"Polycythemia Vera (PV): Epidemiology, Prognosis and Real-world Outcomes" and "Overcoming hypomethylating agent failure in acute myeloid leukemias and myelodysplastic syndromes"
December 16, 2020Information
Yale Cancer Center Grand Rounds | December 15, 2020
Nikolai Podoltsev, MD, PhD and Thomas Prebet, MD, PhD
ID6014
To CiteDCA Citation Guide
- 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.