Myeloid Malignancies

Transcript

• 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.