Yale ASH 2021 Highlight: Leukemia

March 28, 2022

Information

March 25, 2022

Hosted by Dr. Amer Zeidan

Presentation by: Dr. Rory Shallis

ID7618

To CiteDCA Citation Guide

00:00Much for joining us today for another
00:04edition of the highlights of the
00:06American State of Hematology meeting
00:07that was held in December 2021.
00:10My name is Ammar.
00:13I'm joined today by Doctor Nicola and
00:16Doctor Rory Chalice and we will be together
00:20presenting on myeloid malignancies.
00:22I will start by talking about
00:25MD's for around 15 minutes.
00:27Doctor Cialis will follow
00:29with highlights of XAML.
00:31For another 15 minutes and
00:32then Doctor will finish.
00:33Will highlights of Milo
00:36proliferative neoplasms?
00:37Feel free to post your questions in the chat.
00:42At the end,
00:43we are going to have 10 to 15 minutes.
00:45We'll try to finish around 12:50 so that
00:48you can ask your questions directly.
00:50Or if you want,
00:51if you prefer,
00:52you can type them during the presentations
00:55so that we can also tackle them at the end.
01:00Thank you so much for joining
01:01and I'm going to get started.
01:07So for MTS, basically, UM,
01:10this has been a very exciting field.
01:13These are my disclosures.
01:14There has been a lot of new developments
01:16in MD's over the last couple of years,
01:19and I think this is an area where we
01:21continue to have new drugs approved.
01:23So one of the drugs that has been recently
01:27approved is a combination of oral.
01:30Put in so the site being is a standard
01:32of care treatment for higher risk
01:34MD's that's given intravenously.
01:36The problem is that this drug cannot
01:39be given orally because it undergoes
01:41first passed in the liver and the gut
01:45and therefore has not been able to do
01:48orally subsequently which inhibits
01:50the enzyme cytidine dominates as
01:52you can see in this slide basically
01:55allows the desire to be in to be given
01:58orally and in a phase three trial.
02:00All that certain trial that
02:02we participated in at at Yale.
02:04It was shown to have the
02:06same pharmacokinetics,
02:07which is the primary endpoint of the study,
02:09such as intravenous decided
02:11and based on this data,
02:13the drug was approved in the year 2020.
02:16The clinical results have
02:17been presented more than once,
02:19but the paper has not been published yet,
02:24so this is the presentation of the
02:27overall data from 2020 where the
02:29complete response rate was shown
02:31to be around 20%.
02:33And many patients achieved as you
02:36can see platelets and erythrocytes.
02:38Transition independence around
02:4050% of patients.
02:42And you can see the CR was
02:45durable around 14 months.
02:46The patients are still being followed for.
02:49Long term survival I think.
02:53Important update that was presented
02:56in in this ASH in December was
02:59the activity in the lower risk.
03:01Andy Ashby,
03:01'cause some patients had intermediate
03:041 tips and as you can see the
03:07complete response rate was also
03:10seen in those patients around 23%.
03:13So it seems that even for lower
03:15risk MD SIDEK has activity,
03:17which is something we see.
03:19Also the intravenous decide.
03:22However,
03:22it's not clear if this is the
03:24right dose for these patients,
03:26because we certainly see neutropenia
03:28and thrombocytopenia and therefore
03:30a phase two study randomized phase.
03:32Two study was initiated where
03:34the Sidik is given in two doses,
03:37lower doses than the approved dose
03:39in patients with lower risk MD's
03:41who are not responding to her
03:44therapist stimulating agents.
03:45So this study is open currently
03:47at the main campus for any lower
03:49risk MD's patient,
03:50feel free to discuss any patients
03:52who might have. For this study.
03:55Another drug that has been also approved
03:57in the year 2020 as Los Patterson,
04:00solo spatter said,
04:01basically is a transforming
04:03growth factor pathway inhibitor.
04:05So these transforming growth
04:08factor pathway proteins have been
04:11shown to interfere with.
04:13Luis is and what does low specific
04:16do its ligand trap so it removes it,
04:18removes the inhibitory effect
04:21on erythropoiesis and therefore
04:23stimulating red blood cell production?
04:25The drug has been shown to improve
04:28transfusion independence rates.
04:30You can see here the pivotal
04:32trial results from the MIDDLE'S
04:34trial which was published in 2020
04:37yet participated in that around
04:401/3 of the patients achieved
04:42transfusion independence, so this was.
04:44Refractory setting after yes, a failure.
04:47We currently have the commands trial
04:50which is in the frontline setting,
04:52so this is open actually in
04:54several of the Cancer Center.
04:58Satellite centers basically this
05:00is available for a front drawing.
05:03Randomization against erythropoiesis,
05:04stimulating agents and this is
05:07regardless whether you have the
05:08patient has rings to drop class or not,
05:10so please feel free to refer patients
05:14for this or again it's open in many of
05:17the care centers so the patients can
05:19be treated on the trial right there.
05:22That is another drug first in class
05:26TELOMERS inhibitor that has shown
05:28also good data in the refractory labs.
05:31Lower risk MD.
05:32As you can see here the presentation
05:35from the phase two part of the
05:38emerge study which showed a rate of
05:41transfusion independence of around 42%.
05:43So a good number of patients are achieving
05:46transfusion independence with this drug.
05:48So this trial has a phase
05:50three component called.
05:52Also the emerge which has been open
05:55at the main part of the study has
05:58actually been fully accrued and closed.
06:00But there is an extension of this study.
06:02So currently if you have patients
06:04who have lower risk MD's who are.
06:08First line,
06:09they can be considered for the
06:11commands trial if they have received
06:13essays and they are not responding.
06:15We have two options.
06:16I merge trial with that as well as
06:19the lower dose of the oral disability
06:22being available for these patients.
06:25How about higher risk MD's so many
06:27of you are aware of any talk lacks
06:31having very good activity in XAML.
06:34It's a standard approved drug.
06:36Now it's an oral pill that's given for
06:39older patients with acute myeloid leukemia,
06:41and we've been using it
06:43for several years now,
06:45so there has been a lot of interest in
06:48exploring that in patients who have higher
06:50risk MD's as well with excess players,
06:53and we have preclinical data
06:54suggesting synergy with.
06:55There's a side to Dean because one of
06:58the common resistance mechanisms to.
07:01Cited in is actually up regulation
07:03of PCL two,
07:04so trial was two trials were
07:06designed basically as early phase
07:08trials in the frontline as well as
07:10in the relapse refractory setting.
07:13After HMA failure,
07:15combining venetoclax with you
07:17can see in this slide that those
07:20escalation design of that study that
07:23subsequently went to those expansion
07:25and this is in the frontline setting.
07:28Very important to note that venetoclax
07:30here was given for 14 days.
07:32So it's not continuously given
07:34like it is in AML only 14 days and
07:37doses 400 milligram,
07:38which is the same dose that
07:40we do in patients with AML.
07:42However has a lot of drug interactions
07:44and it's important to adjust those
07:47accordingly and monitor the patient
07:49closely for infections which are
07:51common because you get neutropenia,
07:53those patients should be
07:56on prophylactic antibiotics
07:57and should be treated very
07:58aggressively if they have an infection.
08:00They need a lot of transfusion care as well.
08:03Especially during the
08:04first one to two cycles.
08:06So the patient should be seen at least
08:08twice a week and given transitions as needed.
08:12With all of that being said,
08:13basically we are seeing early
08:16activity in with this combination,
08:19so the complete response rate is around 35%,
08:22which is similar to what
08:24was observed in XAML.
08:25However, many of the other patients
08:27are achieving also more OCR where the
08:29plants are less than 5% and they are
08:32achieving hematologic improvement.
08:33You can see that the response
08:36is achieved relatively quickly.
08:38The first response is seen within one
08:40month and those responses are durable.
08:4212 months you can see also that
08:45there is and this is the main update
08:47that was presented in ASH 2021.
08:49You can see that many patients achieve
08:52no molecular clearance where the TP 53
08:55for example molecular load is decreased.
08:58However,
08:58the question in TP 53 in particular is
09:01whether overall survival is improved or not.
09:04So I think this data is encouraging.
09:07Clearly, however,
09:07this is a single ARM study.
09:09It's not randomized.
09:11Study less than 70 patients were enrolled.
09:13And therefore we have an ongoing
09:16registration study called DEVARONA.
09:18Which is also open at Yale.
09:21This is a randomized phase three
09:23study in which patients are
09:24randomized in a double blind,
09:25placebo controlled fashion to receive.
09:28Either as a sighted in with venetoclax
09:31or azacitidine with placebo,
09:33and we have presented the schema
09:36of this study in ASCO 2021.
09:38You can see here 500 patients will be
09:41enrolled and this study continues to
09:43be open and we encourage you to refer
09:45patients who have higher risk MD's.
09:48I currently discourage people from using.
09:52Plaques off label in the frontline
09:54setting because we still don't
09:56fully understand if it actually is
09:59better than is cited in monotherapy.
10:01And that's I think another reason to
10:03consider enrolling patients on this study,
10:05which is open at yet.
10:07In the refractory relapse setting,
10:10Yale has participated in a study
10:12that was led by.
10:14The sponsor or organized by the sponsor,
10:18similar design,
10:18those escalation followed by those
10:21expansion and this was a smaller
10:23study than the frontline study.
10:2444 patients were treated same dosing,
10:27400 milligram of Veneto class given for
10:29two weeks and venetoclax was added to
10:32a society in so the patient had a failure.
10:35But the patient continued in the MA so it is.
10:39And you can see here that
10:42response rate was seen in 39%.
10:44However, many of those were more hours.
10:46The CRA was 7%,
10:48but those responses were durable.
10:50As you can see, the duration was nine
10:53months of the CR or the more OCR.
10:56But most importantly,
10:57we are actually seeing.
10:59I think mean clinically meaningful responses.
11:02You can see that platelets and red blood
11:05cell transfusion independence among
11:07patients who were transfusion dependent.
11:09OK fine, so the patient was needing
11:12blood or platelets around 1/3
11:14of those patients are becoming
11:16transfusion independent with by
11:18adding venetoclax to exercise and you
11:21can see that many patients achieve
11:24hematologic improvement as well,
11:2543% and the median overall
11:27survival was 12 months.
11:29We know historically that median
11:31overall survival after a jammy
11:33failure is around six months,
11:36so it does seem that.
11:38We are seeing promising activity with this
11:42combination in the refractory labs setting.
11:46I think another important study
11:48from this hash meeting was the
11:51phase three update using that,
11:53so people need this stat.
11:54Is it activating enzyme inhibitor?
11:56It works upstream of the protein zone so
11:58this is a negative phase three study.
12:00The reason why I think this is an
12:03important presentation is because there
12:05has been a lot of early data with.
12:07That we had a randomized phase
12:10two study with people instead that
12:12showed the CR rate was 50% more than
12:15double death of his immunotherapy,
12:18and we had durable responses.
12:21So there was a lot of excitement
12:23about this drug and we did participate
12:25in the phase two part of this.
12:27Evaluation, but not in the phase three.
12:30However,
12:30you can see here in the phase
12:32three that there was.
12:33No difference in the event free survival,
12:35which was the primary endpoint.
12:37No difference in the overall survival.
12:40And even in the CRA there was
12:42no improvement with the combo.
12:44So that I think highlights why it's
12:46very important we enroll patients
12:48in phase three trials and not just
12:51assume activity based on phase two trials.
12:54How about immune checkpoint inhibition?
12:56As I'm sure you know,
12:57in solar tumors immune checkpoint
12:59inhibition has led to very important.
13:03Progress in very difficult to treat
13:05tumors such as Melanoma and lung cancer.
13:08Early data with immune checkpoint
13:11inhibitors in MD's has not been
13:14so far particularly great.
13:16With this is an example of this study
13:19that was conducted at several centers,
13:22including Yale,
13:22where we showed that there was no
13:25difference by adding door volume app,
13:27which is an approved PDL 1
13:29inhibitor that already has.
13:31Meaningful clinical activity and solid
13:33tumors by adding it to a society.
13:37However, there are novel.
13:38I think immune checkpoint
13:40inhibitors that seem to.
13:42Early and early results seem to
13:45have a promising clinical activity.
13:47One of them is about so sabatelli map
13:51works on a receptor called Team Three.
13:53So term 3 basically is an inhibitory
13:56receptor that is not only expressed
13:59on the adaptive cells,
14:01such as the T cells,
14:02but also it's expressed in
14:04the innate immune cells,
14:06including the macrophages,
14:07but also importantly on the leukemia
14:11stem cells. So this is being.
14:14Presented as as an immuno myeloid agent?
14:17Because it leads to activation of
14:20the T cells and then it immune system
14:24but also it directly inhibits.
14:28A loop of self renewal within the
14:31leukemia stem cells by interfering with
14:34the ligand called galectin 9 that binds
14:37to team three on leukemia stem cells.
14:39So this drug was combined with Dean
14:42and Decitabine in a phase one trial.
14:44You can see here the early data
14:46that was presented in actually
14:48in more than one ASH meeting.
14:51And, uh, the CR rate was not very
14:55high compared to a similar therapy.
14:58However, in certain subsets like
15:00TP 53 for example, the CR rate.
15:04The CR was durable.
15:05The median duration of response
15:07was 21 months,
15:08which again in a very difficult
15:11field such as CP3, I think,
15:13is very exciting,
15:13but we are also seeing hints of
15:15durability and other subsets,
15:17so clearly there is also excitement
15:21about this agent.
15:22There is actually a randomized phase
15:24two and a randomized phase three trial.
15:27Both of them were open at Yale and
15:29they are fully enrolled and we have
15:31two other studies with this drug,
15:32one in combination with oral.
15:34Typo methylating agents.
15:35So you can give the sidik the
15:37oral decitabine with this drug,
15:39and another study of a triplet
15:43where is cited in with venetoclax
15:47and will be given for patients
15:49with high risk MD's and both of
15:50those studies will open at the end.
15:52Lastly,
15:53the idea inhibitors this is dawn of
15:57the precision era in MD's like other.
16:12Malignancies in leukemia, where we do
16:14it more so approved clearly and MD's,
16:17but we have seen 2 presentations
16:19from the French group and ash where
16:22we are seeing basically activity and
16:25responses within a signal for IDH 2
16:28mutated MD's and I was sitting there
16:30for IDH 1 mutated MD's so I think
16:33this is an option clearly off label.
16:35But in the absence of a clinical trial,
16:38I do check for IDH mutations for patients
16:40with MD's and consider using these drugs.
16:43Lastly, CPX 351 or liposomal
16:46daunorubicin was approved for secondary,
16:49AML is also being studied in high
16:52risk patients who have access plus
16:54in particular and we are seeing
16:56encouraging activity.
16:57Again this is single ARM study.
16:59Small number of patients.
17:00Those are not your typical MD's patients.
17:03Those are younger fit patients
17:04who go to transplant.
17:05So this probably does not
17:07apply to most patients,
17:08and this is intensive chemo,
17:09so there is high risk of toxicity.
17:11Those patients should be monitored
17:13the same way you would consider
17:15someone who is getting 7 + 3.
17:17So in summary, a lot of active.
17:21Instigation for new agents in MD's,
17:23I think the field is clearly
17:25very exciting with looking like
17:29a therapeutic revolution similar
17:30to what's happening in XAML,
17:32and I think to continue with that
17:34we need to continue to refer
17:36patients for clinical trials.
17:37So thank you so much.
17:39This is my email.
17:42Many of you have my cell as well
17:44and feel free to reach out for
17:46any questions about MD's or any
17:48other questions you might have.
17:50Thank you so much and I will move
17:53to Doctor Challace who will talk
17:55about acute myeloid leukemia updates.
18:02I have to confirm it's just
18:03presenter view or the standard view.
18:09It's a present, sorry it's
18:11your for you. You need
18:12to. Such. How's that look good? Yeah, but.
18:19So alright thanks Doctor
18:21Sadanand all of you for joining.
18:23I'll be reviewing some of the
18:25highlights from this past meeting
18:26as it relates to similar disease.
18:28Akuma leukemia touching on a few that
18:31caught our attention as a community we
18:33can start with a retrospective analysis.
18:35First, liposomal done rubison sutera
18:39been or CPX 351 and hypomethylating
18:42agent plus band have shown vantage
18:45as frontline therapies for older
18:48and we call adverse risk AML.
18:50Although HMA van is approved for
18:53ineligible patients who are ineligible
18:55to receive intensive therapy,
18:57there's an increased use of this
18:59combo in older intensive therapy.
19:01Eligible patients including
19:02adverse risk disease.
19:03Furthermore, there's no getting around the
19:05fact that CPX is just pretty darn expensive,
19:08and we also recently published data on
19:10this and listen to classical 7 + 3,
19:12but getting back to CPX and ban there
19:14have been no randomized trials.
19:16So the two treatments have not
19:18been appropriately compared.
19:19There have been a number of.
19:20Retrospective analysis comparing them.
19:21But as upfront therapy for
19:23newly diagnosed AML.
19:24But this would be the largest thus far,
19:27so this was a multicenter retrospective
19:30study from 4 centers northwestern,
19:33Moffitt, Cornell.
19:34And yeah,
19:35I think Sloane,
19:37presented by Pinkel Desai and included
19:39211 patients treated with CPX 351 and
19:43server 220 that got then you could
19:45see here the overall population on
19:47the left baseline characteristics.
19:49The meeting ages were different between.
19:51Groups as expected,
19:52more adverse risk disease in the
19:54HM Event group.
19:55Like I mentioned,
19:55there's also a trend towards being a
19:58more enriched for P53 mutated disease,
19:59but the CPX group was more likely
20:02to have received prior HMA relevant
20:04consideration given these patients
20:06probably progressed from MD's.
20:07The study team is also interested
20:09on the right here.
20:10You could see in patients aged
20:1260 or 75 years,
20:13which was the original
20:15age group studied for CPX.
20:17351 on the randomized phase three
20:19and differences between groups were
20:20about the same as you can see here.
20:22With regards to outcomes,
20:24more patients achieved CR in the CPX group,
20:26but more CRI in the HMA Venn Group
20:28as you would expect given the
20:31continual the cyclic continuous
20:32mouse oppression that's encountered
20:34with phonetic lack specifically.
20:36However,
20:37these differences appear to offset when
20:39looking at the overall or composite.
20:42Rate.
20:44And there was a trend towards better
20:47CR CR I in the TPP related subgroup.
20:50And interestingly,
20:51no differences in response rates for
20:54patients with prior looking to the right.
20:56You can see that real free survival
20:58RFS was longer than CPX group,
21:00actually more than doubled but did
21:02not meet statistical significance.
21:03However,
21:04meeting OS was better in the
21:07arm at 17.3 months.
21:10Among patients aged 60 to 75 years,
21:12similar to the overall cohort
21:14or FS was no different,
21:15but neither in this case was
21:17OS in multivariable analysis.
21:19After adjusting for things like age,
21:22Ellen Risk,
21:23history of permanency and
21:25importantly prior receipt of HMA,
21:27there was an advantage favoring
21:29CPX for with regards to
21:32S in the P53. Sorry TP. 50 mutated cohort.
21:35However, it should be noted that among
21:38this population age 60 or 75 years.
21:40The shy 50% of patients in the CPX arm
21:42went to transplant compared to just 520.
21:45In the ACE event or sorry HM Event group.
21:48So more than double in this is
21:50important because you know,
21:51transplant was a significant
21:53predictor of RFS and OS.
21:55They conducted another MVA in patients that
21:58were aged 65 years who did not receive a
22:00transplant and found no difference in OS.
22:02So, in conclusion, this there was a
22:05significant difference favoring CPS and the
22:07overall cohort and in several subgroups,
22:10although in no difference in C.
22:12However, this is very likely related
22:14to a better rate of outlook transplant
22:15in the CPX group or likely had.
22:17As you'd imagine,
22:18if you were morbidities and thus
22:20you know CPX could still be the
22:21standard for for younger fit patients,
22:23even with at risk risk disease.
22:26Switching gears to some clinical trial
22:28updates starting with targeted agents.
22:30Given the the dawn of a new era,
22:32that Doctor Zaidan had appropriately
22:34mentioned and specifically starting
22:36with frontline trials,
22:37we could talk about each one mutated disease,
22:39which are found so mutations in IDH
22:421 mutations are found at about 5
22:44to 10% really diagnose patients.
22:46Ibis Sydney is an oral IDH 1 inhibitor
22:50that's FDA approved for two population,
22:52specifically adults with factory
22:54mutated disease and those with newly
22:56diagnosed disease, but are just.
22:58Older 75 years plus,
23:00or if commodities that quote UN quote
23:02preclude the use of intensive therapy
23:04there already data from a phase.
23:05One study of think it was 2425 patients
23:08with newly diagnosed disease that
23:10showed a favorable safety profile
23:12and pretty encouraging clinical
23:14activity for the combination of
23:16either sitting in a society and for
23:18that reason and also for the fact
23:21that this trial started enrolling.
23:23I think I wanna say March or April 2018,
23:26before we had the valley a data.
23:29This prompted a double blind randomized,
23:31placebo controlled phase three study
23:33where patients were randomized 1 to
23:35one to receive Asia or Asia plus I've
23:37acid nip with the primary endpoint.
23:39As you can see in the right here
23:41of event free survival,
23:42which was defined as a time frame
23:44randomization until treatment failure.
23:48146 patients have been enrolled as
23:49of this day to cut with the data.
23:51Cutoff was March of 2021 and as shown here,
23:54these were older patients with
23:56a median age of 75 to 76 years,
23:58a third with Anika performance status of two.
24:01Also about 1/4 of patients had
24:03defined poor risk disease.
24:06In looking at responses,
24:07which was not the primary end point,
24:09there was a statistically significant
24:11difference in CR as well as composite CRH
24:14favoring the Asia plus I've Sydney more,
24:16which namely demonstrated a 53% rate of CRC,
24:19RH, and half of these patients
24:21experienced a mutational clearance
24:23which is increasingly becoming.
24:25Is being recognized as a predictor
24:27of a durability of response and
24:29improvement in event based outcomes
24:32in the intent to treat population
24:34in line with the better rates of
24:36response and deep response by.
24:39There was a better EFS in the
24:41Asia plus Ivy Sydney farm.
24:42This is also translated into better
24:44OS for that for that arm as well.
24:46Quite striking at 24 months
24:48compared with eight months.
24:49As you can see here for patients
24:51just getting as alone and this
24:52is generally what we expect for
24:54patients getting a zoumana therapy.
24:56Did it come at the cost of more toxicity?
24:58Not really in looking at human logic talks,
25:00but perhaps a little more neutropenia.
25:02Pina Nonheme talks was also about the same,
25:05but the frequency of all grade
25:08differentiation syndrome, but concerned with.
25:09Ibis Sydney Pomona.
25:10Couple other targeted agents
25:12as assessed by investigators,
25:13was about 14% in the combo arm,
25:16compared to 8%.
25:18Think 70% on the monotherapy arm,
25:21although grade 3 differentiation
25:23syndrome was only about 4%.
25:25However, in both arms,
25:26so not terribly different.
25:28And looking on the right here you can
25:29see these are patient reported outcomes
25:31and measurements of quality of life.
25:32You can see that Ivo plus Asia
25:34appear to be a bit more favorable,
25:37so in some there wasn't.
25:40Recommendation that further enrollment
25:42be prematurely discontinued given the
25:44evidence of a benefit for the combination.
25:46So I would say, how does this
25:49translate into clinical practice?
25:50In short,
25:50as yet it remains to be determined for
25:53the patient with ID terminated disease,
25:55whether he or she is best served
25:57with a so plus van or a soap.
26:00I am personally aware of any
26:01randomized trial at the moment,
26:02but suspect that is a that is coming soon.
26:06Sticking with the same theme
26:08for frontline randomized trials,
26:09we should discuss the LACEWING trial,
26:11which was just presented by Eunice
26:13Wang at the meeting and this is a
26:16trial that randomized patients with
26:17newly diagnosed AML and who were
26:19inappropriate to receive intensive
26:21therapy to either get a Cerezo plus
26:24gilteritinib which is a footer
26:26inhibitor that demonstrated efficacy
26:28and safety and patients with ribs
26:30refractory for the mutated disease and
26:32what's known as the atom whole trial.
26:34Similarly,
26:34this trial was launched before
26:36the results of the alley A.
26:37Were known the primary endpoint
26:39of this trial was overall
26:40survival, so not FS and not or
26:42more of a response based endpoint.
26:45Patients were originally randomized 1 to
26:47one to one either get filter written at
26:50monotherapy built plus as a or as alone.
26:53But due to the website it as
26:55being a preferred therapy change,
26:56it was modified to randomize patients 2 to
26:59one to get either guiltless ASA oracea alone.
27:03Baseline characteristics are shown here and
27:05demonstrate that this was as expected and.
27:07Older population with meaning ages 77
27:09years and also a good proportion with
27:11any card performance status of two
27:13plus with perhaps some imbalance in
27:15favor of the Asian monotherapy arm.
27:17As expected, there were about 80% IT
27:20mutations and similar rates of it.
27:21High disease without at least from my eyes.
27:24Clear imbalances.
27:27It's pretty much up for this slide
27:29with regards to responses CR rates,
27:32not the primary endpoint,
27:33which is OS like I mentioned,
27:35we're somewhere between arms,
27:36but the rates of CRI and CRP which
27:38are less than CR response is still
27:40to be clinically meaningful were
27:42higher in the combination are nearly
27:43three times actually for a composite
27:45C area of about 58% for the combo
27:48and the 26% for as a monotherapy.
27:52However, it it's pretty clear
27:54from this KM curve that overall
27:56survival was not different between
27:57arms at about nine months.
27:59It should be noted, however,
28:00and this was discussed at the
28:02meeting and I believe it that this
28:04may be explained by a couple things.
28:06Subsequent email therapy was
28:08received by 20% of patients on
28:10guilt ASA and just shaved half of
28:12patients on the ASA monotherapy arm,
28:14meaning time to that next therapy
28:16was a bit longer in the ASA.
28:18Sorry, the combination arm.
28:19It was like 8 versus 5 months.
28:22So this might have influenced OS
28:23in addition to the imbalance and
28:25performance status that I showed
28:27you earlier on the right here.
28:29Looking at unplanned subgroup analysis,
28:31improved overall survival with guilt
28:32as it was really not observed in any.
28:34Although some trans were noted for
28:36patients that were more fit and
28:38also here with Highet delic ratio,
28:41I didn't show any adverse event data
28:43here because they were largely similar
28:45between arms including grade 3 plus events.
28:47So in some,
28:49although a negative trial
28:50still an informative 1.
28:52Supporting the contention that
28:53a zevan as based on the alley a
28:55may be the preferred combination
28:57for older patients who were
28:58inappropriate to receive intensive
29:00therapy with mutated disease.
29:01At the moment, I guess I can always change.
29:06Last year I had reviewed the data for
29:08Asia and McGraw map which is an anti
29:10CD 47 antibody that blocks the quote.
29:12Don't eat these signal on
29:15macrophages and specifically.
29:17Pretty robust efficacy for patients
29:18that have both P fitted mutated disease
29:20and wild type disease. Actually,
29:22for the pilot for the mutated cohort,
29:24I just over 12 months would be
29:26the longest meeting OS reported
29:27for that particular subgroup.
29:29But like everything else,
29:30this has to be combined with a zven, right?
29:32But I will say there are a number
29:35of preclinical studies which do
29:37support synergy for this combination,
29:40so this leads to the trial,
29:43which was a phase 1B2 trials divide with
29:46the triplet and patients with both.
29:47Newly diagnosed disease but
29:48restricted to P footage.
29:49Mutated disease as well as factory disease.
29:52Regardless of Peachtree status,
29:53the latter being the only cohort
29:55for the phase one portion and
29:57the primary endpoint for this
29:59trial was a composite rate of.
30:03Here are some baseline characteristics
30:05to date. I should mention that.
30:10Skip that part so.
30:12It's basically nothing out of the ordinary.
30:15In line with what I mentioned as how
30:17the kind of codes were divided up.
30:18You could see that you know the ages,
30:20maybe a bit younger in the mutated cohorts
30:22and the rips or factories specifically,
30:24then naive cohorts,
30:26as you would imagine.
30:27But other than that,
30:29no major surprises from a baseline
30:30characteristics standpoint and looking well.
30:33Just go over some safety data.
30:34No DLT's were observed in the Phase 1B
30:37portion and the RP 2 randomized phase.
30:39Two dose recommended phase two dose
30:41was established at 30 milligrams
30:42per kick with about a two week
30:44kind of priming dose ramp up and
30:46then eventually gets a bit easier
30:47for the patient every two weeks.
30:49Cycle 3 going forward.
30:51So getting to some efficacy data.
30:53Global findings first.
30:54The rate of CR being based
30:57on 14 patients with.
30:58TP50 mutated disease with 64% double what you
31:01would expect with with with a sub N alone,
31:04and this has been attributed
31:05to at least at the meeting.
31:06A quick depth of response with
31:08more than half being negative by
31:10flow and a first response in less
31:12than a month without really any.
31:14As you can see here,
31:15any early mortality and what I would
31:17consider to be a reasonable time
31:18to blood count recovery felt to be
31:20meaningful and really landing with
31:22the definition of what we call CRH.
31:25Frontline treatment for wild type
31:27patients was even more impressive
31:30with a CR CRA of 90%.
31:31Conversely, and this is,
31:32you know, one of the downsides.
31:33This doesn't appear to be a
31:34meaningful option for patients
31:35who've already been failed by vanetta
31:37klax based regimen with the CRA.
31:38As you can see here, based on 15 patients,
31:40but still zero and only 20% rate of CRI
31:43and at the bottom here you can see a 20%.
31:45It gets phone numbers but 20%
31:47rate of pearly mortality here.
31:49Look at this plot that was
31:51presented at the meeting.
31:52Much of what the last slide kind of showed,
31:54but also including data demonstrating that.
31:56There was 100% six month OS so short
31:58follow up as you could see here as well.
32:00For patients that had mutated disease and
32:02five of the 14 that were able to get to.
32:06Some form of response.
32:07We're able to get the transplants
32:08about 35% of course.
32:09Again short follow up,
32:11so maybe more will get the transplant.
32:12We'll get a better sense of the median
32:14OS and see how it stacks up to 12
32:16months noted for the Asian Macro Delta
32:18data that I presented to you last year.
32:22Frequent I share some more toxicity
32:23data frequente, ease of all grades.
32:26Hypokalemia, hypophosphatemia,
32:27hyperbilirubinemia, about half of patients,
32:29and some otherwise.
32:30He talks you would expect
32:32with as event itself,
32:33not necessarily mad or attributable.
32:35Among 17 patients that were newly diagnosed,
32:39and thus TP50 mutated,
32:41the median drop was just about
32:431 gram per deciliter this after
32:45the first dose,
32:45and even lesser after the second dose.
32:47So with close monitoring,
32:48this anemia was manageable and the anemia,
32:50which just to give a refresher.
32:52There is some on target hemolytic anemia,
32:54just that you know was a bit
32:56troublesome early on in the trial,
32:58but appears to be manageable
32:59with you know no SAS,
33:01no interruptions or discontinuations
33:02due to this anemia specifically,
33:04so this is promising and position
33:06to possibly be a new standard.
33:08I mean maybe a little ambitious,
33:10but for frontline treatment
33:11both for TP 53 mutated disease
33:13and even wild type disease.
33:14But of course need more data
33:16and more follow up and of course
33:19randomized trials to confirm this
33:21added benefit they are underway.
33:23One last combination and this one is
33:25one that's restricted to patients
33:26with RIPS or factory disease and
33:28one that may have some promise for
33:30patients with molecular subgroups
33:31that of interest and maybe patients
33:33who have been failed by better clocks
33:35today to critical area of need
33:36after patients are failed by then,
33:37it's essentially.
33:40A black hole Blackstone ever
33:41metaphor you want to use.
33:43This is another combination
33:44that adds to as event,
33:45but for which there is
33:47sound clinical rationale.
33:48This is a therapy that targets CD 123,
33:50which is the alpha subunit of the
33:52aisle 3 receptor and is overexpressed
33:55on leukemic blasts Immunogen 632.
33:57It's a CD123 targeting ADC comprised of
34:00a high affinity anti CD 123 antibody
34:03coupled to a novel DNA alkylating payload.
34:08Goodsell,
34:08Linedata Goodyear in PDX modeling
34:11or experiments good synergy between
34:13Immunogen 632 in Asia and Dwarven,
34:15including being able to overcome
34:17a certain resistance.
34:19So For these reasons, this is a phase one.
34:21Two trial of that product combined with
34:22a 7 and patients with as you'd have guessed,
34:25CD one or three positive AML to date.
34:29The triple combo escalation
34:30is consists of five cohorts,
34:324 with the investigational product
34:34dosed on day, seven of each cycle,
34:37and one cohort where it's dosed
34:38on the first day.
34:39Each cycle make it a bit more
34:40convenient for the patient at the
34:42time of this analysis presented.
34:44Obviously at the last meeting,
34:4635 patients have been enrolled
34:48based on characteristics are shown
34:49here in meeting age was about 65,
34:51so it was somewhat younger
34:52population with median 2 lines or
34:54prior therapy up to three,
34:56so not relatively terribly pretreated,
34:59but half of patients did receive
35:00prior medical acts important to know
35:02the talks profile was manageable,
35:04and this inherently goes factory
35:06population with multiplier
35:07therapies become an S were.
35:10Infusion related reactions.
35:11About 1/3 of patients with only two
35:13percent being grade 3 and otherwise
35:15things you would expect with a Savannah loan.
35:17One patient in the day one cohort
35:21had to discontinue because of an
35:23infusion reaction was considered DLT,
35:24but early mortality defined it at the
35:27bottom here 30 days with zero percent.
35:29So my last slide among the 29
35:33percent 29 patients who are valuable
35:35efficacy was seen across kind
35:37of all cohorts, doses and schedules.
35:39The response rate was 55%.
35:41And looking at the composite remission rate,
35:43it's about 30%, you know,
35:45with maybe higher rates in the higher
35:48dose cohorts of no patients prior
35:51van had good Angeliki make activity
35:53as seen here on the right, waterfall
35:56plot and overall response rate of 40%.
35:59Other subsets of note
36:00flipper mutated disease.
36:01Even more striking.
36:02I'll be at 9 patients,
36:03but 80% rate of composite emission.
36:05So in some encouraging in some molecular
36:07subsets and then treated patients,
36:09but certainly.
36:10Like the other studies I presented
36:12more data to assure these values
36:14don't regress to the mean like
36:15unfortunately many other similar studies.
36:18That's my last slide.
36:18There are a few more presentations
36:20from match that I wish I could discuss,
36:21but last only 15 minutes and
36:23I'm sure I'm over that already,
36:25so I apologize to Doctor Podolsky and
36:27look forward to your questions at the end.
36:32Can you unshare? Sure can.
36:35Go. Still cannot share the screen.
36:40Right here we go. Thank you alright,
36:43so let me find my presentation here.
36:53Sorry about this technical difficulty.
37:17Here we go. Alright, here's my view OK?
37:24Yes, OK, so this is my disclosures,
37:27so I'm going to go onto the outline.
37:29So I'm going to present four studies
37:32which I selected based on disease.
37:36Talk about devera,
37:38myelofibrosis and one other
37:41condition which is infrequent.
37:43Myeloid lymphoid neoplasm is in
37:45Affilia and FGFR 1 rearrangement,
37:48so the first study I would like to
37:51talk about is the study which is.
37:54Lookout Trust restaurant type or PTG 300
37:59and its control of human grade levels
38:01in patients with polycythemia Vera.
38:05So the rationale for the study is.
38:09Which is looking at Hillside and medic.
38:13Right is the fact that in patients with
38:17polycythemia Vera iron is necessary
38:19to make red blood cells in the marrow,
38:21which is affected by Jack.
38:22Two V 617 FM PM.
38:26So as you can see on the left,
38:28ferroportin is the main transporter
38:30of the iron from outside,
38:33from inside the macrophage to the
38:35circulation and then delivered by
38:37transparent to the bone marrow
38:39which is utilized to make excessive
38:41amounts of red blood cells by Jack.
38:432 mutated. Red blood cell precursors.
38:46So the hepcidin as well as
38:49restricted which is hepcidin.
38:51Medical shut down the gates ferroportin
38:54and decreases the amount of iron
38:58which is available for transparent
39:00to transport to the bone marrow
39:02so it's kind of shutting down the
39:04door but perhaps not the window.
39:06A little bit of line is available
39:08and the idea is that there is no
39:11iron deficiency state which is
39:12otherwise created by phlebotomies
39:14by therapeutic phlebotomies.
39:16Leading to decreased quality of life of
39:18this patients due to tissue and efficiency.
39:20So this is a phase two trial over spare
39:23type in patients requiring phlebotomy.
39:27Patients with PD diagnosis based
39:29on 2016 W criteria were included.
39:31At least three phlebotomies in the
39:34last six months were necessary.
39:35Patients were treated with or without sector.
39:39Reductive therapy and therapy,
39:40so the primary endpoint was proportion of
39:43patients in randomized withdrawal period.
39:45Who schematic rate is maintained.
39:46Without the need for phlebotomy,
39:49the secondary endpoints is the
39:51response of 29 weeks.
39:53Absence of liberty eligibility,
39:54and that's what I'm going to
39:55talk about today,
39:56as well as total symptom score
39:58for those patients who are
40:01receiving treatment register type.
40:03The idea is that symptoms will get
40:05better while they're receiving this
40:07treatment because planning deficiency state,
40:09which is otherwise present in patients
40:11treated with therapeutic phlebotomies,
40:13will be gone,
40:15so the study.
40:17As the three parts,
40:19the first one is those findings
40:21part that 28 weeks,
40:22then there is blinded withdrawal and
40:24then open label part is part three,
40:26so we're talking about 63 patients
40:29currently enrolled enrollment
40:31between October 2019 and May 2021,
40:33and patients were treated up to 18
40:36months between 8:00 and 92 weeks.
40:38So you can see here that initial
40:42period is describing six months
40:45preceding the first dose of the drug.
40:47Yeah,
40:48and patients are getting phlebotomy
40:49is that by you can see this by red
40:52triangles right after those there
40:53are very few red triangles,
40:56so this is going to be for optimization.
40:57That's what we looking for.
41:0184% of patients did not require 14%
41:05required one and only 2% required 2
41:08phlebotomists so very significant we self
41:12eliminating phlebotomies in almost all
41:14of the patients within the 1st 28 weeks.
41:18Treatment, so this was actually true for
41:20both patients who received such a reductive
41:22therapy and who didn't on the left.
41:2431 patients who didn't require center
41:27adaptive therapy on the right 30 put
41:29in two patients who did so from the
41:32standpoint of assessment of symptoms.
41:36Scoring system was used weekly and
41:39you can see on the left at baseline
41:42the score as well as the score
41:45after 2020 weeks of therapy.
41:47So there is significant reduction of
41:49treatment out of symptoms with this
41:52treatment and specifically 1/3 of patients
41:55reported at least 40% reduction of
41:57symptoms based on MPN soft TSS at 28 weeks.
42:01So it is the drug is effective at the
42:04eliminating the need of phlebotomy.
42:06This is a continuous injection which
42:09patients self inject once a week.
42:11So from the standpoint Bruce of
42:13X to summarize,
42:14basically the main side effect
42:17was injection reaction.
42:1920% of patients and it was transient
42:22and did not require discontinuation.
42:26In summary,
42:26research type war that PTG 300 is hepcidin,
42:32mimetic subcutaneously injected
42:33for PV patients,
42:35leading to elimination of therapeutic
42:38phlebotomy needs of majority of patients
42:41within the 1st 28 weeks of treatment.
42:43Also,
42:43reversing iron deficiency,
42:45which was evident by increasing MCV
42:48MHC and 13 of those patients that was
42:51positive impact on PV related symptoms,
42:53perhaps because of.
42:56Negating some of the iron deficiency
42:58related to therapeutic phlebotomies,
43:00it was safe and well tolerated without
43:03grade 3-4 adverse events and we are
43:05planning to open phase three randomized
43:08control study at Yale for this patients.
43:11So the second study is for my
43:14love fibrosis patients and it's
43:16gone collaborative wanna therapy
43:18for patients with myelofibrosis?
43:19This is update of ongoing study.
43:22I presented this study last year so
43:27it uses it utilizes this knowledge
43:30that promo domain and extra terminal
43:34domain proteins promote myelofibrosis.
43:37You can see the activation of NF
43:40Kappa B targeted genes leading to
43:43increased inflammatory response.
43:44Aberrant,
43:45or through a differentiation
43:47and aberrant megakaryocytic
43:48differentiation manifestations.
43:49So far my love fibrosis,
43:52inflammatory response causes systemic
43:54symptoms as well as cytopenias,
43:57including an email from both.
43:59Cytopenia conceit can be seen in my life.
44:01I prove this difference,
44:02so collaboration is the subject of
44:05this study, also known as CPI 0610,
44:07which is a first in class selective oral,
44:11small local inhibitor,
44:12bit bad proteins.
44:14Got it modifies the expression of
44:16genes and Bolton Kappa B signaling.
44:19Decreasing the cytokines.
44:21Also promoting erythrocyte
44:23differentiation and normalizing
44:25megakaryocytic differentiation.
44:27So that's the background for this study.
44:30The study is currently ongoing.
44:32It's manifest trial,
44:33global study and at this pace to trial.
44:36So there are three arms and the arm.
44:40I'm going to focus on this
44:43patients who are receiving.
44:44A collaborative and second
44:46line so they were previously
44:48treated with rock solid nib
44:50or were not able to take Luke Slim
44:52for some reason so the dosing is
44:54it's an oral drug so this is given
44:57to its one one week off schedule and
44:59there are two cohorts in this arm.
45:02One part of the study,
45:03one of them is transfusion dependent cohort,
45:0636 out of 60 patients accrued and
45:08there's ongoing enrollment and the
45:102nd cohort cohort one be finished.
45:13Enrollment 50 patients. So the.
45:15Primary endpoint for transfusion
45:16Dependent Court court is transfusion,
45:18independence for patients and one cohort 1B.
45:22It's it's splenic volume response,
45:2635% reduction spleen volume.
45:27So the patients were enrolled
45:30were either Ching knowledgeable,
45:32jacked to intolerant,
45:33and the biggest group is jacked
45:34to refractory resistant patients.
45:3656% this is a group of patients
45:39with poor outcomes.
45:40Median survival is about 14 months,
45:42so the SDR 35 response at week 20.
45:46War was a primary endpoint for
45:48group 1D which is non transfusion
45:50dependent cohort and it was 18%.
45:53Most of the patients had
45:55some splenic response,
45:5618% had reduction by 35%.
45:59So the symptom reduction by 50% at
46:05the end of the 24 week period was
46:07observed in 20% among all study
46:10participants transfusion dependent and
46:11not transfusion dependent participants.
46:13Finally the group 1B.
46:17Primary endpoint the transfusion
46:19dependence converting to transfusion
46:21independence occurred in 16% of
46:24patients overall in the whole
46:26population there was observed
46:27improvement in hemoglobin levels.
46:30As you can see on the right hand side
46:32and among transfusion independent patients,
46:3438% had improved hemoglobin
46:36level by 1.5 grams per deciliter.
46:39At the end of the 2424 week period.
46:42So there are some exploratory
46:44endpoints including evolutional.
46:46Fibrosis in the marrow,
46:48and about quarter of patients
46:51had improvement,
46:52including about 6.7% of patients
46:54who had improvement by two grades
46:57of Milo fibrosis in the .0.
46:59Improvement in fibrosis correlated
47:01with improvement in hemoglobin levels,
47:04so the side effects are summarized
47:06on this slide.
47:08For the sake of time,
47:1019% of patients reported adverse events
47:12which led 2 collaborative discontinuation.
47:15Most of the side effects were great.
47:18One and two.
47:19So, in conclusion,
47:21this is manifest on one looking
47:24at 64 patients planned enrollment,
47:26110 patients,
47:27there was a decent reduction of
47:30the spleen volume among transfusion
47:32dependent patients,
47:34and there was an improvement in hemoglobin,
47:36including among patients who are
47:38transfusion dependent and the 16% of
47:41them became transfusion independent.
47:43Marrow fibrosis and I didn't
47:44present this data.
47:45Plasma cytokines decrease suggested
47:47potential disease modification by
47:52majority of the most common treatment.
47:54Emergent adverse events were low grade
47:56and we are planning to participate in
47:58manifest 2 study randomized phase.
48:01Three study,
48:02double blinded between
48:06CPI 0610 and looks lit new versus
48:08placebo and looks lit nip at Yale.
48:10So the next step is and this is
48:13about the symbol of the drug which
48:16was recently approved for patients
48:18with CML as a third line treatment.
48:21People who were enrolled in the study
48:25received at least two TCR's and the
48:28presentation I'm focusing on today is
48:31update of what was previously presented.
48:34So this is the drug which is in
48:38which hits BCR ABL on core protein.
48:41Activity specifically targeting
48:43able marstall pocket.
48:45It's a different way of inhibiting BCR ABL,
48:48as you can see, even with key for one point,
48:509 mutation.
48:50Weighty people get this changed,
48:52and regular guys cannot attach a synonym,
48:56was able to inhibit people
48:58one kinase activity.
49:01Study is a phase three trial
49:04which randomizes patients.
49:06Between pursuit net 500 milligrams once
49:08a day and a 740 milligrams twice a day.
49:11Once again,
49:12there's a patients who were previously
49:14treated for chronic phase CML with
49:16at least two different keys and the
49:20initial presentation at previous ASH
49:24meeting looked at primary endpoint,
49:27which is major molecular response
49:29at 24 weeks.
49:31This presentation updates
49:33the results by expanding.
49:36Observation period for additional
49:387 1/2 months.
49:40So basically in 19.2 months
49:42from randomization period.
49:44So the key secondary endpoint is Mr
49:48rated 96 weeks is not presented yet,
49:50so this is the first.
49:53Presentation in 20 Dash 2020,
49:56which was also the data was
49:58also published in Blood.
50:00Last year,
50:01so the synonym was better than pursuit
50:03nip from the standard primary endpoint,
50:06which is major molecular
50:08response at 24 weeks by 12.2%.
50:11So the updated 48 week results
50:15continue to show the higher
50:18major molecular response rate.
50:20So basically at one year is 29.3% which
50:24is 16% higher than with pursuit nip.
50:26Also the reduction of desirable
50:28transcript to less than one.
50:30Or something blood is seen more
50:32frequently in a semi warm 42%
50:34versus 19% more than double.
50:37So the deep responses are also better
50:39in a synonym as you can see on our
50:424.57 point 6 versus 1.3% and Mr.
50:45410.8 versus 3.9% when compared to episode.
50:49So we're all adverse events that
50:53were less common in patients
50:56with severe then with mood dip.
50:59So nevertheless pretty much
51:00everyone had some kind of adversity.
51:02But adverse events leading to
51:05discontinuation again less frequent in
51:07a similar treating patients treated patients,
51:10so this is the most common all
51:13great adverse events as seen
51:14in more than 20% of patients.
51:16You can see that a synonym is better
51:18than other than cytopenia switch.
51:20I seen more frequently among patients
51:22who are treated with a similar,
51:24but this was transient fact at
51:26the beginning of treatment,
51:27usually related to the disease itself
51:29rather than to the treatment so.
51:32Adverse arterial occlusive events
51:37that were comparable in both groups,
51:38but it is challenging to say
51:40what would happen to the certain
51:42patients because they were observed
51:43a lot less than a similar patient.
51:45So, in conclusion, this is the first
51:48control study comparing tiki for resistant,
51:50intolerant patients using
51:52first and class specific drug,
51:54which is specifically targeting
51:56able one restoril pocket.
51:57Superior efficacy was demonstrated
51:59for synonym against BOSUTINIB, and.
52:02More patients remain the treatment
52:04at the end of 48 week period,
52:06so it has favorable safety profile.
52:08Now this is the drug which is available as a
52:10standard of care option for our CML patients,
52:12particularly with resistant with
52:15resistance and influence to two
52:17TK eyes or more so finally, the.
52:22They got me up for patients with the
52:25nominee and rearrangement of GFR one.
52:27So just to map that this is one
52:29of the myeloid malignancies.
52:32We spoke about MPN's pH
52:33positive and negative so far,
52:34but this is the myeloid lymphoid
52:36neoplasm with is an affiliate affiliates.
52:39Hallmark feature of this group of
52:41malignancies myeloid malignancies.
52:42I'm going to focus on this particular one,
52:44which is, I mean,
52:45all of them are not very common,
52:47but nevertheless it's an
52:49interesting disease which is.
52:51I'm due to translocation of eight P.
52:5411 leading to constitutive
52:56activation of FGFR,
52:58one that's 16 known partners.
53:00Chronic phase of this disease
53:02may present as MPNMDS or MDSMPN.
53:04That's why it is important to
53:05check if patient has is an
53:07affiliate for this rearrangement,
53:08usually treated with hydroxyurea and keys,
53:11including non selective
53:13ponatinib and might historian.
53:1550% of patients are in blast phase after
53:1712 months and meeting all survival
53:19and unfortunately only nine months
53:20without stem cell transplant one term.
53:22Oceans are possible with transplants.
53:24Las Vegas may present as a
53:27MLTOB cell and mix phenotype.
53:29Acute leukemia once again important
53:31test to do to select this patients
53:34and there is treatment with
53:37specific induction chemotherapy,
53:38perhaps with the tiki with one year survival,
53:40one with 30%.
53:41Those who achieve CR will abduction,
53:43Kima have superior survival obviously,
53:46and long term remissions are
53:47reported with transplanted patients.
53:49So this disease is rare.
53:52And also not very good to have because
53:54of lack of specific treatments
53:56as well as poor outcomes with
53:58available therapy at perhaps other
54:00than transplant which is available
54:02for limited number of patients.
54:04So is this drug which is currently
54:06approved by FDA as well as in some
54:09other countries for patients with
54:11cholangiocarcinoma previously treated
54:13and respected locally advanced it
54:15was FGFR 2 fusion and rearrangements.
54:17The drug inhibits FGFR 1/3 and that
54:20led to its study in this flight.
54:23Two or three trial.
54:25So this is a swimmer sport showing
54:28ongoing responses for majority
54:30of patients with chronic phase.
54:32There are 18 of them and then there is.
54:34This is the 13 patients with blast phase.
54:38Unfortunately less responses here.
54:39A lot of patients,
54:41especially in the black box who died
54:43from this disease in the blast based.
54:45Nevertheless,
54:46some were breached to allogeneic stem
54:48cell transplant. So in conclusion.
54:52Is the first therapy to demonstrate
54:54durable and high rates of CR&amp;CCYR
54:56in this group of patients.
54:59Previously, these patients were
55:01treated with other treatments.
55:03Majority of them progressed,
55:04including intensive chemotherapy and
55:06chemotherapeutic stem cell transplant.
55:08Kaplan Meier median duration of CR
55:10and overall response have not been
55:12reached in those treated with Pamela
55:14Gardner clinical and cytogenetic.
55:15Responses were less frequent in
55:17and durable and blood space,
55:19but nevertheless some patients
55:20were able to breach too.
55:21Collagen in stem cell transplant.
55:23See if there were no surprises and
55:25safety profiles and die of this
55:27treatment consistent with Jeff
55:29Gordon condition and this may be a
55:31good option for long term treatment
55:33for patients with Melanie with FGFR
55:35rearrangement ineligible for transplant
55:37or facilitate bridging tool transplant.
55:40Thank you.
55:43Thank you Doctor Badasci
55:44thank you Doctor Cialis.
55:45Great comprehensive presentations and.
55:49We are going to take a few questions
55:51from the audience if any has,
55:53so please feel free if you want
55:55to type your question or if you
55:57want to ask directly, you can.
56:00I think Lenny can mute you
56:02and you can ask the question.
56:04I'm gonna actually start one question
56:06for Doctor Sheraz where we are waiting
56:09so Rory treatment of AML historical.
56:147 + 3 or really not much aside from that,
56:20so can you walk us through your
56:22thinking of the different options
56:23for a patient that potentially could
56:25be seen in any of the care centers.
56:2874 year old male. Walks with a cane,
56:33but otherwise in good shape.
56:34Who comes with acute myeloid
56:37leukemia outpatient?
56:41And the patient has a flip 3
56:44mutation and mutation which we can
56:46see certainly in some patients.
56:48So how do you work through the
56:51different treatment options as you
56:52consider what to do with this patient?
56:56Well, I could think my practices
56:58is fairly evidence based with some
57:00rare exceptions, and you know,
57:02I'd say this is a double edged sword.
57:04I mean, it's very fortunate that the field
57:05is moving very quickly with novel agents,
57:07novel combinations with.
57:08You know a recent preference
57:11for randomized trials,
57:12but by the time a trial is launched,
57:14let alone completed,
57:15maybe the reference standard,
57:16the comparator arm is obsolete, so.
57:19At the moment,
57:20you know a 74 year old is,
57:22you know, age isn't all ages,
57:25more of an imperfect surrogate
57:26for other patient specific
57:27factors like end organ reserve.
57:29And I'd say maybe I put a bit
57:32more emphasis on the disease
57:34biology and with two troubling
57:36mutations and intensive therapy
57:38appropriate eligible candidate.
57:40I mean,
57:40I would probably say this is a patient
57:42that probably would be treated with
57:44an intensive backbone plus midostaurin
57:46you didn't give me a fits it high or.
57:50But I think we can all agree
57:52this is probably a patient best
57:53served with that triplet regimen.
57:55You know at the patient was not intensive,
57:56they would be eligible in the clinic.
57:58You know, you know,
57:59eyes in the beholder.
58:00Then it's a it's dealers choice.
58:02As event is probably still appropriate
58:04just based on the Lacewing data,
58:06you know that Eunice Wang had
58:08presented and until we have a
58:11randomized trial looking at sequencing.
58:13Just flip three.
58:14I think the question is still unanswered,
58:16but it's hard to stray from
58:17what we know from the belly.
58:18I think as of them still be the
58:20standard if the patient is need to
58:22not be intensive therapy appropriate
58:23and maybe in the next couple of
58:25years you might have a randomized
58:27trial that looks at that and maybe
58:28a seven could be superior to even
58:30classical intensive therapy,
58:31but at the moment that's the
58:33dichotomy I would say.
58:37Perfect so clearly a lot of options
58:39for this patient. This patient
58:40could go with his even potentially.
58:43Some patients can still do IDH 2 monotherapy
58:47could be aids with IDH 2 inhibitor could be.
58:5210 + 3 could be 7 + 3 with middle story and
58:54you still could consider transparent or not.
58:56So clearly many many different options.
58:58And clearly the best option
58:59is always a clinical trial,
59:00which we always encourage.
59:02So I'm pretty sure you know in the care
59:05centers these patients are seen all the
59:07time and I encourage people even if the
59:09patient does not want to come to the
59:11main campus or cannot travel to call
59:14one of us and go through some of the
59:17potential options that we have Nikolai.
59:21So fibrosis things are also clearly changing
59:24issue that some of the clinical trials
59:26that are in progress but currently 4.
59:29Doctors in.
59:30In practice,
59:30one of the most common I think tough
59:33situations is patients with myelofibrosis
59:35who are on rock solid and anemic.
59:39So the patient basically
59:41has controlled spleen.
59:42They are not having constitutional
59:44symptoms but they are needing
59:45transfusions and they are on.
59:49Let's say 20 milligram P opyd.
59:53Now we have a drug approved that we
59:57have a drug nib and there's another
60:00drug in front of the FDA molet nib.
01:00:02And you know a bunch of other things,
01:00:04he says androgens and potentially.
01:00:09So how do you think about these
01:00:11different options as you approach
01:00:12your patient like this?
01:00:14So from the standpoint
01:00:15of FDA approved therapy,
01:00:17we have right now for awhile and
01:00:19looks like name is obviously
01:00:21dominating the market since 2011,
01:00:23so I think that was approved for
01:00:25similar group of patients from 2019
01:00:27and usually considered as a second
01:00:29line for those patients who are
01:00:31not satisfied with that rock solid.
01:00:33Networx limp is not working
01:00:36anymore with variable results,
01:00:37So what we have approval is.
01:00:40A grid Neb out on the 1st of March
01:00:42was FDA approved for patients
01:00:43who have low platelet count so
01:00:45called cited piknic Milo fibrosis
01:00:47and perhaps this drug can be used
01:00:49not only for patients who have
01:00:51platelet count less than 50 so,
01:00:53but maybe between 50 and 100 because
01:00:56effective dose sometimes is not
01:00:58feasible for this group of patients.
01:01:00So none of these drugs address anemia
01:01:03sore from momentum study which was
01:01:05just presented that you know the data
01:01:08was presented as a company release,
01:01:09so there's no publication about
01:01:11that at the end of January.
01:01:12So this drug is geared towards
01:01:16patients with anemia,
01:01:18who are progressing after sliding.
01:01:21Now this was a randomized
01:01:23study against Danazol,
01:01:25which you argue may not be the
01:01:26best randomization strategy.
01:01:27So there is some improvement in
01:01:29patients who have anemia there,
01:01:30but the drug is for symptom control,
01:01:32more just for anemia.
01:01:33Fix the patient you were talking
01:01:35about at the beginning.
01:01:36Looks solid, treated, patient with anemia.
01:01:38There is a there is a study called
01:01:41Independents trial looking at luspatercept.
01:01:42This group of patients we know that
01:01:45was part of Sept is approved for
01:01:47MDS with doing Super Blast right so
01:01:49and perhaps some people can get it
01:01:51off label to treat these patients,
01:01:53but I think it is a little premature.
01:01:54We have to see how this results
01:01:56are going to bend out.
01:01:59So what would you do
01:02:01so you know, for patients who first
01:02:03of all don't give up slip to patients
01:02:06whose main problem is an email, right?
01:02:08So because an email becomes worse,
01:02:10is the drug to fix the symptoms,
01:02:12and some patients would be happy to
01:02:15take crooks because they have bad
01:02:17symptoms and receive transfusions
01:02:19because their quality of life,
01:02:20even though transfusions may be a little
01:02:22bit more frequent, becomes better.
01:02:24So we can sometimes try to give
01:02:27everything like Derby Poitin 150 weekly
01:02:29or 300 weekly to those patients.
01:02:32In conjunction with within those
01:02:34country intuitive.
01:02:35Because rooks,
01:02:35lithium is Jack stat pathway
01:02:37inhibitor and worth reporting
01:02:38actually activates that pathway,
01:02:40but Bruce Lipton was not there 24/7,
01:02:42so we allow some hematopoiesis in between.
01:02:45So by doing that and some of the patients
01:02:47may have less transfusion requirement,
01:02:49so it's either supportive,
01:02:51care with transfusions or trying to give
01:02:53darbepoetin to those patients who need
01:02:56or trying to decrease the looks lit nap,
01:02:59which of course is a you know may lead to.
01:03:02Reoccurrence of some of the symptoms
01:03:04and worsening of symptomatology
01:03:06in those patients.
01:03:07So no perfect solution to this
01:03:08group of patients at this time.
01:03:12Would you consider adding danazol also or
01:03:15so danazol would be one of the options
01:03:17with Retropulsion doesn't work with
01:03:19overall response rate of about 20%,
01:03:21which may last up to two years.
01:03:23Again, monitoring of liver function,
01:03:25test PSA and man would be important
01:03:26for this group of patients.
01:03:28Yes, this is the second line
01:03:29option for an email management.
01:03:31Can I ask you a question?
01:03:33So because we have to move
01:03:34to the tumor board.
01:03:35I just have this question so if
01:03:36there is no clinical trial and your
01:03:38patience and your patient with MD's
01:03:40high risk MD's didn't respond to HMA,
01:03:43would you try to do off label addition
01:03:46of donetta clocks two weeks on,
01:03:47two weeks off to this patient?
01:03:49If you can get it covered by the insurance?
01:03:51No clinical trial available.
01:03:55Yeah, so that's again like the
01:03:57dilemma we have with those patients
01:03:58because we don't have anything that's
01:04:00FDA approved for those patients,
01:04:02so I would consider it.
01:04:03However, I would, you know,
01:04:05be very clear with the patient about
01:04:07the limitations of this being off
01:04:09label and we don't have a lot of data.
01:04:11I do think it's quite a suppressive regimen,
01:04:14so for some patients you have to expect
01:04:17that they are going to need to come
01:04:19three times a week to the clinic,
01:04:21need frequent transitions they will
01:04:23need to be on prophylactic antibiotics.
01:04:25So I consider it more in the setting
01:04:28where I'm thinking about bridging
01:04:30the patient to a transplant.
01:04:31If the patient does not have
01:04:34a transplant option.
01:04:36Think about it,
01:04:37but not as strongly,
01:04:38except in situations where the
01:04:40patient is in relatively good shape.
01:04:42The problem is that many of those
01:04:44patients are very old and they
01:04:46have a lot of comorbidities and
01:04:48therefore supportive care could be.
01:04:51Also, I think appropriate in some patients,
01:04:54but just take one last question because I
01:04:56see it from doctor to doctor Szeles about.
01:05:00Why do you think there was no
01:05:02overall survival advantage with
01:05:03his guilt compared to.
01:05:055% Neb with guilt in in in the agile.
01:05:12I actually answered in the trap,
01:05:13but I guess in brief I mean there
01:05:15were some imbalances between the
01:05:16groups were only talking about the
01:05:18you know the Lacewing trial which
01:05:20which is the gold ribbon trial.
01:05:22More patients on the ASA monotherapy
01:05:24arm were able to proceed to subsequent
01:05:26therapy which of course could influence
01:05:29any OS for that group as well.
01:05:31I think it was more.
01:05:31I think it was like 40 versus 20%.
01:05:33It was almost double and there is
01:05:35also about a four month difference
01:05:37in time to next therapy.
01:05:39So patients who already committed
01:05:41so that could probably.
01:05:42You know, explain some of that.
01:05:44There were also.
01:05:45There was also striking imbalance
01:05:46in the performance status,
01:05:48which is more of a surrogate for frailty,
01:05:50which is again debated itself,
01:05:52but more patients on the ASIC guilt
01:05:54arm were just higher performance
01:05:56status you talked to was I
01:05:58think I wanna say 30% wallpaper
01:06:00so you know I thought the second
01:06:02line treatment with guilt in those
01:06:03who were treated with ASA you know
01:06:05so would be also the main reason
01:06:07why there was no at the end of all
01:06:09survival difference in this too.
01:06:10And they were, you know.
01:06:11So it's just very difficult
01:06:12to show overall survival.
01:06:16Yeah, I think with all of
01:06:17these trials I you know, I,
01:06:19I think doing this postmortem is,
01:06:22you know, a good thinking exercise.
01:06:24But at the end of the day,
01:06:25all of this should be thought
01:06:26before the trial and what we
01:06:28have is what we need to go with.
01:06:29So thank you so much. Again,
01:06:31if anybody has any additional questions,
01:06:33feel free to send us an
01:06:36email or call any of us.
01:06:37Thank you so much and I think
01:06:39we have the tumor board. Yes,
01:06:40tumor board please.