Sickle Cell – Hope, Hype, and Cure: Four-letter words and novel therapies for sickle cell anemia with Yoram Unguru, MD, MS, MA, HEC-C

May 16, 2024

May 15, 2024

Sponsored by the Yale Pediatric Ethics Program and the Program for Biomedical Ethics

Sickle Cell – Hope, Hype, and Cure: Four-letter words and novel therapies for sickle cell anemia

Yoram Unguru, MD, MS, MA, HEC-C

Attending Physician, Division of Pediatric Hematology/Oncology

The Herman and Walter Samuelson Children's Hospital at Sinai

Chairman, Sinai Hospital Ethics Committee;

Associate Professor, Johns Hopkins School of Medicine;

Core Faculty, Johns Hopkins Berman Institute of Bioethics

Information

ID: 11681
To Cite: DCA Citation Guide

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00:00Get the game going.
00:05All right. We're going to get started.
00:07Thank you so much for coming tonight.
00:11My name is Mark Mercurio.
00:12I'm the director of the Program for
00:14Biomedical Ethics here at Yale.
00:15This is our last session
00:17of the academic year.
00:18We're going to finish up with a bang,
00:19but we'll be back in September,
00:21and hopefully you're all on our mailing list,
00:23and we'll hear about that later.
00:24But for tonight,
00:26let me tell you about tonight.
00:29Tonight's guest is Yaram Unguru,
00:31who is both a very well known
00:34pediatric bioethicist as well as a
00:36pediatric hematologist oncologist.
00:38Educationally,
00:38he's a product of the University of Maryland
00:41for a bachelor's and master's degree,
00:43as well as Toro for another master's,
00:45as well as Technion, Israel,
00:47where I just learned tonight,
00:48'cause my friend never told me that he was
00:52valedictorian when he got his MD. And no,
00:54there weren't just like 5 kids in the class,
00:56it was a big class. Come on.
00:58And he was the valedictorian.
01:00He is the leader of the bioethics group
01:02for the Children's Oncology Group.
01:05He's very well known in in in
01:07pediatric oncology circles,
01:08Also in pediatric bioethics.
01:10He's been an ethics advisor,
01:12if he will,
01:13to the American Academy of Pediatrics,
01:14the American Medical Association,
01:17to the FDA,
01:18and I even think to the Homeland
01:20Security Group at some point.
01:23He is chairman of the Ethics
01:26Committee at Sinai Baltimore.
01:28He's also on the faculty at Johns
01:30Hopkins and and core faculty at
01:32the Berman Institute and the
01:34Berman Institute at Johns Hopkins.
01:35For those of you who don't know,
01:36is a lot like the Program for
01:39Biomedical Ethics at Yale,
01:40kind of like LeBron James is a
01:44lot like your little brother in
01:46terms of playing basketball.
01:48I mean the the the the Berman
01:49Institute is is where it's going on.
01:51And Yaram's been an important part
01:53of that for a long time since
01:54his fellowship days.
01:55He actually did his fellowship
01:57I think at Children's National.
01:58Yes.
01:59And did residency work at the
02:01University of at Sinai where he's back now.
02:05So chair of an Ethics Committee,
02:07a well known clinician and a
02:09national I'll go to person on
02:12various important issues related to
02:14pediatric oncology and hematology.
02:16So and I've known you wrong for years,
02:19he's been here once before,
02:20did a marvelous job.
02:21So I was so grateful when he
02:23agreed to come back tonight.
02:25What's going to happen,
02:26as is our usual, is Doctor Roguru
02:28will speak for about 45 minutes,
02:31give or take,
02:32and then we'll have a conversation.
02:34And when the conversation happens,
02:36just to remind you on if you're here on Zoom,
02:39please send your questions via the
02:40Q&amp;A function and hopefully I'll
02:42get to some of those questions
02:43for the folks who are on Zoom.
02:44For the folks in the room,
02:45if you have a question,
02:46wait'll I call on ya and and Karen
02:48or Amir bring a microphone to you
02:50so that everybody can hear you cause
02:52'cause I can't hear much and cause
02:54the folks who are on Zoom can't
02:55hear you at all unless you have the mic.
02:57So we'll have that conversation and there'll
02:59be a hard stop at 6:30 and at 6:20,
03:02eight.
03:02I'm pretty sure it's going to
03:04stop raining for about 15 minutes
03:06just to allow you to get to your
03:08cars without getting wet.
03:09So this should work out just right.
03:12That's the plan for the evening.
03:14Hope, hype, and cure.
03:16Four letter words and novel
03:18therapies for sickle cell anemia.
03:20Please join me in welcoming
03:21a Doctor Yiramun guru.
03:22Thank
03:27you, Mark.
03:30I am always hot and the best
03:33thing about the weather was that
03:35my damn blazer got really wet.
03:38And it would be a shame if I went home to
03:41my wife and my adult daughters with a cold.
03:43Wouldn't it mark?
03:45Because I wore this God forsaken thing.
03:47Now my mother, who's almost 90,
03:51is going to find one of you and say,
03:53did you're on, look presentable?
03:55Didn't wear a blazer and a top.
04:00Now you can tell my mom. Yeah. See.
04:03Absolutely the best, best dressed figure.
04:05I mean, come on now.
04:08So I'm gonna try this, but it's wet
04:11and I get hot and I may take it off.
04:14And then my sister, who's a designer,
04:17is cringing at the short sleeves and the tie.
04:20Oh my God, you did it again.
04:21I told you it's so unfashionable.
04:24You look like a nerd with my sister.
04:26Contact you.
04:27You can say that all you saw was this,
04:29and you can imagine that there were
04:31some sleeves poking through here.
04:32OK. But I'm very happy to be here.
04:35I want to thank Mark for that
04:38lovely introduction.
04:38And Mark is humble and Mark
04:41is smart and Mark is kind.
04:43And my career has blossomed,
04:47in part due to Mark's collegiality
04:50and his mentorship.
04:51And I truly am grateful.
04:53And today is the first time that Mark and I,
04:56they've seen one another in a little bit.
04:58And so I thought this would be a good start.
05:01Mark,
05:02we're putting the band back together again.
05:06We're on a mission from God.
05:09So I'll leave it to you to
05:10decide which one of us is Jake
05:12and which one of us is Elwood.
05:17So unlike The Supremes,
05:18Thomas and Gorsuch and Dr.
05:20Balsaga from Sloan Kettering and
05:22George Santos and the Trump family,
05:24I'm APT Monk guy who does bioethics
05:27and I have no disclosures.
05:29So this evening we're
05:30going to talk about hope,
05:31hype and cure and in clinical medicine
05:34and in pediatric hemonk in particular.
05:37And we're also going to look
05:38at the impact of language and
05:40communication and how these
05:42influence medical decision making.
05:44And we could easily focus on
05:46cancer to examine these concepts.
05:48But I actually prefer to view
05:50these four letter words through
05:52the lens of sickle cell anemia.
05:53And yes, the focus of my talk
05:55is going to be on sickle cell.
05:56But throughout I will share some
05:58examples of four letter words in cancer.
06:00And this 1913 article from the New
06:03York Times is an early example of
06:05how cure is portrayed in the media.
06:07So what I'd ask you to do throughout
06:09the time that we have together
06:11think about our patients and how we
06:14also internalize these statements.
06:17Now I realize that not everybody
06:19here has made the brought wise
06:20decision to devote your career to
06:22he Monk and I'm sorry to hear that.
06:24So maybe a little bit of background
06:26about sickle cell would be helpful.
06:28What you see on the left here
06:30is a cartoon representation of
06:31the inside of a blood vessel,
06:33and you can see sickle shaped red blood
06:35cells and normal red blood cells.
06:37And on the right the arrows are
06:39showing you what an actual sickle
06:41cell looks like under the microscope.
06:43And some of the consequences of
06:44sickle cell were captured in a
06:46recent New England Journal piece,
06:47and the authors observed that.
06:49As you can see,
06:50a diagnosis of sickle cell disease
06:52portends a lifetime of crises
06:54marked by substantial pain,
06:55infections,
06:55anemia and increased risk of stroke.
06:58And that's only half of it.
07:01Too often we think of our disease
07:04burden through our US centric lens,
07:06and broadening this perspective beyond our
07:08own bordens is important for lots of reasons.
07:10As we'll talk about shortly,
07:12how common is sickle cell vary.
07:15About 300,000 infants are born each
07:16year worldwide who have sickle cell
07:18and as you can see from these he maps,
07:20most of them are in sub-Saharan Africa,
07:22India, the Mediterranean,
07:24the Middle East and in some
07:26African countries.
07:27As many as 40% of people have
07:30sickle cell trait so kind of common.
07:33Circling back to the US,
07:34there's about 100,000 people who have sickle
07:37cell and as you can see from the map here,
07:40most of them live in these 10 states.
07:42You can also see that one in 365
07:45African American kids has sickle cell.
07:47Sickle cell is more than three
07:49times as common as some other
07:50genetic diseases that happen in the
07:52US that you may be familiar with,
07:54things like CF and hemophilia.
07:56Excuse me,
07:57and I'll come back to this
07:59a little bit later.
08:01So given how common sickle cell is in the US,
08:04you might be surprised to know that
08:07universal newborn screening has only
08:08been around for fewer than 20 years.
08:11But the impact of that screening really
08:13has been nothing short of remarkable.
08:15Since its implementation among kids ages
08:181 to 4, mortality has decreased by 50%
08:22and overall life expectancy has increased
08:25from around a median of 14 to close to 50.
08:28And there's various reasons for this,
08:30as likely as a result of early
08:33initiation of penicillin prophylaxis,
08:35early treatment of infectious complications,
08:38just education and awareness both
08:40by clinical people and by parents.
08:43Newborn screening,
08:44though it also allows for early
08:47identification of at risk couples,
08:48that allows for genetic counseling
08:51regarding future pregnancies.
08:52Now arguably, early identification and
08:54genetic counseling are good things.
08:57And in his excellent book
08:58Dying in the City of Blues,
08:59Keith Whalu makes the argument
09:01that genetic screening amounted
09:03to veiled eugenics in an attempt
09:05to control the black population.
09:07And in this quotation from Keith's book,
09:09what we see is that what makes sense
09:11from a public health perspective may be
09:14viewed by individual groups as problematic.
09:17And you can hear see what Keith has to say.
09:19And sometimes if you hear it out loud,
09:21it really drives it home.
09:23Looking back at the controversy geneticists
09:25and health policy makers frequently recall,
09:27the backlash is a warning sign that the
09:29use of hereditary knowledge can pose
09:32unforeseen dangers to individual self
09:34determination, promote discrimination,
09:35and,
09:36when directed at a single minority group,
09:39feed legitimate fears of a return
09:41to eugenics and genocide.
09:43Huh.
09:45Although the complications of
09:46sickle cell accumulate with age,
09:47there's no question that infants
09:49and kids are at risk for many
09:51life threatening complications.
09:53In fact,
09:53by the time a kid with sickle
09:54cell becomes an adult,
09:56they've probably had more than one scare.
09:59Also,
09:59these complications they can
10:01result result in irreversible
10:03organ damage and even early death.
10:05And I want you to remember this
10:08notion of irreversible organ damage
10:10when we talk about gene therapy
10:12and bone marrow transplant.
10:14In the US though,
10:15most kids with sickle cell
10:16live to become adults.
10:18But as you can see,
10:19life expectancy is still 20 years
10:21lower than what it is for the general
10:24population and mortality is highest
10:25during that period of transition
10:27from pediatric to adult care.
10:29But as we see also in developing countries,
10:32it's a very different story.
10:33Life expectancy is much lower.
10:35You can see that in sub-Saharan
10:37Africa many kids with sickle cell
10:39die before age 5 and in India
10:42one in five dies before age 2.
10:44And here you can see just graphically
10:46the progress that's been made in places
10:48like the US in terms of life expectancy.
10:50But this really drives home the
10:53significant difference depending
10:54on one where happens to be born
10:56and lived and their disease.
11:00These are red blood cells.
11:02For those of you who are wondering
11:03best thing you know in the world better
11:06than neonatology and vents and numbers
11:07and better than psychiatry and couches
11:09and better than all you know, blood.
11:11It's all about the blood.
11:13OK, so here you can see normal red
11:15blood cells and you can see sickle
11:17cells and current therapies for
11:19sickle cell are divided into what
11:21we call disease modifying agents and
11:24potentially curative treatments.
11:26And it wasn't until 1995 that was
11:28in most of our lifespans that
11:30the first drug for sickle cell,
11:32hydroxyurea was approved for adults
11:35and it took 22 years until 2017 the
11:38hydroxyurea was approved in children.
11:40So that was definitely not that long ago.
11:43And after hydroxyurea was approved,
11:4623 years went by until the next drug,
11:49L glutamine, was approved for sickle cell.
11:51And since then,
11:52there have been two other drugs
11:53that have been approved,
11:54prisenalizumab and voxelator.
11:56And prisenalizumab actually was
11:57shown recently in phase three trials
12:00to be no better than placebo.
12:01So yes, there's been a lot of movement,
12:03but we still have a long way to go.
12:05And then there's these potentially
12:07curative treatments that we're
12:08gonna talk about in a moment,
12:09bone marrow transplant and
12:12in particular gene therapy.
12:14What I want to show for you in this
12:17slide is that really there is no organ
12:19that's not involved in sickle cells.
12:22If you just think about it,
12:23I showed you those slides jokingly
12:25of the blood cells.
12:26But blood really is everywhere in our body,
12:28truly from head to toe.
12:30And so patients with sickle cell are
12:32at risk for stroke and retinopathy
12:34and heart failure and pulmonary
12:36hypertension and liver and kidney failure.
12:38Their spleen doesn't work well,
12:40so they're going to compromise.
12:41They get Bony pain and Bony disease,
12:44skin ulcers,
12:45fertility issues.
12:46So it really can be a disease that
12:50can cover the gamut of complications.
12:54And to appreciate the frequent
12:55interactions that patients with sickle
12:57cell have with the healthcare system,
12:59I think there's no better way
13:00to capture this than fever.
13:02I just mentioned to you a second
13:04ago that kids with sickle cell,
13:05adults with sickle cell,
13:06their spleen doesn't work well,
13:07so they're in a compromise.
13:08What this translates to is that
13:11patients with sickle cell,
13:12when they have a fever,
13:14it's a medical emergency.
13:15They have to drop what they're
13:16doing and they have to be evaluated.
13:18Now I imagine some of you have children.
13:20Think about how often your own child,
13:22who probably has an intact immune system,
13:25gets a fever,
13:26and imagine middle of the night,
13:29weekend holiday,
13:30dropping everything and coming to
13:33the hospital.
13:34And imagine how those frequent
13:36interactions will color both your
13:38attitude as the parent and the
13:41kid and the clinician's attitude.
13:43So something just to keep in
13:46mind as some of you likely know,
13:48vase occlusive or painful crises
13:49over the hallmark of sickle cell
13:52and vase occlusive crises can
13:53affect any part of
13:54the body and what you see in the
13:56upper left hand corner here is
13:58something that we call dactylitis.
14:00And dactylitis is something
14:01that affects infants with sickle
14:03cell and often is the first
14:05manifestation of disease if you will.
14:07And it's painful swelling
14:09of the hands and feet.
14:10Well, dactylitis is actually one
14:12of the only types of this sickle
14:15cell pain that can be seen.
14:17I mean, we can all appreciate
14:19that this kids hands are swollen.
14:21That, as well as the fact that it affects
14:23infants means that many clinicians
14:25actually want to treat dactylitis pain.
14:28Unfortunately,
14:28that doesn't always happen in older
14:30kids and adults who have pain.
14:32And we'll come back to this when we
14:34talk about some of the inequities.
14:36This is Carlton Haywood.
14:37Carlton was a dear colleague of mine
14:39at the Bioethics Institute and Carlton
14:41was a sickle cell researcher and
14:43educator and a champion for HealthEquity.
14:46And Carlton died at age 46 on
14:48New Year's Eve of 2021 due to
14:51complications of sickle cell.
14:53And among Carlton's many
14:54contributions to the field,
14:56he developed and validated a tool
14:58to assess clinicians attitudes
15:00towards people with sickle cell.
15:01And what Carlton showed was that
15:04by showing clinicians something as
15:06simple as a video of people with
15:07sickle cell outside the clinical
15:09world in the real world,
15:11it changed many clinicians attitudes
15:13and judgments about sickle cell.
15:15And in describing the sensation
15:17of a sickle cell crisis,
15:18Carlton was always eloquent,
15:20as you can see here.
15:22And I remember talking to him once
15:23because his office was next to mine.
15:25And he also described it
15:26as a rainstorm of daggers.
15:28I mean he had a way with words and
15:31this is a fact that we know that
15:33over half of adults with sickle
15:35cell experience pain on more
15:36than half of their days.
15:38So again this is pathognomonic
15:39for the disease if you will.
15:44Patients with sickle cell
15:45repeatedly face stigma and bias,
15:47often from the very people who
15:49are responsible for their care.
15:51Patients with sickle cell are more likely
15:53to be labeled as so-called drug seekers.
15:55And there's numerous well designed
15:56studies that show that patients
15:58with sickle cell get lower doses of
16:00pain meds in patients with cancer,
16:02patients with arthritis,
16:03patients with muscular dystrophy and
16:06patients with sickle cell are often
16:08times pejoratively called sicklers.
16:10And when clinicians call somebody a sickler,
16:13they're defining the patient
16:14based upon his or her disease,
16:16and it's dehumanizing rather than
16:19calling them as an individual.
16:21When patients with sickle cell
16:22go to the ER to get care,
16:24when they go to infusion centers,
16:26many clinicians doubt that
16:28they actually need pain meds.
16:30And here too,
16:31studies have shown repeatedly
16:33the clinicians opinions and our
16:35judgments are based upon cultural
16:36accounts that are linking sickle
16:38cell to the drug problem.
16:40Also,
16:41there's no real objective measure of pain.
16:45I can tell you right now that
16:47I have horrible pain and I may
16:49look really cool and comfortable.
16:51This is another reason why patients
16:53with sickle cell often time don't
16:55get the meds they need because
16:57clinicians simply don't believe it.
16:59Your vitals look good.
17:00You're on your phone.
17:01You're texting away.
17:02Patients of mine have told me that
17:05sometimes when they have a horrible
17:07crisis before they go to the ER,
17:09they feel as though they have
17:10to put their best face on.
17:12And what does that mean?
17:13That means they did do something
17:14that's anathema to me.
17:16Dress up, wear a suit.
17:18Or some of my young adolescent female
17:21patients tell me they actually put on,
17:23make up and put on a nice
17:24blouse to look good.
17:25So imagine that.
17:26You've got horrible, Bony pain.
17:28It's been equated to,
17:30you know,
17:30a dagger of rainstorms.
17:32But first you got to spend
17:34time beautifying yourself so
17:36you'll be taken seriously.
17:38Earlier I mentioned that sickle cell's
17:40more than three times as common as
17:41other genetic diseases in the US,
17:43like CF and hemophilia.
17:44Yet funding for sickle cell has
17:46lagged far behind these less common
17:49diseases that primarily affect white
17:51populations and this has been known for many,
17:54many decades.
17:55As far back as 1968,
17:58voluntary organizations
17:59raised $2,000,000 for CF,
18:02$8 million for muscular dystrophy,
18:0550,000 for sickle cell.
18:07President Nixon, some of you may recall,
18:09coined the term a war on cancer.
18:11Well that allowed for really important
18:13funding for cancer and at the time
18:16$2.6 billion was allocated for cancer.
18:19At the same time,
18:21the government allocated $5
18:22million for sickle cell.
18:24That was an extremely common disease
18:27and hemophilia is another example.
18:31It's cared for through 340 B
18:34national drug pricing programs.
18:36But unfortunately there's no similar
18:37government sponsored program for sickle cell.
18:39So what that means is that
18:41defining a standard of care falls
18:43to individual clinicians.
18:44And because of our own biases
18:46and because of centers differing
18:48priorities and budgets,
18:49these inequities happen.
18:50And then take a look at this data.
18:53This is current data CF.
18:55It's three times less common,
18:56but it gets three times
18:58as much Federal funding.
18:59Foundation expenditure still far outpace
19:01for CF than they do for sickle cell.
19:05There's more research articles
19:06and more drugs approved for CF
19:08than there are for sickle cell,
19:12so as we strive to make inroads,
19:14we can learn a lot by looking back.
19:16And a few slides ago I referenced
19:18Keith Whalu's excellent book on
19:20the intersection of politics,
19:22Race, and health as viewed
19:23through the lens of sickle cell.
19:24And if you've not read Keith's book,
19:26I really encourage you to 1972 saw
19:30passage of the Sickle Cell Control Act,
19:32and this provided funding for research,
19:34patient care, reproductive counseling.
19:36And as Keith notes in his book,
19:39and this is a quote,
19:40for many black Americans,
19:41the term Control Act was an ominous
19:44indicator that the real goals of
19:46genetic counseling were eugenic in
19:48nature in a form of population control.
19:51And these fears were well founded
19:53beyond the historical experience.
19:54Think Tuskegee, Linus Pauling,
19:56credited with discovering the
19:58molecular basis for sickle cell,
20:00actually said and published.
20:01That every person with sickle cell
20:04trait and disease have a tattoo
20:06on their forehead as a warning to
20:08the other person so that the two
20:10wouldn't procreate and you have
20:11more people with sickle cell.
20:13And here's what what Pauling had to say.
20:15And again,
20:16sometimes it it helps drive the point
20:18home when somebody says it out loud for you.
20:20I've suggested that there should
20:22be tattooed on the forehead of
20:24every young person a symbol showing
20:26possession of the sickle cell gene.
20:28If this were done,
20:29two young people carrying the
20:30same seriously defective gene
20:31would refrain from falling in love
20:33as though it were that easy.
20:34Legislation along this line,
20:36compulsory testing before marriage
20:38and some form of public or semi public
20:41display of this possession should be adopted.
20:43Pauling then double S down informing
20:45the opinion I presented above.
20:47I made application of what I consider
20:48to be a basic ethical principle,
20:50the principle of minimization
20:52of human suffering.
20:53It's our duty to take these
20:55actions the consequence of rational
20:57consideration of ethical problems.
20:59I believe that almost all ethical
21:01problems and legal problems can be solved,
21:03although often not without effort
21:06and difficulty,
21:07by application of this principle.
21:11This is a review article from
21:12JAMA from a couple years ago,
21:14and seeing statements like these
21:15in our leading medical journal
21:17shouldn't be surprising that an
21:19integral component of someone living
21:21with sickle cell is the perceived
21:23inadequacy of healthcare systems,
21:24stigma, bias, mistrust,
21:26lack of evidence based treatments,
21:28paucity of therapeutic options,
21:31and poor access to trials.
21:33So Fast forward from Pauling in 68
21:35to current times and take a look
21:37at what I bolded in this passage
21:39and the emphasis on building trust
21:41and not only listening to patients,
21:43but hearing and believing what
21:45they have to say.
21:47If we expect patients to
21:48abide our recommendations,
21:49we should be willing to hear them out.
21:51And this is central to culturally where
21:55communication and ethically sensitive care.
21:57There's many ways that we can listen
21:59to and believe patients listening can
22:01happen by hearing the spoken word.
22:03It can also happen by seeing Hertz.
22:06Nazir was a artist and a sickle cell
22:10advocate, and he died also in 2021 at
22:13age 48 from sickle cell complications.
22:15And he used his art to raise
22:17awareness and to educate.
22:18And these three of his paintings
22:21are entitled 10 Redefined,
22:22Hope and Need Not Suffer Alone.
22:26All right, what you been waiting for?
22:28Four letter words.
22:29So let me let me juice up here.
22:36So hope and hype are both four letter
22:37words and we're gonna talk about this.
22:39And when talking about sickle
22:41cell treatment and research,
22:42one can't underestimate
22:44the importance of hope.
22:45But distinguishing were novel
22:47technologies and treatments like
22:49CRISPR and gene therapy live on.
22:51This hope hype spectrum isn't always
22:53easy because both the media and
22:56scientists struggle in describing CRISPR.
22:58The MIT Technology Review went so far
23:00as calling it a miracle of our age,
23:02and in his book Editing Humanity,
23:04Kevin Davies equated it to the
23:06Holy Grail of science.
23:10Many of us in this room likely have a sense
23:13of what hope in the medical world is.
23:15How Hope is portrayed in
23:17other areas is important.
23:18And So what I'd like to do is take a
23:20bit of a tour, if you'll indulge me.
23:22And I want to look and see how hope
23:24is represented in popular culture,
23:26including things like the books we read,
23:28the movies we watch, the news outlets
23:30where we get our information from,
23:32and in advertisements.
23:33So one view of hope from contemporary
23:36literature comes from Ann Patchett
23:38in this book, State of Wonder.
23:41Hope's a horrible Thing.
23:42You know, I don't know who decided
23:43to package hope as a virtue,
23:45because it's not. It's a plague.
23:47Hope is like walking around with a
23:48fish hook in your mouth and somebody
23:50just keeps pulling it and pulling it.
23:54From the recent HBO series
23:56Time Traveler's Wife,
23:57which is based on a movie and a book,
24:00anyone can stand any kind of torture except
24:04hope from Stephen King's Billy Summers.
24:07It's more than a glimmer of hope now,
24:09and hope may be the thing with feathers,
24:11but it's also the thing that hurts you.
24:14From Kazuishiguru's excellent
24:15book Clara and the Sun,
24:18Hope damn Thing never leaves you alone.
24:21And this next quotation is a
24:24discussion between the AI thing.
24:27I don't know what to call it.
24:29And and and a human in the that
24:32I'm going to share with you.
24:34Josie's condition is very concerning.
24:36Even so, I'm hoping soon she'll get better.
24:39Is that merely hoping,
24:40or is it something more solid?
24:41You're expecting something
24:42the rest of us haven't seen?
24:44I suppose it's merely hope, but a real one.
24:47I believe Josie will soon become better.
24:50Maybe you can see things
24:51the rest of us can't.
24:52Maybe you're right to be hopeful.
24:54Maybe you're right.
24:57This is a book who's the protagonist's
24:59daughter is diagnosed with pediatric ALL
25:02and he's having this discussion in his head
25:05and thinking about the pediatric oncologist.
25:07Sometimes 4 letters mean the world.
25:09People fear being someone else's hope.
25:11I understand her,
25:12but I wanted her,
25:13the oncologist to be our hope.
25:18What about for movies?
25:19Hope is a monster and I'm its plaything.
25:23I've been waiting to give a
25:24grand rounds like thing where I
25:25get to give talk about Batman.
25:28So from Batman, there's a reason why
25:30this prison is the worst hell on earth.
25:32Hope. I learned here that there can
25:35be no true despair without hope.
25:38So if contemporary fiction
25:39and movies aren't your thing,
25:40we can turn to Omar Khayyam's 12th
25:43century Persian epic The Rubiad.
25:45The worldly hope men set their hearts upon
25:48turns ashes or it prospers in Anon like snow.
25:51Upon the desert's dusty face lighting.
25:53A little hour or two is gone,
25:56and then from Shakespeare,
25:58measure for measure.
25:59The miserable have no other
26:01medicine than hope.
26:02I have hope that I will live,
26:03but I'm prepared to die.
26:07This recent New Yorker piece adds
26:09additional perspective and I draw
26:11your attention in particular to
26:13the second and third blurbs here,
26:15the 2nd quotation.
26:16Especially this part about selling
26:18something makes me wonder about
26:20another 4 letter word hype.
26:22And then this third quotation is
26:24especially Apartment because it draws the
26:27unique link that science and hope also share.
26:29And so that's what I want to
26:31talk about for a couple minutes.
26:33So there may be truth to the view of hope
26:36that I've just shared with you from all
26:38these books and movies and other things,
26:40but hope is a good thing.
26:41I mean, it drives so much of what
26:43everybody in this room does.
26:45And so let's take a deeper dive
26:47and examine what hope in the
26:49clinical research world looks like.
26:50And here you can see how HOPE and clinical
26:53medicine is leveraged and portrayed.
26:55In the case of Duchesne muscular dystrophy,
26:57the name of the trial incorporates
26:59the word hope. St.
27:00Jude has an entire foundation called St.
27:02Hope and Hope Clinical Research
27:04is the name of a company.
27:07And then in sickle cell,
27:08I showed you one of the medications
27:10that was recently approved,
27:11Oxalatory.
27:11The name of the trial was called
27:13the HOPE trial.
27:17Here's another example
27:18from the oncology side.
27:19Hope has been and continues to
27:21be integral to participation in
27:23cooperative group clinical trials
27:25and the prospect for improved
27:27survival's a powerful tool that's
27:29not lost on clinicians or physicians
27:31or nurses or parents or industry.
27:34And I think we can all appreciate
27:36that faced with a deadly disease
27:37and no guarantee for a cure,
27:39a parent's willingness to offer and
27:41and take any chance that'll prolong
27:43their their kids life even when
27:46that treatment has unknown risks.
27:48And this is especially true for
27:50novel or cutting edge therapies
27:52that are grounded in science.
27:54And in fact studies have shown that
27:56for many parents the sicker their kid
27:58the more they feel as if they have no
28:01choice but to participate in research.
28:03And ethically this is a concern
28:06because parents vulnerability and
28:07their perceived lack of a choice.
28:10It has implications for those of us
28:12who recommend research for kids,
28:14be that the clinician, investigator,
28:16the IRB and etcetera.
28:21Hope is integral to those who live with and
28:23care for kids with life limiting illness,
28:25including parents and clinicians and
28:27viewed through the prism of medical care.
28:30One definition of hope is what you see here,
28:32an inner resource that allows
28:34individuals to transcend the
28:36constraints imposed by illness,
28:37hopes of positive orientation
28:39to to towards the future,
28:41and the anticipation of an improvement.
28:44For parents of a critically I'll child,
28:46hope serves as a buoy.
28:47It allows them to endure,
28:50and understandably Hope assumes different
28:52forms for parents and clinicians,
28:55and it oftentimes evolves based
28:56on the illness trajectory.
28:58And both parents and clinicians
29:00hope for the best medical outcome,
29:02but they may perceive that outcome
29:04is more or less likely to occur.
29:07In a study by my colleague Brian Sisk
29:10and and his colleagues looked at parents
29:12sources of hope and for parents of kids
29:15with cancer who were the study population,
29:18Brian and his colleagues found
29:19that they had many forms of hope,
29:21four of which were child focus.
29:23And yes,
29:23cure was the most obvious.
29:25But it was only one type of hope
29:27and I think it would be really
29:29cool to replicate Brian's study
29:31in the sickle cell community now,
29:33irrespective of a child's condition.
29:35Cancer, sickle cell CF.
29:37Muscular dystrophy.
29:38I would suggest that parental hope for
29:41improved survival and ultimately cure
29:42is a powerful and motivating force.
29:44And understandably,
29:45many parents look to clinical research
29:48as a means to get to that cure goal.
29:51Sampson and colleagues found that for
29:53parents of kids with muscular dystrophy,
29:55they viewed medical research as a means
29:58to a miracle cure through things like
30:00gene therapy and stem cell therapy.
30:02And our colleague Rick Kodish observed
30:05that really any therapy that has
30:07the veneer of cutting edge science
30:10instills and fosters more hope.
30:12What does this mean?
30:13Well, to me,
30:14it means that as physician investigators,
30:16we have a duty to recognize just how
30:19instrumental hope is and not dispel it.
30:21Data shows that even when parents know
30:23their kids dying, they're still hopeful.
30:25Remember, hope is a buoy.
30:26It's a salve.
30:28And so rather than view patient
30:30and parental hope as a failure
30:32to accept facts on the ground,
30:33I think we may be better suited
30:36to recognize hope as fundamental.
30:38And while we support and foster what
30:42I call reasonable and reshaped hope,
30:45exactly how far patients, families,
30:47clinicians, and oversight bodies like IR,
30:50BS,
30:50and FDA are willing to tip this
30:52hope scale in the effort to have
30:54important advances and important
30:56ethical and practical questions.
30:58And these next examples really
31:00drive home the balancing act
31:03between protecting kids involved
31:05in risky research and hope.
31:08In their Seminole 1991 New
31:09England Journal paper,
31:10Kodish and colleagues shared
31:12the results of their study.
31:14And they asked parents of kids with
31:16sickle cell what would you be willing
31:19to trade off in support of a potentially
31:22curative bone marrow transplant?
31:23And what they found was
31:24that over 1/3 of parents
31:26would proceed with the potentially
31:28curative transplant even if the
31:30risk of short term mortality,
31:31meaning death, was more than 15%.
31:34And more than 10% of those parents
31:36would proceed if the risk of
31:38mortality was more than 50%.
31:40Nearly 25 years later in the era,
31:42more widespread knowledge about transplant,
31:45Emily Myers and colleagues
31:47replicated Codish's study,
31:48and they found that nearly three
31:50out of four parents would proceed
31:52with a transplant even if the
31:54mortality risk was greater than 5%.
31:56And more half of the parents would proceed
31:58if the risk of graft versus host disease.
32:00A very bad transplant complication was
32:04gonna happen more than 10% of the time.
32:06And then when adults with sickle
32:08cell were asked what would you
32:09be willing to trade off for a
32:12potentially curative transplant,
32:13nearly two out of three would do so if
32:15the risk of mortality was more than 5%.
32:17And more than 10% of the adults
32:19with sickle cell would proceed with
32:21a curative transplant even if the
32:23risk of dying was more than 40%.
32:25So when I see this data,
32:27the first thing that comes to mind
32:29is sickle cell is a bad disease.
32:31But the other thing that I think
32:33about is what are patients and
32:36families hearing about these
32:38potentially curative therapies that
32:39may explain their reasons and their
32:42willingness to accept such risks.
32:44And this is a just published
32:46study from December of 2023 that
32:49asked the exact same question,
32:51not about transplant but about gene therapy.
32:54The researcher asked adults with
32:55sickle cell and parents of kids with
32:58sickle cell what would you be willing
33:00to trade off in in exchange for a
33:03potentially curative gene therapy,
33:05and the authors concluded that both
33:07of those groups view gene therapy
33:09as acceptable and they thought
33:11there was a good option.
33:13They also found that patients
33:15with more severe disease were
33:17actually more accepting and were
33:19willing to have less of a benefit.
33:22They also found,
33:23which was really interesting,
33:24that parents more than adults with sickle
33:27cell had a much higher level of risk
33:30tolerance and that they were willing
33:32to accept less than the adults were.
33:34And the author surmised that one
33:36of the contributing factors for
33:38this maybe for this high risk
33:41tolerance maybe media attention that
33:42triggered some form of of hope.
33:45And I'm gonna come back to this study
33:48a little bit later because there's
33:50some concerns with its design,
33:51I think, and and its findings.
33:55A few slides back I mentioned that hope
33:57and hype are both four letter words.
33:58And here are a few examples of
34:00how the two are portrayed in lay
34:03in academic communities.
34:04In 2016, Eric Lander,
34:05founding director of the Broad
34:07Institute of MIT and Harvard penned
34:08this op-ed in the Boston Globe.
34:10And what did Lander have to say?
34:13The Hope,
34:13hype contradiction highlights a thorny
34:15challenge in the ongoing conversation
34:17between scientists and the public.
34:21What about hype?
34:22Well, here's one definition of hype,
34:23and for our purpose,
34:25I'll qualify this as public exaggeration
34:28about the expected benefits of research.
34:30And because hype can impair decision making,
34:33it's worth, I think,
34:34talking a little bit about excuse me.
34:38So what I'd like to do is show you
34:41some examples now about how medical
34:43breakthroughs in research that's
34:46promising are portrayed in the media.
34:48From the New York Times,
34:49Hype springs eternal in medicine,
34:51and you can't imagine what you're
34:54gonna see over the next 30 years.
34:57Confronted with devastating
34:58diseases like sickle cell,
34:59it's not hard to see why so many of us
35:01really want to believe in a better way.
35:03And this following example really
35:05illustrates the line between hope and hype.
35:08When this story aired,
35:09some patients with sickle cell feared
35:12that they were trading their sickle cell
35:14for HIV in order to get the gene therapy.
35:16So what does this say about
35:18how information is presented,
35:20Explained, perceived?
35:21Being thoughtful and being careful
35:23with words applies equally to
35:25every one of us in this room,
35:27but also to our health journalist colleagues.
35:30We all have to communicate responsibly and
35:33clearly about treatments without bias,
35:35even if it risks a less sexy headline.
35:38And this is a really interesting
35:40article by Mandy Young and Craig
35:42Stewart that from a social science
35:45perspective is looking at that whole
35:4760 minute story and how the mental
35:49models of patients with sickle cell were
35:52influenced by what they saw compared
35:55to those people who don't have sickle cell.
35:58This is a screenshot taken from a talk
36:01given by Melissa Creary back in 2021.
36:03Melissa is a sickle cell researcher at
36:05University of Michigan and you can see
36:07what this doctor said at the time of
36:10the gene therapy trials in sickle cell.
36:12It would just open the door of hope
36:15for these patients in November of 2021.
36:18Again from the Times,
36:19sickle cell is cure at a hand.
36:22The same time November 2021
36:24in Scientific American,
36:254 success stories in gene therapy.
36:28March of 2022 in The New Yorker
36:30Are we about to cure sickle cell?
36:33And then just so you don't think that
36:35this is isolated to the popular media,
36:37take a look at some of our journals.
36:39Gene therapy,
36:40the Ultimate Cure for Hereditary
36:41Diseases and From Catastrophe to cure.
36:44In 20 years,
36:47as positive trial data emerged,
36:49we saw even greater use of four
36:51letter words including hope and cure.
36:53Take a look at what Doctor
36:55Tisdale from NHLBI had to say.
36:58And then as many of us know,
37:00on December 8th of last year,
37:02the FDA approved these two gene
37:04therapies for sickle cell.
37:05And this quotation from Gina Colada
37:07and the Times really captures,
37:09I think the challenges that are
37:11associated with these new promising
37:13treatments and hopeful parents and
37:15clinicians are going to be constrained
37:17by the limited number of centers
37:19that can offer this treatment.
37:21Experts estimate that no more than 10 a
37:24year are going to be able to be done.
37:27And so with not enough product
37:29to serve all patients,
37:30the needed expertise and the high cost,
37:32how centers allocate this scarce
37:34resource is a real dilemma.
37:36And right now there is no uniform
37:38approach and centers are making
37:39it up as they're going along.
37:41So for example,
37:42CHOP has said they plan on doing
37:44gene therapy on a first come,
37:46first serve basis.
37:46And Children's National has said
37:48they're going to do the sickest first.
37:49And some folks in Boston say
37:51you know what we're going to do
37:53this piece meal one patient at a
37:55time to work out the wrinkles.
37:56And so it seems like national
37:58guidance or at least some kind of
38:01clinical criteria are needed for
38:03figuring out how to proceed with gene
38:06therapy and then hot off the presses.
38:07Some of you may have seen the story just
38:10last week and this was the first patient,
38:13a 12 year old boy at Children's
38:14National in DC who is getting the
38:17approved now no longer research
38:18but approved gene therapy and the
38:21challenges of allocation of this
38:23expensive and sought after treatment
38:25were covered in the story Children's
38:27National David Jacobson who heads
38:29up BMT and cellular Therapeutics
38:31stated exactly what the expert said.
38:33We're not going to be able to do
38:35more than ten of these a year,
38:36but there's a long list of people who
38:38are waiting to for these treatments.
38:40And David also noted that our MO is
38:43we're going to prioritize the sickest first,
38:45but insurance payment comes into
38:47this and so we have the situation
38:50of haves and have nots.
38:51There can be a very sick kid
38:54but his insurance company is not
38:55willing to foot the bill.
38:56And so that kid may get pushed to
38:59somebody who may not be as sick but whose
39:02insurance company is willing to pay.
39:04And in this story there's a
39:06subheading called chances and hope.
39:08And these are the parents of this young
39:10boy and you can see what they said.
39:12They were very hopeful for gene therapy,
39:14but when they found out the cost,
39:16they lost some of their hope.
39:18And this,
39:18I think is a really telling
39:20statement from the parents.
39:21We're nervous reading through the consents
39:23and what he'll have to go through.
39:25And for obvious reasons,
39:26which wasn't the focus of the
39:27story, they didn't go into that.
39:28But you have to get chemotherapy
39:30before you get gene therapy.
39:32And so it would be nice to know
39:33a little bit more about this.
39:35And then four letter words again,
39:37this is from the boy himself.
39:38He wants to be cured,
39:40wants to play basketball, he said.
39:41Understandable.
39:44This is to remind me to drink all the
39:49all right. Doing all right with the jacket,
39:50huh? Looks really good.
39:52Just remember when my mom finds you.
39:54All right? So with all the focus and
39:57talk about cure, maybe it would be
40:00helpful if we actually define it.
40:01And as you can see,
40:03there's more than one definition of cure.
40:06And I would tell you that
40:07really when talking about cure,
40:09perspective is important.
40:10For a person who's stranded on an island,
40:13that boat on the horizon is salvation.
40:15But for that person who's on the boat,
40:17that island is salvation.
40:18And so the BMT or cellular physician
40:21would probably define cure as
40:23persistence of that novel hemoglobin
40:26and a lack of Graf versus host disease.
40:29The hematologist, on the other hand,
40:30would say no, no, no,
40:31that's not how we define cure.
40:32We define cure based on no need for
40:35disease modifying treatments like
40:37hydroxyurea and packed red blood cell
40:39transfusions and patients and families
40:41are probably saying you guys are crazy.
40:43That's not how we define cure.
40:45We probably would think that patients and
40:47families define cure as resolution of
40:49pain and restoration of organ function.
40:52And so before we talk about cure,
40:53maybe like this cartoon suggests,
40:55we need to put ourselves in each other's
40:57shoes and agree on a definition.
40:59And just so you think that,
41:01and I am biased towards hematology,
41:03oncology 'cause it's the coolest
41:04thing out there,
41:05but this isn't just impedes HEMONT.
41:07This is an article that was
41:09just released two days ago.
41:10And these are all the various FDA and
41:14European Medical Association approved
41:15gene therapies for kids as of December 2023.
41:19And you can see this is across
41:21disciplines and and diseases.
41:23And in this article,
41:24the authors note that right now
41:26there's more than 40 gene therapy
41:28products on the market and dozens
41:30and dozens in clinical trials.
41:31And so gene therapy is very sexy.
41:34It's also a big business.
41:36And this certainly is true for sickle cell.
41:39And I want to thank my colleague
41:41Akshay Sharma at Saint Jude
41:42for lending me this slide.
41:44And what Akshay is showing in this slide
41:47is what some of the current efforts
41:49are to find a cure for sickle cell.
41:51And since Akshay produced this slide,
41:54a number of companies have dropped out,
41:57as you can see.
41:58And they've dropped out for various reasons.
42:00A.
42:01This is hard.
42:01Finding a cure is really hard,
42:03but also it may not be in the
42:05business interest of the company
42:07to pursue these treatments.
42:11Earlier I mentioned that some of the
42:13equity concerns about sickle cell,
42:15especially in the US compared to other
42:17diseases like CF and multiple dystrophy
42:19that primarily affect white populations,
42:22gene therapies are really expensive.
42:24CRISPR and Vertex's gene therapy
42:27$2.2 million for one treatment,
42:29Bluebirds $3.1 million for one treatment.
42:33These make them among the most costly
42:36drugs out there, or treatments,
42:38how everyone wants to call it.
42:40So in high income countries paying for these
42:44therapies is really challenging and it
42:47raises all sorts of policy considerations.
42:49But in middle and low income countries
42:53where 60% of the world's 120 million people
42:56with sickle cell live, it's impossible.
43:00And we have to also think what happens if
43:04this treatment of the gene therapy works,
43:07but you need a second treatment
43:0910 years down the road?
43:1015 years down the road?
43:11Are insurance companies going to cover it?
43:14Keep in mind that the average cost over
43:16the lifespan of a person with sickle
43:18cell in the US $1.7 million and that the
43:22US healthcare system spends $3 billion
43:24a year on sickle cell related costs.
43:27And so now maybe if you're the
43:29drug company that's making these,
43:31you're you're,
43:31you know not so far off in in
43:33charging these high prices.
43:35So a lot of questions here about
43:37access and equity when we're thinking
43:39about these these costly treatments
43:41and here's one example that CMS is
43:44trying to implement for patients
43:46with sickle silhouette Medicaid.
43:48And essentially what CMS is trying
43:51to do is saying on a voluntary basis
43:53states can partner with us and
43:55based on outcomes associated with
43:57the gene therapy for sickle cell,
43:59we will offset some of the cost.
44:02But these are voluntary and it's early days,
44:04but this is some of the thinking that's
44:07happening because again 2.2 million,
44:09three-point 1,000,000,
44:11I mean these are astronomical costs.
44:14So hopefully I've been able
44:15to convince you that hope,
44:16hype,
44:16and cure exist on a continuum and the
44:19three really influence one another and
44:21our understanding of what these means.
44:24And the world uses hope as a marketing tool.
44:27And I am not singling out these excellent,
44:30excellent centers.
44:31I just want to show you how all
44:34of us use these words and what
44:37we're saying to ourselves and what
44:39we're saying to our patients.
44:41At the same time though,
44:42I think we need to be careful
44:43about the words we use,
44:45especially around words like science.
44:47We need to be about clear,
44:48about risks and benefits,
44:49and we need to speak about them in lay terms.
44:53We need to address the emotional risk,
44:55and that doesn't happen enough.
44:56And hope includes real things and
45:00emotional things like Rick Kodish.
45:02My colleague GAIL Geller at the Bioethics
45:05Institute has appreciated that medical
45:07and scientific breakthroughs often
45:09times are understood and translated
45:11and marketed as a hope for a cure.
45:14And understandably,
45:15many patients and families hold
45:17on to this hope,
45:18even when the data suggests otherwise.
45:21And, GAIL says, as you can see here,
45:23the promise of advances in biomedical
45:25research can have a paradoxical effect.
45:28Rather than reducing suffering,
45:29the expectation of cure can be a burden.
45:33And as many of us know
45:34from our clinical lives,
45:36if cure is even remotely a possibility,
45:39some, many, certainly not all.
45:41But at least some patients and
45:43families will push forward despite
45:45the cost on physical and emotional
45:48well-being and their quality of life.
45:50Hope can also be accompanied by anxiety.
45:52Absolutely.
45:53Patients are hopeful that
45:54they're gonna benefit from the
45:56next latest and greatest thing,
45:57but at the same time they're worried.
45:59Am I gonna live long enough
46:00until it comes to market?
46:01Am I gonna be eligible for the clinical trial
46:04if it's still on a in a research setting?
46:06How am I gonna deal with the side effects?
46:08And when it comes to sickle
46:10cell and gene therapy,
46:11one wonders do patients and families
46:13understand that when we use the word cure,
46:16this is a potentially curative treatment.
46:19We are not going to reverse organ damage.
46:22We are not gonna restore organ function.
46:25And cure really comes at a cost.
46:27And that cost itself sometimes
46:29can cause more suffering.
46:30In order to get a bone marrow transplant,
46:32in order to get a gene therapy,
46:34you have to get chemotherapy.
46:36And then there's also some larger,
46:38I would argue, policy considerations.
46:42We're talking about cure.
46:43We're marketing cure.
46:44Like I said,
46:45we see it everywhere when promised
46:48for a cure isn't realized.
46:50This can undermine public trust in
46:51science and in the research enterprise.
46:53And so one more thing for us
46:56to potentially think about.
46:58So in the time that I have left,
47:00I wanna share with you some data
47:03about a multi center study that
47:05colleagues and I are working on.
47:07And what we're interested in learning
47:09from patients with sickle cell and
47:12caregivers of patients with sickle
47:13cell are what are their attitudes,
47:15what are their preferences about
47:17these so-called high risk,
47:18high reward treatments like gene therapy?
47:20And we call ourselves SCD Gene.
47:23Not a four letter word,
47:24but gene is a four letter word.
47:27And what we found is really interesting.
47:29What we found is that fewer than
47:315% of the respondents in our group
47:34said that they felt extremely
47:36knowledgeable about gene therapy
47:38and 2/3 said they had no knowledge.
47:41And maybe not surprisingly,
47:42the more people said that they
47:44knew about gene therapy,
47:46the more comfortable they were that gene
47:48therapy is a safe and a good treatment.
47:50And a question that I have is how and
47:53why does being more knowledgeable about
47:55gene therapy translate to a greater
47:57willingness to accept it as a safe therapy?
48:00Is that cause of hope?
48:01Is that because of hype?
48:03Is it because of something else?
48:06Families are absolutely aware of the
48:08toll of these curative therapies.
48:10And in fact,
48:11our findings directly oppose those
48:12findings of that study I shared
48:14with you on gene therapy that
48:16found that adults and parents of
48:17kids with sickle cell were accepting
48:19of gene therapy and willing to
48:21have a very high risk threshold.
48:24So far we've, you know,
48:25qualitatively coded 45 parent
48:27interviews and only five parents out
48:30of the 4511% said they think the gene
48:33therapy would be right for their kid.
48:35Of 14 patients who've already
48:37undergone gene therapy,
48:39two of them told us they would
48:41not do it again.
48:42And nearly 60% of patients who
48:44we interviewed said they didn't
48:46think that the benefits of gene
48:48therapy outweighed the risks.
48:49In fact,
48:50most of the respondents in our
48:52research said they don't think that
48:54their own sickle cell or their kids
48:56sickle cell is severe enough to warrant
48:59the risks associated with gene therapy.
49:01And those risks are things like infertility,
49:03organ damage from the myelo ablative
49:05chemo that you have to get.
49:07And from a just overall kind of
49:10research enterprise perspective,
49:12they also told us that they have an
49:14uneasiness with medical research and
49:15they have concerns about the novelty,
49:17the newness of gene therapy and
49:20this notion of changing one's genes.
49:23From a pediatric bioethics perspective,
49:25what parents told us was super interesting.
49:28The majority of parents said,
49:29you know what,
49:30this is not our decision to
49:32make for our kids.
49:33This is a decision that
49:35our kids need to make.
49:36And the clinicians in the room will
49:39understand that the longer one waits,
49:42the outcomes of gene therapy and bone
49:45marrow transplant as well can change
49:47because you've had more organ damage,
49:48you've gotten more treatment
49:50related toxicity.
49:51So it makes sense that
49:53parents say that perhaps,
49:54but of course there's always the other side.
49:58Take a look at these observations from
50:01patients and caregivers and especially
50:04know the need to equally highlight the
50:07downside and the side effects of gene
50:09therapy and not just sell the upside.
50:11And you can see how from these quotations
50:13how hope comes into this whole issue.
50:17Maybe not surprising to this group,
50:19but what we learned was that trust is really
50:23important in how people get information.
50:27People also said honest communication,
50:30transparent communication is important,
50:32relatability is important.
50:34And what I what I interpret relatability
50:37to mean is we've talked about the fact
50:39that there's very few centers that
50:41have the expertise and the ability
50:43to provide these new treatments.
50:44And so my center certainly does not.
50:46So I'm gonna be sending my
50:48patients to you guys, for example.
50:50Well, my patients don't know you,
50:53you're you're you're, you know, strangers.
50:55And if we know that trust is important
50:58and relatability is important,
51:00we need to earn that trust.
51:02But also I think that suggests that
51:04there's got to be a role for the
51:06primary hematology team throughout
51:07this entire process to stay engaged.
51:09And it's not where we send our patient off.
51:11And six months later,
51:13they come back and there was no contact or
51:16there was only contact between the teams.
51:18What did we take away?
51:20Avoid jargon, check for understanding,
51:23Allow time for questions.
51:24Don't gloss over things.
51:26Don't rush things.
51:29What you see here in descending order.
51:31And I'm dating myself because
51:32for those you don't know,
51:33that's Dave Letterman.
51:33And he used to do every night
51:35this top ten thing.
51:35That was awesome.
51:36But what you see here is not
51:38Letterman's top ten list.
51:40This is what the people in our study
51:42told us were the top 10 things that were
51:45important to them about novel treatments,
51:47and they may not be the same top ten
51:50important things that we consider.
51:53So as I'm wrapping up,
51:55I'll leave you with these ideas.
51:57I would say that physicians with others shape
52:00and alter both patient and parental hope,
52:03especially when we're talking
52:05about a poor prognosis.
52:06We have to be intentional in our interactions
52:08and we need to recognize our influence.
52:10That's clear and subtle.
52:12Changes in how hope is understood
52:14not only can contribute to hype,
52:16but also to perspectives on cure.
52:19And rather than dissuade hope,
52:21we need to respect the ranges of hope
52:24that patients and families express.
52:27And we have to give patients an
52:29opportunity and the chance to hope.
52:31Through listening and by engaging
52:33with patients and families,
52:35we can better understand what hope means.
52:39This slide is also from my colleague Akshay,
52:41and I've adapted it a little bit.
52:43So we're hopeful that soon
52:45we'll have treatments.
52:46And for a lot of genetic diseases,
52:48communication is important.
52:50Noam Chomsky said words matter.
52:53And so yes, we can qualify by
52:56saying potentially curative,
52:56but maybe we need to get rid of the word
52:59cure altogether and corrective, right?
53:01We're not gonna restore organ damage.
53:03We're not gonna reverse things that
53:05have already happened. Absolutely.
53:06We need more long term data.
53:09And then when we do use words like cure,
53:11we need to remember that cure
53:13for me is not cure for Mark.
53:15You know it's not cure for the rest of you.
53:17Each one of us has our own idea.
53:19If I can't play tennis every chance I can,
53:22then you know that's what's important to me.
53:25For Mark, it's being on his boat with
53:26his family, maybe etcetera, etcetera.
53:31Melissa Crary showed this slide
53:33at the inaugural Carlton Haywood
53:34Memorial Symposium back in 2022,
53:36and it's called the Burden of Sickle Cell.
53:39And so we've got the burden of sickle cell.
53:41And then we have a lovely beach in
53:44near my hometown. And I think, Mark,
53:47we've got time for some Q&amp;A. Yeah, OK.
53:49And I want to thank you guys and
53:52I'm very proud that I left this on.
53:55But thank you.
54:00You want me over here. You
54:01know that was so. Yeah.
54:03So you someplace comfortable?
54:06I'm right here. You can you can sit
54:09up here if you'd like and if that
54:11works have this and and and I'll
54:14look at this and and how we doing.
54:16We're doing good.
54:17I'm just gonna put the last slide up.
54:18Sure. So
54:23first of all, as far as when you
54:25invite a guy who named his dog Elwood,
54:27you gotta. And you know, I just,
54:30I I never carry sunglasses.
54:32But I just happened to have come from
54:34vacation and so I had my you know,
54:35I can, I can I can I can play the
54:40part I can sure
54:41I can be Jake. I could be Jake.
54:44Blues. You know the the chance the
54:47chance of hearing about Batman and the
54:50Blues Brothers in the same lecture,
54:51it's pretty it's pretty low.
54:53So I'm going to give you
54:54a lot of credit for that.
54:55But I have to tell you,
54:56this was for me a Tour de force,
55:01a very powerful lecture and very sobering.
55:03And sometimes it's interesting to
55:06check ourselves and ask ourselves how
55:08do we feel at the end of a lecture.
55:11And I'll tell you just personally,
55:16I feel sad
55:19this didn't leave, that I worry that
55:21we do a lot of harm with these words.
55:25And I know that this was your message
55:27and it was and it was taught very well.
55:29I think there's, you know,
55:30our responsibility about how we use words.
55:32I remember years ago with a surgeon
55:35whose name doesn't need to be mentioned.
55:37Voldemort. No, I would be in the operating
55:41room with him and as a as an intern
55:42and he'd say to the medical student,
55:44he'd always say, he said to her,
55:47this is like a ritual.
55:48What's the definition of false hope?
55:50And she was always supposed to say
55:52there's no such thing as false hope.
55:54And I think, well, I didn't exactly.
55:56Right, because sometimes there
55:57is such a thing as false hope.
56:00But but I worry a lot about the
56:04damage we do with these words.
56:07And it it, I mean,
56:08your heart can be broken in many
56:10different places in this talk,
56:12from what was the word,
56:13a rainstorm of daggers to the idea that
56:17we can potentially stop a child suffering,
56:19but it'll cost $3,000,000.
56:20And then the question is how many
56:22children can we help like that?
56:26I guess
56:30in my I, I, I
56:32I'm having trouble putting my
56:33thoughts into words on this,
56:35'cause I was a very much moved by your talk
56:37and about hope and I and words do matter,
56:40and this made me worry about our
56:42responsibility in the words we use,
56:44that we can actually hurt people.
56:47If I saw the glasses half full,
56:49I would say, well, wow,
56:50there's an awful lot of suffering that
56:52likely in the years to come is going
56:54to be addressed in a very helpful way.
56:57So. So that part is good.
56:59Anyway, that's my reflections on
57:01what I thought was an extremely
57:03insightful and powerful talk and
57:05I and I truly appreciate it.
57:07We have some time and what I would
57:09like to do is OfferUp the chance here,
57:11starting with Doctor Cardone,
57:12if you wait just till someone
57:14brings your microphone, please.
57:15Lori.
57:22Hi, I'm Lori Cardone, I'm pediatric
57:25psychologist and I worked for
57:27many years in hematology and oncology.
57:29I'm wondering if you might have
57:33some thoughts about the Ascent
57:35process with the patient themselves.
57:38And how do we balance providing
57:43psychoeducation in a way that
57:46is developmentally appropriate,
57:46much like our wonderful child life
57:48colleagues do who create wonderful coloring
57:51books and stories to explain a procedure.
57:54But this is not that.
57:56And so how do we think about a scent?
57:59I I was listening for you to
58:01say something about that.
58:02You talked a lot about informed
58:05consent from the parents,
58:06but what about the child?
58:09Is this on? Can you hear me?
58:12Yes. So I got. I cut my teeth in
58:15pediatric ethics and a scent and
58:17I've been trying to escape from it
58:19for 25 years and I'm never able to.
58:20I'm always drawn back to it,
58:22which is totally fine and thank
58:23you for the question because it's
58:25a totally appropriate question.
58:27What I didn't tell you about this
58:29study that we're working on is that the
58:32second part of the intervention if you will,
58:34is coming up with really well designed
58:39validated decisional aids that help patients,
58:43kids as well as adults,
58:45but also families reconcile the very
58:48difficult choices that they face.
58:51And part of the whole idea there is,
58:54as you know as a pediatric psychologist,
58:56you know, Ascent is not diet consent,
58:58it's not, you know, consent light,
59:01it's developmental, it's maturational,
59:04it's frontal lobe, it's,
59:07it is neurocognitive functioning.
59:09It's a very,
59:10very complicated process and we owe
59:14our patients the ability to be able
59:17to a be part of these discussions
59:20as developmentally appropriate.
59:22As Laney Ross, who some of you may know,
59:25who's a pediatrician and pediatric
59:27ethicist has said,
59:28we shouldn't involve kids and allow them
59:31a decision if we don't plan to listen to it.
59:33It's disingenuous,
59:34right.
59:34If if I say Mark,
59:36you know,
59:39give me your opinion and then I
59:40I never intend to listen to it,
59:42that that's not cool.
59:44And so part of the idea here is
59:47that we need to do a better job.
59:49And I would, I would suggest
59:51that it's not just dissent.
59:52Dissent is probably harder, of course,
59:54but also with the consent process.
59:57Because what we know from reams of studies,
60:00decades of research is that patients,
01:00:03parents and often clinicians
01:00:05don't do a good job understanding
01:00:08and working through these steps.
01:00:11And so the group that we're working
01:00:14with to create these decisional aids.
01:00:17Is a multimedia company where
01:00:20both of them are docs,
01:00:21but one of them's a an artist
01:00:24and the other I don't know,
01:00:26he's he's just remarkable.
01:00:27I can't remember what his background is
01:00:29but using audio visuals to create these.
01:00:33Now, people have done quality of ascent
01:00:36and quality of consent tools forever,
01:00:39and there's probably more
01:00:40than one good way to do this.
01:00:42But that is the way that we have
01:00:45decided that we need to try
01:00:47to slim the gap a little bit,
01:00:48if you will,
01:00:51Krish, please.
01:00:52Hi, I'm Lakshman Krishnamurthy.
01:00:54And when I. And I have to tell you,
01:00:55I forgot to mention before these
01:00:57microphones that you've got,
01:00:58some of you guys have heard me talk about it.
01:00:59It's a, it's a function of these
01:01:01microphones that if you can't talk to,
01:01:03you've got to actually hold it up like that,
01:01:05like you're got it.
01:01:06Rock star, Krish, which you are.
01:01:08So, OK, there you go
01:01:10in. In Full disclosure,
01:01:12I'm both a pediatric hematologist and
01:01:14a transplanter actively involved in
01:01:17consenting patients for gene therapy.
01:01:19Every week, a wonderful talk,
01:01:22I got to hear a part of some
01:01:24of this content at ASFO.
01:01:26I have two comments to make.
01:01:28One, cost, because I think we've
01:01:31all talked so much about cost,
01:01:34but we fail to recognize how the federal
01:01:37government has taken a huge step forward.
01:01:39And you briefly alluded to it,
01:01:41but the whole story is that
01:01:43the federal government,
01:01:44CMS will negotiate on behalf of 50 states
01:01:48for the cost and the companies are
01:01:51coming to the table starting this month.
01:01:54So I think that we might may may
01:01:56solve the OR alleviate the cost
01:01:58problem sooner than we think.
01:02:01You know India is already making
01:02:02big investments in gene therapy
01:02:04and they're just this year,
01:02:05this week published you know in
01:02:08vitro gene editing for sickle cell.
01:02:11I think the global gene therapy
01:02:15initiative is taking the NIH,
01:02:17you know non commercial IP and want to
01:02:20take it to Africa and India and stuff.
01:02:23So.
01:02:23So you know really cost is great
01:02:26but it's not hopefully I mean
01:02:29we all saw how quickly the cost
01:02:32of whole genome sequencing you
01:02:34know went from being impossible.
01:02:36I don't need to say this to to this group.
01:02:40The second comment I want to make is the,
01:02:44you know, understanding. Is there hype?
01:02:49Is there misrepresentation?
01:02:51I honestly believe the largest
01:02:54problem is that people's lives are
01:02:57so wrapped up in sickle cell disease
01:03:00in the narrative of I am suffering.
01:03:03So it probably was meant to be and I can't.
01:03:08I don't have a Doctor Who knows
01:03:10anything about gene therapy to send me
01:03:13to somebody who knows something about
01:03:15gene therapy and and I can't believe anybody.
01:03:19So the larger problem is how are
01:03:21we going to reach all of these
01:03:23people who could actually benefit,
01:03:26you know,
01:03:27if they only were able to wrap their
01:03:29head around this whole problem.
01:03:31And I see this from a perspective of
01:03:33a deeply held belief that ordinary
01:03:35people can comprehend extraordinarily
01:03:38complex information, you know,
01:03:40in in informed self-interest.
01:03:42So I think those are probably
01:03:44too big and so but lovely talk.
01:03:46I'm so glad I showed up to hear you again.
01:03:49Thank you for those amazing
01:03:51observations and comments.
01:03:52And I think your patients are probably
01:03:57among the lucky few who have you
01:03:59who are is able to walk through
01:04:02this difficult process with them
01:04:05because if you're both serving as
01:04:07a hematologist and a you guys call
01:04:09yourselves now cellular physicians,
01:04:11right, not just transplanters
01:04:12but whatever you want to call
01:04:15yourself they're lucky.
01:04:16So thank you.
01:04:20You know I I what what potentially may
01:04:23happen in the US with CMS is great.
01:04:26I still struggle with what's going
01:04:28to happen in the rest of the world.
01:04:30But I also to your second point
01:04:33about getting to the masses.
01:04:35I've made a point since gene therapy.
01:04:37The preliminary data seem to
01:04:39suggest that it's probably positive.
01:04:42I made a point of and there are days where
01:04:44in my clinic and I I do heme and ARC.
01:04:46So there's days where I see kids with
01:04:48heavy menstrual bleeding and sickle cell
01:04:50and anemia and days where I see ARC and.
01:04:52But there's some days where most of
01:04:54the kids I'm seeing happen to have
01:04:56sickle cell and I made a point of
01:04:57of talking to patients and parents.
01:04:59You heard of this thing called gene
01:05:01therapy and it's amazing to me which
01:05:03patients and parents say yes and which
01:05:06ones kind of look at me Gene what and
01:05:08and I think we failed in that regard.
01:05:10We with a royal you know W and and that
01:05:16to me is is a Clarion call and we need
01:05:19to do a better job getting out to the masses.
01:05:21And then equally important is our
01:05:24message and how do we convey that.
01:05:26But I I think you are spot on spot on.
01:05:30Thank you. Yes, Howard,
01:05:34thanks. It was very interesting.
01:05:36I was very taken with your
01:05:38numbers and you said that 40%,
01:05:41if I heard you right of the
01:05:43parents that had gotten it
01:05:45said they wouldn't do it again.
01:05:49And I there were 14 patients
01:05:51in our group who had
01:05:53already had gene therapy, 22411 percent
01:05:55said they would not do it again. I see.
01:05:58Just two small numbers. Very small
01:06:00numbers. Well, what were the reasons?
01:06:04I don't have the I honestly,
01:06:06I don't have that data yet.
01:06:08Our colleagues who are doing the
01:06:10coding hadn't gotten that far.
01:06:12But of course that's the that's
01:06:14the that's the the money, right?
01:06:17Yeah. Stay tuned.
01:06:19When Mark invites me back when it's
01:06:21not raining I'll I'll part due.
01:06:23I'll I'll I'll share that Hold.
01:06:25I say the blame. The rain
01:06:27is primarily your fault.
01:06:28Definitely my fault. You've
01:06:30talked about girls. It's always my
01:06:34girls, you know, and and and Chris made
01:06:35a really good point about the cost,
01:06:37of course, for everything we've seen.
01:06:38We and I gave a lecture on this myself
01:06:40not long ago on various technologies,
01:06:42how the cost of these things tend to
01:06:45go down sometimes quite dramatically.
01:06:47And so I feel maybe more hopeful
01:06:49than I did 10 minutes ago that maybe
01:06:52more kids are actually gonna get some
01:06:54relief of suffering kids and adults.
01:06:57Other thoughts, comments, questions.
01:07:04If not, then you're wrong.
01:07:07If you don't, I don't want
01:07:08to put you on the spot.
01:07:08So I'm going to ask you if
01:07:10you have any final words.
01:07:11So maybe before you do I'll just take a
01:07:14a minute or two to thank you so much.
01:07:16This was for want of a better word
01:07:21of powerful talk and it and it
01:07:23it for those who are involved in
01:07:24caring for people with sickle cell.
01:07:26I think there was much to be learned
01:07:27for those of us who care for a
01:07:30very different patient populations.
01:07:31Nevertheless,
01:07:31there was a lot to be learned
01:07:33about the responsibility we have
01:07:35in the words that we use it.
01:07:39It leaves us very thoughtful And
01:07:41and I and I and I will amend my
01:07:44initial comments and say that that
01:07:46not a bit as a sad that so many
01:07:49are suffering and will continue
01:07:50to suffer for some time but with
01:07:53some hope that there will be less
01:07:55suffering thanks to the work above.
01:07:57So many folks in the audience who
01:07:58haven't spoken up here today,
01:08:00but a lot of people who have spent
01:08:02their lives making life better
01:08:03for these kids and adults.
01:08:05And and if I may, if you'll indulge me,
01:08:06first of all I want to thank you for I mean
01:08:09being the the clean up hitter for the season.
01:08:11I mean that's a huge honor.
01:08:13Thank you for letting me, you know close
01:08:15up the shop for the academic season.
01:08:17But I don't want you guys to
01:08:19think that I am not hopeful.
01:08:20I mean I'm a pediatric chemonk doc.
01:08:22I mean it's in my DNA to be
01:08:25hopeful and to be positive.
01:08:27And and I think that there's these, you know,
01:08:31euphemisms that we use and you know,
01:08:34I'm, I'm always qualifying
01:08:35by putting potential before,
01:08:38but I am absolutely hopeful.
01:08:40And in my young career and
01:08:42it has been a young career.
01:08:44I'm not that you know that that old.
01:08:46I'm
01:08:47not that young either.
01:08:47But go ahead, but keep going. Yeah,
01:08:50but it's been remarkable to see
01:08:54you know the the, the advances that
01:08:56that obviously we we have made.
01:08:58But I think that the lessons that
01:09:01maybe we see from the sickle cell
01:09:04community absolutely translate to
01:09:06every single area of clinical medicine,
01:09:09in particular those that involve
01:09:11life limiting illnesses.
01:09:13And to be present to me,
01:09:15it's been very humbling to learn
01:09:18and to hear from patients,
01:09:21but to be present and to hear and
01:09:24to try to simply understand what
01:09:26patients are going through in
01:09:28their perspectives is so important.
01:09:30So thank you. Thank you.