"Polycythemia Vera (PV): Epidemiology, Prognosis and Real-world Outcomes" and "Overcoming hypomethylating agent failure in acute myeloid leukemias and myelodysplastic syndromes"

December 16, 2020

Yale Cancer Center Grand Rounds | December 15, 2020

Nikolai Podoltsev, MD, PhD and Thomas Prebet, MD, PhD

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00:00But it's 1202 an Why don't we
00:02get started 'cause I want to make
00:04sure everyone has time.
00:06I welcome everybody.
00:07This is actually our last Cancer
00:09Center grand rounds of calendar year
00:112020 and what a year it has been. A
00:15lot of lot of things
00:18have happened, a lot of great work and it
00:22seems almost fitting that actually theme
00:25for our our last grand rounds is our.
00:28Our division of hematology.
00:31And which we are extremely proud. And among
00:34the highlights of all the many
00:37accomplishments in the division
00:39was actually the results of our
00:42search for our new division chief.
00:45As, as you've heard, we had a
00:48national search an without question.
00:50There was one person that
00:52the committee felt very
00:54strongly rose to the top,
00:57and that is Doctor Stephanie
00:59Allyne a recognized.
01:01Physician scientists,
01:02clinician educator, leader,
01:03and which is so pleased to have
01:06Stephanie now in that role in
01:09the really extraordinary legacy
01:11of accomplishment in hematology
01:13detail. So I'm going to turn it
01:16over to Stephanie to introduce
01:18our esteemed 2 speakers.
01:21Like Italian, thank you for this honor.
01:24So I'm really honored to introduce two
01:27over my dear dear colleagues and friends,
01:30and our first speaker of the day
01:33is Doctor Nikolai productive.
01:35He's associate professor,
01:36internal medicine, hematology, and Sir.
01:38Just as the associate director of
01:41Hematology Oncology Fellowship program,
01:43he is also the from T for
01:45education on the Duffy service.
01:48Nicolai received his MD and PhD
01:50from Saint Peters Burg State,
01:52Pablo Medical University and completed his
01:54fellowship at Yale in hematology oncology,
01:57after which we get to keep him and Nikolai
02:00Nikolai's clinical practice and research
02:02are focused on my light neoplasms,
02:05including acute minor.
02:06Kenya models plastic syndromes and
02:08in particular my lucrative neoplasms
02:10in which he really is an expert.
02:13Nikolai serves as a Pi for a
02:16number of clinical studies.
02:17Their industry sponsored cooperative
02:19group investigator initiated and
02:21his clinical care and his trials.
02:23He really makes a difference
02:25for his patience.
02:26So nicholi,
02:27we look forward to your time.
02:29Thank you Stephanie,
02:30for this kind introduction.
02:32I'll be talking about
02:34polycythemia Vera today.
02:35I will talk about Epidemiology, prognosis.
02:37And a real world outcomes.
02:40Are these are my disclosures?
02:42So, first of all,
02:44polycythemia Vera belongs to
02:46the Group of Milo proliferative
02:48neoplasms based on W2 2016
02:51classification mpanza divided into
02:53pH positive or BCR ABL positive?
02:56Or also known as chronic myeloid
02:58leukemia as well as BCR,
03:01ABL negative Milo proliferative neoplasms,
03:03and among them there are classical
03:06mpanza including polycythemia
03:07Vera we're discussing today.
03:09Also essential thrombocythemia.
03:11And primary myelofibrosis so the
03:14definition is based on WTO 2016
03:17criteria represented on the slide.
03:19To diagnose the very you have to have
03:22three major criteria on the left or
03:25two first 2 first major criteria and
03:28then minor criterion on the right.
03:31The major criteria include
03:32elevation of hemoglobin.
03:34This is the hallmark feature
03:36of this condition,
03:37and that's what makes it different from
03:40other classical Milo proliferative neoplasms.
03:42The bone marrow.
03:44Biopsy is necessary and
03:45usually shows up on my loses.
03:48Excessive presence of red blood
03:50cells and myeloid precursors,
03:51as well as megakaryocytes and then.
03:54Finally,
03:54there is one of two Jack two mutations,
03:57Jack 2V617F mutation or Jack.
04:00Two exon 12 mutation in very rare
04:02circumstances, about 2% or less.
04:04When this mutations are not present,
04:07you need lower throughput and level
04:10to diagnose polycythemia Vera.
04:12So the history of Mila proliferate
04:15diseases is interesting if at
04:17first they were described as a
04:20group by Doctor William Damashek,
04:23he immigrated with his family from
04:26Russia to Massachusetts at the age of
04:29three and then stayed in Massachusetts,
04:32was working in Tufts when he described
04:36myeloproliferative diseases.
04:37This group of conditions became
04:39reportable to seer the lodge.
04:42Registry of cancer patients in the
04:45United States in 2001 and in 2008
04:48W show renamed MP dies to MPs,
04:51so from Milo proliferative diseases,
04:54they became I'll of proliferative
04:56neoplasms in Part B, cause in 2005,
04:59Jack 2V617F mutation was identified
05:02as a driver mutation in majority of
05:05patients with PD ET an Milo fibrosis
05:08in 2006 nipple exam 10 mutation another.
05:12Driver mutational Jack Stat pathway which
05:14is activated in those malignancies,
05:17was discovered and then in 2007,
05:19another Jack mutation Jack.
05:21Two exon 12 mutation was described.
05:24Finally in 2013 call reticular
05:26mutation was described and if you
05:28look at polycythemia Vera which is
05:31the subject of my presentation today,
05:34most of the patients will have
05:36Jack 2V617F mutation 97 percent 1%
05:39will have Jack to exam 12 and then.
05:432% of patients will have other drivers.
05:47So the polycythemia Vera Epidemiology
05:50was recently summarized in our review.
05:53As you can see the patients with
05:56this diagnosis are older,
05:58median age of diagnosis is 65 years.
06:02It's not the most common malignancy.
06:05The incidence is only .5 to
06:08400,000 person years.
06:10Estimated prevalence in the USA
06:12is 25 to 57 per 100,000 persons.
06:16And median overall survival is
06:1812 to 14 years,
06:20which is less than expected
06:22in age and gender matched
06:24population.
06:255 year relative survival is 84 to 89%.
06:29Uh, so if you look at this graph,
06:32you will appreciate that males
06:33diagnosed with this condition the
06:35little bit more common than females.
06:38You can see males and blue.
06:40This is divided in different age groups.
06:42One other thing you can appreciate here
06:44is that this condition is extremely
06:47rarely diagnosed in younger patients.
06:49Those who look way younger than 40.
06:52So this is one of the large cohort studies
06:54in one institution and Mayo Clinic,
06:57which looked at survival of.
06:59Patients with classical Milo proliferative
07:01neoplasms and here you can appreciate
07:04that 80 survival yellow line is less
07:07than survival of general population.
07:10The dark blue line and polycythemia
07:13Vera in red is worse survival than ET.
07:18So the etiology of Milo prolifera.
07:22Trackmania plasma goes beyond
07:24driver mutations.
07:24We know the driver mutations.
07:26We also just figured out that
07:29they may occur many,
07:30many years before MPN diagnosis.
07:32During this ash meeting a week ago,
07:35there was a presentation which showed that
07:38these mutations may develop in neutral,
07:40but factors leading to the acquisition and
07:43development of MPN are much less clear.
07:46So in fact,
07:47MPM doesn't develop in everyone
07:50who has Jack two mutations.
07:52The other interesting observation
07:54is that there is higher incidence of
07:57mpanza in first degree relatives.
07:59It's actually 7 times more likely.
08:03The patients that first degree relatives
08:06are seven times more likely to develop
08:09MPs and German driver mutations inject
08:11to color it economical genes uncommon.
08:14It is felt that congenital predisposition
08:17due to certain polymorphisms help
08:19to acquire MPM and families overall
08:21within 5 to 10% of MPN patients
08:24have germline predisposition.
08:26So we started the extrinsic factors
08:30influencing on the development
08:32of polycythemia Vera,
08:34among other myeloproliferative neoplasm's,
08:36and for that we used in HRP,
08:40diet and health study cohort with
08:43more than 450,000 participants.
08:45Median follow-up was 15 1/2 years.
08:48490 ampion cases were discovered
08:51among them 190 PV cases.
08:54So it is well known that tobacco
08:57is a bad carcinogen,
09:00and we were able to show that
09:03there is increased risk of MPs
09:05velopment one smoking women.
09:07So the other interesting finding of
09:10this study was identification of
09:12coffee intake as protective against
09:15development of polycythemia Vera.
09:17You can see that high versus low
09:19coffee intake was associated with
09:22decreased incidence of that diagnosis.
09:25Consumption of decaffeinated coffee
09:27did not have protective effect.
09:29We also looked at different micronutrients.
09:35And food groups and identified
09:37food consumption is one of the
09:39risks of the development of PV.
09:45He as well as sugar intake,
09:48which is also associated navaira.
09:50So to conclude, it's good to have
09:52a Cup of coffee in the morning,
09:55but not with sugar and without a cigarette.
09:58So the common clinical features.
10:00Of polycythemia Vera include microvascular
10:03complications like headache,
10:05aerothermal, alja dizziness,
10:06paresthesias and blurred vision
10:08microvascular complications,
10:09including heart attacks,
10:11strokes and venous thrombotic events.
10:14Patients with PD may suffer
10:17from constitutional symptoms,
10:18including fatigue, night sweats,
10:20weight loss, and teaching.
10:23Specifically aquagenic parictis.
10:25Splenomegaly occurs in less than
10:27half of the patients and patients
10:30with PD may have splenomegaly
10:32associated symptoms as well.
10:35Most of morbidity and mortality in this
10:38group of patients comes from thrombo SIS,
10:41arterial and venous thrombosis
10:44occur in about 20%.
10:46Of patience and you can see that this is
10:49the data from cohort of more than 1500
10:51patients with them in follow up of 6.9 years,
10:54but not only promote transposes,
10:56the danger that these patients
10:58can also develop major hemorrhage,
10:59and it is known that polycythemia
11:01Vera is strong,
11:02but humor odijk disorder.
11:05So what is feared most
11:07is disease progression,
11:08and patients with polycythemia may
11:11progress to post PV myelofibrosis
11:13about 10% of patients in 10 years.
11:15But even more scary with progression to
11:18last phase of Milo proliferative neoplasm
11:20or secondary acute myeloid leukemia.
11:23As you can see,
11:254% of the patients will develop
11:27AML after 10 years of follow up.
11:30It is a little bit more than 80 but much
11:34less than the primary myelofibrosis.
11:37So also we sometimes can observe
11:41evolution of essential thrombocythemia
11:43Jack Two V 617 mutation positive
11:47two polycythemia Vera.
11:49Can we predict the risk of disease evolution?
11:53Can we predict progression to Milo
11:55fibrosis or acute myeloid leukemia?
11:58So we participated in this multicenter study,
12:01which looked at the largest
12:03US based PV data set.
12:06We contributed 100 patients to
12:08this 500 patient cohort and what
12:11looked at is Lucas Cytosis over
12:14year and its Association with
12:16disease evolution and thrombo SIS.
12:19It turns out that this.
12:23White cell count trajectory did
12:25not associate with thrombosis,
12:27but was associated with increased risk of
12:31transformation to post TV Milo fibrosis,
12:33as well as MPs.
12:35Unlike my with leukemia,
12:37this study used very interesting
12:39statistical approach,
12:40so-called group based trajectory
12:42modeling which is usually used in
12:45social and behavioral Sciences
12:47and this allowed to capture
12:49infrequent or delayed phenomena
12:51from the landmark start point.
12:53Over the course of the disease,
12:56as opposed to other studies which looked
12:59at Lucas Cytosis at one time point.
13:02So is WBC increases surrogate marker
13:04or of disease evolution potential
13:06or is a prompt for cytoreduction,
13:09allowing us to prevent it?
13:11This particular question is not answered yet.
13:14I am privileged to represent our
13:16Cancer Center 1 NCM guideline,
13:18panel developing guidelines for Milo
13:21proliferative neoplasm and I'm going to.
13:23I show you the section which is related
13:26to management of polycythemia Vera.
13:28So the goals of management is to
13:31reduce the risk of thrombosis
13:33and hemorrhage control.
13:34The symptoms and try to prevent
13:37and delay disease transformation.
13:38Everyone with a diagnosis of PV
13:41should be receiving low dose
13:43aspirin as well as be phlebotomist.
13:45Two hematic rate goal of less than
13:48545% cardiovascular risk factors have
13:50to be managed as well as this as
13:53cardiovascular mobility and mortality.
13:55Is common among these patients,
13:57so the evidence behind aspirin in
14:00polycythemia Vera comes from this
14:02study which was published in 2004
14:04in New England Journal of medicine.
14:07Is this so called?
14:09The CLAP study evaluation of aspirin
14:11in polycythemia and it looked at
14:14probability of survival free of marker.
14:19Action and stroke and death from
14:22cardiovascular causes as well as P and DVT.
14:24That was the combined endpoint the
14:26aspirin uses as opposed to placebo.
14:29Users had 60% risk.
14:30Reduction of adverse events and
14:32incidents of major bleeding episodes
14:34was not significantly different
14:35in this low dose aspirin group.
14:37So the next recommendation in the guidelines
14:40is to keep him at ecrit below 45%.
14:43The study which was published in New
14:45England Journal of Medicine in 2013,
14:48confirmed this goal, which we actually.
14:50Using practice for many years,
14:52even before this article was published,
14:55it turns out that this stricter control
14:58of hematocrit using Phlebotomies
15:00as well as cytoreductive therapies
15:02is associated with four times
15:05decreased risk of traumatic events.
15:07So in regards to management of
15:10cardiovascular risk factors.
15:12Our group looked at use of statins
15:15and survival among older patients
15:17with polycythemia Vera using serum
15:20Medicaid and Medicare data set,
15:22so we identified them 721
15:24polycythemia Vera patients.
15:26Little bit more.
15:27Half of them use statins after diagnosis.
15:30Using univariate analysis on the left,
15:33we showed that starting users
15:35had improved survival.
15:37In multivariate analysis.
15:38We also showed that proportion
15:41of these covered.
15:43By 10 increase of proportion
15:45of discovered by 10% led to
15:48reduction of risk of death by 18%.
15:51So status is certainly beneficial
15:53for this group of patients.
15:56All the patients with polycythemia Vera,
15:59so the center of the algorithm
16:01of management of patients with
16:03polycythemia is there risk risk
16:06stratification based on 11 criteria.
16:08So patients are considered high
16:11risk for traumatic events,
16:13arterial and venous.
16:14If they are older than 60,
16:17or if they had history of Trumbo
16:19SIS so this patients beyond
16:21aspirin phlebotomy to America,
16:23lesson 45 and modification of
16:25cardiovascular risk factors should be
16:28on site to re directed therapy and
16:30frontline therapy recommended to this
16:33patience is either hydroxyurea or interferon.
16:35So of course if patients are not high risk
16:38and they developed worsening of symptoms,
16:41they have new traumatic
16:43events or bleeding events.
16:45They do not tolerate phlebotomy,
16:47which they continuously require,
16:49or they have elevated white cell
16:52count as well as platelet count.
16:54Cytoreductive therapy may be used as well,
16:57so there are no randomized
16:59studies looking at hydroxyurea in
17:00patients with polycythemia Vera.
17:03The reason why we're using it is
17:05mostly extrapolation from the studies,
17:08which were done for essential
17:10thrombocythemia patients,
17:10so we looked at 820 older patients with TV,
17:14once again using CR Medicee.
17:16Medicare data set and found out
17:20that about 40% of those patients
17:23who are high risk under did that,
17:26and looking at the treatment with
17:29everybody and specifically with hydroxyurea,
17:32we found out that every 1010% increase
17:36in proportion of days covered by
17:39hydroxyurea led to decrease risk
17:42of death by 8%.
17:44Similarly, increase of PTC by 10%.
17:47Lead to decrease of trim bushes by 8%,
17:50so this is certainly an effective
17:52treatment which are not only helps
17:55to prevent traumatic events but
17:57also improves survival in older
17:59patients with polycythemia Vera.
18:01As you can see, the benefit of lobotomy
18:04was also confirmed in this study.
18:07So why hydroxyurea works for PV patients?
18:10It's an oral chemotherapeutic
18:12agent that inhibits ribonucleotide
18:14reductase and interferes with the
18:16process of DNA synthesis and repair.
18:19It is cheap and has a reasonably
18:22favorable toxicity profile as well as
18:25long term safety data, including in
18:27children with sickle cell disease.
18:30Its mechanism of action in PV is debated
18:33but may include impact on blood counts.
18:37Ability to reduce neutrophil activity.
18:39Decreased expression of the filial
18:41adhesion molecules and in use
18:44of nitric oxide generation.
18:46Side effects occur and the drug is not
18:49tolerated by about 20% of patients.
18:51The side effects include mild suppression,
18:53mucocutaneous ulcers,
18:54non Melanoma skin cancers.
18:56It is also teratogenic.
18:58So the big question,
19:00which is still debated during MPM
19:03meetings and on the pages of publications,
19:07is hydroxyurea relationship
19:09with second malignancies,
19:10that hydroxyurea increase
19:12risk of 2nd malignancies.
19:14We again use your Medicare data set to look
19:18at second malignancies and one MPN patients.
19:23As you can see we started
19:26more than 3000 patients and.
19:29About 40% of them had polycythemia Vera.
19:32This patients were followed up to 10 years.
19:35Median follow-up was 2.67 years and
19:37median age of diagnosis was 77 years,
19:40so it's a little bit older than
19:43General PD population because of
19:45Medicare requirement for this study.
19:47So 65% of patients used hydroxyurea,
19:50allowing us to look at two groups,
19:53hydroxyurea users and nonusers.
19:55It is well known that second
19:58malignancy is common in.
20:00Patients with mild proliferative neoplasms,
20:02it is not really clear exactly why that is,
20:06but you can see that in our
20:10cohort of patients,
20:11about 8.8% developed second malignancy,
20:13more than half solid second malignancies,
20:16and among patients with
20:18hematological malignancies.
20:19Majority developed AML and MD
20:21S as expected in this group of
20:25patients with myeloid neoplasms.
20:27So when we compare two groups,
20:30hydroxyurea users and non users
20:32using univariate analysis,
20:34we found no difference in incidence
20:37of 2nd malignancies.
20:38In the multivariable analysis of
20:40hydroxyurea use and type of 2nd
20:43malignancies we found no difference in
20:46occurrence of all second malignancies,
20:49solid second malignancies and he
20:51metalogic non myeloid second malignancy's.
20:54We also did an analysis specifically.
20:57Aimed at my Lloyd second malignancies
20:59and there was no difference here either.
21:01So moving on this algorithm,
21:04if cytoreductive therapy stops
21:07working or is not tolerated.
21:11Have an option of second line
21:13sector reduction with ruxolitinib,
21:14which is the only FDA approved
21:16drug by the way,
21:18in polycythemia Vera neither hydroxyurea
21:20nor interferon I approved at this
21:22time in the United States by the FDA.
21:25So the interferon is used in Milo
21:29proliferative neoplasms for many years,
21:31and it is associated with decently
21:34high rates of haematological response
21:37reduction and independence form.
21:40Phlebotomies improvement of symptoms,
21:42and in some patients up to 30%
21:46significant reduction and disappearance
21:48of Jack 2V617F positive cells.
21:51Side effects include flu like symptoms.
21:55Psychiatric conditions and that's
21:56why this drug is not given
21:58to patients with psychiatric disorders
22:00as well as autoimmune side effects.
22:02Side effects are better
22:03with regulated preparations,
22:04which can be given once a week.
22:07One other thing which is quite important,
22:09this drug is not teratogenic and is
22:12preferred for younger patients with P Viera.
22:15So it has potential for disease modification
22:17by targeting the malignant clone,
22:20which is evidenced by disappearance
22:22of Jack 2V617F positive cells
22:25and some of those patients.
22:27This meta analysis of 41 studies,
22:30including 12181 patients,
22:31more than 500 of them had PV.
22:35The overall response rate was 75% with
22:38complete haematological response of 50.
22:41He presented in meta regression analysis.
22:43There was no different from between.
22:46No difference between Montag later than
22:48pig related interference in regards
22:51to response rates and thrombo embolic
22:53events and treatment discontinuation
22:55due to adverse events were not
22:57frequent .5% and 6.5% per year,
23:00respectively.
23:00Molecular responses,
23:01which is certainly interesting because
23:03we hope that this drug is disease.
23:06Modifying could not be analyzed
23:08in this particular meta analysis.
23:10You took heterogeneity.
23:11Of definition and outcome assessments.
23:13In conclusion,
23:14we thought that both regulated
23:16interference and non peculated
23:18interferon can be effective and safe.
23:20One term in P.
23:22Vera patients.
23:23So this is the response study
23:25which led to have the approval of
23:28Jack inhibitor rock solid Nip for
23:30second line treatment in patients
23:32with Vera with primary endpoint
23:35being composite reduction of spleen
23:37volume and hematocrit control.
23:38As you can see it was accomplished
23:41in 21% of patients separately.
23:43Reduction of spleen volume by 35%
23:46was seen in almost 40% of patients
23:48and 60% of patients could accomplish
23:51schematic control with this treatment.
23:53This is important anti-inflammatory
23:55medication and one of the side effects
23:57may be infections including herpes Auster.
24:00So we recommend Shingrix vaccine to
24:02all of our patients on rock solid net.
24:05Another side effect can be non
24:07Melanoma skin cancers which has
24:09increased incidence in Brooklyn of
24:11users but also in hydroxyurea users.
24:14So I refer all my patients for German
24:17irregular dermatological evaluations.
24:19So we looked at 5 year relative
24:22survival probability for PV patients
24:24in the United States.
24:26Patients who are diagnosed between
24:282001 and 2011 with end of observation
24:31in 2016 and as you can see this five
24:35year relative survival unfortunately
24:38is not getting better,
24:40so we need new drugs which may improve
24:43survival by modifying the disease.
24:46So this study looked at GNU interference
24:49formulation so called role peg interferon.
24:52This is a European study phase three
24:56trial comparing group peginterferon.
24:58Against hydroxyurea in high risk
25:00TV patient frontline treatment.
25:02The goal of the study was to
25:05show Noninferiority of Ro peg
25:08to hydroxyurea an at one year.
25:10Interestingly enough,
25:11they did not accomplish that primary
25:14endpoint of the hydroxyurea was
25:16superior from the standpoint of
25:19inducing complete haematological
25:20responses as well as you can see here,
25:23molecular responses at six months
25:26were higher among patients treated
25:28with hydroxyurea.
25:29So interferon in general takes time to work,
25:32and that's what we observed over
25:35the course of this
25:36study. So this is the publication which shows
25:40data up to three years of follow-up data,
25:43and you can see that in the second part of
25:46the study interferon did better from the
25:49standpoint of haematological responses,
25:52which were statistically significantly
25:53better than among patients taking
25:55hydroxyurea as well as molecular responses,
25:58and you can see that.
26:01This is actually improving overtime.
26:03This ash the follow up of the study
26:06five year follow up was presented
26:09showing continues that this translate
26:12continuing as well as there are
26:14no significant new side effects.
26:16So this new formulation of the
26:19interferon can be given once every
26:22three to four weeks after the first
26:25year of treatment and is now approved
26:28in Europe by European Medicines Agency.
26:31The company making this medication
26:33is bringing up to the bringing this
26:36to the US market and it is likely
26:39that this medication will become
26:41available for our patients next year.
26:44So there are few new treatments
26:47I wanted to mention before I end
26:50this talk and few clinical trials
26:52we're planning to participate in.
26:55Is giving ability to all patients to enroll
26:58on this study is offering new treatments,
27:01some of them?
27:02Maybe this is modifying so.
27:04First of all, this is the given
27:06a staff the age Deccan hitter,
27:09so leading to a situation of the histone.
27:13That transcriptions of genes
27:15responsible for cell growth,
27:17arrest, differentiation, apoptosis.
27:18This drug is wanna be started in the
27:22phase three trial against hydroxyurea
27:24for the frontline treatment of PV
27:27patients with high risk disease.
27:29So the other class of drugs which
27:32may be interesting is MDM.
27:34Two inhibitors.
27:35As you know MDM two inhibits TP53 function,
27:39and by inhibiting MDM two way
27:42allowing TP 53 to perform.
27:44It's wrong,
27:45not in the malignant cell,
27:47by the way,
27:48interfere on one of the mechanisms
27:49of action of interferon would
27:51be activations of genes,
27:53increasing transcription of TP 53
27:55so the last study I want to mention
27:57phase two trial of hepcidin analog.
27:59It's nice to see after discovery of
28:02hepcidin 20 years ago that we have
28:04an analog and you know we now have
28:07a test we can check for hepcidin.
28:09Very expensive.
28:10I never was able to do it but
28:14now we also have a drug.
28:16Which basically shuts down transport
28:18of iron and locks it in the cells
28:21and this drug is used for patients
28:24with severe who need phlebotomies
28:26and in an attempt to avoid iron
28:29deficiency which may have detrimental
28:31effects on quality of life.
28:33The preliminary results
28:34which office to study,
28:36which were presented at Ash week ago,
28:39were quite promising.
28:40No side effects and pretty much everyone on
28:43this drug does not require phlebotomist.
28:46Anymore.
28:46So I'd like to conclude that
28:49polycythemia Vera is driven by Jack
28:522V617F mutation in the majority of
28:55cases in 97% sugar intake increases
28:57and coffee intake decreases the risk
28:59of polycythemia Vera development.
29:01In fact,
29:02consumption of coffee moderate amounts
29:04can be considered part of normal lifestyle.
29:07Increased white cell count is
29:09associated with PV evolution.
29:11To post PD, Mila, fibrosis,
29:13MD, SNL user status should be
29:15considered in PV patients for.
29:18Cardiovascular disease risk reduction,
29:19hydroxyurea safe and effective,
29:21but interference holds promise to be disease.
29:24Modifying and normal treatments to
29:26prevent or delay disease transformation.
29:28I need it.
29:29At the end I would like to acknowledge
29:31funding from the Frederick Dilucca
29:34Foundation Yellow Corporate Center,
29:36allowing us to conduct the studies and
29:38my collaborators thank you very much.
29:42Nikolai absolute proof.
29:43So you can't see my coffee tears.
29:45It was coffee right now.
29:48Getting my very soon.
29:50Yeah, I think we just have.
29:52It may be time for just one
29:54or two questions because we
29:55want to give him his time.
29:57So are you thinking right?
29:58So for example in the other matters.
30:00Order in chronic malaria leukemia.
30:02We're thinking about Q or we
30:04want to get people off these
30:06long years of medication?
30:08Do you for see something
30:10like that for polycythemia
30:11Vera? You know you would hope that
30:13there is known driver and inhibiting
30:15it will cure this patience.
30:17But unfortunately, like now,
30:19with rooks Lid NAP,
30:20which is in an incubator of Jack two,
30:23we don't really see that.
30:25In fact it is not disease modifying
30:28if you ask me that you know so.
30:31Unfortunately,
30:32the successes we've had in CML did
30:35not translate to pH negative MPs,
30:37but you know,
30:38we have promising future medications.
30:40Or perhaps we'll have something which
30:42is going to decrease or eliminate
30:45that difference in survival.
30:47Our PV patients have when
30:49compared to regular population.
30:51OK, I see we have a comment from armor,
30:54great talk and many new exciting
30:56options available for these patients.
30:58So that was thank you Emerson.
30:59I share you enthusiasm.
31:01It is actually very challenging
31:02to do study for those patients because
31:04they have such a good prognosis
31:06comparing to all other cancer patients.
31:08So really have to have drugs which are not
31:10only working well but also well tolerated.
31:13Yeah, excellent.
31:14Well hematology is going to be
31:16around for many many more years.
31:18So thank you, Nicola.
31:19I think we should move on with Tama talk,
31:22so let me introduce Doctor to Microbee.
31:24He's associate Professor of Medicine
31:26and the medical director informed
31:28Chief of Operations and Quality.
31:29And I think everybody knows that
31:31tomorrow with the entire Smilow
31:33team has gotten the he malignancy
31:35service through the 1st surge of
31:37Covid an now the second surge.
31:39So thank you so much for that
31:41tomorrow also serves as the disease
31:43aligned research team or direct
31:44leader from my light malignancies.
31:47And tomorrow completed his doctorate
31:49in hematology oncology in Lyon,
31:50France, and then joined the Institute
31:52Power Lee comment in Marseille,
31:55in France,
31:55and he completed a fellowship at Johns
31:58Hopkins University as a Fulbright alumnus,
32:00and I think that's how eventually
32:03we got tomorrow to join us here.
32:05So Demott is focused on again
32:07pilot malignancy's leukemia,
32:09and I think his top will speak for his
32:12amazing expertise in treating these
32:14diseases and taking care of patients.
32:17So. To my valuers.
32:26Hope that everybody is seeing my screen now.
32:30OK so for today I want to focus my
32:35presentation and one on the topic of
32:39Milo dysplastic syndrome and more
32:42precisely, on the patient exposed,
32:45hyperventilating agent and we experience
32:48hyper mediating agent failure.
32:53Anne. So here are my disclosures.
33:01An ad to start wanted just to
33:03to do a really quick reminder
33:06on my love dysplastic syndrome.
33:09Stressing that we have with this disease,
33:13Arelia turgeon's group of
33:15clonal bone marrow neoplasms,
33:17we have the cytopenias due to the
33:20ineffective in multiple years is
33:23we have abnormal blood and bone
33:26marrow cell morphology and the risk
33:29of clonal evolution and progression
33:32to acute myeloid leukemia.
33:37From a molecular standpoint,
33:39these diseases are extremely generous with
33:43some main driver spliceosome mutation,
33:46such as the three one mutation
33:51epigenetic targeted mutation such as
33:54at Ted 2 for example, and EMT 3A and.
34:01This eternity is also something
34:03we see in the prognosis.
34:05I'm not going to go in the
34:07details of the risk stratification
34:09of Milo dysplastic syndrome,
34:11but I just want you to focus your
34:13attention on the right side of
34:16the panel where you would see that
34:18when we see a patient with mild
34:21dysplastic syndrome in clinic,
34:23we can see someone who has a median
34:26overall survival of more than eight years,
34:29as well as people that.
34:31In the worst case scenario,
34:34can progress to leukemia and
34:36die within a year,
34:38and so addressing this eternity
34:41is something that is on your mind.
34:45Each time we're seeing patient
34:48from the treatment standpoint,
34:50we can go from a pure observation
34:53for patients without any symptoms
34:56or significant cytopenia to some
34:59low intensity treatment such as.
35:02Activating stimulating agent
35:03for patients with anemia,
35:04but in the context of the
35:07higher risk disease,
35:08the mainstay of treatment as being
35:10to use iPod mitigating agent,
35:12namely as cited in or decide to be in.
35:16Over the last few years and for the
35:19few patient eligible allogeneic stem
35:22cell transplantation is obviously
35:24something that we would consider frontline.
35:28That's a pretty classic for all NDS talk.
35:33That's basically the registration
35:35study of as a sighted in MD's,
35:38showing that with Asia we are able
35:42to prolong the median overall
35:45survival of probably nine months in
35:48median as compared to conventional.
35:52Care we definitely have evidences
35:55that the 24 months of median overall
35:58survival that we see in this study
36:01are probably a bit overestimated as
36:03compared to what we see in real life.
36:07Probably around 18 months.
36:08And that's many works from basically
36:11the registry studies such as the group
36:14Uncle Phone, Digital Displays E,
36:16but also some really nice work of
36:19Stephen Armor. For example on CS.
36:24Data. So.
36:25What do we call activating agent failure?
36:29Because we know that at the end 90
36:32to 95% of the patient that we start
36:35treating with this iPod mediating
36:37agent will experience on the real failure.
36:41We classically defined that as a
36:43lack of response or progression
36:45after at least four to six cycle
36:48of iPod mediating agent,
36:50there's no difference between as cited in
36:53or decided in from this standpoint and.
36:56One of the main features that
36:59we see is really,
37:01really limited overall survival
37:03for patients experiencing failure
37:05treatment within average four
37:07to six months median survival,
37:09and that's something that,
37:11as that we initially described almost
37:1410 years ago and that has been since
37:17reproduced in many different studies.
37:20So Interestingly,
37:21we have many reason why this hyper
37:24mitigating agent resistant can developed,
37:26but so far we can say that we have
37:29a home run we don't consider that we
37:33have a unifying theory to explain
37:36why we have this failure of this
37:39iPod engagement.
37:39We see phenomenon of clonal
37:41selection and clonal evolution,
37:43maybe potentially with some difference
37:45of profiling between the patient that
37:48are completely refractory to the disease.
37:50In the patient that.
37:52Response and then progress after treatment.
37:55But many other mechanisms have
37:57been potentially put on the table
37:59as explaining what we see or to
38:02fatty affect change in nucleotide
38:04analogue transporter expression of
38:07immune checkpoint inhibitors and
38:09regulators and we will circle back
38:11on that later in the presentation.
38:14So for the moment there's still a
38:17lot of open questions on explaining
38:20this hypomethylating agent failure.
38:23There's obviously also something
38:25that is pretty clear which is
38:28the role of the stem cell.
38:31Quiescence and resistance MD's are stamps,
38:34stem cell diseases,
38:35and even in responding patients.
38:38For example,
38:39correct there IMO globin and that
38:41have a decrease in their blast counts,
38:45like here in there in the blue line,
38:49we can still detect
38:51cytogenetics abnormalities.
38:52And more Interestingly,
38:53we can still detect stem cells
38:56like LTC IC's for example,
38:57that harbors marker of the
38:59minor dysplastic syndrome,
39:00and so that's something that is
39:02important when it comes to the
39:04way we're considering treatment,
39:06not only for relapse,
39:07but on a more general basis from
39:10the from the from the get go on
39:12the diagnosis of this patient.
39:17Let's talk about the treatment now.
39:20We reviewed a few years ago.
39:23What were the option for this patient
39:26with some health care treatment?
39:29And let's say that nothing is really
39:32satisfying with the exception of the few
39:35patient that can potentially transition to
39:38an allogeneic stem cell transplantation,
39:41either directly after relapse, or,
39:43for example, after intensive cytoreduction.
39:46With chemotherapy,
39:47so there's been a lot of basically
39:50investigation around what we can do
39:52when it comes to intensive treatment.
39:54Brute force approaches for HMA failure.
39:56We try to dig deeper, a bit on the data that.
40:00We initially generated.
40:02On induction, as we may have a lot
40:06of different type of induction,
40:08we can potentially use in this context.
40:12Conventional 7 + 3 regimen like we would
40:15be doing in newly diagnosed AML Internet
40:18to hide those site arabien regimen.
40:21And that's something we're doing,
40:23mostly on the European side as well
40:26as pure in analog based regimen
40:29such as flag or flag idea that.
40:33We see on both side of the of the Atlantic,
40:37and so we gather basically group
40:41of 15 different.
40:43Investigator you ran in the US and put
40:47together basically a data set of 307
40:50patient with maladies plastic syndrome
40:53treated with induction chemotherapy.
40:56We found that roughly.
40:5941% of the patient will achieve
41:02a complete remission with only a
41:05median overall survival of 11 months.
41:07The two take home message from this
41:11work that we developed at here with
41:14Brian Bowl a few years ago was one
41:18that we do not so any real significant
41:22difference between the conventional 7
41:25+ 3 the intensive hydac regimen or the.
41:29Genopro,
41:29Fabian based regimen and I think also
41:33pretty importantly that all patient
41:35that did not have a chance to bridge to
41:38analogy in transplantation died within
41:40a year of the initiation of treatment.
41:43So that's pretty telling on the
41:46fact that we definitely need to
41:48develop more option for this patient,
41:51including from the initiation of response,
41:53but also on the transplant to make
41:56sure that we can maximize access.
41:59Uh, to transplant for all of these patients.
42:05One of the extension and one of the.
42:08Development following this initial
42:10study was to maybe try to use a
42:14better drug for induction chemo
42:16chemotherapy for this patient,
42:18and we had CP351D liposomal formulation
42:20of Donna Mycin and Sitara been that
42:24was approved two years ago three years
42:26ago now for acute myeloid leukemia
42:29arising from Milo dysplastic syndrome.
42:32And so we're thinking about this
42:35internally approaches that was kind of a
42:38natural conclusion to basically try to use.
42:41Pretty similar drug to achieve response in
42:44HMA resistant BI lo dysplastic syndrome.
42:48That's a phase two study that we
42:52developed with Prajwal Bodo at
42:55Yale as a multicenter IIT,
42:57and the plan is basically to give two
43:01cycles of induction with two days
43:05of CPX in acute myeloid leukemia.
43:08We usually use three days of CPX, 4.
43:12Induction,
43:13but there's some data showing that from a
43:16safety standpoint,
43:17especially in elderly patient two days,
43:19maybe probably more appropriate,
43:21and the patient that are responding,
43:23we can continue for six cycle of
43:26maintenance with one day of civics or
43:28transition to bone marrow transplantation.
43:31The study is open to accrual after
43:34the Covid adventures that we had over
43:37the last year and we open running.
43:40So all these non selected approach,
43:43induction chemotherapy but also
43:45basically non targeted agent that
43:47we have developed over the years.
43:49For the moment,
43:51let's say that we have not found
43:54any real good candidate to
43:56be a standard of care option,
43:59especially for patients that are
44:01not eligible for aggressive chemo.
44:03I've just listed here a few of
44:07the studies but as you can see.
44:10In lots of these general studies
44:13without any real targeting,
44:15when situation where the response
44:17rates are low and more importantly,
44:20the overall survival seems still
44:23stuck below below one year,
44:25so we definitely need to do better.
44:30And that goes back to the way we
44:33considering the pathophysiology
44:34of this disease,
44:36and acknowledge that this HMA failure or not,
44:39and imaginas situation,
44:41just to give an example.
44:43We see that from just a clinical
44:45standpoint we see different outcome
44:48in patients at our primary refractory
44:51and really do not respond at
44:53all to hyper mediating agent in
44:55patients with relapsing disease.
44:57That basically seems to have
44:59a bit more favorable.
45:01Outcome in this context so
45:03still a lot of work to do on the
45:07translational and basic science side.
45:09One way we've tried to tackle this
45:13difference of outcome based on this
45:15clinical finding was to deal with
45:18the stable disease with a slightly
45:21different term than just using.
45:24Regular treatment by adding on
45:26on the hyperventilating agent,
45:28potentially drug that may be
45:31synergistic based on their mode of
45:34action or based on in vitro studies.
45:37We had several attempts at this
45:40over the last years.
45:42An easy combination and logical
45:45combination was to add on the
45:48almighty engage in the second
45:51epigenetic targeted agent.
45:52As such, as H.
45:54Dark inhibitor,
45:55then we treated 19 patient with vorinostat,
45:59which is one of the first in
46:02Class Age document or with,
46:04unfortunately,
46:05pretty limited outcome really
46:07knows how that rate of only 10%,
46:10but the median survival of 12 months in
46:14potentially a pretty selected population.
46:17We also tried to use a bit more recently,
46:20and that's not a fully public published yet.
46:23The addition of a smooth and
46:25inhibitor to try to use really
46:27work on the stem cell component.
46:29There's some individual data showing that
46:32this moves on emitter can potentially.
46:35Abrogates the resistance
46:36to hypomethylating agent,
46:37but so far the results were
46:40pretty disappointing too.
46:41Well not to be completely gloom.
46:44There's end at the at the probably
46:47light at the end of the tunnel.
46:50I need to highlight the
46:52work presented by armor.
46:54If you have a year ago.
46:57Basically at the ash meeting
46:58on the add on of venetoclax in
47:01maybe less selected population.
47:0424 patient is. Resistance with this
47:06edition of the BCL, two inhibitor or some
47:10real complete remission and some marrow.
47:14Chimia Free State with a six months program.
47:18French fries survival 76% that from our
47:21standard is pretty pretty promising.
47:23So statue and we will have more information,
47:27but that's one of the Avenue that
47:30we are currently investigating.
47:33Stop. That's. Pretty good,
47:35that's basically based on a
47:38combination of mode of action.
47:41That's still not something that really
47:44address the specificity of the clone
47:46of the Milo dysplastic syndrome,
47:49and maybe instead of using brute
47:51force to try to induce a response,
47:55we can maybe try to outsmart the
47:58disease rather than just using those
48:00intensity or non selected approaches
48:03in the context of Milo dysplastic.
48:06Syndrome,
48:06where a bit less fortunate that
48:08in the acute model in the world,
48:10as we don't have so many targeted agent that
48:13we can use at the majority of the patient,
48:16will have as a freebie wanted two
48:19SS two mutation that are for the
48:21moment at least non targetable,
48:23even if there's some basically
48:25development on the side and I'm going
48:28to take the example of some product
48:30we have done in the in the IDH world.
48:33And that can potentially be avenues
48:36that we going to explore in the
48:38future to try to get a better
48:41outcome for these patients.
48:43So we have this idea inhibit
48:45or letter basically allosteric
48:47inhibitors from IDH two and IDH one.
48:50I did too.
48:51That's in a Sydney IDs, one that's evil.
48:54Setting it in both of the phase.
48:57One study of this compounds model,
49:00spastic syndrome patient were allowed
49:02after at least one line of treatment.
49:0676% of the patient seems to be able to to
49:10respond with the IDH two sorry 559% of the
49:15patient seems to be able to respond to IDH,
49:19two inhibitor and maybe a bit more in the
49:23IDH one subclone with a 71% response rate.
49:27As you can see,
49:28that's pretty small samples of patient.
49:31There's ongoing investigation
49:33with this IDH inhibitor,
49:35single agent or combination.
49:36The one thing that is pretty striking,
49:39the fact that we're probably in a
49:41situation where the duration of
49:43response is still pretty limited,
49:45so.
49:45Potentially we can try to
49:48find some alternatives to IDH
49:50inhibitor on this context,
49:52and that's potentially when I was
49:54mentioning outsmarting the disease.
49:56I'm not that smart guy,
49:58but I had the chance and that will
50:00work with really intelligent people
50:02branded Bindra Stephanie Allen,
50:04for example,
50:05and you may know the story that
50:08was developed by Ranjit over the
50:10last years about the fact that
50:13when you have an IDH mutation
50:15that was initially basically.
50:17Developed and found in gliomas the
50:21fact of having these two hydroxy
50:25glutarate will basically impair the
50:29activity of the X Rays in the cell,
50:33decrease malicious recommendation,
50:36repair and create a braknis phenotype.
50:40That obviously is interesting as a
50:43potentially chemo radio sensitizer,
50:45but from all standpoints were
50:48especially interested in our.
50:50Potentially, we can use pop emitters
50:53to create synthetic lethality with
50:55this agent, and when we tested,
50:58basically when we move from gliomas to
51:01leukemias and Milo dysplastic syndromes,
51:04indeed, that's what we found that
51:07we were able to potentially.
51:10Induce apoptosis in samples of patient
51:13that were exposed to hyperventilate.
51:16Engagement that were exposed to IDH
51:20inhibitor an that I came to development
51:24with NCI study right now of the olaparib.
51:28The 1st in Class I DH pop inhibitor
51:32for patient offering IDH mutation.
51:36So that's patient that as a diagnosis of.
51:40Acute myeloid leukemia or marriages.
51:43Plastic syndrome with an IDH one
51:46or IDH two mutation and at least
51:49one prior line of treatment,
51:51including in lot of this patient
51:54I permitting.
51:55Agent there are four cohorts
51:58that are currently investigated.
52:00One for patients with IDH, one IDH,
52:03two mutant email without prior
52:05exposure to IDH.
52:07And if it or one with my
52:10dysplastic syndrome without.
52:12Exposure to ideas,
52:13debit,
52:13or an arm two and four are for patient
52:17in acute myeloid leukemia and maladies
52:19plastic syndrome that were already
52:22exposed to IDH inhibitor in the
52:24patient that are naive of IDH inhibitor.
52:27We have an early response assessments
52:30after one cycle and if we do not
52:33see any clear clinical benefit,
52:35this patient are usually discontinued.
52:37An transition classical IDH
52:39inhibitor for the patient that are
52:41responding to the patient that were
52:44previously exposed to accommodating.
52:46Agent and IDH numitor.
52:48We are reassessing response after three,
52:5169 and 12 cycles,
52:52continuing the treatment until progression.
52:55The study has been activated this
52:58year and we're pretty happy to
53:00have over the last few months.
53:03Three patient included an in treatment
53:07an three patienten screening right now.
53:10One of the big interest of this
53:13work is also to see the pretty
53:17extensive collaboration we have.
53:19From a translational standpoint,
53:21that's collaboration with the
53:23NCI through more calf or what
53:26exam sequencing and sequencing.
53:28That's a lot of study done in hours
53:31at Yale with Ranjit and Stephanie
53:34to explore from ex vivo samples.
53:38DNA damage.
53:39Response,
53:39but also all these cells will
53:42behave put in the Mr Jimmys model
53:46that Stephanie is developing.
53:48We have collaboration with Domino's
53:50thanks to Pat Larusso and that
53:53collaboration with Jiggly to assess the
53:56evolution of the two hydroxy glutarate
53:59and some metabolomics marker Anne.
54:02Right now we are starting starting to work
54:06with winning Wong from the West Campus.
54:09On single cell sequencing for this.
54:15Specific samples an studies,
54:16as we definitely think that we
54:19will have some clonal selection as
54:21potentially one of the mechanism
54:23of resistance in this context.
54:25So stay tuned.
54:26That's a bit early to make any
54:28any conclusion.
54:30We just have a few patients
54:32in a few months on treatment,
54:34but that's a developing story.
54:38As I was saying earlier,
54:39one of the things that has also been
54:42mentioned as a mechanism of resistance,
54:44and I try to go fast on that.
54:48Is uh,
54:48even though logic escape of the matter.
54:51Dysplastic syndrome.
54:52We have an over expression of PD,
54:55One PD L1 and C A4 in.
54:59Patient with hypomethylating agent
55:01failure and that's led to several
55:04several studies I'm mentioning here.
55:07Studies with basically ipis,
55:08nivo or Pam bro.
55:10I also need obviously to to mention
55:13that the study led by armor with
55:16basically edge darkening bitters
55:18plus checkpoint blockade inhibitors
55:20that was recently published.
55:23For the moment,
55:24let's say that we are not at the point where.
55:30It's a game changer.
55:31There may be some kind of response,
55:34but for the moment,
55:35nothing that is really perfect.
55:37So still a lot of work to do.
55:40One way we thought about that is
55:43potentially to try to bring this.
55:46Potentially checkpoint inhibitor
55:48earlier in the development,
55:50and for instance,
55:52we're currently developing a study in
55:56an MD S an email of idea 2012 plus
56:01nivolumab in Phase one pilot study for
56:05patients that were already exposed
56:08to chemotherapy or iPod mediating agent.
56:14Another study has been on all and has
56:17to be restructured because of covid,
56:20but we're back in business
56:22and open to accrual oor.
56:24Since basically lost last week.
56:27Once again translation and collective
56:29studies are really important and
56:31we have some ongoing collaboration
56:33with Stephanie and will in one so.
56:37If I need to to summarize a bit where
56:40we are really quickly for the moment
56:43for this patient with permitting
56:45agent failure with Steven situation
56:48where aggressive management for
56:50transplant allogeneic transplant
56:52candidate makes sense as we don't
56:54have any really reliable other
56:57option besides maybe some targeted
56:59therapy on small number of patients,
57:01we do not have a reliable standard of
57:04care for patients and fit for treatment.
57:08Maybe even eight o'clock,
57:09maybe some other drug will come
57:11and will be confirmed as option,
57:13but for the moment that's still
57:14pretty struggling.
57:17The way the field is moving is
57:20interesting and we are learning
57:22a lot from the email world.
57:24At the same time, we probably
57:27cannot really completely extrapolate
57:29everything we do from the email side,
57:31we know that the microenvironment,
57:33for example in Milo dysplastic
57:35syndrome is definitely different.
57:37We know that the ability of this
57:40patient to sustain any aggressive
57:42treatment is definitely less than what
57:45we see in AML on other malignancy so.
57:48That's something that we need
57:50to work on and so.
57:52The best way we have to deal with this
57:55HTML file is ready to try to avoid it
57:58and optimize the frontline treatment.
58:00We have lots of currently really
58:02exciting drugs in the pipeline.
58:04Lots of data that we presented at the Ash
58:07this year on Venetoclax Magnolia Map team.
58:10Three BitTorrent.
58:11Amar has been part of some of these studies,
58:14so statue MBS Field is really moving
58:18and we hope to see the type of.
58:21Change in landscape that we have seen over
58:24at the last year in acute myeloid leukemia.
58:27So in conclusion,
58:28this this situation of hyper mediating
58:30agent failure really represent some
58:31academic challenges we need to improve
58:34our understanding of the Physiology.
58:36Pathophysiology of this situation to
58:37be able to help us to better define
58:40the standard of care for this patient,
58:43we need to build resources we need to build,
58:46represent repository and logical.
58:47Follow up for this patient which
58:50is sometimes challenging.
58:51I.
58:53In the context of a disease that is
58:55treated in both small and big centers,
58:58we need to collaborate around
59:00academics to be able to really have
59:02significant number of patients to be
59:05able to answer the right question.
59:07I also think that it's important
59:09to keep in mind that there are some
59:11clinical care challenges for that.
59:13The access to innovation to Center
59:15of excellence is not something that
59:17is a modulus in the country or
59:19just a modulus in Connecticut.
59:21And that's definitely one of the mission.
59:23I think we have at scale to be able
59:26to promote the access to innovation
59:28and promote the access to the Center
59:31of excellence that that we have.
59:34We know that patients in Connecticut
59:36without without snowstorm like
59:38tomorrow will have potentially some
59:40some issues limiting the ability to
59:42to basically get to academic centers,
59:44get to clinical trial,
59:46and so I think that one of the
59:48mission that we have as academics
59:51is also to make sure that we can
59:54potentially bring research.
59:55Bring basically knew therapy and exciting
59:58therapy to the different sites where
01:00:01the patients are treated close to their home.
01:00:04With that I would like to thanks everyone.
01:00:08Right?
01:00:08Participate to this effort for sure.
01:00:11The Yellow Cancer Center
01:00:13group alphabetically.
01:00:14Steve Gore.
01:00:15My mentor Stephanie for lot of collaboration.
01:00:18Nicolai,
01:00:18Rory and armor for being such
01:00:20trooper an such a great group to
01:00:23work with my dear colleagues,
01:00:25colleagues from the group Francophone,
01:00:27the Mirror Displays E,
01:00:29as well as collaborators in US,
01:00:31Europe. And now I should say,
01:00:34knew K should probably split.
01:00:36You can Europe now two weeks anyway.
01:00:39On that I'll take any questions
01:00:41I would like to thank you for
01:00:43your attention. Thanks so much.
01:00:46Sounds fantastic to my thank you so much.
01:00:49Really true for some, and MD's and AML and.
01:00:53You know, as we are presenting,
01:00:55you've actually answered
01:00:56like my burning questions.
01:00:57We just get rid of a society in, you know,
01:01:00and use it for salvage after everything else.
01:01:03And that is certainly very exciting
01:01:05to see how you and the whole team are
01:01:08going to come up with exciting trials.
01:01:10I think we're a little bit after the hour,
01:01:14but maybe. Say something sad,
01:01:17or Nickelodeon request and then
01:01:18we have to let people go for two
01:01:21or getting kicked out of the room.
01:01:23Which is correct?
01:01:26No, I think that's definitely
01:01:28the HMA is a sign of care,
01:01:30but that's not a perfect one.
01:01:33So developing new agents or
01:01:34new formulation, for example,
01:01:36we have now access to oral formulation
01:01:38of these hypomethylating agent.
01:01:40That's definitely something that we
01:01:42want to continue to develop with the
01:01:45idea that even if it may not improve
01:01:48the response rate or the overall
01:01:50survival and that may be something
01:01:52we can discuss as the way we can.
01:01:56I use this medication is a bit
01:01:59different than conventional
01:02:00accommodating age and we can
01:02:02improve quality of life of the.
01:02:04And access to care,
01:02:05so that's definitely something
01:02:07that is that is important for sure.
01:02:10Yeah, fantastic so Charlie,
01:02:11do you want to tell me?
01:02:14We probably have to break.
01:02:15No thank you tomorrow and
01:02:17Nikolai for two superb talks
01:02:19really as two to four's on two
01:02:21important areas of human logic.
01:02:23Malignancy's, thank you.
01:02:25Thank you alright.
01:02:26Well thank you so much and look forward
01:02:29to tackling these problems over
01:02:31the years. Thank you.
01:02:32Thanks everyone. Alright bye.