Classical Hematology

February 15, 2021

Information

February 15, 2021

Presentations by Drs. Sabrina Browning, George Goshua, and Alexander Pine.

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00:00OK, good afternoon everyone it's 12:00
00:03PM on this beautiful Friday and today
00:07is the next session and our yield.
00:11Hematology hash highlights from
00:13the 2020 American Society of
00:15Hematology Meeting highlights.
00:17So as you can see on the agenda
00:21in the last few weeks,
00:24we covered multiple myeloma,
00:26lymphoid malignancies, myeloid malignancies,
00:28and pediatric leukemia and hematology.
00:31And today we will be discussing
00:35classical or B9,
00:37but not so benign hematology.
00:54So as usual, many abstracts are
00:56presented in about classical hematology
00:58in the ash mythology meeting.
01:00However, due to time limitations the focus
01:03will be on the most prominent abstracts,
01:06and the ones that have the
01:08highest clinical relevance to
01:10practice on on a day-to-day basis.
01:13The abstracts will be grouped
01:16in areas of clinical.
01:18Unmet need and there are many other
01:21abstracts of course that are very good that
01:24we do not have the time to cover today.
01:26Important to note that
01:28these abstracts represent.
01:29Often preliminary presentations and
01:31data that has not been yet completely
01:33vetted or peer reviewed or finalized.
01:36So we have to take that into consideration.
01:39As we discussed the data we like
01:41to thank the authors who shared
01:44their presentations with us and the
01:47recording of this session and the
01:50other sessions will be available.
01:52Over the next week or so,
01:55for those who cannot attend the live
01:58sessions and the CME credit will be
02:01available after filling up receive
02:04feedback on the seminars and how
02:07we can improve him going forward.
02:09So today it's a pleasure to be joined
02:12by my colleagues Sabrina Browning,
02:15who's our instructor in medicine and
02:18section of Hematology who will be
02:21covering bleeding and hemostasis.
02:24Sam Alexander Pienaar,
02:26associate professor of medicine.
02:28Who will be covering from bosses
02:31an antithrombotic therapy?
02:33Advances from ash and then our
02:35bright fellow George Joshua will
02:37finish their presentations,
02:39covering other important and
02:41relevant classical hematology topics.
02:43At the end we will have Professor
02:46of Medicine Doctor Robert Bona,
02:48and our Associate Professor of Medicine,
02:51Doctor Alfred Lee,
02:52who will moderate your questions
02:55and also be available to help
02:57the speakers in answering.
02:59Any of the questions that are
03:02relevant to the abstracts presented,
03:04or any other abstracts from the
03:07meeting that are important.
03:10So it's my pleasure to present our
03:13first speaker, doctor Sabrina Browning,
03:15who will discuss bleeding and
03:17hemostasis without so Sabrina.
03:19Feel free to share your screen.
03:26Thank you Doctor Zayden and welcome everyone.
03:30For those interested,
03:31we've included QR codes throughout
03:34our presentation that will link
03:35you directly to the ASH abstracts.
03:37You can access these by
03:40using your smartphone camera.
03:42I have no disclosures to report.
03:45So this slide outlines the abstracts
03:47that I will cover today which span
03:49disorders of platelet number or
03:51function disorders of coagulation
03:52and fibrinolysis and von Willebrand
03:54disease and at the end I will
03:56briefly touch upon abstracts that
03:58were presented at ASH on the role
04:01of convalescent plasma therapy
04:02in the management of COVID-19 and
04:04provide an update on where we stand
04:07with this treatment currently.
04:09So to begin,
04:10doctor Charlotte Bradbury from the
04:12University of Bristol in the United
04:14Kingdom presented a late breaking
04:16abstract on the flight trial,
04:18which is a multicenter,
04:19randomized trial evaluating the addition
04:21of mycophenolate to standard of care.
04:23Corticosteroids in the management
04:25of patients with newly diagnosed
04:26immune thrombocytopenia.
04:27This study was developed due to the
04:30heterogeneous responses in ITP to
04:32first line steroids and concerns
04:34regarding their long term side effects.
04:36Evidence for mycophenolate or MF and
04:38second line treatment and beyond
04:40really comes only from Russia's
04:42retrospective studies at this time.
04:44This study recruited adult patients
04:46with ITP and a platelet count of less
04:50than 30,000 who were requiring therapy.
04:52Subjects were then randomized
04:53to standard corticosteroids,
04:55which could be in the form of dexamethasone,
04:57pulsed, at 40 milligrams daily for four days,
05:00up to three cycles,
05:02or Prednisolone 1 milligram
05:03per kilogram daily,
05:04followed by a taper or
05:06corticosteroids plus MMF,
05:07which was initially dosed at 500
05:10milligrams twice daily and then
05:12escalated to a Max dose of 1 gram
05:14daily with a plan to taper and then
05:17stop after six months of treatment.
05:19The investigators from this
05:21trial hypothesize that MF,
05:22combined with steroids,
05:24would be more effective than steroids alone,
05:26and the primary outcome measured was time
05:29from randomization to treatment failure,
05:31defined as a platelet count
05:32less than 30 and a clinical need
05:35for second line treatment.
05:37Secondary outcomes are outlined
05:38here and included bleeding events,
05:40side effects,
05:41and patient reported outcomes both at
05:43baseline and AT246 and 12 months as
05:46measured by validated questionnaires.
05:49120 patients were included in this study,
05:52with 59 on the MF ARM and 61
05:54patients receiving steroids alone.
05:56The median follow-up was 18 months.
05:5852.4% of patients were male
06:00with a median age of 54,
06:02so it was noted that more than
06:051/4 of patients enrolled in the
06:07study were over the age of 70.
06:09The primary outcome of proportion of
06:11patients without treatment failure is
06:13illustrated in the Kaplan Meier curve.
06:15Here on the left of the slide
06:18and favored the MF arm with an
06:21adjusted hazard ratio of 0.41.
06:23Interesting Lee.
06:23Similar responses were observed
06:25in the two groups at 2 weeks,
06:27despite the less refractoriness that
06:28was seen in the MF cohort and a
06:31statistically significant increase
06:32in plate in patients who reached a
06:35platelet count greater than 100 before
06:37they required in second line treatment.
06:40There were no differences observed in
06:41bleeding events or hospitalizations,
06:43and there were comperable rates of
06:45treatment side effects in both groups.
06:47However,
06:47there were some aspects on quality
06:50of life questionnaires that were
06:51observed to be worse in the MF arm,
06:53including both physical
06:55function and fatigue scores.
06:56So to summarize this abstract,
06:58this is the first randomized control
07:01trial using MF to treat ITP,
07:03and it illustrated good overall
07:05efficacy and tolerability when added
07:07to first line corticosteroids,
07:08including in a cohort of patients
07:10that had included elderly patients.
07:12However,
07:13there were some negative affects on
07:15quality of life that were observed
07:17in the treatment arm and the
07:19investigator suggested that this
07:21regimen could be considered in some,
07:23but not necessarily all,
07:26patients with newly diagnosed ITP.
07:28The nest next abstract I'd like
07:30to share was presented by Doctor
07:32David Kuter from Massachusetts
07:34General Hospital and highlights the
07:36clinically active and the durable
07:37platelet response that were observed
07:39with the oral BTK inhibitor reels of
07:41Bruton IB in patients with heavily
07:44pretreated ITP as illustrated in
07:45the figure here.
07:47On the left rules ibrutinib is a
07:49reversible and selective inhibitor
07:50of BTK that aims to target the
07:53disease mechanisms leading to
07:54platelet destruction in ITP,
07:56though it's without the effects on
07:58platelet aggregation that we often see.
08:00In the drug ibrutinib the trial,
08:03this trial of Phase 1 two open label
08:05trial was a dose finding study and
08:07that enrolled adult patients with
08:09relapsed or refractory ITP who had
08:11responded to at least one prior
08:13line of ITP therapy and had two or
08:15more platelet counts that were less
08:17than 30 at the time of study entry.
08:20Subjects could be on stable doses
08:23of concomitant corticosteroids
08:24and or thrombopoietin receptor
08:26agonist during this trial.
08:28The dose escalation phase of this
08:30study was previously reported at
08:32ASH with a minimum effective dose
08:34of 400 milligrams twice daily.
08:36The primary endpoint of this part of
08:39the study was achieving two or more
08:41consecutive platelet counts that
08:43were greater than 50,000 with an
08:45increase of more than 20,000 from the
08:48patients baseline without requiring
08:50any rescue or additional medications.
08:52The investigators also performed subgroup
08:54analysis to determine the impact
08:56of certain prior treatments
08:58on this primary endpoint.
09:00A long term extension study was also
09:02conducted to further assess safety
09:04and durability of this medication,
09:06and so this specific abstract
09:07presented on 38 patients who
09:09had received the dose of 400
09:11milligrams twice daily and the 13
09:13patients who entered the long term
09:15extension study at this same dose.
09:20So patients in the 400 milligram twice
09:22daily cohort had a median duration of
09:25ITP of six years and had received a
09:27median of six prior lines of therapy.
09:29Their median age was 50, with a little
09:32more than half of patients being female.
09:35At the time of data cutoff,
09:37which was July of 2020, forty 2% of
09:39patients had achieved the primary endpoint.
09:42Furthermore, responses were relatively
09:43similar whether or not these patients
09:46had responded to prior therapy,
09:48as outlined here,
09:49including thrombopoietin receptor agonist,
09:50rituximab, or fostamatinib,
09:52and notably responses were quite rapid,
09:54with 53% of patients achieving a
09:57platelet count of more than 30 by day 8.
10:00And and responses were also
10:02durable in nature.
10:03A real rose alot nib was generally well
10:06tolerated in all portions of the trial
10:08with approximately half of patients
10:10experiencing grade one or two side effects
10:12that were transient and mostly GI.
10:14In nature,
10:15though there were no serious adverse
10:17events or treatment related bleeding or
10:19thrombotic complications during this study.
10:22So, in conclusion,
10:23reels reels of Bruton AB therapy at
10:25a dose of 400 milligrams twice daily
10:28achieved significant rapid and long
10:29lasting platelet responses in about
10:31a slightly under half a percent
10:33percentage of this patient population
10:35with heavily treated pretreated ITP,
10:37and this was observed irrespective of the
10:40response to prior lines of treatment rules.
10:42Ibrutinib was granted fast track
10:44designation by the FDA in October
10:46of this past year and further
10:49clinical trials with this drug.
10:50That drug is current.
10:52Currently on going.
10:56In the plenary session,
10:57Doctor Terry Gurne Shime are from the
11:00University of Washington School of Medicine,
11:02presented the results of the American
11:05trial using tranexamic acid and
11:07thrombocytopenia or the a treat trial.
11:09This study specifically examined
11:11the effects of tranexamic acid or
11:13txa prophylaxis on bleeding outcomes
11:15in individuals with hematologic
11:17malignancy undergoing treatment therapy.
11:19And it was supported by understanding
11:21of the high incidence of bleeding
11:23in this patient population,
11:25even despite our evidence based use of
11:28platelet transfusions prophylactically
11:29and while anti fibrinolytic therapy
11:31has certainly been used with pain in
11:33patients with hematologic malignancy
11:35undergoing treatment evidence,
11:36evidence of its benefit has really
11:39been lacking.
11:40So the Atria trial was a multi center,
11:43double blinded,
11:44placebo controlled trial aimed to
11:45assess the safety and efficacy of
11:48prophylactic transit tranexamic acid.
11:50Which is seen in this schematic,
11:52here included on the left of the
11:54slide block slicing binding site on
11:57plasminogen an inhibits and its activation,
11:59thus halting fibrinolysis.
12:01And the train exam IC acid was used as
12:04an adjunct to routine platelet transfusions.
12:06As was previously studied.
12:08Patients undergoing therapy for
12:10hematologic malignancy whom were
12:12expected to have platelet counts
12:13less than 10,000 for five or more
12:16days were eligible to be enrolled
12:17in the study and were randomized to
12:20receive either tranexamic acid at a
12:22dose of 1 gram Ivy or 1.3 grams opeo
12:25every eight hours or placebo with
12:27the start of the study drug after a
12:30platelet count had dropped below 30.
12:32Tranexamic acid or placebo was
12:34discontinued after 30 days or when
12:36platelet counts had re platelet count
12:38had recovered to more than 30,000
12:40and the trans transfusion thresholds
12:42used during the study where per
12:45standard of care the primary endpoint
12:47was the proportion of patients with
12:49WHO grade two or above bleeding with
12:51Grade 2 being moderate bleeding Grade
12:543 being severe bleeding requiring
12:56transfusion of red blood cells or
12:58other intervention and grade for being
13:00life threatening or debilitating bleed bleed.
13:03Additional secondary and safety
13:04endpoints are outlined on the slide
13:07here and include rate of thrombosis,
13:09vino occlusive disease and mortality.
13:15There were 330 patients,
13:16a valuable in the study with 165 on each arm,
13:19and the two groups were well balanced by age,
13:22gender, and type of therapy.
13:24Only 9% of the patients actually
13:26completed 30 days on drug,
13:28with an average of 12 days on train exam.
13:31IC acid or placebo.
13:32And as you can see in the
13:34table here on the left,
13:36the primary outcome of proportion of
13:38WHL grade two or higher bleeding was
13:40no different between the tranexamic
13:42acid and placebo, placebo arms,
13:44and this was also true irrespective of.
13:46The pre specified treatment
13:48subgroups that included allogeneic
13:50stencel stem cell transplant,
13:52autologous transplant,
13:53and chemotherapy alone.
13:55The time to 1st WH O2 or more
13:57two or higher bleeding or death
13:59was also remarkably similar,
14:01with the lines overlying each other
14:03in the graph, seen here on the right.
14:06Mean platelet transfusion mean
14:08days alive with WHO two or more
14:10bleeding an mean red blood cell
14:13transfusion per thrombocytopenia.
14:14Cdai were also not impacted by
14:17the use of tranexamic acid.
14:19There was,
14:19however,
14:20a statistically significant
14:21increase in the overall thrombotic
14:23events on the tranexamic acid arm,
14:25though this primarily was made up of
14:27line occlusions with a trend that was
14:30actually fewer in of non catheter
14:32thrombotic events in the treatment arm.
14:34There was no increase in Vino occlusive,
14:36disease,
14:37or alcors all cause mortality
14:38at either 30 or 20 days,
14:40and no deaths were observed
14:42as the result of thrombosis.
14:44So based on all of this,
14:46train exam IC acid administered
14:48prophylactically,
14:48in addition to routine platelet
14:50transfusion did not seem to increase,
14:52decrease the rate of WHL grade 2
14:54plus or bleeding in patients who
14:56are severely thrombocytopenia
14:57IK as a result of treatment for
15:00their hematologic malignancy.
15:01It also did not seem to alter
15:03transfusion requirements and and
15:05actually resulted in an increased rate
15:07of central line occlusion events,
15:09and so the authors emphasize,
15:10despite these findings,
15:11that the utility of tranexamic
15:13acid in other settings with
15:15thrombocytopenia cannot be excluded.
15:17By this study alone.
15:20So moving on to an abstract presented
15:23by Doctor Steven Pipe from the
15:25University of Michigan on the long term,
15:28durability, safety,
15:29and efficacy of fat userin prophylaxis,
15:31prophylaxis in patients with
15:33hemophilia A or B with or without
15:36inhibitors as seen on the slide here.
15:38So for twos are in is a small interfering
15:42RNA that as described in the schematic,
15:45blocks the production of anti
15:46thrombin and as a result increases
15:49or improves thrombin generation and.
15:51Remote team of stasis and individuals
15:53with hemophilia of phase one.
15:55Study of monthly subcutaneous photographer
15:57to Sarandos ING was previously
15:59reported in the New England Journal
16:01of Medicine in 2017 and demonstrated
16:03that this drug was well tolerated and
16:06also reliably lowered antithrombin
16:07in a dose dependent manner resulting
16:09in decreased bleeding frequency.
16:11So in this trial adult male patients
16:14with moderate severe haemophilia
16:15moderate or severe hemophilia A or
16:17B who had tolerated for chooser in
16:20in the Phase one study were eligible
16:22to continue into this phase.
16:24A2 cohort,
16:25which was an open label extension
16:27portion and they receive photos,
16:29are in at a dose of 50 or 80
16:32milligrams subcutaneous monthly.
16:34The primary endpoints were
16:35safety and adverse events,
16:37and there were key secondary endpoints
16:39that included a calculated median.
16:41Analyze the annualized bleed rate
16:43pharmacokinetics in quality of
16:44life in the in the patient cohort.
16:4934 patients were included in this portion of
16:52the study with a median age of 35.4 years.
16:55And this included 27 individuals with
16:58hemophilia A, A7 individuals with
17:00hemophilia B and 15 out of the group
17:02had inhibitors with 19 individuals.
17:05Not having an inhibitor.
17:06Patients received a median of 3.1 years of
17:10a tutor inducing as of the data cut off,
17:12which was September of 2020 and 12
17:15individuals were on the 50 milligram dose,
17:17with 22 being on the 80 milligram dose.
17:20But user and was noted in this study
17:23to decrease antithrombin levels quickly
17:24with sustained levels that remained at
17:27or below 20% in individuals who remained
17:29on the drug and so this was confirmed.
17:32The findings of the Phase one portion
17:35of the study.
17:36Immediate analyzed bleed rate was
17:38calculated for this cohort after
17:40achieving antithrombin knockdown an
17:42was zero for treated bleeds during
17:44the follow up period.
17:45The figure included here on this slide
17:48is a result from a post hoc analysis
17:51of 258 treated bleeds in 15 subjects,
17:54with each separate graph showing data
17:56on bleed causality, bleed location,
17:58an bleeds severity and from left to
18:01right in patients with hemophilia
18:03A with no inhibitor hemophilia.
18:05A patients with an inhibitor hemophilia
18:07B patients without an inhibitor and
18:10hemophilia B patients with an inhibitor.
18:12So while this is a bit of a busy figure,
18:15the takeaway is really that breakaway
18:18breakthrough bleeds occurred mostly
18:19in the joints or mild in nature,
18:21and tended to be more spontaneous in
18:23those individuals with inhibitors.
18:24These breakthrough bleeds were managed
18:27with factor replacement or bypassing
18:29agent per the study management guidelines
18:31with a focus on reduced doses to try
18:34and minimize the potential thrombotic risk.
18:37However,
18:37in the safety analysis of this study,
18:4097% of patients experienced at least
18:43one adverse event with 38% having a
18:45serious adverse event which included
18:48the events such as an arterial
18:50thrombosis in one patient and a death
18:53that actually occurred in 2017 as a
18:55result of a cerebral vein thrombosis.
18:58So in October of 2020,
19:00Sanofi voluntarily paused enrollment,
19:02inducing with Catoosa,
19:03ran to further investigate these adverse
19:05events and the rate of thrombotic
19:07events in the clinical trials,
19:09these trials have now resumed with
19:12reduced dosing of Fatou Suran,
19:14initially at 50 milligrams every
19:15other month in order to target and
19:18antithrombin level of 15 to 35%,
19:20which was found to be less associated
19:23with the thrombotic events.
19:25So in summary,
19:26for chooser and is an investigational
19:29small interfering RNA therapeutic
19:30and it has the potential use as a
19:33prophylactic treatment in patients
19:35with hemophilia A or B with or
19:37without inhibitors in order to try
19:39and reestablish hemostatic balance.
19:41However,
19:41further evaluation of its safety
19:43is imperative,
19:44and phase three trials of this
19:46drug are are now ongoing.
19:50And so I'll switch gears a bit with
19:52this abstract that was presented by
19:54Doctor Brooks Sadler from Washington
19:56University School of Medicine on Geno
19:58type analysis of adolescents with low.
20:00One willibrand factor,
20:02an heavy menstrual bleeding.
20:04She noted that heavy menstrual bleeding
20:06occurs in about 1/3 of adolescent
20:08women and accounts for 2/3 of patients
20:10who require hysterectomy and the
20:12prevalence of bleeding disorders,
20:14including von Willebrand disease in this
20:16cohort is higher than the general population.
20:19However, no,
20:19no one has looked or evaluated
20:22at other genetic hemostatic risk
20:23factors that may play a role here.
20:26So in this study,
20:2886 adolescent patients who met criteria
20:30for heavy menstrual bleeding and had von
20:33Willebrand activity between 30 and 50%.
20:35Were enrolled in the study and underwent
20:38whole exome sequencing that was compared
20:40to 600 unrelated in-house controls.
20:42The sequencing interesting Lee revealed
20:44in excess of rare stop gain and stop
20:47loss mutations in genes associated
20:49with bleeding or haematologic diseases
20:51as outlined in the slide here.
20:53There was also an excess of rare
20:56pathogenic variants that were
20:57observed in jeans that cause anemia
21:00or cause disease with anemia as a
21:02major symptoms of major symptom.
21:04This included variance in Adams TS 13,
21:07Fink,
21:07CA and G6PD and the other jeans
21:10that are listed here.
21:12There was analysis Additionally for
21:14common single nucleotide polymorphism's
21:16or snips that were that identified,
21:183 common snips infirm too,
21:20and this past genome wide significance as
21:23seen in the figure here on the right firm T2,
21:26encodes a cytoskeletal protein
21:28that is important in hemostasis,
21:30angiogenesis and blood vessel,
21:31home homeostasis, and so.
21:33This was the first whole exome
21:35sequencing study in patients with heavy
21:38menstrual bleeding and suggest there
21:40may be some Association in this group.
21:42With both rare and common
21:44variants in hemostasis and anemia,
21:46genes that warrant further
21:48validation in larger studies.
21:52And Lastly, I wanted to touch upon
21:55the abstracts that presented data
21:57on the use of kobid 19 convalescent
21:59plasma convalescent plasma,
22:01which is collected from individuals
22:03who have recovered from infection,
22:05is a therapeutic modality that's
22:07actually been used for over a
22:09century with the aim to transfer
22:11virus neutralizing antibodies to
22:13patients who have active infection.
22:15However, data on its use in COVID-19
22:18has been limited and quite mixed.
22:20And so I'll highlight here again,
22:23the five abstracts that presented
22:25some additional data.
22:26So in our institutional experience
22:28with 105 patients with severe or life
22:30threatening COVID-19 who were transfuse
22:32one unit of convalescent plasma through
22:34the national Expanded Access program,
22:37we saw that 42.9% of patients had
22:39improvement in their WHO ordinal scale,
22:42which is a score comprised of
22:44functional status, level of care,
22:46and oxygen supplement Tatian.
22:48Interestingly,
22:48we observed a correlation between D
22:51dimer level more than five at 2448
22:53and 72 hours after transfusion.
22:55Convalescent, plasma, and mortality.
22:57Ibrahim and colleagues shared
23:00data on 17 patients,
23:02six of whom were being treated
23:04for a hematologic malignancy,
23:06and these individuals were transfused
23:08one to two units of COVID-19
23:10convalescent plasma that had concert
23:12confirmed positive antibody titer,
23:14and they also observed a decrease
23:17in the mean WHO ordinal score by
23:20two points at the time of discharge
23:23of multi center phase two trial
23:25presented by Doctor Al Hashmi
23:27compared 178 covid convalescent plasma
23:30recipients to 391 matched controls.
23:33Is a significant reduction in 30
23:34day mortality in the treatment arm.
23:36In this study,
23:37though Interestingly they observed that
23:39the hospital and ICU length of stay
23:41as well as duration of intubation was
23:43longer and that was actually longer
23:44in the convalescent Plasma Group.
23:46Another phase,
23:47two matched case control study looked
23:49at a smaller number of hospitalized
23:51COVID-19 patients who received 2 units
23:54of transfusion and there was a trend
23:56in this group towards improved survival,
23:58though this was not
23:59statistically significant,
24:00it was noted in this study that the
24:02donor plasma was quite heterogeneous,
24:04with an increase in antibody
24:06activity observed in some,
24:07but not all,
24:08of the patients included in the study,
24:11and interesting Lee,
24:12those who had undergone anti CD 20
24:14treatment in the last year had a demo
24:17demonstrated an impaired response.
24:18In regards to antibody activity
24:20and Lastly a multi center Phase 1
24:23two trial of 70 patients who had
24:25received COVID-19 convalescent
24:26plasma found that 30 day overall
24:29survival was improved in those
24:31patients who had severe acute
24:33respiratory distress syndrome as a
24:35part of their COVID-19 infection,
24:37though there was an adverse event rate
24:39of 3.65% and there was one patient
24:42who was observed to have transfusion,
24:44associated circulatory overload and
24:46a second that was observed to have a.
24:49A venous thromboembolic event.
24:54So the QR code included here on
24:56this slide links to a section of
24:58the ash website that discuss is
25:00our available evidence on COVID-19.
25:03Convalescent Plasma provides a summary.
25:05As you can see, just from
25:07the data presented today,
25:08information on its effectiveness
25:10has been somewhat mixed and
25:11we're really awaiting data from
25:13larger randomized control trials.
25:15There are some themes that have emerged,
25:17and they include the importance
25:19of both antibody titer,
25:21but more notably neutralizing function in
25:23the donor COVID-19 convalescent plasma.
25:25As well as the benefit of providing this
25:28treatment earlier in disease course,
25:30there has been concern raised by our
25:32group and others regarding whether
25:34COVID-19 convalescent plasma may
25:36actually potentiates the already
25:38increased thrombotic risk.
25:39An end to Ophelia Opathy that we now
25:42know occurs with COVID-19 and further
25:44investigation into this is warranted.
25:46So taking this all into account
25:49as of just actually last week,
25:51the FDA has updated their emergency
25:53use authorization for COVID-19
25:55convalescent plasma.
25:56Really limiting it to use of high
25:58titer plasma for hospitalized
25:59patients that are early in their
26:01disease course and those who may
26:03have impaired humoral immunity.
26:07Thank you and I'll turn it over to Alex now.
26:14Thank you Sabrina. I'm just.
26:33OK, hopefully everybody can see the screen.
26:40Alright, wanted to say thank you to decide
26:44and Megadeth for putting all this together
26:49and everybody who's contributed else.
26:53Um, exciting, serious, and learning a lot.
26:55So I am going to see if I
26:58can move the slides. Yes,
27:01I'm just going to touch upon a few guests. 3.
27:06The abstracts that that that and identified,
27:10and specifically about cancer,
27:12associated venous thromboembolism
27:13and one of the new exciting agent
27:17for reversal of anticoagulation.
27:18And then I'm going to touch
27:22base and our own work.
27:25Thrombosis and COVID-19.
27:27How it actually. Informed us about
27:32in conditions beyond COVID-19.
27:35No disclosures on my end.
27:38Um, so the.
27:39One of the first highlight the
27:42this abstract about machine
27:45learning for prediction of cancer.
27:49Social verbalism,
27:50especially in the setting of new
27:53guidelines that ash guidelines
27:55that have been just released
27:57about cancer regarding cancer.
28:00Associated venous thromboembolism
28:01just the other day and as you all
28:06know we there are several clinical
28:09prediction rules of which comma score.
28:12Is most validated and had been.
28:15Used to stratify the risk in multiple trials,
28:21including most recently a PERT and
28:25Cassini RCT S42 Deluxe prophylactic
28:28regimen versus placebo and recall.
28:33It's pretty simple score to
28:37to use the questions.
28:41We have been raised over the over
28:44over the years is exactly where
28:46the draw the line in terms of
28:49prophylaxis versus which group to sort
28:52of start prophylactic production,
28:54if at all.
28:56And Furthermore,
28:57since Corona score as anybody know,
28:59several other scores have been
29:01released that had also been
29:03addressing certain features that had
29:06not been including current score.
29:08But unfortunately all of them have been.
29:11Not so useful in terms of prediction
29:16because their predicted power
29:18was not was in moderate mild to
29:22moderate sort of territory with
29:25statistics between .6 and .7.
29:28So for Corona score itself,
29:32there's a three categories so long to medium,
29:36high and specifically in
29:39high in the original.
29:41An original paper by Doctor Corona.
29:45We know that the rate of DTE was
29:49about 7% in high risk cohort,
29:52so the authors of this app start from
29:57Libor Sloan, Kettering, US Sameta and.
30:00Microsoft Group they sought to use
30:03to to utilize the machine learning
30:06algorithms to inform about the which
30:09features actually would be more
30:11productive in there for create a
30:14score or update the current score
30:16that potentially could increase
30:18the its predictive power.
30:21So they positive that they
30:24would use known predictors.
30:27It from Corona score.
30:28They would utilize too much
30:30genomic information that they they
30:33collect it in their preferred their
30:36profiling assay with 341 uncle gene
30:38and tumor suppressor genes.
30:40Overall,
30:41they had a significant number of patients
30:45at 12,000 out of those they had about 850.
30:50It's something about like events in
30:52the span of six months from from
30:56the diagnosis from enrollment,
30:58and most frequent cancer along
31:00Bryson colorectal.
31:01They did not include upper extremity
31:04DVT's and their collected.
31:06This is amazing that they collected
31:09all these events from clinic
31:12from review of clinical notes,
31:14radiology reports and text search,
31:17which itself is very valiant effort knowing.
31:20Anne. From now, from my from my
31:25own experience doing similar work.
31:28So as far as the predictors that they
31:31put that they use in the in the model,
31:35which was not really clear how they
31:38selected it, but it seemed like it
31:41was some sort of manual selection.
31:44Not unbiased informed selection,
31:46at least based on their abstract
31:48and presentation.
31:49So the tumor type status of metastases,
31:53age, cytotoxic chemotherapy time since
31:55cancer diagnosis, tumor sampling,
31:57and they included interesting
31:59without the blood counts.
32:00In the prior three months.
32:04Indices of calculation be my end. Of course.
32:08Those somatic genetic alterations on
32:11the jeans in tumor suppression genes,
32:15of which they include 56.
32:18And so when they put it all together
32:21and they used this fancy math,
32:23the random survival forest
32:25basically to create a model to
32:27fit the model using all of these.
32:30Various sets of permutations of the features,
32:33the predictors and what they come up with.
32:36It came up with basically
32:38that if you include all of it,
32:41that gives usage statistics of .7 is
32:44just the kind of worry and people here.
32:47If it's insisted 6.5 is a coin toss,
32:51so basically it doesn't predict
32:53anything and see statistics of one.
32:55It's the perfect sensitivity,
32:57specificity of 5%, of course is unreachable.
33:00So somewhere in between that,
33:02the higher the better.
33:05But .7 ISM is it.
33:08Legitimate number,
33:09and as I would like to remind everybody,
33:13the original credit score
33:15system tistic was also .7.
33:19They also then separated their
33:21population into five groups,
33:23although how they get it not
33:26clearly was outlined as well,
33:29and it's five risk groups based on the.
33:36Incidence of VTE I presume,
33:39and so then they validated this with
33:43the model in the said that that is.
33:48Per their validation metric that was
33:51validated, model was performed well.
33:55With, Interestingly enough,
33:57when they looked at which
34:00predictors had been most predictive
34:03of the venous thromboembolism,
34:05they found that it's a cancer type came,
34:10whether patient received chemotherapy,
34:14platelet count.
34:16PT White count and so on was interesting.
34:20This is out of these features.
34:25Where this is not a selection,
34:27so these features were determined.
34:30The importance of these features was
34:32determined in in sort of post hoc.
34:35These are not the features that
34:39were selected to go into the model.
34:43That's it, that's a key issue,
34:45because in my opinion, because.
34:49If the if you if you if the features
34:52are included in a biased way,
34:55the prediction of course would
34:58potentially suffer as well.
35:00And so out of all the genes that they pulled.
35:05As you can see this STK 11 was found
35:08to be significant and only one of them
35:12based on value of false detection rate.
35:16So every every other one gene
35:19was not considered significant.
35:21And as people probably know,
35:23STK 11 is actually tumor suppressor
35:26gene out of all possible jeans.
35:30So question on my end that I sort
35:32of would like to one of wanted to
35:35clarify was unclear how initial
35:38features were selected,
35:39and again that's important because the
35:42biased it will be by a set of features
35:45if it manually manually selected and
35:48similar to other clinical scoring tools.
35:50So there are some robust methods
35:53exist that feature feature selection
35:55algorithm that you know existed prior
35:57that can be used to to select features
36:00prior to including into the model.
36:02That would be very,
36:04very helpful in China.
36:10Something something like this.
36:12We were actually thinking of doing the
36:15VA and another interesting component
36:17was prior vtu is not included although
36:20has it has a racial quoted somewhere
36:23in between two to three which is not
36:27insignificant risk factor and of course.
36:31Current score is not the dynamic
36:33score and would be interested to know
36:36how variability of the features,
36:38specifically of CBC features assessed.
36:40So overall it's I think it's important
36:43work and I think it's a interesting
36:46how the field of all because again,
36:49even the guidelines have been released,
36:51their sort of,
36:52they still leave a lot of uncertainty
36:55into who which group needs to be
36:58anticoagulated versus whether it's
37:00intermediate group versus high Group.
37:02Um patients for should be inside quite late.
37:05It's still not clear.
37:07I think uncertainties still exist,
37:08and so the the better we have,
37:11the better method we have in terms of
37:14determining which features are important,
37:16I think that's going to be very helpful.
37:20Alright,
37:20so moving on are also an interesting
37:24abstract about than you.
37:26A reversal agent for anticoagulation.
37:31This is really interesting.
37:34Abstract the work has been going
37:37on for quite awhile and I found
37:41references going quite badly.
37:43Even just doesn't 14 but essentially
37:45pseudoprime tag is a small molecule
37:48that was initially designed through
37:51very rational design to reversibly
37:53bind to fractionated heparin low
37:56molecular weight heparin through
37:58noncovalent charge charge interaction
38:00with it was interesting that
38:03they unexpectedly they found.
38:05That it also binds the DOAX,
38:07which prevents their Association
38:09with factor 10 factor to rain,
38:11but it doesn't bind to a lot
38:14of things at a lot of drugs.
38:17It doesn't bind to albumin and
38:20doesn't bind to actual factors,
38:22and so they say uh-huh.
38:24Let's try to reverse.
38:26Let's try to use their parents like
38:29to reverse do act like apixaban oral
38:33molecular weight heparin so they.
38:35They've done that in animals and in humans.
38:40So here you can see that for
38:43instance on the left.
38:45A pain where you can see that several
38:50hours after administration of edoxaban.
38:54Sorry for typo the.
38:59After the silicone flag was administered,
39:01there was a very rapid.
39:04Reversal a curd that actually stayed.
39:08Plateaued for a number of hours
39:10and then on the right side the same
39:13idea with low molecular weights
39:15in same sort of data that,
39:18with different doses of Sopron tags.
39:22The universal was fairly complete.
39:25Below 10% of baseline.
39:27Now the metric that's being used
39:30to determine this is a whole
39:33blood clotting time,
39:34and that's and that's actually important,
39:37because apparently I cannot activity
39:40of Sharon Cycle rather reversal.
39:45Enter calculation cannot be determined
39:47using regular typical methods.
39:49For instance using PT PTT
39:51because your parent act would be
39:55in in the in the in the tube,
39:57in the inner tube of blood.
40:00It would be pulled competitively
40:03inhibited by like say,
40:05citrate or ETA that already
40:07present in the tube,
40:09so therefore they used whole
40:12blood clotting time.
40:13So now the abstract itself actually
40:16presents the two studies to phase
40:19two will see what controlled
40:22RCT one for Apixaban and the
40:24other one for rear axle band,
40:27where they actually.
40:30Looked at reversal Cedar parents
40:33like versus placebo and it's
40:37very simple design in both arms.
40:40Both studies.
40:41Essentially they used doac to reach
40:46a steady state and then they gave
40:50patients Sera parent tag on different
40:54doses and contract the whole blood.
40:59A cloud.
41:00Including time and again because the
41:04other parameters cannot be used.
41:07And in point was that WBC
41:10T should be below 10%,
41:13and so how fast that actually happens.
41:16And So what they showed again,
41:19that in both cases for the Pixel banner
41:23over oxygen that indeed within hours
41:26within actually minutes the for in
41:30different doses of shared parent tag,
41:33the reversal was rather.
41:37Especially in this,
41:38in higher doses like syntax 60 milligrams,
41:41220 milligrams in takes a band and higher
41:46doses in rivaroxaban group as well.
41:50Then they also looked at how fast in again,
41:54how long the reversal remained.
41:57And again,
41:58in both groups fix again,
42:00but were actually in the high
42:04dose single parent tag.
42:06The highest dose children tag in each group.
42:10River traversal was rather fast
42:12within within 660 minutes in
42:15apixaban 100% patients have
42:17been reversed to the target.
42:20Of less than 10% of baseline for
42:22a whole bottle of whole blood
42:24clotting time and in Russia ban
42:27even even faster in 30 minutes.
42:29So it's an interesting concept is
42:32interesting new molecule which product
42:34which is undergoing studies like
42:37phase two and probably would be.
42:39Can soon enter phase three with
42:42a very exciting profile.
42:44There's no prothrombotic signal,
42:46no evidence to promote it signaled they
42:51actually looked at the D dimer and.
42:54Uh, and that was not affected.
42:57There's potential.
42:59The interesting question that could
43:01be raised that whether magnesium
43:05and calcium in Vivo could could
43:08have any effect on sort of pulling
43:11setup Ramtek out of the.
43:13Interaction with the aid with the agents.
43:16Anticoagulation agents but it
43:18probably in molar concentration
43:20such that probably not really
43:22likely an interesting concept
43:24that an anticoagulation,
43:26if necessary can be re stored and re
43:29established 24 hour reversal without any.
43:35In effect cost, of course the issue,
43:38and I'm sure George some point
43:40will do the cost analysis.
43:42I hope if that comes to that and
43:45then with that I'll move to.
43:48To our to my final discussion of the
43:53work that we sort of we presented at ASH.
43:58That in form has been
44:00informing us beyond COVID-19,
44:03which is quite interesting discussion.
44:05So what we wanted to.
44:09Look at is a weather items test 13.
44:13Another imbalance of atoms TS 13 an
44:16Fonville burn factor could potentially
44:18serve as a marker of uniform
44:21doses in patients with COVID-19,
44:24that was our initial goal,
44:26so we last year we right in the
44:30beginning of pandemic we sort of
44:34have this lack of having number of.
44:38Great researchers working,
44:40collaborating with George Washago shoe
44:44and Enchong after deadly and math mileage.
44:48And we.
44:52Show that one from
44:53building factor, of course.
44:55It's been shown since then many,
44:57many times is quite elevated
44:59in patients with coded 19,
45:01and this specifically much more elevated
45:04in patients with critical disease.
45:06We also know from other studies
45:08from studies so far not related
45:10to coordinating at all,
45:12that Adams TS13 deficiency.
45:1613 is reduced in inflammatory states
45:19like cancer stroke and sepsis.
45:21Interestingly enough,
45:22in animal models, Adams,
45:24tutti and efficiency increases.
45:25Release of from building
45:28factor from from platelets.
45:30It increases increases adhesion to white.
45:35Neutrophils,
45:35white count white cells to the civilian
45:37and enhances neutrophil extravasation.
45:39So what we then looked we going back
45:42to the to the cohort to our data
45:45and we will look at what kind of
45:49relationship exists between Adams test
45:5113 an from villain factor antigen activity.
45:54We found that indeed.
45:57In critical disease in patients
45:59with critical disease,
46:01it's indeed lower.
46:02The balance is such that this ratio is lower.
46:07We also showed earlier this year
46:10that there's several markers
46:12of neutrophil activation that
46:13been associated with ICU status,
46:16and we collaborate with this with
46:19adjacency Cheyenne David Friend.
46:22**** and what we can infer that
46:25we show that at the absolute
46:27neutrophil count and image resized
46:30to neutrophils have been associated
46:32and could discriminate mortality and
46:35we used our Dom Kodiaks database.
46:39For that so then when we went to Adams
46:42just watching from Wilburton ratio,
46:46we also showed that that he had
46:49actually inversely related to neutrophil
46:51and initial to lymphocyte ratio,
46:54and Furthermore we when we looked at
46:57whether this disbalance also associated
46:59with the the neutrophil markers
47:02markers of neutrophil activation
47:04is GF resistant Lipo Callanan I'll
47:07eight that indeed we found that.
47:10All those markers were associated
47:14with worsening.
47:15Reducing the rate reduce the ratio for
47:18Adams Tester team to fund building factor,
47:21which again could indicate the
47:23potential prothrombotic process.
47:25Furthermore,
47:25we also looked at the same exact idea about.
47:31L Association with the ratio
47:33with Taiwan with.
47:35Fabulous inhibitor and again the
47:38same situation with where Adams just
47:42looking for the ratio is lower.
47:45So overall we show that lower so
47:47Adam Sistine Info Bill from building
47:49factor Disbalance exist.
47:51So shaded with inhibitor for lysis,
47:53markers of neutrophil activation
47:55and there are four its potential
47:57email somebody in uniform biotic
47:59market foreign botic complication.
48:01What's really interesting now is
48:02that what we do now is actually we're
48:05looking specifically at people at
48:07patients with COVID-19 and without
48:09coordinating but who had actual thrombosis.
48:12So now we actually will be able to.
48:15Tying this with this ratio
48:17with thrombosis itself,
48:18and of course going beyond COVID-19,
48:21all of it applies.
48:23This platform can be scaled up.
48:25This idea can be scaled up to
48:28basically any uniform body disorder,
48:30an also synthetic malignancies,
48:32which we would like to explore as well
48:35and with that will yield the floor.
48:43Thank you so much, Alex and.
48:46For the last part of the talk.
48:49I am going to talk about other
48:51topics in classical mythology.
48:53Good afternoon everybody.
48:54My name is George Joshua and one
48:56of the senior fellows in the Yale
48:59Hematology Oncology Fellowship program.
49:01And it is a pleasure to
49:02be talking to you today.
49:04I have no disclosures.
49:06There are four apps we're going to
49:08cover and I will speak through this,
49:11so we finish on time and we're
49:13going to talk about gene editing.
49:15And we're going to talk about
49:17complement system performance,
49:18health outcomes, research.
49:20And a little bit of coping.
49:2219 So to start off.
49:24First abstract #4 entitled CRISPR CAS
49:269 gene editing for sickle cell disease
49:28and beta thalassemia by doctors.
49:30Frangou and colleagues.
49:30Miss was a plenary talk and
49:32also simultaneously published
49:33in human Journal Medicine.
49:35For context to the reason
49:36why the study is important.
49:40Football.
49:45Emma.
49:47Bo team. Both.
49:54Valve should have.
49:57What is speed? Your line is.
50:03Is script more than one?
50:09For the intervention,
50:10here is analogous selling 001,
50:13and it is edited.
50:19Speak.
50:31OK, I suppose we disconnected there.
50:35Alright. Alright,
50:38so back to the figure as it was saying.
50:41So this is crisper cast 9
50:43technology on the X axis.
50:45You see months before birth and
50:47after birth and on the Y axis globin
50:50synthesis and percentage fetal
50:51hemoglobin goes to adult hemoglobin.
50:53BCL 11 is an important
50:56transcription factor so.
50:57If you take a look at.
51:00The nucleus and the guide RNA.
51:02The target is in the Erythroid
51:04Enhancer region and by disrupting
51:06that with gene editing we can
51:08alter the expression of BCL 11A.
51:10Effectively shutting down.
51:14The production of globin and
51:16increasing fetal hemoglobin.
51:17So you will see the results here in
51:19the first 2 patients presented by
51:21Doctor Strangle and colleagues on
51:23the left you have a patient with data
51:25file on the X axis you have months.
51:27After CTX user,
51:28one infusion on the Y axis,
51:30hemoglobin in grams per deciliter and
51:31on the and on the right panel you
51:34have patients sickle cell disease.
51:35Pay attention to the areas in the
51:37blue as they expand that's fetal
51:39hemoglobin and you see that in
51:41the case of beta Thal the last
51:43transfusion was at one month.
51:44Prior Post 2 CTX 01 infusion and in
51:46the case of sickle cell disease the
51:48last transfusion was at 19 days.
51:50Status Post ETF 001 infusion the
51:53adverse events are listed here
51:56and all of them were treated.
51:59Abstract number 445 is entitled very
52:00inherited defects of the complement
52:02system and poor performance.
52:03This was presented by Doctor Bendapudi
52:05and colleagues out of the Harvard system.
52:07The context here is that PF is on the
52:10extreme thrombotic end of the GIC spectrum,
52:12and elucidating PF quite gladly
52:14may pave the way for a better
52:17understanding of DIC including.
52:18Are you asking in this subset?
52:22Peach boss Richmond Cody, their competitor.
52:29This with this from the NHL VR.
52:35And you will see violin plots
52:37on the left and the right on
52:40the left is the compliment.
52:42You can set the enrichment in PFS
52:44compared to an slips patients
52:46and on the right quality.
52:50At the doctor ******.
52:52Global in the slides looking at
52:54all the unique variants that the
52:57researchers have found so far to date,
53:00but let me summarize it here.
53:0226 out of have one or more
53:04rare putatively delete,
53:05delete serious mutations.
53:19Sorry for the audio difficulties.
53:21I think George you
53:23might wanna like hide your camera.
53:25Maybe that will help the audio connection.
53:28It might be a connectivity issue.
53:31Um, I wouldn't having connectivity
53:33issues at all and all prior talks.
53:35Can you see this summer right now?
53:39Or no, we can. We see you,
53:41but it keeps freezing, yet it keeps
53:43freezing. Not quite. Sorry bout that.
53:47Um? Let me try this again.
53:55Can you see this here?
53:58Yeah, we can see, but probably better if you
54:01hide your camera so that it flows nicely.
54:07Sorry, I'm not sure what you mean
54:09by hide the camera 'cause all I'm
54:11seeing is the screen on the screen.
54:13Let's see here OK.
54:19Alright, just let me know if we get
54:21disconnected again. You can go ahead. I
54:23think we're good now.
54:25OK, sounds good. Thank you.
54:26So with regards to the
54:28bendapudi at all study,
54:29they found that six of the 8 CR
54:313 variants were loss of function
54:33and these are anti-inflammatory,
54:35while three of seven CR 4
54:37variants are gaining function
54:38and these are pro inflammatory.
54:40So overall supporting very
54:42inflammatory milieu in these patients.
54:44Abstract 47 cost effectiveness
54:46of capitalism had been acquired.
54:47Thrombotic thrombocytopenia purpura was
54:48presented by Joshua and colleagues.
54:50The context for this study is
54:52that complexes map is the first
54:54FDA approved medication. In TTP.
54:56It's endorsed in ITP guidelines,
54:57recently approved in the context of
54:59confidential patient access schemes
55:01for use in the National Health Service,
55:03both discomfort in England has
55:05a high list price of 270,000
55:07US dollars per TCP episode.
55:09Here is a cartoon schematic on
55:11the bottom you see the summary
55:12of the two of the phase two in
55:14the Phase three clinical trials.
55:16You have a patient with the disease state,
55:19the hospitalization for TCP,
55:20who then receive treatment with
55:22their capitalism admin standard
55:23of care labeled as a or placebo
55:25standard care labeled as B and
55:26they can either progress to death
55:28or they can go into remission.
55:30Once in remission they can again relapse.
55:32The total cost for each arm are
55:34in front of you, 324 thousand.
55:36For the campuses in my bar,
55:3784,000 for the standard of care arm.
55:41The five year time Horizon incremental
55:43cost effectiveness ratio here was $1.5
55:46million for the use of capitalism
55:47have in addition to the standard
55:49of care with a 95% confidence
55:51interval of 1.3 to $1.7 million.
55:53Of note,
55:54this is the sensitivity analysis and I'll
55:57just highlight one specific area here.
55:59Researchers looked at parameters
56:00that affect the icier for capitalism,
56:02AB and the one that affected the most
56:05by far is capitalism that cost itself.
56:08Finally,
56:08abstract 529 entitled intermediate dose
56:11anticoagulation and aspirin COVID-19
56:13and Propensity Score match analysis
56:14by not this mindless and colleagues.
56:17The context here is the current active
56:19for preliminary an unadjudicated
56:21data which shows 2 main things.
56:23One that therapeutic versus prophylactic
56:26dose anticoagulation in severely ill,
56:28i.e.
56:28Critically ill patients was halted
56:30utility in December and then January
56:32pre specified security boundary
56:34was achieved in moderately elii non
56:36critically ill patients on therapeutic
56:39versus prophylactic dose anticoagulation.
56:40So it is in this background that
56:42optimization colleagues published their
56:44study in the American Journal of Hematology.
56:46This is an observation ULL study
56:47looking at about 2800 patients
56:49with the primary outcome being time
56:51to in hospital death.
56:52The competing risk of discharge.
56:53I'm showing only a portion of the Yale
56:55guidelines for thromboprophylaxis
56:56for hospitalizations.
56:57COVID-19 on the top right,
56:59and you see that there was a D
57:01dimer cut off that was utilized.
57:04This is the overall study design in
57:06overall cohort of some 2800 patients.
57:08Researchers identified risk factors
57:09for in hospital death and then
57:11created two nested cohorts on the
57:13left anticoagulation court that
57:15were Ben City scored matched for
57:17those risk factors and on the right.
57:19Aspirin versus NASCAR,
57:20notably on patients who were not
57:22on home antiplatelet therapy.
57:23And finally the results of the
57:25multiple analysis following
57:26the propensity score matching.
57:28You will see the hazard ratio for
57:31death for the use of intermediate
57:33dose anticoagulation as compared
57:35to prophylactic is .5 two and
57:37again for in hospital.
57:38Aspirin compared to and
57:39no aspirin again .5 two.
57:41So take homes gene editing in Dallas,
57:44EMEA and sickle cell disease
57:46can alter the disease scorers.
57:49Target gene discoveries facility
57:51genomic studies of breakfast
57:52acquisition by bending colleagues,
57:54capitalism, app costs,
57:55and ATP is quite expensive.
57:57And finally we randomized trial data
57:59on intermediate dose anticoagulation
58:00and antiplatelet therapy.
58:02Thank you.
58:03Look forward to taking your questions.
58:06Yeah,
58:07thank you so much George,
58:09and apologies about the
58:12technical difficulties.
58:13For the next 10 minutes,
58:15doctor Bone and hopefully will moderate
58:18questions for those of you have to leave.
58:21As mentioned, this will be recorded
58:23and should be available for
58:25you for subsequent full option.
58:27Doctor Bone and Alfred.
58:31Great, thank you everybody.
58:38So maybe I can start with a
58:39question that came in through the.
58:42Through the chat room so you Sabrina.
58:46How robust or how good do you feel
58:49about the mycophenolate? In addition to
58:51corticosteroids that it
58:52might begin to
58:53alter practice at this point. Yeah,
58:56you know, I I I have pause.
58:58I don't think it's practice
59:00changing at this point.
59:02You know, I think it's interesting
59:04that there were some decrease in
59:07quality of life in the mpharm.
59:09I think it's important to kind of recognize
59:12that clinical response and kind of patient
59:15experience may not always correlate.
59:17You know, the this steroid
59:19alone arm more than 50%?
59:21About 56% of patients actually
59:23at the end of follow up.
59:25Which was about two years,
59:27had not required second line treatment,
59:28so they did well as in addition
59:30and better than prior studies.
59:32So you know, I think it's interesting,
59:34but I I think we need more data
59:36before we move it to the first line.
59:39Thank you.
59:42To be a payment, go ahead.
59:44At the Harford, I figured we could.
59:46We could like pick,
59:47introduce some of the questions
59:49that are are added in there.
59:51Sabrina. Can you also talk a
59:53bit about tranexamic acid in he
59:55malignancy's and thrombocytopenia?
59:56You know there is positive data for its use.
59:58It's been completely lifesaving in trauma.
01:00:00In postpartum hemorrhage,
01:00:01particularly in Third World
01:00:03countries and under resourced areas,
01:00:04do any comments on why you think it didn't
01:00:07work in the setting of hematologic,
01:00:09malignancy, and thrombocytopenia?
01:00:10Yeah things, but I
01:00:11think that's a great great question and a
01:00:14question that came up for the presenters.
01:00:16The authors as well.
01:00:17You know, I think what they they spoke to,
01:00:20which makes sense to me,
01:00:22is kind of the complexity of
01:00:23microvascular and India theal damage.
01:00:25That happens as a rolls result of
01:00:27chemotherapy, 'cause all of these
01:00:29patients were getting treatment.
01:00:31You know, we know that while prophylactic
01:00:33platelet transfusions has helped
01:00:35in terms of of bleeding incidents,
01:00:37there are still a good proportion
01:00:39of patients that do have bleeding.
01:00:41So you know,
01:00:42I think there may just be more complex
01:00:45pathophysiology in terms of why these
01:00:47patients believe that is beyond low
01:00:50platelets and impaired fibrinolysis.
01:00:52But I agree that I think there are
01:00:55definitely rules and you know,
01:00:56I think even within this population,
01:00:58there may be a role for this in
01:01:00patients who are bleeding or who need
01:01:02procedures or other kind of subgroups.
01:01:05Great Bob, do you want to just sort of
01:01:07tag team back and forth? Uh, sure, in
01:01:09less anyone in the audience
01:01:11has a question, you could raise
01:01:12your hand and will unmute you.
01:01:16But still waiting for
01:01:18that. I I had a question for Alex.
01:01:21So Alex, the data on Adams 13
01:01:24and BWF levels. Do you think
01:01:27that could be the basis for
01:01:29identifying high risk patients who
01:01:32then might be part of a randomized
01:01:35control trial of anticoagulation or not?
01:01:39In in COVID-19 and perhaps other
01:01:42people who are severely infected.
01:01:46Yes, but thank you.
01:01:47Thanks for question. Indeed.
01:01:49I actually have great hopes
01:01:52until data shows otherwise,
01:01:53but I have great hopes that this
01:01:56imbalance Adams just routine for
01:01:58Willebrand factor in balance is,
01:02:01you know for the lack of a better
01:02:04word may be fundamental to Infosys it.
01:02:08Whether it is a marker or A cause,
01:02:11that's I think it remains to be.
01:02:15Is to be seen.
01:02:17But from from Pathophysiologic
01:02:19understanding of how Infosys happens,
01:02:22I think this two markers would be
01:02:25potentially could have that that
01:02:28could have that fill that role.
01:02:31Thank you.
01:02:34Another question for you Alex again,
01:02:36great session, great summaries.
01:02:37All of you guys you know
01:02:39for predicting cancer,
01:02:40associated thrombosis.
01:02:41You kind of mentioned this that you know
01:02:43the Corona score has been around awhile.
01:02:45There been other scores.
01:02:46There's been positive data to support
01:02:48the use of prophylactic integration
01:02:50for years and years and years,
01:02:51but an even most recently with doacs
01:02:54and yet no major consensus group has
01:02:56come down to support that practice.
01:02:58So so do you feel that this machine
01:03:00learning algorithm will change
01:03:01clinical practice in that regard?
01:03:03Or do you still feel that we need?
01:03:05Better tools to predict who will
01:03:08actually get cancer thrombosis.
01:03:10So I'm a big believer in machine
01:03:13learning just because it make it
01:03:15can crunch a lot of data in that.
01:03:18From that perspective,
01:03:19I think as a data generator and
01:03:21hypothesis generator generating technique,
01:03:23I think it's very important tool
01:03:25in we should not shy from it
01:03:28and utilized as much as we can.
01:03:30The question becomes sort of whether
01:03:33it's become sort of garbage in
01:03:35garbage out kind of situation.
01:03:37If we feed something that biased to this.
01:03:40So the machine learning algorithms
01:03:42algorithms we're going to get
01:03:43something totally useless,
01:03:45so we have to be very careful about
01:03:47what we really feed these algorithms
01:03:49and how we use these algorithms.
01:03:52And I think we need to collaborate
01:03:54with a lot of artificial intelligence,
01:03:56machine learning people to to
01:03:58get the best out of it.
01:04:00But yes, I agree,
01:04:01that's actually could be
01:04:03absolutely indispensable tool.
01:04:07So George question for you if I may.
01:04:12Do you think that the data for complement
01:04:16abnormalities in purpura fulminans has,
01:04:19or will have any therapeutic implications?
01:04:25Thank you Bob, really fascinating question.
01:04:29Really hard question too,
01:04:31especially because we worry about
01:04:34performance often in the infectious setting.
01:04:38One of the first patients that this
01:04:41study was based off of was a patient
01:04:44with Capnocytophaga bacteremia,
01:04:45who ended up having purple foam and ends.
01:04:48So I think that that's
01:04:50that's that's that stuff.
01:04:52At the same time we have utilized compliment
01:04:54in vision therapy when necessary in patients,
01:04:57for example, with catastrophic APS.
01:04:59The difficulty, of course,
01:05:01because when there's a common infection,
01:05:03so I think that becomes a
01:05:05discussion of risks and benefits,
01:05:08including with our infectious
01:05:09disease specialists.
01:05:10Beyond of course,
01:05:11the vaccination and the use
01:05:12of amoxicillin or penicillin,
01:05:13or something like that to be able
01:05:15to cover the next serial organisms.
01:05:18Thank you.
01:05:20Question for Sabrina the convalescent plasma.
01:05:22The most recent recovery is a
01:05:24recovery truck from the UK.
01:05:26Was a negative study,
01:05:27but there's many positive ones,
01:05:29including our own data that
01:05:30you brilliantly presented.
01:05:31Can you reconcile all of this
01:05:33for us and how we should think
01:05:36about using convalescent plasma
01:05:37and COVID-19 patients?
01:05:38Yeah, it thank
01:05:39you all for that.
01:05:40I think it's been challenging 'cause,
01:05:42as you mentioned that the data has
01:05:45been quite mixed and you know,
01:05:47I think just recently we're getting
01:05:49additional information from from
01:05:50larger and more randomized trials.
01:05:52The early trials that were randomized had
01:05:55stopped early for a number of reasons,
01:05:57one being that there were patients that
01:06:00actually actually were SERO positive at
01:06:02the time they got convalescent plasma,
01:06:04and then there were issues with
01:06:07recruitment in other studies.
01:06:09I, I think we're going to have to
01:06:11really kind of look through the
01:06:13details of what antibody titer
01:06:14was an neutralizing function in
01:06:16the convalescent plasma with each
01:06:18randomized trial as well as timing
01:06:20and timing of receiving the plasma
01:06:22and the severity of the disease,
01:06:24because I think there has been
01:06:26signal for patients who get high
01:06:28titer plasma earlier in disease,
01:06:30that there there is benefit there,
01:06:32you know,
01:06:33and I I don't know that there the
01:06:35details of the recovery trial have
01:06:37been released yet in terms of.
01:06:39The timing of convalescent plasma and
01:06:42how heterogeneous the convalescent
01:06:45donor plasma was at that time.
01:06:48Great, thank you.
01:06:53Sabrina question about it
01:06:54for two zaran if I could.
01:06:57So you mentioned that there
01:06:59were some adverse events,
01:07:01notably thrombosis,
01:07:02presumably due to the sustained
01:07:05reduction in anti thrombin levels.
01:07:07Do you know if those individuals
01:07:10were treated with antithrombin
01:07:11concentrates as a as
01:07:13a in in
01:07:14along with anticoagulation?
01:07:15That's a great question but I
01:07:17I don't, I don't.
01:07:18I didn't find any evidence that or any
01:07:20data on whether or not they were treated,
01:07:23so I don't know the answer to that.
01:07:26I do know when dosing was paused,
01:07:28you know they looked at the group
01:07:31and found that patients who had
01:07:33an antithrombin level that was
01:07:35less than 20% and had the higher
01:07:37risk highest risk of thrombosis.
01:07:39And those patients that were greater than
01:07:4120% actually had no thrombotic events,
01:07:43and so that's why the the trials
01:07:44have preceded with the redosing,
01:07:46which is initially going to start at
01:07:48every other month and then kind of
01:07:50increased back to where they had been
01:07:51previously with the goal of monitoring
01:07:53and antithrombin levels closely so
01:07:55that they stay kind of between 15
01:07:57and 35% is what what it's report is,
01:07:59but I don't know about
01:08:01the concentrates. OK, great thank
01:08:02you, that's interesting, thank you.
01:08:05Question for George. So you know,
01:08:07in the abstract that you presented on
01:08:10using CRISPR CAS to target BCL 11 A.
01:08:13I was literally just Googling
01:08:14what else detail 11/8 does.
01:08:16And you know there are interesting
01:08:18reports about it being involved
01:08:20in metal pieces in B cell,
01:08:22lymph, Genesis and so forth.
01:08:24And so I'm just wondering if the
01:08:26investigators talked about potential,
01:08:28you know, humans,
01:08:29allergic effects or immunological
01:08:30effects and and the reason being that
01:08:33you know there there is another set of.
01:08:36Essentially,
01:08:36gene editing treatments that
01:08:37we can use in these disorders,
01:08:39which is stem cell transplant.
01:08:40So it just makes you wonder that
01:08:42if there are these unknown effects
01:08:43with these newer therapies,
01:08:45then
01:08:45why not just go for stem
01:08:46cell transplant instead?
01:08:48Yeah, thank you.
01:08:50Yeah that's a great question.
01:08:52Of course, stem cell transplant
01:08:53also has adverse effects.
01:08:55An events just like gene editing
01:08:57does in the in the initial study,
01:09:00so they've completed follow up in
01:09:02at least two patients and they have
01:09:05another I think 6 to 9 patients in
01:09:08in each of the 111 and STD 121.
01:09:10There is nothing that I saw.
01:09:14Talking about specifically human,
01:09:15logical and immunological effects,
01:09:16notable things were infectious
01:09:18from both of the first 2 pages,
01:09:20but The thing is,
01:09:21those other patients still need at
01:09:23least another year of follow up before
01:09:25we can start talking about this right.
01:09:27And then beyond that long term too,
01:09:30'cause it's not just a year or
01:09:32two that people will live right.
01:09:34Hopefully in that good state so.
01:09:37Yeah, I I don't know more.
01:09:43So I have a question.
01:09:45Maybe for George about the
01:09:47the anticoagulant. I'm sorry.
01:09:48Not George Alex about the
01:09:51anticoagulant inhibitor.
01:09:52Where, where are we
01:09:54in 2021 in terms of first
01:09:57line therapy for reversal,
01:09:58bleeding for, let's say, induce?
01:10:00Buy a doac you think?
01:10:04Well, so we do have access to both.
01:10:11And extra an assistant
01:10:13either season map I believe.
01:10:16I personally have not used them,
01:10:18but I know several people have used them.
01:10:24And, um. I believe it's costly and
01:10:29what's interesting is that the decision,
01:10:33as far as I know,
01:10:36decision is made still on the timing
01:10:40of the last those event equivalent.
01:10:44Furthermore, the both trial
01:10:47trial so far both for.
01:10:50Typical Tran and Doac and the factor
01:10:55of 10 anticoagulants inhibitors.
01:10:58Both those trials for the rest of the
01:11:01reversal agents were without control arms,
01:11:04so with efficacy is not really
01:11:06well established still,
01:11:07so I think there's there's one trial
01:11:09right now is going on next I next
01:11:12one is for the internal hemorrhage
01:11:14reversal of anticoagulation.
01:11:16People patient with intracranial hemorrhage,
01:11:18which is which is randomized trial.
01:11:20I think that's going to be informative.
01:11:24But I I think it's data is not super.
01:11:30Super strong about how to reverse
01:11:33and whether to wait.
01:11:35Just kind of, you know,
01:11:37hours since the last administration.
01:11:39So secret parent tag,
01:11:40as far as I understand it's a
01:11:43small market which is very easy
01:11:45to fairly easy to make,
01:11:47which probably will reduce the cost
01:11:49an it's rapid and you don't need to
01:11:53necessarily think about when was the last.
01:11:56Dose I think that I would think that
01:11:59that might be an advantage of using it.
01:12:02Um?
01:12:04But I think the world of antic
01:12:07of reversal agents is an infancy.
01:12:09Yeah,
01:12:10I agree.
01:12:10I think we're
01:12:11waiting for some head to
01:12:13head trials with some of
01:12:15these drugs in the prothrombin complex
01:12:17concentrates as well. Thank you.
01:12:20Well, thank you so much everybody.
01:12:22Thank you Doctor Pine, Victor,
01:12:23Joshua and Doctor Browning,
01:12:25and the excellent moderation by
01:12:26Doctor Lee and Doctor Bonner.
01:12:28We probably could go another hour
01:12:29with all of these great questions.
01:12:31Please remember you can reach out to all
01:12:33of the speakers and the moderators by
01:12:36email for any questions and there will
01:12:38be a recording of this session for your
01:12:40convenience will be posted next week.
01:12:42Thank you so much.
01:12:43Please remember next week.
01:12:45next Friday is the last session which will
01:12:47be focused on cell therapy and bone marrow.
01:12:50A transplantation and that will
01:12:52conclude our post. Ash highlights.
01:12:54Thank you so much.