Yale ASH 2021 Highlights: Classical Hematology

March 04, 2022

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Hosted by: Dr. Robert Bona

Presentations by: Drs. Kelsey Martin, Alex Pine, and Sudhanshu Mulay

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00:00Welcome to the Yale Ash 2021 highlights.
00:06My name is Bob Bone.
00:07I'm one of the hematologist at Yale,
00:09and I'm happy to facilitate
00:11this session today.
00:12As we are focusing on some of the important
00:16abstracts from the previous ash meeting
00:19relating relating to classical hematology.
00:21And today we have 3 presenters who will
00:24each present abstracts for about 15 minutes.
00:27We'll take questions at the end of the
00:29session and they should be entered
00:30into the chat room or to the Q&amp;A.
00:32Before we start, let me take a
00:35moment to introduce our presenters.
00:38First Kelsey Martin,
00:39who is an assistant professor in clinical
00:42medicine at the Yale School of Medicine,
00:44and she practices hematology oncology
00:46at the Orange Care Center and has a
00:49special interest in classical hematology,
00:51and particularly the intersection
00:53of obstetrical care and hematology.
00:55Doctor Sudhanshu Mulay who is the
00:58medical director of the anticoagulation
01:00clinic at Saint Francis Hospital
01:03and Medical Center and he also has
01:06a strong interest in classical
01:07hematology and transfusion medicine.
01:09He's an assistant professor of medicine
01:11at the University of Connecticut.
01:13And then finally Doctor Alex Pine,
01:16who's assistant professor of medicine
01:18and hematology at the VA Medical Center.
01:22He and his colleagues have done
01:24significant work over the past few years,
01:26detailing the mechanisms of
01:30COVID Coagulopathy.
01:31So without further ado,
01:33I'll introduce Doctor Martin and
01:34let her begin the presentations.
01:40Great, thank you so much.
01:52Good afternoon everyone.
01:54Is my volume OK? Correct, alright,
01:57I'm going to be discussing A3 abstracts
02:00relating to bleeding disorders.
02:04First, abstract is titled efficacy and
02:07safety of the two Serin prophylaxis,
02:10a small molecule RNA interference
02:13therapeutic in a multicenter phase.
02:15Three study called Atlas I NH in people
02:19with hemophilia A or B with inhibitors.
02:22This was presented at the plenary
02:24scientific session by Doctor Gayoung
02:26from University of Southern California.
02:311st, I'll provide some background.
02:33Hemophilia A&amp;B are rare bleeding
02:35disorders that are characterized
02:37by ineffective clot formation,
02:39largely due to impaired thrombin generation.
02:41As a result of severe
02:43deficiency of factor 8 and 9.
02:46Currently our standard of care largely
02:49relies on replacing the missing factor.
02:51There is a high rate of development
02:54of anti factor inhibitors which
02:55is up to about 30% in some of our
02:58patients with hemophilia A and about
03:005% of the patients with hemophilia B.
03:05Subcutaneous fat isran
03:06is a novel therapeutic.
03:08It's a small molecule RNA
03:11interference therapeutic that acts
03:13by binding and degrading at the M
03:15RNA which encodes for antithrombin,
03:17thereby partially silencing
03:19the expression of antithrombin.
03:22This rebalances hemostasis and
03:24restores thrombin generation in
03:26patients with hemophilia or A
03:29and has been demonstrated to be
03:31effective in patients with or
03:33without inhibitors as I'll discuss.
03:35This study demonstrated that
03:37prophylactic use of the two
03:39strands significantly reduced
03:41annualized bleeding rates,
03:43which is essentially bleeding
03:44events on an annual basis in
03:47patients with hemophilia A or
03:49hemophilia B that have inhibitors,
03:51and demonstrated both efficacy
03:54and safety data.
03:56In this study,
03:5757 patients were randomized,
03:582 to one in an open label phase.
04:00Three trial patients were
04:02males over the age of 12,
04:05again with either hemophilia A or B,
04:07with with inhibitors,
04:08and these were patients that
04:10had been receiving on demand
04:12treatment with bypassing agents
04:14for Blake breakthrough bleeding.
04:18There was 38 patients in the phase, two
04:20Syrian group and the dosing of this medic.
04:22This is a subcutaneous therapy that
04:24was given at 80 milligrams once a
04:27month versus 19 patients in the
04:30on demand bypassing Agent Group.
04:32They were followed.
04:33The primary endpoint was looking at annual
04:35bleeding rate in the efficacy period,
04:37which was nine months.
04:40Secondary endpoints looked at
04:42spontaneous bleeding rates,
04:44joints, bleeds,
04:45quality of life metrics,
04:47which by a validated quality of life
04:50tool and also frequency of the bleeding
04:53episodes that happened in the onset period,
04:55which was the first month of therapy as
04:57well as safety and tolerability data.
05:03And and this was demonstrated
05:05to be extremely effective
05:06in the future and patients.
05:08So you can see here on this first
05:10line the median annual annualized
05:12bleeding rate was actually 0.
05:17The estimated rate was 1.7 versus
05:21in the bypassing agent group.
05:23The median annualized bleeding rate was 16.8.
05:28And there was actually the median
05:31for spontaneous bleeds with zero
05:32in the future and category.
05:34There was also demonstration
05:36of significant quality of life
05:38improvements based on the validated
05:40quality of life screening tool.
05:44And it was effective in both
05:47patients with hemophilia A and
05:49in patients with hemophilia B.
05:51And we can see that 29 patients.
05:55And we received for two strand
05:57in the hemophilia A category
05:59and nine patients received it
06:01in the hemophilia B category.
06:02And again this is compared with
06:05the second second line here.
06:07But patient to receive that
06:09bypassing agent only with a
06:11very significant P value.
06:15Overall, the agent was well tolerated,
06:18although the main side effect of
06:21special interest was thrombotic events.
06:24Uhm? There was no deaths of any
06:29kind in either group of note.
06:32Of the patients that had thrombotic events,
06:34the authors reported that that
06:36occurred in some patients that
06:38seemed to have the antithrombin
06:39levels at the lower end of the range
06:41and seen some as low as 10 to 20%,
06:43and which is what they attributed to and
06:46only one patient who had a thrombotic
06:49event ended up coming off study,
06:50and this was a patient who had
06:53a thrombosis in a spinal vein.
06:56Other side effects were increases
06:59in transaminases,
07:00but the authors reported that this did not
07:02impact any of the treatment scheduling,
07:04and no patients had to come off trial for
07:06any changes in hepatic enzyme changes.
07:14So the conclusions were that the two
07:17Serin had significant improvements
07:19in the treatment arm compared with
07:21the on demand bypassing agents.
07:24And this is seen as somewhat of a
07:26game changer in the sense that it's
07:28given monthly and subcutaneous,
07:29which is a tremendous change in
07:31compared to the current standard
07:33of practice where patients are
07:35needing intravenous therapies and.
07:37In a much higher frequency.
07:40Nearly 2/3 of the patients treated with
07:42fattoush Rand had zero treated bleeds,
07:44and the mean median annualized
07:46bleeding rate was zero.
07:48And of note,
07:49this is also efficacious in both
07:51patients with hemophilia and hemophilia
07:53B and its patients with hemophilia
07:55B have really had not had similar
07:57prophylactic similar prophylactic
07:59options as our hemophilia A patients.
08:01So creating a new sort of treatment
08:05approach 7 patients in the treatment
08:07arm had at least one adverse event,
08:10including.
08:10The four thrombotic events and
08:11one of those patients did require
08:13withdrawal from this study.
08:18That concludes my discussion
08:19in the first abstract,
08:20and I'll move on to the second.
08:22The second abstract was titled
08:24rate of prolonged response after
08:26stopping THROMBOPOIETIN receptor
08:28agonist treatment in primary
08:30immune thrombocytopenia results
08:32from a nationwide prospective
08:34multicenter interventional study.
08:36And this was out of France.
08:43Some background information.
08:45There's been several retrospective
08:46studies and a recent prospective
08:48study that reported unexpected cases
08:51of durable remission after TPO
08:53receptor agonist were discontinued
08:54in adult patients with ITP.
08:56This has been seen in up to up
08:58to 30% of these patients.
09:00However, it felt that perhaps some of
09:03the newly diagnosed ITP cases in which
09:05such spontaneous remissions occurred,
09:07may may have been included
09:08in most of these studies.
09:12So the question this study has is what
09:15proportion of patients with either
09:17persistent or chronic phase ITP and no
09:20recent exposure to any potentially curative
09:23therapy such as splenectomy or rituximab,
09:25achieve a long term remission off
09:28treatment at 24 weeks and 52 weeks.
09:31After having on at least three months
09:33of their TPO receptor agonist exposure,
09:36who had a complete response
09:38and persistent phase,
09:39ITP is is defined as those with
09:42ITP between 3 and 12 months,
09:44whereas chronic phases lasting for beyond 12.
09:48Months, so the inclusion criteria.
09:51So again, this was a nationwide prospective
09:53multicenter interventional study.
09:55The inclusion criteria included
09:56patients over the age of 18 with either
09:59persistent or chronic primary ITP.
10:02They needed to have a stable
10:04complete response,
10:04which was defined as a platelet
10:06count of more than 100,000 for more
10:08than two months on their on their
10:11TPO RA therapy and they needed to
10:13have been on treatment with their
10:15TPO RA for at least three months.
10:17Exclusion criteria was patients
10:19who are on either anticoagulation
10:21or antiplatelet therapy.
10:23A patient who had previously failed the
10:25TPRA agent and the patient could not
10:28have been receiving any concomitant
10:30steroid or cortico steroid or IVIG,
10:33and they could not have had Rituxan mab,
10:35nor splenectomy within either the
10:36two months preceding or after
10:38initiation of their TPO or RA therapy.
10:43And the patients underwent a progressive
10:46dose reduction and they had to.
10:48There are TPO therapy or a therapy
10:50had to be stopped by 10 weeks and
10:53they proposed a method whether
10:54it was a Rama, Plasty, Morrell,
10:56Trumbo bag of of a protocol of how to how
11:00to taper off their doses accordingly.
11:02And if a patient relapsed during
11:04after this discontinuation,
11:05the decision to start a new therapy was
11:07left at every investigators discretion,
11:09and so the primary endpoint was
11:11what was the proportion of patients
11:13who achieved an overall response,
11:15which was defined as CR plus R
11:17at week 20 at week 24.
11:18So six months afterwards,
11:20and the secondary outcomes looked at those,
11:22the overall response rate after
11:24a year or 52 weeks, they look.
11:26I didn't looked at patients
11:27who had bleeding events,
11:28and they aimed to try to identify
11:30any predictive factors to see which
11:32patients might be those who achieve.
11:34Such an overall prolonged response.
11:39So 49 patients which included a 30
11:44females with either persistent.
11:45There was an end of two
11:47or chronic and a 47 ITP.
11:49The median age of 58.5 years were evaluated
11:53in this two year period over 22 centers.
11:5640 of the patients had received
11:59eltrombopag and nine around the plastic.
12:01And intention to treat analysis
12:0456.2% so 27 of the 48 patients
12:07achieving the primary endpoint
12:09achieved the primary endpoint and
12:12maintained an overall response at 24
12:14weeks after TPO RA discontinuation.
12:16And of those, half of those,
12:18essentially 55 percent, 15 of those,
12:2027 had a complete response,
12:23which again is defined as a
12:25platelet count over 100,000.
12:27Bleeding events did occur in 61.9% of
12:30the patients and 65.2% of the patients
12:33who did relapse at the 24 week and 50.
12:39Should be weeks or 52 weeks with the median
12:41platelet count of 31,000 at that time.
12:44No severe bleeding episodes occurred.
12:49And they could not identify any
12:52predictive factors. Neither age.
12:53Which agent the patient had,
12:55how long they'd had.
12:56ITP none of these things were
12:58able to predict which patients
12:59were those who were going to
13:01achieve such a sustained response.
13:03So the conclusions of this was
13:05that after 52 weeks and this is
13:07you can seen by the diagram on the
13:09right hand side after after TPR,
13:11a discontinuation overall response was
13:14seen in about half of these patients,
13:1752.1% for those who did relapse.
13:20The median time of relapsing after
13:22tapering was at about 8 weeks,
13:24but the majority of those actually
13:25happened within the first two weeks,
13:27and none of those patients who
13:29relapsed developed severe bleeding.
13:33In among 21 patients who did
13:36relapse before week 2413,
13:37of those were able to be re challenged
13:39with their TPO RA and they were still
13:42able to achieve a complete response
13:44with a medium time of two weeks.
13:48So the conclusion is that there was a
13:50high rate of sustained off treatment
13:52remission after TPO RA discontinuation
13:54in patients with chronic ITP who had
13:57initially achieved at stable CR.
13:58They were unable to die and identify a
14:01predictive factor of which patients were
14:03would achieve such a lasting remission.
14:06But this study strongly supports use
14:08of a progressive tapering off of the
14:10dose of TPRS and patients who do
14:11achieve a stable CR on treatment.
14:13And there may be opportunity for us
14:15to be able to discontinue therapy
14:16in such patients.
14:21The last abstract I'll discuss
14:23was called obstetric obstetrical
14:24and perioperative management of
14:26patients with factor 11 deficiency.
14:28A retrospective observational study.
14:33In the background information
14:35data regarding obstetrical and
14:37perioperative management of
14:38factor 11 deficiency is scarce.
14:42And the question at hand is,
14:43can we create a database of such patients
14:46and identify factors associated with
14:47increased increased bleeding risk in
14:50patients with factor 11 deficiency
14:52during childbirth or surgery?
14:53And this was presented by Doctor
14:55Hanna from the Icahn School
14:56of Medicine at Mount Sinai.
15:01So they did a retrospective chart
15:02review of patients with factor 11
15:04deficiency who underwent either
15:06childbirth or surgical procedures over
15:08a 10 year period within the Mount Sinai
15:10health care system in New York City,
15:12and they collected data on age, sex,
15:15ethnicity, genotype, family history,
15:17personal history of bleeding.
15:19The type of anesthesia used the
15:21estimated blood loss and any evidence
15:23of of periprocedural bleeding
15:25which patients needed blood product
15:27administration and which product
15:29which patients needed hemostatic
15:31agents in the perioperative period,
15:34they defined a bleeding endpoint as acute
15:37postpartum or post operative hemorrhage,
15:39or any bleeding that warranted
15:41non prophylactic administration
15:43of pack red blood cells.
15:45FFP or tranexamic acid.
15:48They performed a logistic regression
15:49to test for the association
15:51between either historical,
15:52laboratory and procedural variables
15:54with the bleeding endpoint.
15:58So overall, 198 patients were evaluated
16:01who had undergone 252 procedures in total.
16:05This included 143 vaginal
16:07deliveries in 64 city sections
16:09and 45 other surgical procedures.
16:1238 of the 252 procedures did
16:15result in bleeding complications,
16:17and they found that both a prior
16:19history of bleeding and a lower
16:21factor 11 levels were independently
16:23associated with the bleeding endpoint.
16:28Interestingly, 8 out of 21 patients,
16:3138% who suffered a bleeding complication.
16:34This happened despite prophylactic FFP.
16:38The mean factor level level for
16:40with patients who receive neuraxial
16:42anesthesia was 50 units per deciliter.
16:45In five patients with a
16:47negative bleeding history,
16:48despite surgical challenges,
16:49we're actually able to receive
16:52neuraxial anesthesia effector
16:53level levels less than 10 and
16:55without any bleeding complications,
16:57and only one of these had
16:59received prophylactic FFP.
17:05So their conclusions were that a personal
17:07history of bleeding was the strongest
17:10predictor of perioperative or obstetrical
17:11bleeding and and that personal history of
17:14bleeding was was actually defined as just
17:16one one report of heavy menstrual period
17:18or bleeding in the operative period.
17:20It just took sort of one one event in time to
17:23define a personal history of bleeding factor.
17:2611 levels were found to correlate with a
17:28slightly slightly lower but statistically
17:30significant odds of surgical bleeding,
17:32and they found that a factor
17:3411 level cutoff of 40 units per
17:36deciliter may predict bleeding risk.
17:37With reasonable specificity at
17:4083% but lacked sensitivity,
17:41they also found that factor 11
17:44levels are stable during pregnancy,
17:46as demonstrated by the diagram
17:48on the bottom right,
17:50showing that repeat measurements
17:51may not be necessary,
17:52which is something commonly done in practice,
17:56and they also found that neuraxial anesthesia
17:58appeared to be safe to use in this cohort,
18:01which clinically is a question
18:03that comes up frequently.
18:04Hey, thank you for your time.
18:07Forward to hearing from our next speaker,
18:09Doctor Malik.
18:13Thanks, Kelsey.
18:26Right, thank you for the
18:29opportunity to talk today.
18:31I'm going to focus on thrombosis,
18:34so I'm hoping to present three
18:36studies that I found of interest.
18:40Have one focus study and then as
18:42time permits and go through the
18:45other two studies with quickly.
18:47The focus state I would I would
18:49like to present is 1 listed here
18:52by Murs ET al from the Brigham
18:55and Women's Hospital in Boston who
18:58looked at anticoagulation use and
19:00outcomes among patients with atrial
19:03fibrillation and vanilla brand disease.
19:07Oral presentation.
19:09The background is that estimated
19:12prevalence of symptomatic 1 willibrand
19:15disease is about one in 1000.
19:18It is estimated that.
19:21Patients with one milligram
19:23disease have similar prevalence
19:25of atrial fibrillation as general
19:27population is about .84%.
19:30The American College of Cardiology
19:32recommends using anticoagulation for those
19:34with atrial fibrillation who have chads,
19:37vascor of two or greater in men
19:39or three or greater in women.
19:41The recent ash ISTHNHF&amp;W SH guidelines
19:48recommend using anticoagulation or
19:51antiplatelet therapy as clinically indicated.
19:54It was a suggestion with low certainty
19:57of evidence and importantly when
19:59I looked into the the actual.
20:04Basis of this recommendation,
20:06it was based on a case series of about
20:0960 patients or really low quality data.
20:14So this the study that was
20:16presented was a retrospective study
20:18in which data was obtained from
20:21the Electronic medical records.
20:23Patient was selected if they had
20:25a diagnosis of 1 lip and disease
20:27noticed or seeking cofactor activity
20:29or any abnormal one will event factor
20:32measurements and also selected for those
20:35who had diagnosis of atrial fibrillation.
20:38The primary endpoint was rate of major
20:40bleeding as defined by the IST criteria,
20:43which is fatal.
20:44Bleeding, bleeding in critical
20:46organs or bleeding causing more
20:48than two grams of two grams per DL,
20:51drop in hemoglobin or more than two
20:54units of red blood cell transfusion.
20:55Sorry with the typo.
20:58The results were that patients in
21:02tribulation patients were between
21:05diagnosed between 1980 and 2020.
21:09For 340,
21:10patients were screened and
21:1189 patients were selected.
21:13For the final analysis.
21:15Out of those 64 patients were female,
21:1828% patients were deceased at
21:20the time of the data pool.
21:22Medium Chance Best Score was three and 89,
21:26so close to 90% had a score of two or higher.
21:30A third of the patients also had
21:32a quote acute coronary syndrome,
21:34which the authors lumped together
21:36STEMI non STEMI and Angela.
21:41In the in the figure over here as we can see,
21:4542.7% of the patients in the
21:48study were on aspirin or they
21:50were ever prescribed aspirin.
21:52About 13.4% of the patients were ever
21:57prescribed P2Y2 inhibitors and 56.2%
22:01were ever prescribed an anticoagulant.
22:05The green color represents people
22:08with antiplatelet agents who also had
22:12diagnosis of acute coronary syndrome.
22:14About 1/4 of the patients were
22:17never prescribed any anticoagulant
22:19or antiplatelet agent.
22:23In these two graphs we can see the
22:26median time to 1st bleeding event
22:28on the left we have antiplatelet
22:31agents and on the right it's
22:33anticoagulants as we can see in both.
22:36It looked like the the median or
22:40the time taken for median first
22:42meeting was greater than 15 years.
22:44For both of these study groups.
22:49Just going into the raw numbers,
22:5310.2 events per hundred patient years.
22:56So the rate of major bleeding was
22:5810.2 events per hundred patient years.
22:59For those on platelet agents,
23:028.9 events per hundred person years.
23:05For those on anticoagulants
23:07without any statistical
23:08difference between the two groups.
23:10Baseline risk of bleeding was one
23:12event per hundred patient years,
23:15so these were the patients who
23:17never got antiplatelet therapy
23:19or anticoagulant therapy.
23:21Concomitant anticoagulant and
23:22antiplatelet agents resulted in
23:24much higher risk of bleeding,
23:26which was about 28 events
23:28per hundred patient years.
23:30The lifetime risk of major beating was
23:33also calculated by the investigators,
23:35which was 32% in those who were
23:39ever prescribed anticoagulants,
23:41and 25.6% who were never
23:44prescribed anticoagulants,
23:45and there was no statistical
23:47difference between the two groups.
23:51Looking at the stroke risk,
23:52the incidence of stroke was
23:55about 15 point 7%. And notably,
23:5811 out of the 14 patients had
24:00never used and equivalent for more
24:02than sorry had not been prescribed
24:05anticoagulant for 90 days or more.
24:08The median chance best score was
24:09three in those who had stroke.
24:14And and also those who are
24:17not anti quietly therapy.
24:19One of those patients who had
24:21a stroke had a fatal stroke.
24:26So the authors concluded that 50% of
24:28the patients in their study group
24:31were ever prescribed anticoagulant.
24:34There was no benefit in choosing anti
24:37platelet therapy or anticoagulant therapy
24:39if bleeding rate is taken into account.
24:43There was no difference in lifetime
24:44risk of bleeding in those who were
24:47prescribed anticoagulants versus those
24:48who were not prescribed anticoagulants.
24:51Limited use of anticoagulant and antiplatelet
24:54therapy has much higher risk of bleeding,
24:57which is not surprising and 57% of
25:01patients had thromboembolic strokes.
25:03Most of those who were not therapy.
25:07So my take away from this study
25:08was that it was one of the largest
25:11studies looking specifically at this
25:13population of one will appendices.
25:15Individuals who also have April fibrillation.
25:18It was a retrospective study,
25:19so has its own limitations,
25:21but it still provides one of the
25:24largest studies or largest evidence,
25:27which makes us probably feel a little
25:29bit more comfortable using anticoagulant
25:31in these patients with appropriate risk.
25:34Assessment of bleeding.
25:37Oftentimes antiplatelet agents are
25:40prescribed over antique violence as
25:42a way to reduce the risk of bleeding,
25:44but this study sort of makes
25:47us doubt that assumption.
25:48Details of 1 milligram disease
25:51subtypes were missing,
25:52and as we know,
25:54the severity of lung disease or
25:56the type of 1 disease could make a
25:58difference to the bleeding risk.
26:00We also have noted recently that
26:03ristocetin cofactor activity may not
26:05be appropriate to diagnose patients
26:07with type 21 blip and disease,
26:09so some of those individuals were
26:11typed as one group and disease back
26:13in the previous years may actually
26:15not have one web and disease.
26:18Similarly,
26:18practice patterns for A-fib management
26:20as well as the choice of anticoagulation
26:23has changed quite a bit since 1980s,
26:26so that would certainly people founder.
26:31We're gonna move on to the next.
26:34So this was a man and also an
26:38oral presentation.
26:39Presented on behalf of Doctor Connors.
26:44It was it was a meta analysis of
26:47direct oral anticoagulants versus low
26:49molecular weight heparin for treatment
26:52of cancer associated thrombus.
26:57In the in this study, the authors
27:00looked at 6 randomized control trials.
27:04The. This was an update to
27:07the previous meta analysis,
27:08which had four of these trials
27:10mentioned over here. The top four.
27:12So the two bottom ones were
27:14included in this meta analysis,
27:16so there were a total of 3690 patients
27:20out of which 1850 got direct oral
27:23anticoagulants and 1840 got local.
27:28The authors looked at the risk of
27:31recurrent venous from embolism,
27:32and it favored use of
27:35direct oral anticoagulants.
27:37Incidence rate of recurrent VTE was 5.5%.
27:43In the electrolytic group
27:44and eight point 3% in the low
27:47molecular Weight Heparin group.
27:50With the risk ratio of .67 favoring director.
27:57Risk of major bleeding was about
27:59the same in the two groups,
28:02so the incidence was four point 3%
28:05in the direct oral anticoagulants
28:06group and three point 7% in the low
28:09molecular Weight Heparin group.
28:11And statistically, there was no
28:13difference between the two groups.
28:14The clinically non the clinically
28:18relevant non major bleeding.
28:20Favored use of heparin,
28:22so it was the incidence was 9.5%
28:28of this bleeding in the direct or
28:31anticoagulant group and five point 7% in
28:33the low molecular weight heparin group.
28:35The risk was 1.6 and statistically favoring
28:38low molecular weight heparin group.
28:43All 'cause mortality was
28:44similar in the two groups.
28:47The conclusions drawn from this study
28:50of from this paralysis for that to
28:53act significantly reduce the risk of
28:55recurrent VTE compared with heparin,
28:57without increasing the
28:59risk of major bleeding.
29:01However, use of direct oral
29:03anticoagulants was associated
29:04with increased risk of clinically
29:06relevant non major bleeding.
29:10Finally, the last oral study that I
29:14would like to present was about impact
29:18of race and ethnicity on cancer,
29:20associated thrombosis among
29:22underserved patients with cancer.
29:24This was an oral presentation
29:26presented by Doctor Decosta.
29:30In this study, a retrospective
29:33analysis was done and the investigators
29:38identified 9353 patients.
29:41After those, 49.3% were Hispanics,
29:4527.6% were non Hispanic blacks,
29:4850.5% were non Hispanic
29:50whites and 7.6% were passed.
29:53Islanders interestingly,
29:5774.7% were uninsured, and.
30:01The reason for this was the
30:03study was primarily focused on a
30:05safety net hospital in Houston,
30:07which has this demographic of population.
30:11The incidence of cancer associated
30:13thrombosis was seven point,
30:153% at six months and 9.6% at 12 months.
30:19Of previous studies which
30:21have looked at this,
30:22which were primarily focused
30:25on Caucasian population,
30:26the risk at 12 months is much lower,
30:30about 2.3%.
30:30So something to keep in mind.
30:35On the graph on the left,
30:37we can see, as expected,
30:39pancreatic upper GI where the OR
30:42patients with pancreatic or upper GI
30:44cancers were the ones with highest
30:47risk of cancer associated thrombosis.
30:49The interesting part was the top.
30:51Sorry, the bottom right figure where
30:54we can see that non Hispanic black
30:57population and non Hispanic white
31:00population seem to have similar
31:02cumulative incidence of cancer
31:04associated thrombosis at 12 months.
31:06While Hispanic population and Asian
31:10population seem to have a lower risk,
31:13so this contradicts what we have
31:16traditionally known about thrombosis,
31:18which is reported to be higher in
31:23individuals with black ancestry.
31:25And Hispanic population have
31:27been traditionally known to have
31:28a lower risk of thrombosis,
31:30so that is congruent with that knowledge.
31:36When the authors did the
31:38multivariable analysis,
31:39they again found Hispanic race
31:42and Asian race were to have an
31:46impact on the risk of getting
31:48cancer associated thrombosis.
31:52The conclusions drawn were
31:54higher incidence of cancer.
31:55Associated thrombosis was noted
31:57compared to the European registries.
32:00Non Hispanic blacks had similar
32:03incidence of cancer associated
32:05thrombosis to non Hispanic whites.
32:08Hispanic and Asian Pacific Islanders
32:09had a lower risk of cancer associated
32:12thrombosis compared to non Hispanic
32:14whites and non Hispanic black population.
32:17And treatment with chemotherapy
32:19or immunotherapy associated.
32:21It would help you or immunotherapy was
32:24associated with increased risk of thrombosis.
32:27That concludes my talk.
32:33You said that she.
32:48I'm just gonna start my groups.
32:53The right one.
33:02Hopefully this is the right one.
33:05Alright, I'm so let me just start moving.
33:10OK so hello buddy and Alex Pine and I
33:15wanted to briefly briefly everybody
33:18on 3 potentially 4 abstracts.
33:21If we have time and.
33:25The first three are sort of have
33:28this ITP flavor and a couple
33:30of them has kovid color,
33:32so the first one is actually the
33:36first two kind of have the same motif,
33:39and they both studies actually looked into.
33:45What happens to patients with
33:47persisting thermoset opinion
33:49when they receive COVID that
33:52vaccines and so the first study?
33:56Which was out of Cornell.
33:59Essentially they were operating
34:01on the premise that play,
34:04let's play play quite a bit of
34:07a role in immune immune system.
34:11And also in their cohort,
34:15different cohort but in their center
34:17thrust opinion happened in 27% of
34:21patients with just COVID-19, so they.
34:24Actually postulated,
34:25or at least developed the concept further.
34:30That in COVID-19,
34:32especially severe COVID-19, there's a a.
34:35This is normal glycosylation of the
34:37spike protein antibodies is is a
34:40prothrombotic signal for platelets,
34:41especially through.
34:46Direct receptor these complexes of
34:49IgG and virus operate through the
34:53Cy come receptor and So what they?
34:59They also. There was also a
35:02clinical sort of observation.
35:04Then there were some reports of ITP in post
35:07vaccine settings in a single institution.
35:10I believe I'm GH.
35:11There was a 52 patients and there
35:13were 12% of ITP dissertations.
35:16So they asked the question.
35:19Several questions is in fact what is the
35:21effect of vaccines on platelet count,
35:23risk of bleeding events?
35:26What kind of what kind of effect
35:30is in repeat dosing of vaccines?
35:31You know the second vaccine
35:33booster and so on,
35:34and what the risks of
35:36the actual exacerbation.
35:37What sort of plays a role in
35:39exacerbating so their cohort was
35:44retrospective from patients 10
35:46university affiliated patients
35:48that we actually also participated.
35:50So it's 117 patients.
35:54With a pretty long history of ITP 12 years.
35:57And of course they were.
36:00You know at the time where the
36:01study was sort of conducted,
36:03yeah,
36:04the patients were getting vaccinated
36:07were older patients.
36:09So breakdown of what therapies
36:13were administered,
36:14either on therapy or off therapy
36:17or prior prior therapy.
36:18So
36:21TPO, RA's and we talk smack word
36:25bulk of the of the treatments,
36:27and colectomy was also in 21% of
36:29patients and at the time of the study 40
36:32patients were off treatment and 16 of
36:35those were with normal platelet count.
36:37This is a breakdown of.
36:39See the exchange that we received.
36:43Simon, of course majority and
36:45then definitions how they sort
36:47of were assessing the response.
36:49So stable platelet count was plus
36:51minus 20% of the pre vaccine level,
36:53and ITP exasperation was defined as either.
37:01Much higher than 50% reduction of
37:04platelet count or 20% reduction if you.
37:08If the if the native platelets
37:10below 30,000 or the use of rescue
37:13treatment and So what?
37:16They found that there's a
37:18three groups of patients.
37:20So in about.
37:23I would say third or close to third
37:27quarter places actually increased
37:29platelet count increased in.
37:31Happened in middle part like a 40%.
37:34Nothing happened and in
37:36about third so to speak,
37:39it's actually decreased and this is
37:41the first Test of the second dose.
37:43Sort of similar and they pointed out
37:46that it may not be the same patience.
37:49So they broke it down into
37:53into into several groups.
37:56Specifically,
37:56so they assessed all patients in
38:00terms of incidence of post vaccine
38:02ITP reservation splenectomy patients,
38:04patients with me in patients with very
38:06heavily pretreated with five more than five,
38:08five, and more prior therapies,
38:11and so,
38:12interestingly enough,
38:12if you look at this point to me,
38:15it's they they saw a significant
38:19significantly higher incidence of.
38:25I've played loads of ITP reservations
38:29as well as patients with who are
38:31very, very heavily pretreated.
38:36Now when the when the post vaccine
38:38rescue therapy was administered,
38:39it was it was effective was administered
38:41about 30% of patients and they they
38:45reported no serious bleeding events.
38:47From a patient with.
38:52Patients with stable or
38:54increased platelet count after.
38:57The first vaccine,
38:58so that was those 43 patients,
39:01and after those number 26 patients have
39:05platelet count, decreased below 30.
39:09So factors that are found not
39:11predictive of estimation were age,
39:13gender, vaccine type and
39:15presence of autoimmune disease.
39:18They actually had access to two
39:21surveys and they sort of tried.
39:23They tried to validate their findings
39:26and they they looked into these surveys.
39:31These are two surveys.
39:32One is from a base in the United States,
39:35one is from UK especially.
39:36They track the track.
39:40Similar data. And so they found
39:44that in indeed in patients who
39:47had platelet count decreased.
39:50There were a lot more
39:52people with splenectomy.
39:54And then when they looked
39:57into your CTP cohort.
40:00Also survey based they found
40:03sort of breakdown of similar.
40:06Similar breakdown of decreased
40:07platelets about the third of patients
40:10indeed had ITP assassinations,
40:11and they also in the same
40:13survey found this book to me.
40:15Was the shade with a 2 fold
40:17increase of risk of decreasing
40:19in platelets by more than 50%.
40:21So they acknowledged the speed
40:23limitaciones that there's no lack of.
40:26There's there's no unvaccinated
40:29control group 2.
40:31To compare,
40:31there was a possible selection
40:33bias because they were following
40:35a lot closer to the people who
40:36are had refractory GP already.
40:40They were they didn't account
40:42for titration for concurrent sort
40:43of interventions in terms of how
40:45they affect the platelet count,
40:46including the titrations of the of
40:48the medications of the treatment
40:50that the patients were already on,
40:52and the technology that the possible
40:54overlap between cohort might effect
40:56might affect the platelet count,
40:58but overall they felt that the
41:00major point was that there was
41:03no bleeding in refractory TCP
41:05in refractory thrombocytopenia.
41:07Following vaccination and the major.
41:12.0 there was like if it's
41:14if it's a splenectomy.
41:15Patients follow closer.
41:16If it's a patient,
41:17were the difficult control
41:19ITP or heavily pretreated.
41:20Follow them closer.
41:23And so that was main main idea and then
41:28in a sort of in the in the in the post
41:31in a additional question sort of session
41:34following the abstract presentation.
41:35Somebody was asking, how would you counsel
41:38consultations and who actually did not,
41:40perhaps did not who I had
41:43from Selena after the first.
41:44Actually would you, you know,
41:45give the second vaccine, and so the
41:48presenter actually said that she usually.
41:52She would actually recommend
41:54but with close observation.
41:56Alright, so moving on to the second
41:58one so the second study was similar.
42:01In fact, they just followed one another.
42:03This one is from.
42:05Dutch study the benefit of this
42:07study was a prospective cohort,
42:09but the question was fairly similar
42:11to what happens in patients with
42:14ITP with pre-existing ITP when
42:16they receive COVID-19 vaccine.
42:18This study had a control arm.
42:21It had about a similar twice
42:24as much patients,
42:26218 in about the same number of 200.
42:29Healthy controls.
42:30Breakdown of vaccine was a little different,
42:33most of them received Moderna that was.
42:36Holland come in.
42:37All healthy controls received.
42:40Moderna 15 patients required
42:42rescue treatment.
42:44Now this is a breakdown of the treatment
42:48that patients were received or were on.
42:53So quite a number were on steroids
42:55in at a time and then also
42:59about 10% were Hispanic to me,
43:02definition of ITP dissertation
43:04was fairly the same.
43:07In fact, exactly the same.
43:09And sorry and So what they?
43:12What they found here on the
43:15graph below is that the.
43:19Both pleasant count in both
43:22normal controls and in.
43:27Patient stated patients actually
43:28decreased and they I believe
43:31they said it's decreased by 6.3%
43:33in both in both in both groups,
43:36so they didn't really feel there
43:37was a difference in reduction,
43:39but they both platelets
43:41in both groups went down.
43:46In fact, this is the better image of that.
43:54And so they further look
43:55into risk factors as well.
43:57And here they found interesting piece
44:00which is a contradicts the previous study.
44:03They found that split me actually was
44:05associated with increase of platelets,
44:07quite substantial cruise of platelets.
44:10And a current treatment was associated
44:15with a decrease of platelets and.
44:18Age was associated with small decrease
44:21in platelets following vaccinations.
44:25So this is again sort of a tally that
44:283030 patients developing masturbations
44:3115 required rescue treatment.
44:34The bleeding they did report bleeding,
44:36and interestingly enough and and in
44:40a post in a in a in a in a question
44:43period they were asked about this,
44:46so all the five bleeding episodes
44:48happened in patients with platelet
44:50count of higher than 100,000.
44:52And in fact one patient who had a
44:56fatal fatal gastrointestinal bleeding
44:58also had platelet count of 100.
45:00So their answer was that it's.
45:05It was not related to vaccination at all,
45:06it was comorbidities,
45:07and in fact in the patients who
45:09had a GI bleed fatal jab bleed,
45:10it was a severe liver disease.
45:15Few patients require transfusions
45:17over plated or.
45:19It helps so the conclusions here is,
45:22it's actually kind of similar.
45:23The effect of code in vaccination
45:26is similar in health in healthy
45:28controls and ITP patients.
45:30Dissertations were only a
45:32few very few ITP patients.
45:34There was a good response
45:36to rescue treatment.
45:38And essentially vaccination is safe and
45:40monitoring is advised and is actually
45:43was recommended by ASH guidelines.
45:47Come and this is sort of the additional
45:49questions that they were asked.
45:51Somebody asked whether they check
45:52for platelet antibodies and they
45:54said they did not evaluate for
45:56platelet antibodies directly,
45:57but but there's no association with
46:01high levels in health healthy controls.
46:06So,
46:06so I want to just finish up with this
46:09third study, which is which is also.
46:14ITP related studying.
46:15In fact,
46:16this is an interesting trial about use
46:20of BTK inhibitor will support NIP in.
46:25A refractory relapsed ITP's.
46:27The premise of the of the of the trial
46:31was was I think it was five for face,
46:33face,
46:33one face,
46:34two sort of update on on on the
46:37phase one phase two trial.
46:38The the premise was that pertain
46:41inhibitors modulate quite a bit of a quite
46:44a number of different effector cells.
46:46B cells and macrophages.
46:49Then also signaling signaling of the
46:52basilar receptor and inhibitors decrease
46:55our reactive antibodies in so there's a.
46:59There's an interest in evaluating
47:01this group of class of medications.
47:04Class of drugs in it P.
47:06And specifically.
47:07While I'm really Brittany was chosen because.
47:12Is believed to be very selective,
47:13so out of different kinases
47:16it's it's pretty selective.
47:18It inhibits quite quite nicely, but.
47:23But not others, rather occupy.
47:27Target potentially, but not others.
47:29It's quite reversible.
47:32And why not in Britain for instance?
47:35Well,
47:35so there's association of
47:37play legation with liberty,
47:39but not as shown here when.
47:45Was tested against collagen
47:48so much much. He come.
47:54Specially associated with
47:56aggregation more than rules.
47:58So the trial instant criteria was
48:01fairly straightforward, its response.
48:03It's essentially adults response.
48:06They have to have at least had to have
48:09at least response to one prior treatment,
48:12and there's no other available
48:14to them or not approved.
48:16And there should be at least two platelet
48:19count less than 30 thirty thousand
48:22brother on 2 occasions and concurrent
48:26therapists were allowed, including.
48:28Storage entity arrays.
48:30There was a dose escalation as a phase one,
48:34but in kind of a phase two
48:36phase of it part of it they use
48:38actually 400 milligrams VID,
48:40which I'll show soon.
48:42Primary in point was essentially.
48:45Account of greater than 50,000
48:47on two occasion at least,
48:50and an increase of 2020 thousand of the
48:54baseline without use of rescue medication.
48:57And they actually had a long term
49:00extension also for 400 milligrams PID.
49:02And so here's what happened.
49:04So this is kind of a overall study diagram,
49:07so this is the 400 the ID group.
49:11So this is 45 patients.
49:13And so here's the results.
49:17So out of this 4518 that is 40% reached
49:21the primary endpoint so greater
49:23than 50 in with 20 greater than.
49:2850% fifty thousand increase.
49:31Sorry, greater than 50,000 platelet count
49:35increased 20,000 from the baseline,
49:37so that's 18 patients reached that end
49:39point and it was very rapid improvement,
49:42so this is it's probably hard to see.
49:45But this is days and so within,
49:48you know this is actually 20.
49:49I think it's 25 or 29 days,
49:52so it's a really rapid improvement
49:54and it's actually sustained.
49:55And of course these are not responders and
49:58you can see here that this is sort of a.
50:01Better.
50:03Way to assess sort of duration of response.
50:05So this is greater than 30 number
50:08of number of weeks achieved
50:10in 20 and then 15 and 14.
50:15So then, whoops.
50:21And so they made a point
50:23that it's indeed very rapid,
50:25very rapid increase in fact,
50:28median time to greater than 30,000
50:31level was achieved in 8.5 days
50:35greater than 30,000 + 20,000 above
50:37the baseline in basically 12
50:39days in greater than 50,000 play
50:41account in just about the same
50:4412.5 days and median time for the
50:46primary response was about a month,
50:48so it's very very rapid.
50:51And then they also showed the.
50:54What happened in this long long extension?
50:58Arms, so to speak,
50:59and they said that it's basically
51:02it was quite robust.
51:08Especially it's a.
51:10It's a maintain the maintained the
51:13response alright and then adverse effects.
51:17Basically it's all grade one grade,
51:19one grade, two diarrhea and nausea,
51:22fatigue. And again this is all
51:25about 400 milligrams twice a day,
51:27so conclusions. Mr.
51:31Bracnet provides.
51:34Inhibition of phagocytosis.
51:39And 40% of patients on 400
51:42milligram VID achieved endpoint
51:44primary endpoint at 18 patients.
51:46Response was rapid and was well
51:50tolerated and response was maintained.
51:53So there's open going
51:55face the Luna three trial,
51:56which further will address this.
52:01This this modality in additional questions.
52:06I think there was nothing really
52:08particularly interesting,
52:09but they said there's no,
52:10nobody, nobody was on any.
52:14Antibiotic prophylaxis and
52:16there was no infections.
52:18So I think in interest of time I finish,
52:20I stop here.
52:23If we have some questions, well,
52:25thank you all very much for those very
52:27informative and very clear presentations.
52:32If people do have questions,
52:33if they could put them in the chat
52:35that there are a couple there.
52:37Maybe we can start with those.
52:39So I'm Kelsey.
52:41You mentioned in your abstract with
52:43factor 11 deficiency that some patients
52:46bled despite getting fresh frozen plasma.
52:50What what might be some alternatives
52:52to treat those individuals?
52:53Or do you have any any thoughts about
52:55why those people still had bleeding?
52:58Yeah, it's interesting.
52:59I mean the half life of factor 11 is long.
53:03I think about two days or so,
53:04and so it's it's.
53:06It's intriguing, but I think something
53:07we've all experienced in practice.
53:09I think that may happen,
53:10perhaps just the quantity effect
53:12or Lebanon is not concentrated.
53:15You know, you never maybe know
53:17exactly what you're getting in the FP,
53:18and maybe one element.
53:20And I, you know there are
53:22cases reported of inhibitors,
53:23so perhaps some of those
53:24patients that didn't respond,
53:25maybe inhibitors.
53:28I think that I think Novoseven could be used,
53:33but I think with caution and maybe
53:34at a lower dose or maybe particularly
53:36in someone who had an inhibitor.
53:38I think there would be a role there,
53:39and then maybe sort of leaning more
53:42heavily on anti fibrinolytics might
53:44be useful, but I mean I think it's.
53:48A challenge we've all seen and experienced
53:50that sometimes is hard to pinpoint.
53:53It's a great question,
53:54great, thank you.
53:55Thank you and and Sudan shoe. You.
53:57You mentioned that there was an
53:59increase in the clinical clinically
54:00relevant non major bleeding and
54:03individuals who are getting doax
54:05for cancer associated thrombosis.
54:07So when when you prescribe either
54:09a low molecular weight heparin
54:10orado act to a patient with cancer
54:13associated thrombosis, how do you?
54:14How do you?
54:17Decide on the benefits, risks there,
54:19and what what agents do.
54:20You tend to choose and are there.
54:22Are there things about the
54:23patient that may point you
54:24in One Direction or another?
54:28So the clinically relevant non major
54:31bleeding was really of concern,
54:33which was higher in doax and
54:35that has been pretty consistent
54:37throughout all the six trials.
54:39So it wasn't just one study.
54:42And the way it impacts my practice
54:44is if if I do look at the patient's
54:47underlying bleeding risk.
54:49If there isn't an individual where I
54:51would be more concerned about bleeding,
54:53perhaps someone who had immediate
54:56postoperative thrombotic event,
54:58or perhaps with somebody who's going
55:00for a surgery or has a known history
55:03of underlying bleeding or faults.
55:05I might be more inclined to use
55:09those individuals rather than doax,
55:11so that would be my approach and.
55:13How I would use that information?
55:15Thank
55:15you very much, don't you?
55:17And Alex, are there any situations
55:20in patients with ITP, and in in,
55:22in which you might hold off on giving
55:26COVID vaccine COVID-19 vaccine?
55:28So individuals who are recently flared
55:30or have very low platelet counts and
55:34requiring intense therapy, for instance?
55:38You know, so this is interesting
55:40because the data they really didn't
55:42actually include specifically,
55:43like they didn't address the question
55:47of whether patients who were in right,
55:50right, or right now on inactive.
55:55ITP destinations,
55:57prior to prior to vaccination. They were.
56:00They only had patients who were on
56:02sort of chronic chronic therapy,
56:04so I I don't think we have data per
56:09say in that regard, but personally,
56:12I think if there's a flare actually flare,
56:17I probably would hold off,
56:20just not to disturb.
56:23You know it. You know,
56:25in in in response further,
56:28I think it would might what might be
56:31really interesting is in in this situation
56:33to address further whether they're truly.
56:36Uh and antibody platelet antibody,
56:39which none of them really looked into.
56:43Great, but but I think I would
56:45probably hold off until there's some
56:46stabilization of platelet count.
56:49Seems very prudent. Yep, OK, alright.
56:53Well it's it's just about 1:00 o'clock,
56:55so I want to thank our speakers for again.
56:58Excellent presentation that
57:00were informative and I think
57:02highlighted some really important
57:03areas in classical hematology.
57:05And thank you all for for joining us.
57:08Thank you very much.
57:09Have a great day everyone. I.