:55I would note that 11 patients
29:58or 2524% of the 45 responding.
30:00Patients proceeding to
30:01transplant with these patients,
30:03patients really enjoying more
30:04than 90% survival at one year,
30:06which when compared with the
30:08folks not getting to transform
30:10with 69% but a difference,
30:11did not reach statistical significance.
30:13Likely in the setting of just,
30:15you know,
30:16obviously a small early phase study.
30:20So just going to switch
30:22gears a little bit with AML,
30:24one of the first decision we have to
30:26make is whether patient is quote unquote
30:28intensive therapy eligible or not.
30:30The first 2 trials I mentioned were
30:32really geared towards patients that
30:34are intensive therapy ineligible.
30:35But what about patients receiving
30:37intensive therapy generally felt to be
30:39the standard of care for those who are
30:41eligible with some specific exceptions?
30:43Of course if prompted debate,
30:44but that's a discussion for another.
30:46Another presentation.
30:47Here is the schema for a trial also
30:50out of MD Anderson and evaluating
30:52the addition of genetic lacks.
30:53To CPX, 3/5 one or the brand name
30:56being fix EOS which is standard of
30:59care for patients with AML MRC and
31:02therapy quote unquote related AML.
31:04The design included cohort for adults with
31:07newly diagnosed AML as well as looks.
31:09Factory disease, with the latter
31:11allowing prior phonetics exposure.
31:12Quite important criterion.
31:13A dose escalation phase or safety
31:15run included.
31:16Of course, all the patients,
31:18irrespective of whether they
31:19were Dinovo slash,
31:20newly diagnosed or realtor factory.
31:24Of note CPX 3/5 one was given
31:26at the standard dose on label.
31:28Essentially event began fairly
31:29quickly on day two with a three day
31:32ramp up to a target dose of 400,
31:34again with the standard dose
31:36reductions you would expect or should
31:38be considering with concurrency 3A
31:39four inhibition as well as toxicities
31:41prompted prompting dropping to
31:43lower dose levels as they came up.
31:45Essentially this was then was given for
31:47three weeks during induction as well
31:49As for 20 three weeks during each cycle.
31:51Consolidation.
31:52In this case they allowed up to four cycles.
31:55Of consolidation,
31:56in contrast to the standard on label CPX 351.
32:01Monotherapy consolidation.
32:03Here the characteristics of the
32:05patients who had a broad range
32:07of age instead of genetic risk,
32:08I'll call your attention to the right
32:11where you can see that 30% of patients
32:13had disease characterized by the
32:15presence of a TP 53 mutation and after
32:17including ASL one and runx one mutations,
32:20the majority of patients did in fact
32:22have guillain adverse risk disease.
32:26Only 6% of patients achieved CR,
32:28but CR CRA was the rate of CRC.
32:31I was 39% still fairly low with a
32:34median one cycle time to response.
32:37The most common reason for coming off of
32:39study was actually proceeding to transplant.
32:42This occurred in 31 patients were but
32:45generally 50 half of the patient population.
32:48The most common grade 3 plus
32:50ease were human logic in nature,
32:52pneumonia amongst other infections didn't.
32:55Did also occur 30 and 60 day
32:58mortality were weren't nominal
33:0010% at 30 days and 20% at 60 days,
33:04so a fairly toxic regimen with again
33:07relatively limited efficacy in comparison
33:09to the other guys I've presented.
33:13The median overall survival was six months
33:15with a 6 month OS rate of about 53%.
33:18Just to be specific and 46% at one year.
33:22So not terribly different.
33:236 versus 12 months among responders,
33:25the median OS and RFS were not reached,
33:28and the six month OS and RFS
33:31were essentially about 8590%.
33:32You can see that patients without
33:34prior medical exposure did better.
33:36However, again, given the small numbers,
33:38this did not reach statistical significance.
33:42Sticking with this is another trial.
33:44Sticking with intensive therapy
33:46eligible patients.
33:47What about adding then to other
33:49intensive backbones beyond CPX 351,
33:51here's a schema which demonstrates that
33:53patients with both newly diagnosed
33:55disease and relapse refractory disease
33:57received a fairly standard flag.
33:59Ida regimen and dosing with Medical X added,
34:02especially specifically during days
34:03one through 14 at a target dose
34:06of 400 in standard target dose,
34:08but not without a ramp up and then high
34:11debt consolidation had been incorporated.
34:14Days one through 14.
34:16So a complex slide,
34:18but hopefully that kind of summed it up.
34:20Here are the patient demographics or sorry
34:23patient characteristics specifically,
34:24noting that the relapse refractory
34:26cohorts were a bit more enriched
34:28for adverse risk disease.
34:29And as you would otherwise expect and
34:3238% had received prior allogeneic
34:34Amanda poetic stem cell transplant.
34:38The toxicity was what you would
34:40expect with intensive therapy and
34:42addition of class including based on
34:44what I just presented. For C PX351.
34:49CRC is 90% and in the newly diagnosed cohort
34:5360 to 75% in the roaster factory cohorts.
34:56So and fairly good rates of MRD negativity.
35:01And this is essentially just looking at at.
35:05Based on their their disease,
35:06the disease cohort specifically.
35:08So I'll just kind of wrap it up
35:11with just promise two more slides.
35:13So those updates for therapies
35:14we already had.
35:15But what about just one update
35:17on an agent or regimen?
35:19We do not yet really have.
35:21This is Google Map or the this
35:24is the humanized anti CD.
35:2547 IgG, four monoclonal antibody
35:27product from from Gilead Sciences,
35:29relevant as tumor expression
35:30of CD 47 prompts evasion from
35:32an 80 minute survaillance.
35:33Specifically macrophage mediated.
35:35Microcytosis and in fact pre
35:36clinical data support that AML,
35:38leukemic blast doing factor,
35:39or enriched for CD 47 Express expression.
35:41So this was studied in combination
35:43with Asia and a phase one.
35:45B2 trial that armored actually touched on
35:48earlier most in the context of high risk
35:51MD S but I'll just focus on the AML cohort.
35:55Specifically,
35:5590 except sorry,
35:5670% porous surgeon attics 70% P
35:59three mutations with a robust
36:00median vaf which would otherwise
36:02predict biallelic loss of function.
36:05So essentially a very,
36:06very,
36:07very poorest population and not the
36:09toxicity profile was generally what
36:11you would expect with as a monotherapy
36:14other than I'd say a mild transient
36:17on targeting me that was reversible.
36:19Know whether grade 3/4 plus 80s
36:21and no immune related AE's given
36:24macros mechanism of action.
36:26This is a slide hammer showed
36:28you this is the AML cohort,
36:30essentially a 20% rate of see better
36:33in comparison to generate 20%
36:35rate of expected as a monotherapy.
36:3760 ish percent,
36:38essentially with essentially
36:39in the waterfall plot.
36:41Here nearly all patients experiencing
36:43Meryl Blast percentage reduction
36:44with many being robust reductions.
36:46The median OS at last day to cut
36:48off of patients in the trial was
36:5118.9 months and even after isolating
36:54patients that had a P3 mutation.
36:56And we still 12.9 months,
36:58which to be honest is the longest
37:00median OS I believe ever reported
37:02for this population,
37:03so quite striking as you can see,
37:05four or five patients are still
37:07alive more than two years out,
37:09so quite impressive.
37:10So I am a little bit over and
37:13I apologize to Nikolai.
37:14Mostly this is raw,
37:15conclude my section and look
37:17forward any questions at the end.
37:19So next I'd like to introduce
37:21Doctor Nikolai Pedulla civilly
37:22discussing the ash 2020 updates
37:24in there almost perfect NPS.
37:29Alright, thank you Oriel let
37:31me share my slides with you.
37:34How does it look?
37:35Does it look like one screen?
37:41We don't see slides head.
37:43Sadly you don't see slides OK,
37:45just a second. We just see you.
37:48Oh interesting. Alright,
37:50so hold on let me escape from here.
37:53And so I'll do this. How about now?
37:58Do you see two right and I need to swap?
38:02No, we still don't see them.
38:04You don't see them.
38:15Did you share a video girl OK?
38:19Yep, now we see alright.
38:21You see this one slide right?
38:24Alright, OK,
38:25alright so I'll be talking about.
38:28Milo proliferative neoplasms and I had to
38:31be selective because of the time frame,
38:33so this are my disclosures.
38:36I'll go over 4 studies and the first
38:38one was presented as a late breaking
38:41abstract is not the interventional study
38:43I thought would be important to mention.
38:46I just have one slide about it.
38:48This is about driver mutation,
38:50acquisition in pH, negative MPs,
38:52and this study managed to show that this
38:55mutations are quite as early as in utero
38:58until disease develops decades later.
39:00So the goal of the study was
39:02timing of driver, mutation,
39:04acquisition,
39:04and clonal expansion evolution
39:06dynamics of the clones.
39:08The methods used by UK investigators
39:10included studying 10 patients with Jack.
39:13Two mutations of this is Jack
39:16two mutation for Stevens.
39:17This patients were between H20 and 76.
39:20The single cell derived
39:22hematopoietic colonies were studied
39:24using whole exome sequencing.
39:26There was targeted resequencing of
39:28longitudinal blood samples from the
39:31stem patients and something which
39:33is still not clear very clear to me,
39:36but they were able to create those.
39:39Polygenetic trees or of hematopoiesis,
39:41allowing them to understand when
39:44initial driver mutation occurred
39:46as the result it was found that
39:49mpanza originate from driver
39:51mutation quite very early in life,
39:54including before birth,
39:55and then there is lifelong
39:57clonal expansion and evolution.
39:59So this.
40:00Results are quite amazing because they
40:02tell us that this Jack two mutation,
40:05which eventually leads to
40:07development of MPN late at life,
40:09is present in utero and perhaps if we can
40:13understand how it develops and evolves,
40:15we may use some preventative strategies
40:18in the future to prevent expansion
40:20of this clone or its evolution.
40:23Moving onto interventional studies,
40:25first of all,
40:27I will talk about CML and again
40:30another late breaking abstract second.
40:33I will talk about one study using
40:36new drug for Milo fibrosis patients,
40:40and finally I'll finish with
40:42the study for PVR patients.
40:45So the second study I would
40:48like to talk about looked at a
40:52synonym also known as able 001.
40:55This is the first class stamp inhibitor.
40:58An stamp is specifically targeting the
41:01Belmira stole pork it so its allosteric BSL,
41:05one BSL BCR ABL one inhibitor
41:07which is different to advertising
41:10kinese inhibitors which targeting
41:12ATP pocket on April 1.
41:15So as you can see on the cartoon
41:18from New England Journal Medicine
41:20article discussing Phase One
41:22results with this medication.
41:25There is Mr Lated and terminal
41:27which auto inhibits able one
41:30an with BCR ABL translocation.
41:32This N terminal piece of.
41:36Peace is gone,
41:37so you have PCR and now there is
41:40no auto inhibition and there is
41:44constitutive activation of ABL kinase
41:46Aciman app targets that fork it and
41:49can allosterically inhibit PCR able?
41:52So as you can see,
41:54the other tiki eyes we have currently
41:57in practice and use in practice
42:00go to ATP binding site and the
42:03Aciman app actually affects able
42:05one kinase inhibits able one kinase
42:08using this mirror style pocket,
42:10hence the name specifically
42:12targeting the able Morris to pocket.
42:15So it works even when mutations
42:18like T315Y inhibit ability of the
42:21tiki eyes to inhibit able one.
42:23Like in this particular situation,
42:25in the cartoon you can see that
42:27the teising kinase inhibitor
42:28cannot attach to the pocket due
42:31to change of its confirmation,
42:33but a synonym still able to attach to
42:35Bristol Pocket inhibiting able one kinase.
42:38So this is a phase three study was
42:40Simonette versus Design IP in patients
42:43with chronic phase CML previously
42:45treated with at least two tiki eyes,
42:47two different guys and this is
42:49an important study because the
42:51drug is now undergoing review
42:53for approval and I'm hoping that.
42:55It will be available as yet
42:58another medication to treat chronic
43:00myeloid leukemia later this year.
43:03So the selection criteria listed and
43:06patients were included had chronic
43:08phase two or more GIS used before
43:11and patients have to change treatment
43:14either because they were intolerant
43:16or resistant to treatment and so
43:19the patients was 2315 I mutation
43:21or V299L mutations were excluded
43:24because pursuit Nip is not.
43:26Active against this mutation.
43:28So this is specifically the study which
43:31didn't include T315I mutated patients.
43:34This particular group of patients was
43:37addressed by the Phase One study and
43:40the drug is active against the BCR
43:43ABL with this particular mutation,
43:45so patients were randomized.
43:47As you can see in two to one fashion,
43:51and the demographics were slightly
43:54different in two groups I highlighted.
43:57In yellow here that a similar patients
43:59there were more men than women.
44:02Also in a similar patients,
44:04the switch of therapy was less likely
44:06to be due to lack of efficacy and more
44:09likely due to be taller ability and
44:12that basically is characteristic of
44:14a group of patients which may be more
44:18responsive to the next line of treatment.
44:20And finally also in a similar barm
44:23less patience than in pursuit.
44:25Newbomb received three or more tikis.
44:28So this is the primary endpoint of
44:30this study which showed improved
44:32major molecular response rate at
44:3424 weeks at six months,
44:36and the difference between two
44:39groups was twelve point 2%.
44:41So taking into consideration the
44:43differences between two groups I
44:45showed on previous slide that the
44:47logistic regression analysis was done
44:49and showed that odds ratios adjusted
44:51for those things which were different
44:53in two groups were quite similar
44:55towards ratios without adjustment,
44:56which gives us hope that the improved
44:59outcome in a similar treated patients
45:01is not related to the difference
45:03in the population.
45:05So the side effect profiles a lot of
45:08patients get different side effects,
45:10but overall a similar patients have less
45:12side effects than positive treated patients.
45:15One thing I would like to highlight
45:17here that a similar group there
45:19were two deaths related to arterial
45:22embolism won an ischemic stroke.
45:24Another Iman positive patients.
45:25One patient died due to septic
45:28shock, so the side effect profile was
45:30different, so anemia and thrombo cytopenia.
45:33Sorry, Trump said opinion neutropenia were
45:35similar in both groups and then GI side
45:38effects in the left abnormalities were
45:40more common in bosutinib treated patients.
45:43So in conclusion, this assemble
45:45study was the first control study
45:48comparing tikis for treatment.
45:50Assistant Intolerant CML
45:52population and assimilate,
45:53which is first class stamp inhibitor,
45:56showed superior efficacy compared with
45:59bosutinib with favorable side effect profile,
46:02so this is upcoming hopefully.
46:06Approved in the near future
46:08treatment option for CML patients,
46:10particularly with resistant and
46:11intolerant disease.
46:12After treatment with two different guys.
46:15Also, the drug is effective in
46:17treating patients with T315I mutation,
46:19so moving on to the next study.
46:21I wanted to present today you will understand
46:24towards the end why pick this particular one?
46:28There are a number of drugs where there
46:30are a number of drugs being developed
46:33in patients with myelofibrosis.
46:35I think they're up to 10.
46:38A phase three randomized phase
46:40three studies in this field.
46:43So this particular study presented
46:45by John Mascarenhas is about CPI,
46:480610.
46:49Bromodomain angusta terminal domain
46:51protein or BET inhibitor in combination
46:54with reflective for Jack inhibitor naive
46:57Milo fibrosis patients or manifest study.
47:00So one word about bet so bromodomain and
47:04extra terminal domain protein promote.
47:08Symptoms of Milo fibrosis by
47:10activating bet targeted genes leading
47:12to increase production of cytokines
47:15responsible for inflammation,
47:16extramental hematopoiesis,
47:17and bone marrow fibrosis.
47:19All manifestations of patients with
47:22primary myelofibrosis as well as
47:25modify process after PD and 80 so the
47:28other influence of bat is activations
47:31of target genes leading to aberrant
47:34erythroid differentiation as well as
47:36aberrant megakaryocytic differentiation.
47:38And this patients may have an email.
47:40Thrombocytopenia,
47:41as you know.
47:42So CPI 610 inhibits bat and may suppress
47:45cytokine production as well as promote
47:47erythroid differentiation as well as
47:50normalized megakaryocytic differentiation.
47:51So let's see how this drug
47:53did in this phase two studies.
47:56So first of all,
47:57the study had three arms,
47:59so they are mine going present.
48:02Today's I'm three which looked at Jack
48:04inhibitor naive patients and use the
48:07combination of CPI 610 and Rosslyn.
48:09If the other two arms were add on CPI,
48:12six dental clinic patients
48:14who didn't have full benefit.
48:16From Brooklyn balloon treatment
48:18and monotherapy with CPI,
48:200610,
48:20this study was also presented as an
48:23abstract as a poster during ash meeting,
48:26so I'm three,
48:27basically Jack inhibitor naive Milo
48:30fibrosis patients who need treatment.
48:32They received two drugs,
48:33rock Solid Nap standard of care but
48:36in additional CPI 0610 better hitter.
48:39So this drug better hitter was
48:42administered two weeks on two weeks,
48:44one week off and.
48:47The endpoints which we were looked at was.
48:51Spleen volume response 35% spleen
48:53world in response at 24 weeks as
48:56well as total symptom score 50%.
48:58Reduction of symptoms by 24 weeks.
49:01So this is primary endpoint which
49:03basically it was achieved by 67%
49:06of patients so again the drug
49:08probably worked a little
49:10bit better for patients who are low risk but
49:13it was compatible 7273% for intermediate 160.
49:16Four 66% for intermediate to high risk
49:19based on the IP SS and IP address.
49:23Most of the patients cadres, reduction
49:25of spleen volume only one had increased.
49:28This is out of 70 patients studied,
49:30so the second endpoint at the
49:32symptoms decreased by 50%.
49:34Again, this was seen in 57% of patients.
49:37Most of the patients get this clinical
49:39benefit in the study at week 24,
49:41so one of the interesting finding when
49:44you start looks lit up in patients
49:46with myelofibrosis you expect a dip
49:48in hemoglobin about three points,
49:50so here the dip was not as deep.
49:53And then, as you can see,
49:55hemoglobin improved overtime.
49:56In fact, baseline increased a little
49:58bit higher than the baseline, so this.
50:00Awful actually looks at patients who had
50:03hemoglobin more than 10 and less than 10,
50:05but didn't require transfusions.
50:07And as you can see,
50:08after initial small dip there is improvement
50:11in anemia in this subgroup of patients,
50:13which is quite impressive.
50:14So one other thing,
50:16at the bone marrow's,
50:17their biopsies were done at the
50:19beginning as well as during the study
50:21and there was improvement in fibrosis.
50:23Great in 1/3 of patients and most of
50:26the improvements observed were observed
50:28during the first six months of treatment.
50:30Only two patients get worsening of
50:33fibrosis and you can see that there
50:35is also a sign that there is improved
50:38air throughout differentiation and
50:41normalization of megakaryocytic
50:43histopathology.
50:44So the side effects the CPI 16 in
50:47combination with Link was generally
50:50well tolerated.
50:51So 87% reported at least one
50:54treatment emergent adverse event.
50:5644% reported, one grade,
50:58three treatment emergent adverse event.
51:00So the most common ones were
51:02haematological and now this was
51:04an email from both cytopenia.
51:06Of course this may be manifestations
51:07of the disease itself,
51:09the most common and non human to
51:12logic was diarrhea or which was
51:14mild moderate Grade 1 two so.
51:16Great five were two events.
51:18Multiorgan failure with due to
51:20sepsis times two.
51:21So overall the drug was pretty
51:23reasonably well tolerated.
51:25The combination of drugs I have
51:27to say because we're looking at
51:29the side effect profile of two
51:31drugs administered together.
51:32So finally conclusions 67% of patients
51:35achieve CVR 35 comparing to historical phase,
51:37three studies simplifying comfort studies.
51:39This is looks better even though we
51:42cannot compare apples to oranges in
51:44those studies with ruxolitinib alone,
51:46the response was 28 to 42%.
51:4857% in the study achieved improvement
51:51and symptoms.
51:5150% reduction of symptoms and there
51:53were improvement in bone marrow findings
51:56suggestive of potential disease modification.
51:58So it was well tolerated combination an
52:01phase three study is planned and this
52:03would be a randomized study for treatment.
52:06Naive patients looks lit up
52:08against ruxolitinib Sir,
52:09plus CPI six 110 versus wrestling
52:11plus placebo,
52:12which allows crossover down the road.
52:15We are planning to open it at Yale this year.
52:19So the final study I want to present is PG
52:22300 study hepcidin mimetic as you know,
52:26hepcidin was discovered about 20 years ago,
52:28master regulator why and metabolism
52:30with high hepcidin level shutting down
52:33for a port and transport of ferritin.
52:35And so the reason to use it in polycythemia
52:39Vera is of course this patient need
52:41phlebotomies as the main part of their
52:44treatment which lead to iron deficiency.
52:47Perhaps keep citing analog PG 300?
52:49Can do this instead by shutting down
52:52availability of iron to every throw pesis so
52:55eligibility requirement PV diagnosed based
52:57on most recent to double check criteria,
53:00three phlebotomies in the last six
53:02months or more necessary primary endpoint
53:04is proportion of patients randomized
53:06withdrawal period whose cymatic Rick is
53:09maintained without need for phlebotomy.
53:10Secondary endpoint response at Week
53:1229 as well as improvement in symptoms
53:15using MP NTSS. So complicated schema.
53:17What we're looking at is just
53:20initial phase of this study.
53:21First 18.
53:22Patients enrolled who went through
53:24the first part of the study.
53:26Those finding at 28 weeks.
53:27There's those escalation,
53:28trying to identify how much
53:30subcutaneous injections once a week.
53:32You need to control phlebotomy
53:33and you know when you identify it.
53:35You kind of continue with that dose.
53:37Then you reach the second part of
53:39the study blinded withdrawal.
53:41Some patients continue real thing others
53:43and switch to placebo to see how it's
53:45going to affect the phlebotomy requirement.
53:47And finally,
53:48there is open label extension so
53:50that the report only dealt with
53:52this red part of the study.
53:54And as you can see in the red
53:56dots are phlebotomy requirements.
53:58Before initiation of the study,
54:00before the 1st dose and then after
54:02the first was only three patients
54:04required one phlebotomy Chen,
54:06those were getting the low level of the
54:08medication with which was further escalated.
54:11So pretty impressive effectiveness.
54:12As you can see,
54:14ferritin increasing significantly,
54:15showing that iron deficiency is gone.
54:17Total symptom score improving with time.
54:19And this is subset you know you
54:21can see improved concentration,
54:23fatigue, itching for writers,
54:24and though this is.
54:26The scoring system used to assess
54:28MPN scores MPN symptoms.
54:29We can say that perhaps some of it
54:32is related to the fact that iron
54:34deficiency is gone because I am
54:37deficiency can cause the symptoms
54:38as well was well tolerated.
54:40More than 90% had drug related adverse
54:43events, but all of them were sorry,
54:45not more than 90% of those who had
54:48adverse events were great one,
54:50so I would like to conclude by
54:52summarizing this study.
54:53It was PG 300 subcutaneously
54:55administered once a week,
54:56was safe and well tolerated, no Grade 3/4.
55:00Adverse events related to treatment.
55:02It was effective in eliminating
55:04the therapeutic phlebotomy's and
55:06reversing iron deficiency impact on
55:08previous symptoms is being studied,
55:11and this study is also planned
55:13for opening at Yell this year.
55:16Thank you.
55:20Thank you Nikolaj and Rory great
55:22talks and I think very important
55:24updates from from the meeting
55:26since we're a little bit overtime,
55:29will actually take 10 minutes
55:30beyond 1:00 PM for any questions,
55:33but I will start with a question for Doctor.
55:36But also as he needs to go out
55:39at 1:00 PM for another meeting.
55:42Actually two questions.
55:43So one of them is.
55:45Are there any immediately practice changing
55:47updates you take from from the ash meeting?
55:51In terms of what we do day today and the
55:54second question is from Doctor Isufi,
55:57she's asking whether the ampion
55:59driver mutations were acquired
56:01that were acquired in nutri,
56:03worthy, germline or somatic.
56:04Also please free to type your
56:07questions and if you want to
56:09ask live or any can unmute,
56:11you just just indicating
56:13the chat Nikolai so no immediate
56:15practice changing presentations.
56:17I think a similar but the
56:19drug for CML will be.
56:21Changing our practice when the
56:23drug and if the drug is approved,
56:25which I think should be you
56:28know towards the end of 2021,
56:30so you know I presented two studies
56:32where the drugs are very interesting
56:35and for that reason this studies will
56:37be available to our patients at Yale.
56:40So in regards to the mutations in utero, no.
56:43Those are somatic mutations.
56:45Those are not germline mutations.
56:46This is somatic mutations which acquired.
56:50So Doctor God actually follows up on on
56:52the CML presentation and he's asking
56:54if this drug is actually approved.
56:56Does that change your calculation and
56:58whether you transplant patients would
57:00would CML as they go through multiple
57:02tiki eyes and maybe to follow up on that?
57:04Like would you put this drug ahead of
57:07assertive in your kind of lines of therapy?
57:09If the drug is approved?
57:11Or how would you approach it?
57:13Yeah, so you know,
57:14I, I think it's too early to say
57:16if this is going to eliminate
57:19transplant for some of our patients.
57:21So, but yes, you know,
57:23based on the study which I presented today,
57:26it may be before positive for
57:28patients who had two tiki eyes prior.
57:31You know, looking at the results here.
57:35So unless there are other
57:37questions for doctor adults,
57:39if I will go to Doctor Challace.
57:42So Rory, any immediate practice changing
57:45abstracts for what people do to
57:47leukemia in their practices right now,
57:50whether in the community or in
57:52the academic centers that you
57:54take out from the ash meeting.
57:58Great question. Thanks
57:59amarum. I guess I'll kind of piggyback,
58:02but Nikolai said I mean at the
58:04moment I would say nothing imminent.
58:06Clearly some interesting interim data,
58:07although not yet practice changing.
58:09I'm most interested in the data for Kinetic
58:12lacks added to the dual nucleoside therapy.
58:14Cladribine motive sutera
58:15been alternating with visa.
58:17You know, it's hard to argue with 93%
58:19CRC or I rate with you know meeting one
58:21cycle response and meeting OS not reached.
58:24This compares very favorably with you.
58:25Know that the data phrase event you know 15
58:28months OS on the median OS on Bailey a trial.
58:31However,
58:32we've learned this year a few times over.
58:34Unfortunately,
58:35that single arm studies of agents,
58:37despite great clinical
58:38preclinical rationale, a priority.
58:40Or excellent similar data can
58:42fall short, so this needs to
58:44be confirmed in a randomized study.
58:46The same goes for Magnolia Map,
58:48which is currently being evaluated
58:49in phase three in comparison days,
58:51amount of therapy, but the double
58:53edged sword you know, pretty
58:54exciting preclinical data is
58:56very exciting.
58:56Single arm data begets more.
58:58Add on therapy notes with Phase
59:00one trial of triplet with days
59:01of medical acts makrolon map.
59:03Now Aizen Gilteritinib
59:04phonetic lacks, so I mean
59:05there's kind of divergent goals
59:07here. But to
59:08answer your question directly,
59:09I'd say nothing that's immediately
59:11practice changing, but.
59:12Excited for this to be a
59:14different conversation,
59:15maybe a few months to a year.
59:17Yeah, look a lot of exciting
59:19agents in development.
59:20This is a question from Doctor
59:22Isufi about Sabbato Lima.
59:24Basically, she's asking whether this
59:25targets the leukemia stem cell or does
59:28it work as an immune activator and
59:30this is a great question arrested.
59:32There's there's a lot of
59:34ongoing research on this issue,
59:35but currently the thinking is
59:37that it's a dual targeting drug,
59:39meaning that there is direct evidence
59:41that it affects the leukemia
59:43stem cells by interfering with.
59:45One of the leg and that is important for
59:47self renewal of the leukemic stem cells,
59:50and I think this is an interesting
59:52differentiator from other
59:53immune checkpoint activators,
59:54but there is also clearly data that
59:57also activates the immune response
59:58at the level of the T cells.
01:00:01How do we dissect the clinical
01:00:03efficacy in terms of being related
01:00:05to one or the other?
01:00:07I think it's a question that
01:00:09we are currently exploring and
01:00:11ongoing clinical trials,
01:00:12but I think this would be
01:00:14very important to explore.
01:00:18I think there's a question here
01:00:20from Doctor Gowda about CD 447.
01:00:23Inhibition is asking whether CD 47 inhibition
01:00:26does not cause many immune side effects.
01:00:29Thoughts, this is actually a good question.
01:00:32I will let also really give his his insight.
01:00:35I think this is one of the
01:00:39important things in terms of like.
01:00:42Issue related to like single arm
01:00:45studies and needing to know more data
01:00:48so CD 47 is actually expressed in most
01:00:51of their cells in in the normal body.
01:00:54However, they seem to be overexpressed
01:00:57by the leukemia cells and the idea here
01:01:00is that you're exploring a therapeutic
01:01:03window where using the CD 47 you are
01:01:06preferentially targeting the leukemia cells.
01:01:08However, because City 47 is also
01:01:11expressed on. Red blood cells.
01:01:13We do see hemolytic anemia,
01:01:15and some of those patients which
01:01:17can be actually quite severe and it
01:01:19has to be managed quite carefully,
01:01:21especially during the initial phases.
01:01:23And This is why they prime this drug
01:01:26and carefully monitor patients, it, etc.
01:01:28But I think it's a very good question
01:01:31about why no activity against other
01:01:33CD 47 expressing cells are being seen.
01:01:35I think what's gonna tell us really?
01:01:38The answer is once we see randomized
01:01:41data and try to.
01:01:42You know,
01:01:43explore whether some of the things
01:01:44that get attributed to the disease,
01:01:46for example,
01:01:47are really disease related or some kind
01:01:49of subtle immune related adverse events.
01:01:51But I think what is clear.
01:01:54Is we are not seeing the typical
01:01:56immune adverse effects that are seen
01:01:58with the PD one or CTL A4 type of
01:02:00drugs such as pneumonitis colitis.
01:02:02It doesn't seem that this is commonly
01:02:04seen or or do you have any additional
01:02:06insights on this that was very well said?
01:02:08I mean,
01:02:09I think the key
01:02:10points are the transient,
01:02:11presumed immune mediated hemolytic anemia,
01:02:13which really is why do you know the
01:02:15priming dose is sort of incorporated,
01:02:17but I think you're right.
01:02:18I mean, there's some element of
01:02:20specificity for those cells on
01:02:22which CD 47 is just enriched.
01:02:24Which happens to be within cells,
01:02:26and I mean outside of like you said,
01:02:28subtle or maybe even delayed
01:02:30immune IR A ES that sort of thing.
01:02:32And I think we have what median
01:02:34fourteen 1516 months of follow up?
01:02:36I mean, maybe there are delayed
01:02:37events that did not yet occurred,
01:02:39but I think it comes down to
01:02:41specificity and more of a different
01:02:43mechanism of action comparison.
01:02:44So you know more of
01:02:46a direct cell effect.
01:02:48Thank you so much for a
01:02:50few minutes past hour.
01:02:52Be very cognizant of the time.
01:02:54On a Friday afternoon,
01:02:55I'd like to thank everybody who
01:02:57joined us for for this session and if
01:02:59there are any additional questions,
01:03:01feel free how to free to
01:03:03email their speakers directly.
01:03:04Thank you so much and looking
01:03:06forward to seeing you next week with
01:03:09their next session next Friday.
01:03:10Have a great weekend everyone.
01:03:12Thank you.