Yale ASH 2022 Highlights: Classical Hematology

Transcript

• 00:03All right. Good afternoon, everybody,
• 00:06and welcome to the classical
• 00:08hematology review of the American
• 00:10Society of Hematology meeting in 2022.
• 00:13Thank you for joining us.
• 00:16My name is Robert Bona.
• 00:17I work here at Yale in the section of
• 00:20hematology and I'm very excited and happy
• 00:22to introduce our three speakers today.
• 00:25I will be brief with their introductions
• 00:27since I don't want to take away
• 00:29time from the important things that
• 00:30they're going to talk with us about.
• 00:32Lila van Doren. We'll begin our discussion.
• 00:34Lila joined.
• 00:35All three of our faculty actually
• 00:37have joined the classical hematology
• 00:39program at Yale this academic year.
• 00:41And Lila joined us from Columbia and
• 00:43she brings a wealth of experience
• 00:45and knowledge with her.
• 00:47And at Yale she is going to be
• 00:49focusing on sickle cell diseases and
• 00:52iron disorders of iron hemostasis
• 00:54in particular iron homeostasis in
• 00:56particular in the area of of Women's Health.
• 01:00Doctor Gashua,
• 01:02Yale fellow.
• 01:03And graduate of the Harvard Public
• 01:05School of Health is focusing his work
• 01:08research work here at Yale on decision
• 01:11science analysis and hematologic disorders.
• 01:14And Annie Sharda joined us from the
• 01:16Beth Israel Deaconess Medical Center.
• 01:17He has a active laboratory program
• 01:20looking at endothelial function and
• 01:23in particular the expression and
• 01:25secretion of von Willebrand factor.
• 01:28So again,
• 01:28we're,
• 01:29I'm very excited to to to have them
• 01:31present their work to us today or their.
• 01:34Their review of some of the ash.
• 01:37Up hot abstracts and please put
• 01:40your questions in the chat room
• 01:43or in the Q&A and we'll get to
• 01:46those at the end of the session.
• 01:47Each of our presenters will present
• 01:49for about 15 minutes and then
• 01:52we'll take questions at the end.
• 01:54So without further ado,
• 01:55Doctor Van Dorn,
• 01:57would you like to get us started?
• 02:00Share my screen. And. There we go.
• 02:06OK, these are my disclosures. All right.
• 02:09These are the two abstracts that
• 02:11I'm going to be discussing today,
• 02:12so we'll just jump into it.
• 02:14The first abstract is focused on
• 02:16inherited thrombophilia and pregnancy,
• 02:18anticoagulation and thrombophilia testing.
• 02:22So I wanted to start out with the case first.
• 02:24It's a 38 year old patient who presents
• 02:27for evaluation at 8 weeks gestation.
• 02:29She's the history of three miscarriages
• 02:31in the first trimester anti phospholipid
• 02:34antibody testing was previously negative but
• 02:36she was found to be positive for Factor 5,
• 02:39Leiden heterozygous mutation.
• 02:41And the question is would you recommend
• 02:44anticoagulation during pregnancy for this
• 02:46patient to increase her chance of live birth?
• 02:49So the background is that studies
• 02:51have shown an association.
• 02:53Between recurrent miscarriage and inherited
• 02:55thrombophilia for women with a PLS,
• 02:58we know that the use of heparin or low
• 03:00molecular weight heparin and combined
• 03:01with low dose aspirin is an effective
• 03:04treatment for recurrent miscarriage.
• 03:06And the thought about the role of
• 03:08thrombophilia recurrent miscarriage
• 03:10is that it can be explained partially
• 03:12by the concept of thrombosis of the
• 03:15microvasculature of the placenta.
• 03:16And so it is thought that anticoagulant
• 03:18therapy might reduce miscarriages and
• 03:21adverse pregnancy outcomes in patients
• 03:23with inherited thrombophilia as well.
• 03:25However,
• 03:25there's a lack of solid
• 03:27evidence for this practice.
• 03:29And so in 2010 a study was published,
• 03:33a life study that was a randomized
• 03:36placebo-controlled study investigating
• 03:37whether aspirin plus low molecular
• 03:40weight heparin or aspirin alone
• 03:43combined oh compared to placebo
• 03:44would improve the live birth.
• 03:46Among 364 women,
• 03:47so there were three different arms
• 03:49and what this study showed was
• 03:51that there was no difference in
• 03:53the live birth rates between the
• 03:55study groups with the relative risk
• 03:57of 1.03 and in patient specific.
• 04:00Thrombophilia,
• 04:00there was also no difference,
• 04:02although the number of patients
• 04:04in the study with an inherited
• 04:07thrombophilia were was very low and so.
• 04:10Which brings us to the a life two study,
• 04:12the first abstract,
• 04:14which was a late breaking abstract
• 04:16at ASH in December 2022,
• 04:18and it was ten years in the making.
• 04:20So the objective of the A life two
• 04:23study was specifically to evaluate
• 04:25the efficacy of low molecular weight
• 04:27heparin and women with an inherited
• 04:30thrombophilia with recurrent miscarriage.
• 04:31And so the way this study was
• 04:33designed is that patients who had a
• 04:36history of two or more miscarriages
• 04:38with an inherited thrombophilia,
• 04:40no more than seven weeks gestational
• 04:42age could be enrolled.
• 04:43They were randomized 1 to one to
• 04:45receive either a low molecular weight
• 04:47heparin and those are the different
• 04:49ones that that were used in the study
• 04:51plus the standard of pregnancy care
• 04:53or a standard of pregnancy care alone.
• 04:56The outcomes was the primary efficacy
• 04:58outcome was the live birth rate,
• 05:00secondary efficacy.
• 05:01This miscarriage or adverse
• 05:03obstetric outcomes and then safety
• 05:05was looked at as well.
• 05:06And so these are the
• 05:07characteristics of the patients.
• 05:09The mean age was 33 and
• 05:11the majority of patients
• 05:13actually had three or more miscarriages.
• 05:16The most common inherited thrombophilia
• 05:18was the factor 5 Leiden heterozygous
• 05:20followed by prothrombin gene mutation,
• 05:22heterozygous protein ESTA efficiency
• 05:24and then a mix of antithrombin combined
• 05:28thrombophilias and then protein C deficiency.
• 05:32And the outcome of the study was that there
• 05:34was no difference between the standard of
• 05:37care and low molecular weight heparin plus
• 05:39standard of care in the live birth rate.
• 05:42So the odds ratio was 1.04 when
• 05:44this was adjusted for age.
• 05:46So less than or greater than
• 05:48or equal to 36 years old,
• 05:50the number of miscarriages or the center.
• 05:52So if the patient was treated at a
• 05:54tertiary center or a non tertiary center,
• 05:56or by country UK versus the Netherlands,
• 05:59there was still no difference
• 06:01between the live birth rate.
• 06:02In the different arms.
• 06:05In terms of the differences
• 06:07in adverse effects,
• 06:08there were more adverse effects in patients
• 06:10receiving low molecular weight heparin,
• 06:12such as easy bruising,
• 06:14skin reactions,
• 06:15that injection site and minor bleeding.
• 06:18And so the conclusions of this study
• 06:20was that low molecular weight heparin
• 06:22did not result in a higher life birth
• 06:25rate in women who had greater than
• 06:27or equal to two pregnancy losses and
• 06:30confirmed inherited thrombophilia.
• 06:31And the recommendation is to not use
• 06:33low molecular weight heparin in women
• 06:35with recurrent pregnancy loss and
• 06:37confirmed inherited thrombophilias
• 06:39to prevent pregnancy loss.
• 06:41And so this also speaks to,
• 06:44not against,
• 06:45the routine testing for inherited
• 06:48thrombophilia in women with
• 06:50recurrent pregnancy loss.
• 06:52So that is the first abstract.
• 06:54The second abstract will focus on
• 06:56sickle cell disease, diarrhea,
• 06:58and diminished ovarian reserve.
• 07:01So second case,
• 07:02a patient comes to you 12 years old.
• 07:05She has a history of avascular necrosis
• 07:08and very rare vasal clusive crises
• 07:10she presents for initial visit.
• 07:12During the visit you discussed
• 07:14the importance of hydroxyurea as
• 07:16a disease modifying therapy.
• 07:18She notes that her previous provider
• 07:20told her she does not require hydroxyurea
• 07:22therapy due to infrequent basal,
• 07:24occlusive crises.
• 07:25But furthermore,
• 07:26most concern for her is a Facebook,
• 07:29Facebook group that she's a part of
• 07:31recommends not taking it for those
• 07:33who desire to have children in the
• 07:34future as it leads to infertility.
• 07:36So there is quite a bit of evidence for
• 07:40hydroxyurea and fertility in males.
• 07:42We know that it leads to lower sperm counts.
• 07:45Which improves with cessation of hydroxyurea.
• 07:48But we don't have a lot of data
• 07:50available for the use of hydroxyurea
• 07:52and diminished ovarian reserve in in
• 07:54female patients with sickle cell disease.
• 07:57And so from the evidence that we do have,
• 07:59we do know that patients with sickle
• 08:01cell disease have a higher rate of
• 08:04diminished ovarian reserve compared
• 08:05to those who are age and age,
• 08:07race and sex match to to patients
• 08:10with sickle cell disease,
• 08:12there is much more of a sharper
• 08:14trajectory of decline.
• 08:15Of diminished ovarian reserve.
• 08:17And the thought is that this is and
• 08:20it was a theory again it had not
• 08:22previously been proven.
• 08:23The thought is that this is related to
• 08:26hemolysis and anemia based occlusion.
• 08:28Basically any organ that can be
• 08:30affected by sickle cell disease,
• 08:32which is every organ in the body,
• 08:33the ovaries included, can.
• 08:35This can all lead to
• 08:37diminished ovarian reserve.
• 08:39And one thing that we don't know
• 08:41is that is hydroxy hydroxyurea,
• 08:43is it a friend or a foe?
• 08:45So we know that hydroxyurea causes.
• 08:48Reduction and disease severity.
• 08:50So in theory it should be preventing this
• 08:53accelerated age-related loss of eggs,
• 08:56but does it actually also contribute to
• 08:59the accelerated age-related loss of eggs?
• 09:02And that is the question that
• 09:04we don't know the answer to.
• 09:06And so this study was actually
• 09:08this is a background study.
• 09:10So this was done from the MULTICENTRIC
• 09:13study of hydroxyurea and it was
• 09:16the pivotal trial that showed the
• 09:18benefits of hydroxyurea in patients
• 09:21to present to prevent organ damage.
• 09:23And what this shows here is that
• 09:25you can see at every age level
• 09:28starting from 20 to 25,
• 09:30we see that there's an age associated decline
• 09:33in the AM H level which is a marker of.
• 09:36Administration ovarian reserve when the MH
• 09:38level is less than 1.1 nanograms per ML.
• 09:41This contributes to the definition
• 09:42of diminished ovarian reserve.
• 09:44The dark lines here are the median
• 09:46age control match ADH levels and
• 09:48the the the Gray boxes here these
• 09:50are patients with sickle cell.
• 09:52So we see even at age 20 to 25 years old,
• 09:56there is lower a MH levels compared
• 09:59to the controls and it's not until
• 10:01age 40 to 46 where we see that
• 10:04the controls as well as patients.
• 10:06Sickle cell disease both have
• 10:09AMH levels of less than 1.1.
• 10:13And so we what do we know?
• 10:15We know that patients with sickle cell
• 10:18have higher rates of diminished ovarian
• 10:20reserve at least starting 25 to 30 years old.
• 10:23The relationship between diminished
• 10:24ovarian reserve and pregnancy
• 10:26outcomes and live births in sickle
• 10:27cell does require further study
• 10:29because that doesn't answer the
• 10:30question we don't have an answer to.
• 10:32But the data regarding venata toxicity
• 10:34in women with sickle cell disease who
• 10:37are taking hydroxyurea is limited,
• 10:39and it's thought that hydroxyurea
• 10:41use might be a surrogate.
• 10:43The disease severity rather than
• 10:45the hydroxyurea itself causing
• 10:47diminished ovarian reserve.
• 10:49And so this is an next abstract and
• 10:52their study aimed to assess this
• 10:55does hydroxyurea and does basal
• 10:58occlusive crises cause diminished
• 11:01ovarian follicle density?
• 11:03And in girls and young females
• 11:06with sickle cell disease?
• 11:07And so this study,
• 11:09it was designed 88 patients with
• 11:11hemoglobin s s genotype underwent
• 11:13ovarian tissue cryopreservation
• 11:15prior to stem cell transplant.
• 11:17Ovarian tissue was evaluated
• 11:19histologically by two independent
• 11:22investigators and the primary
• 11:23outcome was ovarian follicle density
• 11:26and here are the characteristics.
• 11:28So most of the patients had
• 11:30not reached puberty.
• 11:31Puberty of 45% were treated with hydroxyurea
• 11:34with a median dose of 23 milligrams.
• 11:37It's per kilogram and the
• 11:39vast majority of patients did
• 11:41report vasal clusive crisis.
• 11:43Of those patients who had vasoactive crisis,
• 11:4649% were on hydroxyurea.
• 11:4894% of patients receive pack red
• 11:51blood cell transfusion at some point
• 11:53with the median applied units of 22.
• 11:56And so the outcome of the study showed
• 11:58that the follicle density was similar
• 12:00in the hydroxyurea group compared to
• 12:02those without hydroxyurea exposure.
• 12:04But for the first time,
• 12:06a study did show that the follicle density
• 12:08was significantly higher in patients
• 12:10who did not have vasal occlusive crisis.
• 12:12And so this suggests that it's
• 12:15actually the disease itself rather
• 12:17than hydroxyurea that is leading
• 12:19to diminished ovarian reserve.
• 12:21And so the conclusions of this
• 12:23study as as I said,
• 12:25were the hydroxyurea exposure did not
• 12:27appear to reduce cortical follicle density
• 12:30in females with sickle cell disease.
• 12:32And for the first time,
• 12:33the study could show an influence
• 12:35of VOC on ovarian follicle density,
• 12:38possibly related to reduced blood flow and
• 12:40all the effects of sickle cell disease.
• 12:42What we don't know is what.
• 12:46What the?
• 12:47Ovarian follicle density would look
• 12:49like in a patient who has been on
• 12:52hydroxyurea for a much longer duration,
• 12:55because the median age of the patients
• 12:58in this study was nine years old.
• 13:01And the evidence that we have for
• 13:03diminished ovarian reserve and
• 13:04patients with sickle cell really
• 13:06starts at age between 20 and 25,
• 13:08that multicenter study of hydroxyurea
• 13:10that I showed you previously.
• 13:14And lastly, longitudinal data are
• 13:16needed to evaluate if genotype and
• 13:19severity of disease accelerate
• 13:21diminished ovarian reserve.
• 13:22Thank you and that's it.
• 13:30It is a pleasure to follow Doctor Vandoren,
• 13:33and so I will take over the screen sharing.
• 13:39Beautiful. Good afternoon, everyone.
• 13:42Thank you for joining.
• 13:43My name is George Joshua.
• 13:44I am an assistant professor of
• 13:47medicine and hematology here at Yale,
• 13:48and I'm the Pi for a quantitative
• 13:52decision sign and some lab.
• 13:55So without further ado,
• 13:56let's talk about 3 hard hitting abstracts.
• 13:59I have no disclosures.
• 14:01The first, we're gonna go and talk
• 14:03through cold gluten and disease
• 14:05and immune thrombocytopenia.
• 14:07We're going to start with all of these,
• 14:09by the way, our orals,
• 14:11one of them is a plenary,
• 14:12as I'll point out in the next talk.
• 14:14And the last talk will be focused on
• 14:17a phenomenal study actually done by
• 14:19a trainee from the Cleveland Clinic.
• 14:22So talking about patient reported
• 14:24outcomes 1st and septima abuse and our
• 14:26patients with cold agglutinin disease.
• 14:28And so this is the schematic for
• 14:31cadenza and this is a trial that
• 14:35focused on transfusion independent
• 14:37individuals with cold agglutinin disease.
• 14:41You can see part A and Part B.
• 14:42Part A has been reported on
• 14:45previously at this year's Ash,
• 14:47Alexander Roth and colleagues
• 14:48reported on Part B,
• 14:49and so that that is what I'll focus on.
• 14:52But for anchoring,
• 14:55part A was a double-blind period of
• 14:58randomization to sitemap versus placebo.
• 15:01You see that there's a screening
• 15:03observation period there of six
• 15:04weeks leading into that study.
• 15:06And Part B was then the continuation
• 15:08of the open label phase component
• 15:11of patients who are on similar map
• 15:13on similar mab and patients who are
• 15:15on placebo going to similar map.
• 15:17So in the open label extension,
• 15:19Part B,
• 15:19all of those patients who completed
• 15:21part A were eligible then to receive
• 15:23biweekly doses and this was weight
• 15:25based as you can see in front of you.
• 15:27What we'll focus on in the next slide
• 15:29will be the patient reported outcome
• 15:30endpoints and there are five of them.
• 15:34And so the objective here again is to
• 15:36look at transfusion independent patients.
• 15:38This is cadenza trial as opposed to
• 15:41transfusion dependent called gluten
• 15:42disease patients that would be cardinal.
• 15:44And the follow up here is immediate
• 15:46treatment over 99 weeks and the
• 15:48patient reported outcomes are you
• 15:49can see them in front of you here,
• 15:51the facet fatigue, the PGS,
• 15:53the PG,
• 15:54I see the 12 item SF12 and I noted
• 15:56for specific reasons that you'll
• 15:57see on the next slide what that
• 16:00includes both physical and mental
• 16:02component scores and finally
• 16:03the euroqol visual analog scale.
• 16:07And here are the baselines and the patient
• 16:11sample sizes and the mean effects.
• 16:14And in the right column here I put for
• 16:16you what the investigators reported
• 16:18as clinically important changes that
• 16:19were derived in private prior studies.
• 16:21So we can actually interpret what
• 16:24is cleanly clinically meaningful or
• 16:26potentially clinically meaningful.
• 16:27So the mean age of these patients
• 16:30was 6780% of them were women and
• 16:33you can see the facet fatigue score
• 16:35with an improvement of 8.8.
• 16:37Right in the middle there,
• 16:38with the standard error of 2.1,
• 16:39you'll note a reported clinically
• 16:41important change which is
• 16:43available here is more than five.
• 16:45You have to think about that in the
• 16:48context of the standard error now,
• 16:50the SF 12,
• 16:51the physical and the mental
• 16:53cognitive scores as well.
• 16:54Hit above the report of clinically
• 16:57important changes with statement lab
• 16:59use and you'll see an added about 4.9
• 17:02points for the physical component,
• 17:044.0 points for the mental component.
• 17:07And the last piece within the rows you
• 17:10see the EQ visual analog score scale
• 17:12again and add an improvement there,
• 17:15but there is not a study that has
• 17:17derived invalidated a reported
• 17:19clinically important change here.
• 17:21And so that is that's why I put
• 17:22that as a non applicable.
• 17:24Now if you look at PGI S&P GIC,
• 17:27you can see too that for the pgis
• 17:3031% there was a 31% improvement
• 17:32in the proportion of patients
• 17:35reporting nor mild fatigue.
• 17:36So it more patients by the conclusion of
• 17:39the study reported no or mild fatigue
• 17:42and the delta there was from about
• 17:45mid 40s to mid 70s percentage wise.
• 17:48And finally the PGIC by the end of
• 17:51the study 71 of the patients who were
• 17:53reporting a positive change from the
• 17:55baseline from where they had started from.
• 17:57So take home.
• 17:59So the condenser part BPRO data it
• 18:02appears that September map demonstrate
• 18:04can demonstrate benefits that are
• 18:07associated with its use specifically on
• 18:09fatigue and overall quality of life.
• 18:11The benefits appear to maintain for
• 18:13more than one year and mentioned
• 18:15median follow up in 99 weeks.
• 18:17And and this is important patients
• 18:19previously previously treated with
• 18:21placebo did demonstrate a brisk
• 18:24PR O improvement in Part B.
• 18:26So these are the patients who went from.
• 18:27Cebu to sitemap so they are able
• 18:29to catch up to the patients who
• 18:31had been on sitemap before.
• 18:35Moving to a plenary,
• 18:37this is Edgar Tigard and ITP Egard Tiger mod.
• 18:41Is an IG1 FC fragment and a natural
• 18:44ligand for the neonatal FC receptor.
• 18:47It's engineered to competitively
• 18:49bind to FCRN with a high affinity and
• 18:52prevent the recycling of endogenous IG,
• 18:54but it doesn't affect albumin.
• 18:56This drug has been improved in
• 18:58myasthenia gravis and here I present
• 19:00to you the results from advanced 4
• 19:02which is a phase three multicenter,
• 19:03double-blind, placebo-controlled RCT.
• 19:06In patients with immune thrombocytopenia,
• 19:09generally speaking when we think about
• 19:11pathogenic autoantibodies and ITP,
• 19:13we think about increased platelet
• 19:14clearance as one of the mechanisms
• 19:16in inhibiting platelet production
• 19:18and impacting platelet function.
• 19:19You see all of those listed in a
• 19:21schematic to the left and then on
• 19:23the right the the schematic for the
• 19:26recycling of your endogenous IG and
• 19:30where F guys taking mod is is acting.
• 19:35Now for this RCT,
• 19:36you had to have been an adult,
• 19:39so at least 18 years of age and to have
• 19:41chronic or persistent ITP and as a reminder,
• 19:44chronic ITP,
• 19:44ITP of duration at 12 months or more,
• 19:47persistent is 3 to 3 to 12 months.
• 19:50You have to have two platelet counts
• 19:52of less than 30,000 during the
• 19:54screening period and the screening
• 19:56period lasted 2 weeks for this trial.
• 19:57And you had to have been on at least
• 20:00two ITP treatments or one prior
• 20:02treatment and one concurrent treatment.
• 20:04Those are the eligibility criteria,
• 20:06an important point for this trial
• 20:08that's not listed on the slide because
• 20:10it was an eligibility criteria.
• 20:12But once the trial started,
• 20:13these patients needed to be maintained
• 20:15on the same dosing of whatever they
• 20:18were on previously for their IT.
• 20:20Be without those escalations.
• 20:22So the treatment period was 24 weeks
• 20:24and patients were randomized 2 to
• 20:26one to Edgar Sigma 10 milligrams per
• 20:29kilogram intravenously versus placebo.
• 20:31And there was a period as you can see
• 20:34in front of you here where you could
• 20:37have those adjustments of I've got taken mod.
• 20:40At the end of the trial,
• 20:41as we'll talk about,
• 20:42there's a follow-up period and more
• 20:44than 90% went on to enroll in the
• 20:47Open label extension called Advanced
• 20:49Plus that is in its early phases now.
• 20:52These are the baseline characteristics
• 20:54for these patients.
• 20:55You can see that they match
• 20:57up reasonably well.
• 20:58In particular,
• 20:59I'll point out The Who bleeding scores
• 21:02pretty similar across the board patients
• 21:05with three or more prior ITP therapies,
• 21:08patients that we technically think
• 21:09of as quote UN quote refractory.
• 21:12That's how the trial referred to them
• 21:14as well and that's about 6 to 7 out
• 21:17of 10 patients in both arms and to
• 21:20the concurrent ITP therapy types.
• 21:22Baseline being utilized, steroids,
• 21:24tipra,
• 21:24is,
• 21:25and other immune suppressants
• 21:26all reasonably nicely matched,
• 21:28and so here in this case,
• 21:30you can see that this random allocation
• 21:33has probably served its purpose
• 21:35of controlling for confounding.
• 21:37The endpoints here are the
• 21:39here's the primary endpoint and
• 21:41also key secondary endpoints all
• 21:42to say that all platelets specific
• 21:45secondary endpoints were met.
• 21:46The primary endpoint was the proportion
• 21:49of patients with a sustained count
• 21:51response and as typical in ITP literature,
• 21:53this was defined as a platelet count
• 21:56of 50,000 or more and in this case on
• 21:58at least four out of 6 clinic visits
• 22:01during the conclusion of this period,
• 22:03in this case weeks 19 through 24,
• 22:06of course in the absence of ITP.
• 22:07Others and then key secondary endpoints
• 22:09include cumulative weeks of Disease Control,
• 22:11so just the number of weeks
• 22:13of Disease Control,
• 22:14something called sustained
• 22:15platelet count response.
• 22:17And the durable sustained platelet count
• 22:19response which is just extending that
• 22:21risk exposure period out to week 17.
• 22:24And so there's a significance on the
• 22:26platelet count and all of these the
• 22:28take homes from this plenary abstract
• 22:30whereas that lowering total IG levels
• 22:32by targeting the neonatal FC receptor
• 22:34appears to demonstrate statistically
• 22:35significant improvements in primary
• 22:37and secondary platelet endpoints.
• 22:39The drug also appears to be well tolerated
• 22:42without new safety signals that did not
• 22:44have an opportunity to include that here.
• 22:47But most adverse adverse events were
• 22:49reported as quote mild to moderate.
• 22:51And finally the open label extension
• 22:54period is ongoing currently.
• 22:56Now to wrap up this little portion with
• 22:58a third abstract from the Cleveland
• 23:01Clinic of 300 plus consecutive patients
• 23:04treated with splenectomy for a variety
• 23:06of different immune cytopenias.
• 23:08So the investigators here wanted to
• 23:10identify whether they could isolate
• 23:12risk factors that could potentially
• 23:14predict response to splenectomy and
• 23:16adult patients with immune cytopenias.
• 23:18On the right,
• 23:19you see a schematic of total splenectomy
• 23:22cases that they reviewed over the
• 23:23course of 20 years from 2000 to 2020.
• 23:26And here you had 1800 patients.
• 23:28There was a bunch of patients excluded
• 23:30as they were trying to hone in on
• 23:32cytopenias and then ultimately
• 23:33on immune cytopenias.
• 23:35And at the very bottom I circled
• 23:36for urine red.
• 23:37You can see what the diagnosis
• 23:39were that they considered ITP,
• 23:41autoimmune hemolytic anemia,
• 23:42Evans syndrome and autoimmune neutropenia,
• 23:44neutropenia in general.
• 23:46This was a retrospective study,
• 23:49339 patients and the majority were
• 23:53ITP and autoimmune hemolytic anemia.
• 23:55Their results are are a little bit
• 23:57remarkable even for the fact that
• 23:59this is retrospective study and here
• 24:01you can see ITP autoimmune hemolytic
• 24:03anemia and autoimmune neutropenia
• 24:05at the very least being presented
• 24:07and simple pie charts for having
• 24:09complete versus partial versus no
• 24:11responses to splenectomy.
• 24:13And at the bottom you actually also see how
• 24:15fast those responses occurred in weeks.
• 24:17The overall response for all patients
• 24:20with 74% complete response rate of
• 24:2286 and a partial response of 14%.
• 24:25In these patients,
• 24:27but perhaps the bigger take home
• 24:29point was the following.
• 24:31And one out of five cases there
• 24:33was a discordant diagnosis from
• 24:35pre to post operation on the left.
• 24:37In the left column you see
• 24:39the splenectomy indication.
• 24:40In the middle you see what the
• 24:42actual postoperative pathologic
• 24:44diagnosis was and the frequency of this
• 24:46occurring in total to be exactly was 19%.
• 24:49So 19% of patients were discordant
• 24:51from pre to post operative
• 24:53diagnosis again in these 300.
• 24:56Ask consecutively treated patients
• 24:57over the course of 2000 to 2020
• 25:00twenty years in the Cleveland Clinic.
• 25:02And to wrap up with one final take
• 25:05home is the investigators did try
• 25:07to isolate the risk factors that
• 25:10could predict response versus not
• 25:13predict response and these are being
• 25:15parsed out further as I understand
• 25:17in the actual manuscript that's
• 25:18being written up and probably
• 25:20published in the next 6 to 12 months.
• 25:21But the big take home points here,
• 25:23most of these are crossing
• 25:25your odds ratio of 1,
• 25:27but you'll see that young age in particular
• 25:30age less than 40 years seem to predict.
• 25:33Their response to splenectomy as
• 25:34well as primary ITP also seemed to
• 25:37predict for favorable response to
• 25:39splenectomy on the converse side of it,
• 25:42requiring multiple therapies predicted
• 25:44for poor response to splenectomy.
• 25:47So take homes.
• 25:48From the studies that splenectomy
• 25:49remains a valuable option,
• 25:51specifically in patients whose values
• 25:53and preferences align with surgery.
• 25:55And there's a surprisingly high proportion,
• 25:58one out of five that had an added value of
• 26:02the diagnostic component in their course.
• 26:06And so with that,
• 26:08I want to say thank you and I'm going
• 26:10to transition over to Doctor Sharda.
• 26:20Thank you, George.
• 26:24I have nothing to disclose as well.
• 26:26I will mostly be concentrating on
• 26:30some abstracts, interesting abstracts
• 26:32in the thrombosis realm and mostly
• 26:36cancer associated thrombosis.
• 26:38The first one is the the catheter three
• 26:41study which was a prospective study of
• 26:44apixaban for central venous catheter,
• 26:47associated upper extremity,
• 26:49venous thromboembolism and cancer patients.
• 26:52And this was, this comes from at
• 26:55least three senators in Canada.
• 26:58So this was a a multi center
• 27:02prospective cohort study.
• 27:07In patients with CVC associated upper
• 27:11extremity DVT they were treated with.
• 27:15On a low molecular weight heparin
• 27:17dalteparin in their case for seven days
• 27:20followed by a full dose of apixaban for
• 27:2211 weeks and and and the patients were
• 27:25followed for for at least 12 weeks.
• 27:28The inclusion criteria was all adults
• 27:31with with active malignancy and
• 27:34and clinically significant that is
• 27:36symptomatic upper extremity DVT in
• 27:39association with the counter a CVC
• 27:41and the main exclusion criteria were.
• 27:44Patients with active bleeding or clip
• 27:47bits less than 75 or a need for dual
• 27:51antiplatelet therapy as well as most
• 27:53of the patients with hematologic
• 27:56malignancies or planned for stem cell
• 27:58transplant as well as pulmonary embolism
• 28:01with only with hemodynamic instability.
• 28:08The primary outcome was catheter survival
• 28:11at three months and the secondary
• 28:14outcomes were any types of symptomatic
• 28:17recurrent venous thromboembolism as
• 28:20well as bleeding both major as well
• 28:23as clinically relevant non major
• 28:25bleeds and deaths from any causes.
• 28:27Umm, so here on the the
• 28:33patients demographics here,
• 28:35the 70 patients from 3 senators
• 28:38majority were female, about 60%.
• 28:40Median age 62.
• 28:44The diagnostic modality used
• 28:46in most patients were Doppler
• 28:49ultrasounds and as you can see
• 28:51these are symptomatic events.
• 28:52So almost 75% of the patients
• 28:55actually have proximal upper
• 28:57extremity DVT involving subclavian,
• 29:00at least subclavian veins.
• 29:05And this is perhaps slightly
• 29:06different from our practice,
• 29:08so about 80% of the patients.
• 29:09So these were mostly outpatient.
• 29:12The patients being treated outpatients
• 29:14and and about 80% of them had picks
• 29:17and only 20% had portacaths and as
• 29:20you can see the type of cancer about
• 29:23a third were breast and a third were
• 29:26colon and the remaining were others.
• 29:28So coming to the primary outcome,
• 29:30so catheter survival so adds 12 weeks,
• 29:3440 patients had so which is about 5760%
• 29:39had catheter still present and functioning.
• 29:45But if you can see the reason for removal
• 29:49actually most of the patients who had
• 29:52it removed was because of end of the
• 29:55therapeutic need which is about 20.
• 29:57One patients or 30% and then a minor
• 30:00proportion of the patients with
• 30:02with other reasons which is you know
• 30:05infection or two patients died and
• 30:07there were no recurrent events and so.
• 30:11If you consider.
• 30:14Or exclude the end of therapeutic needs.
• 30:16The the catheter survival was
• 30:18almost 100% with the pixman therapy.
• 30:22The safety outcomes only one patient
• 30:24had a recurrent DVT and the same arm,
• 30:27and even in this patient the the line
• 30:30was not removed and was a functional.
• 30:33There were twelve bleeds,
• 30:36six major and six minor bleeds
• 30:40and most happened within the first
• 30:43two months of of treatment.
• 30:45There were two deaths and they were
• 30:47both delayed and and cancer related.
• 30:51So limitations of course it's a single
• 30:55arm and most of the patients were
• 30:58outpatients and so perhaps not as ill
• 31:01and with the limited follow but but
• 31:03I I guess for our our practice many
• 31:06of these or most of these patients
• 31:09actually had picks our patient
• 31:11as compared to a Porter cats.
• 31:13So the conclusions were that the
• 31:16pixabaj should promise in treating
• 31:18central venous catheter associated
• 31:21upper extremity DVT.
• 31:22And the observed bleeding rates
• 31:25were lower than as previously
• 31:27described with rivaroxaban.
• 31:30And so here are the the other two studies.
• 31:35Done previously by the same group.
• 31:36So the first one was the catheter
• 31:39study which was low molecular
• 31:41weight heparin followed by widening
• 31:43the antagonist and then the more
• 31:45recent one was a catheter 2 which
• 31:48was River rockband without a lead
• 31:50in with the loonie weight heparin.
• 31:52And here as you can see there are
• 31:54a lot more bleeds and then the the
• 31:57the current bonus the dalteparin
• 31:58followed by Pixar ban with perhaps
• 32:01with less Pittsburgh.
• 32:02I think the most important point is that in.
• 32:05In most of these patients,
• 32:07despite proximal and symptomatic
• 32:10upper extremity DVT's are the lines
• 32:14were not removed and and were not
• 32:18associated with infusion failure and
• 32:20and the lines were were were able
• 32:22to be saved with anticoagulation.
• 32:27So coming to the second one which
• 32:30is abstract #519 and
• 32:35the title of the abstract is only
• 32:37dynamics of C reactive protein to
• 32:39predict risk of venous thromboembolism
• 32:41in patients with cancer treated
• 32:43with immune checkpoint inhibitors.
• 32:45And this comes from Austria, Vienna,
• 32:49Austria. So just to be quick,
• 32:54because I'm an embolism.
• 32:57Is being recognized as a major complication
• 33:01of immune checkpoint inhibitor therapy.
• 33:04The rates have been described as
• 33:06high as 25% but the the prothrombin
• 33:09prothrombotic effect is the these
• 33:12immune checkpoint inhibitors as
• 33:14well as the the the risk factors are
• 33:18unclear because the risk factors,
• 33:20the traditional risk factors and the
• 33:22scoring system such as the KORANA score,
• 33:24they do not function as well.
• 33:27In the setting of checkpoint inhibitors.
• 33:31So basically the goal of the study was
• 33:33to explore early dynamics of systemic
• 33:35CRP levels after initiation of the immune
• 33:38checkpoint habits for prediction of
• 33:40venous thromboembolism in these patients.
• 33:44And why CRP?
• 33:47Because CRP has been shown to be a
• 33:51predictor of poorer outcome or higher
• 33:54designed CRP as well as a CRP response.
• 33:58CRP Flair has been associated with
• 34:01poor outcomes in these patients.
• 34:03And and it's well recognized that the
• 34:07developer systemic antitumoral immune
• 34:09response associated with a major
• 34:12inflammatory response in which CRP
• 34:14has been shown to be a major marker.
• 34:18Umm. So the methods.
• 34:21So this was a retrospective cohort
• 34:24study of about 405 patients.
• 34:26These were patients with cancer
• 34:30treated in in in Med UNI Vienna.
• 34:35The.
• 34:37The follow-up was at least for the
• 34:39duration of IC ICI therapy until
• 34:42subsequent anti cancer therapy
• 34:44death or a maximum of three months
• 34:47of the last cycle of the immune
• 34:50checkpoint inhibitor therapy and
• 34:52and the endpoints were DTE.
• 34:57That were mostly pulmonary embolism and DVT,
• 35:00but also recorded for splanchnic,
• 35:02venous thrombosis,
• 35:04catheter related thrombosis
• 35:06and other other events.
• 35:09In terms of the CRP dynamics,
• 35:11the CRP was measured at baseline
• 35:14that is within the four weeks,
• 35:16within four weeks prior to
• 35:18institution of this therapy and then
• 35:21it was longitudinally monitored
• 35:23for the first three months after
• 35:26the initiation of the therapy.
• 35:28And for the purpose of this study
• 35:30this the the CRP dynamics were
• 35:33defined either as CRP flare which
• 35:36is increase in the CRP by by.
• 35:39At least 2.5 fold over the baseline
• 35:43or a CRP response which was 50%
• 35:46relative decrease from the baseline.
• 35:50Um.
• 35:53So the most important in terms of the
• 35:57cohort demographics is that most of
• 35:59the patients were staged for malignancies.
• 36:04Of of a variety of types,
• 36:07mostly therapies where are cancers
• 36:10known to be known to respond to to
• 36:14immune checkpoint inhibitors and then
• 36:17many of the patients had received or
• 36:20seen multiple lines of therapies.
• 36:24The the median follow up for the
• 36:27study for was about 8.5 months.
• 36:31Umm, so, so defining CRP flare.
• 36:36So among the 405 patients,
• 36:4070% had a CRP flare,
• 36:41which is again a rise in CRP of greater
• 36:45than 2.5 folds over the baseline.
• 36:49And then there, so let me so in
• 36:55terms of the different a definition,
• 36:58so basically some 78 to 80% had the
• 37:03CRP flare and then about a third had
• 37:06CRP response which is drop in CRP.
• 37:11Either after a flare or in about um.
• 37:1714% of the patients without a flare
• 37:19to to less than 50% of the baseline
• 37:23and then about 1/3 of the patients
• 37:26did not or were non responders which,
• 37:28which is their CRP,
• 37:31did not reduce to 50% of the baseline.
• 37:37And then based on the CRP dynamics,
• 37:41the the the authors found that the risk
• 37:44of DVT E the cumulative risk of DVT
• 37:48was about 3.5 fold in in patients who
• 37:53had a CRP flare irrespective of of.
• 38:00A response or not?
• 38:04More importantly,
• 38:05they also found that the the risk of
• 38:08DVT was associated with an increase
• 38:11mortality according to the CRP flare.
• 38:14So the hazard ratio for death after VE
• 38:17Justed for cancer type was about 3.5
• 38:20fold in patients with CRV CRV flare
• 38:23and then adjusted for the stage of
• 38:26the cancer was 3.21 fold again. Um.
• 38:35In patients with with their CRP flare.
• 38:40So the conclusions were that's the early
• 38:44dynamics of systemic CRP levels are
• 38:47associated with the risk of VTE during
• 38:50immune checkpoint inhibitor therapy and
• 38:53the highest risk of DVT was observed
• 38:56in patients with early CRP flare after
• 39:00ICI initiation and then the lowest risk
• 39:04was in patients where the CRP drop.
• 39:08Dropped below 50% with no prior flare,
• 39:10but this was a very small proportion
• 39:14of patients about 12 to 14%.
• 39:16And then they also found a potential risk,
• 39:19a link between immune checkpoint inhibitor
• 39:22induced systemic inflammatory response
• 39:24and risk of CTE in in addition to an
• 39:28independent association of of Vt with
• 39:30mortality in patients who have a CRP flair.
• 39:34So I think with this I'll end.
• 39:44Well, that's great.
• 39:45Thank you all for those
• 39:46great presentations.
• 39:47So thanks so much.
• 39:49I if people have questions,
• 39:51please put them in the Q&A or
• 39:53the chat and while we're waiting
• 39:55for them to come in perhaps
• 39:58some I can start with a few.
• 40:02If Doctor Van Doren is still on,
• 40:04and I know she might have
• 40:05had to go into clinic,
• 40:06looks like she did step off.
• 40:07So George, I I have a question for you.
• 40:11In the study with Subtitle MIB
• 40:15and cold agglutinin disease,
• 40:17you noted that there was an increase
• 40:20in patient reported outcomes.
• 40:23Quality of life improved despite
• 40:25the fact that these individuals
• 40:28did not require blood transfusions.
• 40:30Could you postulate on why they
• 40:32may have had this improvement?
• 40:34In the way they felt without having
• 40:36a need for blood transfusion.
• 40:39Thank you, Bob. Such a great question.
• 40:42There's a thud in the
• 40:44hemolytic community in general,
• 40:46both in autoimmune hemolytic anemia and PNH
• 40:48and other disorders where we see hemolysis,
• 40:50that quality of life is affected by the
• 40:53hemolysis independent of hemoglobin as well,
• 40:55in addition to hemoglobin drops and
• 40:58low hemoglobin hemoglobin levels.
• 41:00The idea being that in
• 41:02a chronically hemolytic,
• 41:03in a chronic hemolytic stage,
• 41:05you have an underlying degree
• 41:06of inflammation.
• 41:07At least that's the theory that's
• 41:09being posited that's contributing
• 41:10perhaps to this fatigue and
• 41:11the idea being that if we can.
• 41:13Shut down the hemolysis or maybe let's
• 41:16say decrease it with ages like symbolab,
• 41:20the monoclonal C1S antibody for cold
• 41:23agglutinin disease or anti C3 and C5
• 41:26therapies for example in pH that we
• 41:28can further improve quality of life.
• 41:30And I think this also underscores
• 41:32too that umm, you know,
• 41:34we we focus a lot in the past on
• 41:36these hard outcomes which are of
• 41:38course important like hemoglobin,
• 41:39but there's an additional component
• 41:42to quality of life.
• 41:43Beyond that now that is difficult
• 41:45to capture and I think that the
• 41:47investigators could have done a
• 41:48better job honestly with similar
• 41:50map and in fact most of phase three
• 41:52investigations currently looking
• 41:53at quality of life use patient
• 41:56reported outcomes which is good.
• 41:58But most of the times they're not
• 42:00validated externally validated.
• 42:01And the one for sure surefire
• 42:04way to robustly look at these,
• 42:06although that takes a little bit
• 42:09more money and effort is to actually
• 42:11measure quality of life directly.
• 42:14With direct patient interviews,
• 42:15that that's a conversation for another time.
• 42:18But that's a conversation I have had
• 42:20with colleagues in the BMT space
• 42:22and other spaces who want to truly
• 42:23capture the quality of life beyond,
• 42:25let's say like just the questionnaire stuff,
• 42:2712 or whatever it is.
• 42:29That's great. Thanks, George.
• 42:30I wonder if some of that could
• 42:32be applied to individuals who
• 42:34have non transfusion dependent
• 42:36thalassemia as well who have fatigue.
• 42:38That's really fascinating. Yeah.
• 42:41Anish, I I have a question for you if I may.
• 42:43So the the last abstract you presented
• 42:46with CRP and immune checkpoint inhibitors.
• 42:49You know, obviously if we were
• 42:53to intervene with prophylaxis,
• 42:55measuring CRP's would be.
• 42:59It would be too late in a sense,
• 43:01so you couldn't measure the
• 43:04CRP and then intervene with.
• 43:07With anticoagulant because
• 43:08it would be after the fact.
• 43:10So my question is,
• 43:11are the CRP changes similar
• 43:13from cycle to cycle?
• 43:15So can you use a cycle of CRP and
• 43:18anticipate that in the next cycle
• 43:20of immune checkpoint inhibitors
• 43:22that change in CRP will be the same?
• 43:28I think it's a very good question.
• 43:32You know, if the majority of the patients,
• 43:35about 7080% had a CRP flare and so my.
• 43:43And and so and.
• 43:45These were the group with.
• 43:47With irrespective of whether
• 43:50they had a response,
• 43:52you know and you know they halved their
• 43:56CRP irrespective of that they were
• 43:59they were at high risk for for events and so.
• 44:03Although it's a very interesting observation,
• 44:08and you know this question comes,
• 44:10it's coming up more and more.
• 44:13It's it's again you know 80% of the of the
• 44:16patients who are at risk and so it's it's.
• 44:19It's again a major, it's a.
• 44:24It I think the this whole,
• 44:26this whole, you know,
• 44:28CRP as a marker of inflammatory response.
• 44:33As a marker for VTE in these patients
• 44:36in this group will have to be refined
• 44:38a little more just because you know
• 44:41they're just the 80% eighty 85% of
• 44:43the patients are at they're claiming
• 44:46or at high risk which does not really
• 44:48help us that much if I didn't answer
• 44:52your question directly but that's
• 44:53what came to my mind and like you
• 44:55know again yes it's interesting but
• 44:56it's you know you're you're telling
• 44:58me that most of the patients are
• 45:00at high risk so so you know
• 45:03so there's a.
• 45:03Question that came in the chat,
• 45:05the question and answer extending
• 45:07this and the the question was are
• 45:10there recommendations that do CRP
• 45:13levels prior to immunotherapy and
• 45:15then monitor them on a monthly
• 45:17basis and is there any role at
• 45:19this point for prophylaxis and the
• 45:21individual asking us about aspirin?
• 45:24I think this was
• 45:24a question that was asked at the
• 45:27meeting as well and and there are none.
• 45:30I'm not sure that our, you know,
• 45:33what the European practice is,
• 45:34but I don't think that it's been,
• 45:36you know, done. It's such a.
• 45:39Such a, you know, such a nonspecific,
• 45:43you know, test among everything else
• 45:45that has been happening and being done.
• 45:47And I'm I'm not sure that
• 45:50it's being routinely done. So.
• 45:54The question of prophylaxis,
• 45:56I think that there are.
• 45:58There are um I, I,
• 46:02I it's it's hypothesis hypothesis
• 46:04generating and it's I wonder if
• 46:06it's you know if these group of
• 46:09patients should be separately sort
• 46:11of included in all the prophylaxis
• 46:13trials that are that are being
• 46:15you know undertaken and and and
• 46:18perhaps a more correlation you know.
• 46:22Those those types of studies be done
• 46:23including CRP and other markers.
• 46:25Yeah, this is fascinating.
• 46:26A lot of area for research for sure.
• 46:29I'm George, I I had a
• 46:31question for you as well.
• 46:33In your study where or in the study
• 46:36you reviewed where a splenectomy was
• 46:40performed for immune cytopenias,
• 46:42you noted that I think about 20% of the
• 46:44patients and new diagnosis was made.
• 46:46So an additional diagnosis as
• 46:49presumably potentially A cause
• 46:51for the immune cytopenia and I'm
• 46:54wondering if the dates what the
• 46:56dates of the of the study?
• 46:59We're done.
• 46:59And in particular I'm thinking
• 47:01that with modern techniques of
• 47:03flow cytometry and molecular
• 47:05studies on the peripheral blood,
• 47:07would we still expect to see that
• 47:10high rate of an additional diagnosis
• 47:12made before a splenectomy is done?
• 47:15It's such a good question, Bob.
• 47:17This abstract I think caught
• 47:19a lot of people off guard,
• 47:20especially because and of course
• 47:22all of these are oralists,
• 47:23but especially because this
• 47:25was a retrospective analysis.
• 47:26So usually don't expect such a hard hitting.
• 47:29Opponent because again these
• 47:31are consecutively treated
• 47:32patients with splenectomy.
• 47:34The years were 2002, 2020,
• 47:36the median follow up they did not report on,
• 47:38but as I was in touch with investigators
• 47:40they noted that they're tabulating
• 47:42it as they're putting together
• 47:43their manuscript now because I was
• 47:45curious you know how many years
• 47:46since also what was not reported
• 47:49and what they're looking at and the
• 47:52question that had asked was are these
• 47:54diagnostic changes and they were,
• 47:56I should just clarify too that
• 47:57investigators are calling them changes.
• 47:59So not only the fact was
• 48:02that initial indication not.
• 48:05They're calling the initial
• 48:06indication is incorrect,
• 48:07meaning that the entire diagnosis
• 48:09was switched to the postoperative
• 48:11diagnosis as opposed to being added on,
• 48:13which is interesting.
• 48:14And so when I asked about.
• 48:17Whether this was time variant or not,
• 48:18meaning that like let's say in the 2000s,
• 48:212005 period,
• 48:22is that where we're catching all of
• 48:24those 20% or is it mostly kind of
• 48:25kind of the same across the board?
• 48:28They weren't able to answer that
• 48:29question only to say that it
• 48:31appeared that there is not like
• 48:33a huge spike in the early data,
• 48:35although it might be a little bit
• 48:37less moving forward it seems like,
• 48:39and we'll see what the manuscript shows.
• 48:40I won't speculate beyond that,
• 48:42but it seems like these misdiagnoses
• 48:44may still be happening.
• 48:45And again,
• 48:46I mean the Cleveland Clinic
• 48:47is a fantastic health system.
• 48:48And so if this is indeed accurate
• 48:50and if this is what they ultimately
• 48:52end up reporting,
• 48:53I think this is something that we all
• 48:54have to pay attention to because if
• 48:56this is happening in the Cleveland Clinic,
• 48:58then I don't think we're immune to that
• 49:00either here at Yale or anywhere else.
• 49:01Yeah, that's really fascinating, George.
• 49:03So diseases that are really truly
• 49:05isolated to the spleen at least
• 49:08by our current techniques to
• 49:09to discover them in the blood,
• 49:10yeah, that's that is fascinating.
• 49:13And Anish and if I may,
• 49:15your catheter ohso so another.
• 49:18So another question came in,
• 49:19this is for you Anish.
• 49:21So many factors affect the CRP
• 49:23level and how do you know the CRP
• 49:26elevation is due to the immune
• 49:28checkpoint inhibitor or infection?
• 49:31That developed afterwards perhaps.
• 49:33Yeah, it's a very good question.
• 49:34I mean it's just such a nonspecific
• 49:36marker but but there's something
• 49:38about it because you know it's a,
• 49:39it's a significant rise and it's a
• 49:42although it's a retrospectively done study,
• 49:44but it's a cohort and.
• 49:49And there there is clearly a pattern that
• 49:52has been previously recognized as well.
• 49:55So one of the citations
• 49:57that had looked into CRP,
• 49:59I don't know how you know well they
• 50:01they can adjust for other things.
• 50:03I mean these are patients with
• 50:05systemic you know metastatic
• 50:06malignancies and but they even
• 50:09previously when when they had reported.
• 50:15CRP Flair and and mortality or poor
• 50:18outcomes they they they it was a similar
• 50:21kind of dynamic so that it had been
• 50:25recognized and and so it's a good question,
• 50:28but it's such a such a nonspecific marker.
• 50:31OK, thank you. And George,
• 50:34if we can go back to you for a minute,
• 50:35the the the amide trial.
• 50:41Fascinating drug.
• 50:42And I assume that there is a
• 50:44potential that this could be used
• 50:47in any autoimmune disease where
• 50:49IG is felt to be the culprit.
• 50:51Is that how you're thinking
• 50:52about this as well?
• 50:54Well, I'll say that's how the
• 50:55pharmaceutical company is thinking about it.
• 50:58Because I've had a I've had
• 51:00a conversation with them.
• 51:02Yeah. So it was approved this,
• 51:05this drug was approved for my
• 51:07senior Gravis just last year.
• 51:08They're looking at it and they
• 51:10have obviously, as I presented,
• 51:11have looked at it and ITP.
• 51:12But I know that they're really
• 51:14excited about the whole host of neuro
• 51:17autoimmune disorders that are out there.
• 51:19And if it works and if it's successful,
• 51:22you can make an argument that
• 51:25this kind of mechanism could then
• 51:27theoretically help with any disease
• 51:29that has this pathologic auto antibody.
• 51:32Component or at least it's worth
• 51:34testing in any disease like that,
• 51:36especially if they ultimately go on
• 51:38to prove that the safety profile
• 51:39is what they claim it to be.
• 51:41Because as we've seen with other drugs,
• 51:43even phase two or phase three studies
• 51:44sometimes are not enough, right.
• 51:46When you post marketing surveillance
• 51:47phase four studies to really see
• 51:49an effect across rare diseases,
• 51:50presumably they're going to be
• 51:51looking at a lot of rare diseases,
• 51:53this autoimmune, neurological space.
• 51:56So yeah,
• 51:57I think there's a good amount
• 51:58of excitement with it.
• 51:58I'm curious to see what happens
• 52:01going forward, but.
• 52:02I do expect that we're going to
• 52:03see a dozen plus trials within next
• 52:0610 years in a bunch of autoimmune
• 52:08mediated disorders with this mechanism.
• 52:12And then presumably since B cells and plasma
• 52:14cells are not being affected directly,
• 52:16the immunosuppression will be
• 52:18less than with the drug that.
• 52:21Causes apoptosis or death of B cells present
• 52:24really good. That's a really good
• 52:26.1 that I hadn't actually discussed
• 52:27with with the pharmaceutical company,
• 52:29but one that makes a lot of sense to me.
• 52:33The data will tell us, I think.
• 52:34I think so too. Yeah,
• 52:36it would be nice, right?
• 52:37Often we're hoping that this is
• 52:39going to be like the next big thing.
• 52:41Hopefully that ends up actually
• 52:42being the case here. We'll see.
• 52:45A doctor Sharda question about
• 52:46the catheter study, if I may.
• 52:48I noted that in the catheter three study,
• 52:51the authors used a low molecular
• 52:54weight heparin for a week and
• 52:56then transition to a doac.
• 52:58Pixabay and that in in the,
• 53:00in the case of that study,
• 53:02do you think that's necessary it
• 53:05seems like that's excessive treatment
• 53:07quote excessive compared to that?
• 53:10I was
• 53:10also surprised to see that.
• 53:11But I think that to increase
• 53:14their recruitment they did that.
• 53:16I think most of us have a bias to I I
• 53:20know many people tell me like you know,
• 53:23you want your patient to cool off like with
• 53:25a heparin and then you know do something.
• 53:27But it, it's strange, you know,
• 53:28this is something that someone would do
• 53:30with say the bigger trend, you know,
• 53:32because that's what the originally
• 53:34studies were kind of designed.
• 53:36But I think this was also to
• 53:39increase the recruitment.
• 53:41And so they allowed like 7 days
• 53:43of of and they made a protocol,
• 53:45I mean everyone's treated about
• 53:47seven days of of of Dalteparin,
• 53:49Romario heparin followed by Pixar lamp,
• 53:51whereas it didn't do it for rivaroxaban.
• 53:54OK. And so you don't think the the
• 53:57issue was people had cancer therefore
• 53:59they might need a heparin like drug
• 54:02before they get switched to a doac?
• 54:04No, I think this is this was done rather
• 54:06quickly and this was done after you know,
• 54:08Adobe Saban and others already.
• 54:11I guess you know, you know the
• 54:14data was already out there. So
• 54:15OK great. I think the most most
• 54:18I think the conclude, the interesting
• 54:19thing was and this often comes up,
• 54:21which is what to do with the line I I
• 54:25liked the fact that these were real
• 54:28like symptomatic proximal events.
• 54:30I mean 3/4 of them had subclavian
• 54:33involves actually many had pulmonary
• 54:35embolisms to and they were able to save
• 54:39like like if you combine especially.
• 54:42The, the the Warfarin trial is from
• 54:452003 four or something like that
• 54:46I think it was published in 2006.
• 54:48But at least if you combine the
• 54:51rivaroxaban and apixaban you can see
• 54:53that you know the lines can be can
• 54:55be saved without really recurrence
• 54:57or symptoms or post traumatic
• 55:00syndrome and can be used very safely.
• 55:03So that's I think is pretty good
• 55:05data to have.
• 55:07Just one follow-up question to
• 55:09you and then we'll we'll end
• 55:10and there may not be data here.
• 55:12But so if if you had a patient
• 55:13who had a symptomatic line
• 55:15associated thrombus and cancer,
• 55:17would you start at all with a
• 55:20low molecular weight heparin
• 55:21or would you just begin with a
• 55:24dull ache apixaban, let's say
• 55:26I would just begin with the,
• 55:28with the, with the doc.
• 55:29I mean I was following the
• 55:30River Rock Seban thing as it is
• 55:32and now we've been using them,
• 55:33you know, kind of interchangeably.
• 55:36So I definitely would just,
• 55:37you know, pick in the.
• 55:39Great. OK. Thank you. Well.
• 55:42And the hour is almost up.
• 55:43I'd like to thank our speakers.
• 55:45I these are really great abstracts
• 55:47you chose to present and they're
• 55:49some of them are clearly going to be
• 55:51practice changing I think for all
• 55:53of us and we're all excited about.
• 55:55Seeing these new drugs and development
• 55:57and new ideas brought forth.
• 55:59So thank you both very much and thank
• 56:03you to the participants who are here.
• 56:05We really enjoyed having you
• 56:07and I hope everyone has a nice
• 56:09rest of the day and weekend.
• 56:11Bye, bye now.