Yale ASH 2022 Highlights: Classical Hematology

February 21, 2023

Information

February 17, 2023

Hosted by: Dr. Robert Bona

Presentations by: Drs. Layla Van Doren, George Goshua, and Anish Sharda

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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&amp;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&amp;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&amp;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.