Yale ASH 2021 Highlight: Leukemia
March 28, 2022March 25, 2022
Hosted by Dr. Amer Zeidan
Presentation by: Dr. Rory Shallis
Information
- ID
- 7618
- To Cite
- DCA Citation Guide
Transcript
- 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&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.