November 30, 2023 • 45 mins
In this episode of The Onco’Zine Brief Peter Hofland talks with Stephen Spellman.
Stephen Spellman is Vice President and Senior Scientific Director at Be The Match and the Center for International Blood & Marrow Transplant Research (CIBMTR).
Hofland and Spellman talk about the outcomes of a study published in Blood Advances, the journal of the American Society of Hematology. [1] The article discusses the impact of cryopreservation of hematopoietic cell grafts on overall survival (OS) and other outcomes within 1 year after hematopoietic cell transplantation.
At the beginning of the COVID-19 pandemic the National Marrow Donor Program as together with other national and international donor registries mandated the cryopreservation of hematopoietic cell grafts during the first 6 months of the pandemic because of patient and donor safety concerns. The reason was that during the early days of the pandemic, delivery of donor products after patient conditioning could not be guaranteed. This was, in part, caused by logistical complexities including travel bans, flight delays and cancellations, rerouting of couriers – as well as closed border crossings… In addition, donors were at risk of being infected with the SARS CoV-2 Virus, the virus that causes COVID-19, which, in turn, resulted in last-minute cancellations of graft collection.
To solve the pandemic-related logistical problems, the authors of the study conclude that cryopreservation should be considered a method to eliminate the potential risks with the use of fresh donor graft products or when fresh grafts are not available.
But what was the impact of cryopreservation on patients receiving hematopoietic cell transplantation compared to the effects among patients receiving fresh donor products? Was there a difference in overall survival, disease free survival, or disease recurrence? Was there a risk in Graft vs Host Disease?
In this episode of The Onco’Zine Brief Hofland and Spellman talk about this and more.
Reference
[1] Devine SM, Bo-Subait S, Kuxhausen M, Spellman SR, Bupp C, Ahn KW, Stefanski HE, Auletta JJ, Logan BR, Shaw BE. Clinical impact of cryopreservation of allogeneic hematopoietic cell grafts during the onset of the COVID-19 pandemic. Blood Adv. 2023 Oct 10;7(19):5982-5993. doi: 10.1182/bloodadvances.2023009786. PMID: 37036959; PMCID: PMC10580174. [Article][Pubmed]
About The Onco'Zine Brief
The Onco’Zine Brief is developed in collaboration with our online journal Onco’Zine, where you can find additional information and the latest news about cancer diagnosis and treatment, and cancer prevention.
The Onco'Zine Brief is distributed in the United States via PRX (Public Radio Exchange). In the United Kingdom and Europe, the program is distributed via UK Health Radio (UKHR). And the program can be downloaded via most podcasts and streaming media services, including iTunes, Spotify, TuneIn, and iHeart Radio.
For more information about The Onco'Zine Brief or how to sponsor or support this public radio broadcast and podcast, visit to download our Media Kit, visit our Patreon page, or contact the sales team.
To sign up for The Onco'Zine Newsletter (open for residents of the United States only), text the word CANCER to 66866.
Support for The Onco’Zine Brief comes from the Oncology Directory and from listeners like you. Funding is also provided by Java Original Coffee and RoastMasterz
Stephen Spellman is Vice President and Senior Scientific Director at Be The Match and the Center for International Blood & Marrow Transplant Research (CIBMTR).
Hofland and Spellman talk about the outcomes of a study published in Blood Advances, the journal of the American Society of Hematology. [1] The article discusses the impact of cryopreservation of hematopoietic cell grafts on overall survival (OS) and other outcomes within 1 year after hematopoietic cell transplantation.
At the beginning of the COVID-19 pandemic the National Marrow Donor Program as together with other national and international donor registries mandated the cryopreservation of hematopoietic cell grafts during the first 6 months of the pandemic because of patient and donor safety concerns. The reason was that during the early days of the pandemic, delivery of donor products after patient conditioning could not be guaranteed. This was, in part, caused by logistical complexities including travel bans, flight delays and cancellations, rerouting of couriers – as well as closed border crossings… In addition, donors were at risk of being infected with the SARS CoV-2 Virus, the virus that causes COVID-19, which, in turn, resulted in last-minute cancellations of graft collection.
To solve the pandemic-related logistical problems, the authors of the study conclude that cryopreservation should be considered a method to eliminate the potential risks with the use of fresh donor graft products or when fresh grafts are not available.
But what was the impact of cryopreservation on patients receiving hematopoietic cell transplantation compared to the effects among patients receiving fresh donor products? Was there a difference in overall survival, disease free survival, or disease recurrence? Was there a risk in Graft vs Host Disease?
In this episode of The Onco’Zine Brief Hofland and Spellman talk about this and more.
Reference
[1] Devine SM, Bo-Subait S, Kuxhausen M, Spellman SR, Bupp C, Ahn KW, Stefanski HE, Auletta JJ, Logan BR, Shaw BE. Clinical impact of cryopreservation of allogeneic hematopoietic cell grafts during the onset of the COVID-19 pandemic. Blood Adv. 2023 Oct 10;7(19):5982-5993. doi: 10.1182/bloodadvances.2023009786. PMID: 37036959; PMCID: PMC10580174. [Article][Pubmed]
About The Onco'Zine Brief
The Onco’Zine Brief is developed in collaboration with our online journal Onco’Zine, where you can find additional information and the latest news about cancer diagnosis and treatment, and cancer prevention.
The Onco'Zine Brief is distributed in the United States via PRX (Public Radio Exchange). In the United Kingdom and Europe, the program is distributed via UK Health Radio (UKHR). And the program can be downloaded via most podcasts and streaming media services, including iTunes, Spotify, TuneIn, and iHeart Radio.
For more information about The Onco'Zine Brief or how to sponsor or support this public radio broadcast and podcast, visit to download our Media Kit, visit our Patreon page, or contact the sales team.
To sign up for The Onco'Zine Newsletter (open for residents of the United States only), text the word CANCER to 66866.
Support for The Onco’Zine Brief comes from the Oncology Directory and from listeners like you. Funding is also provided by Java Original Coffee and RoastMasterz
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:12):
This is the Younger Zaine Brief withPeter Hoffland. In this episode of the
Younger Zam Brief, I'm talking withdoctor Steven Spellman. Doctor Spellman is vice
president and Senior Scientific director at BEthe Match and the Center for International Blood
and Merit Transplant Research. We talkabout the outcomes of a study publishing Blood
(00:36):
Advances to Journal of the American Societyof Hematology discussing the impact of choir preservation
of amopoetic cell graphs on overall survivaland other outcomes within one year after cell
transplantation. Now, at the beginningof the COVID nineteen pandemic, the National
Merit Donor Program mandated the crier preservationof amoto poetic cell graphs. Speak of
(01:00):
patients and donor safety concerns, crierpreservation was considered a method to eliminate the
risk but the use of fresh donorproducts. One of the concerns was that,
as a result of the COVID pandemic, delivery of donor products after patient
conditioning could not be guaranteed. Thiswas in part caused by logistical complexities including
(01:22):
travel bands, flight delays, flightcancelations, rewriting of couriers, and things
like closed borders. In addition,donors were at risk of being infected with
COVID, which in turn resulted inlast method cancelations of graft collection. To
address the problem, the National MerritDonor Program, together with several global donor
(01:44):
registries, required achoo preservation of mostunrelated donor products during the first six months
of the pandemic. But what wasthe impact of crier preservation on patients receiving
hemipogetic excel transplantation compared to the effectsamong patients receiving fresh donor products. Was
there a difference in overall survival indisease free survival or disease recurrence? Was
(02:07):
there a risk in graft versus hostdisease. In today's episode of the Youngest
in Brief, we talk about thisand more. I'm Peter Hoffland and this
is the Youngest in Brief. TheYoungest in Brief is developed in collaboration with
our online journal Ongoisine, where youcan find additional information and the latest news
about cancer diagnosis and treatment and cancerprevention. Support for the Youngest in Brief
(02:30):
comes from the Oncology Directory at Oncologydirectorydot com and from listeners like you.
For more information on how to supportthis program, visit our website Ongozine at
ongozine dot com. And if youare living in the United States and want
to receive our newsletter, text theword cancer to six six eight sixty six
(02:50):
and we will make sure that you'llreceive our newsletter, which includes an overview
of the latest news in oncology andhematology. This is the on Caasine Brief.
For the latest news about cancer andcancer treatment, visit our online journal
(03:12):
on Caazine at www dot oncasine dotcom. On the phone with me is
doctor Stephen Spellman. Doctor Spellman,Steve, Welcome to the Young Gazine Brief.
You're device president and senior scientific directorat bt MATCH and the Center for
International Blood and Merit Transplant Research.Right, tell me a little bit more
about yourself and about your organization youwork for and what you're trying to do
(03:38):
for patients patients that may be affectedwith cancer or hematological malignancies or other diseases.
Sure, happy to answer that,Peter, and thank you for the
invite and the opportunity to share someof our research today with the Cosine audience.
So, as you mentioned, I'mthe vice president of research in the
at the National Maridona Program or theNMDP. I'm also a senior scientific director
(04:00):
in the Center for International Blood andMero Transplant Research, which is a research
collaboration between the NMDP and the MedicalCollege of Wisconsin. So we have had
a long long standing research collaboration thatstarted in the early two thousands where we
have merged our research programs to capturedata on patients proceeding to transplant receiving either
(04:25):
atologous or self transplants allogeneics, sotransplants from donors, as well as cellular
therapies and gene therapies, and sowe have an active registry that has captured
data on over six hundred and thirtythousand patients to date. We use that
data to perform observational research studies ofwhich I'll be speaking today about that experience,
(04:46):
and use that to help guide transplantpractice. So mainly observational studies that
are coming out of the research database, but we also have an active prospective
research program facilitated through our what wecall our Clinical Research Organization Services, which
manages phase early stage, phase one, phase two trials that's based in our
Minneapolis office of the of the CIBMTRas well as participate as part of the
(05:13):
Coordinating Center for the Blood and MarrowTransplant Clinical Trials Network, which is an
NIH funded clinical trials program that supportsmainly Phase three trials in transplant and cellular
therapy. So our goal here isto utilize these data resources to provide guidance
on how transplant should be performed,cellular therapy should be performed, and offer
(05:35):
evidence based guidance for clinical practice.That's a lot. Now you've mentioned observational
studies designed to help you guide transplantpractice. To help our listeners understand the
difference between observational studies and randomized controlledclinical studies, tell me a little bit
about these differences and about these studies. What's the difference between them. Yes,
(06:00):
studies are where we are prospectively collectingobservational clinical data on patients transplanted within
the US and selective international centers thatchoose to participate in the CIBMTR. We
use standardized data collection instruments that captureinformation on donors, their patients, or
the patients, the disease, thetransplant procedure, and then outcomes post transplant,
(06:24):
capturing data at baseline one hundred dayspost transplants, so everything that occurred
from day zero to day one hundredand then at six months, one year,
and then subsequently yearly after that untileither the patients choose to not participate
in research anymore or pass away.So we do capture long term longitudinal data
(06:47):
on those patients. So where wecan use the observational data is to evaluate
things that probably isn't well suited fora randomized clinical trial, such as HLA
match for transplantation, so the ruleof thumb would be matched to the best
potential available donor. Unfortunately not everypatient has a fully matched donor available,
(07:12):
but want to be able to offerthose transplant procedures, the potentially curative therapy
to those patients, So we'll capturethat data and be able to review that
retrospectively through observational research projects to understandthe impact of various HLA mismatches and the
influence that that may have had ontransplant outcomes to better better informs a donor
(07:32):
selection going forward where that really wouldn'tbe appropriate to do, and say a
randomized trial saying assigning people to awell matched donor versus a mismatch donor in
a randomized manner. If you lookat the outcomes of observational studies, the
types of studies where researchers observe theeffect of a risk factor, diagnostic test,
treatment, or other intervention without tryingto change who is exposed to it.
(07:57):
And this is different than, forexample, a randomized UNCLE trial.
You may be able to collect morein depth and impactful data because these studies
generally run longer. Right in someways, yes, I mean you're not
controlling for an intervention as you canon a clinical trial, but so you're
better reviewing more of the overall practicethat's been seen in the community, So
(08:22):
more of a use of real worlddata or as to better understand the impacts
of trends in transplant in treatment practicesand the influence that that has had over
time. So being able to compareeras of treatments and different strategies for treatment,
and segregating even at center level tobe able to evaluate how centers are
(08:46):
actually performing. So lots of otheropportunities to continue to mine observational databases.
So this goes more towards what theUnited States Food and Drug Administration the FDA
requires for DIRUCT trials. Right nowwhat we call real world's data. Right
when you develop the observational studies,the longer time, the more in depth
(09:07):
questioning, that all may help youto get a real picture of what I
think you mentioned is what is goingon in the clinic and how you can
actually adjust studies to treatment options forpatients. Right. Potentially, yes,
it could provide some of those insightsthat maybe aren't going to be a parent
and a shorter follow up on aclinical trial. So really looking at longer
(09:28):
term outcomes, potential longer term risks, really beneficial for really benefit from the
longer term, longitudinal follow up that'sdone within observational studies. The other thing
to not with our observational database iswe do capture biological samples on a subset
of the population, and so wecan go back and review those as well
(09:50):
and explore other factors that may nothave been considered at the time of the
transplant. So in the case ofsay HLA typing, looking at extended low
side a more precise depth of matchingto see if that makes a difference in
overall outcomes where that may not havebeen feasible at the time due to technical
(10:11):
difficulties or even the limitations of theway that data was collected at the time
of those transplants, so we canadd to those databases as well, which
is really really useful for exploring newfactors. That's really interesting. It's actually
very nice to be able to enrichthat information. Let's take a break.
(10:31):
This is the Youngest in Brief.If you're just joining us in today's episode
of the Youngest in Brief. I'mtalking with doctor Steven Spielman. Doctor Spellman
is vice president and senior Scientific directorat BEA Match and the Center for International
Blood and Merit Transplant Research. I'mPeter Hoffland, and this is the Youngest
in Brief. Each day, researchersdiscoveries that bring us closer to the moment
(11:01):
when all cancer patients can become survivors. Their progress is made possible with the
health of clinical trials. Clinical trialsare the brightest torch researchers have to light
their way towards better treatments, andif you've been diagnosed with cancer, they
may be your brightest ray of hope. Speak with your doctor and visit stand
up to Cancer dot org slash clinicalTrials to learn more. Together, we
(11:24):
can stand up for all of us. This is the young Gazine Brief with
Peter Hoffland and welcome back. Thisis the Youngest in Brief. If you're
(11:50):
just joining us. In today's episodeof the Youngest in Brief, I'm talking
with doctor Steven Spellman. Now let'sswitch gears a little bit and look at
the STO you've conducted. What comesto mind is that most people around us,
and I think that involves the listenersas well, are very happy that
the COVID nineteen pandemic is to someextent over and well, COVID is expected
(12:13):
to be with us for a longtime. The actual pandemic, I hope
that's true, though, is actuallybehind us. Having said that the COVID
pandemic has had a major impact onhealthcare, how did the COVID pandemic impact
your organization? And what is moreimportant, how is pandemic impacted patients you're
(12:33):
trying to help during the pandemic.That's a great question. Well, it
was a very substantial impact on ourpatient population. So the parent organization that
I work for is the National AwareDonor Program. We facilitate unrelated donor and
related and core blood transplants, handlingall of the donor search and match,
as well as the logistics for thedistribution of those for the collection and distribution
(12:56):
of those products, unrelated donor alogenicstem cell transplant is a very international business.
About approximately half of all products crossand international border, and that's because,
well, the diaspora of the worldhas really been spread out across the
globe, and so your donor maybeanywhere in the world, and so we
(13:18):
need to be able to harvest thosecells from the donor where they happen to
reside and get them to the patientwho happens to need them. Obviously,
the travel disruptions that occurred during theCOVID nineteen pandemic necessitated a complete change to
the way that we were managing thecollection and distribution of those products due to
(13:39):
inconsistencies and travel schedules, major disruptionsand ability to travel, and even restrictions
on international border crossings during the pandemic, and so we had to work closely
with the State Department to ensure thatwe could cross international borders, also set
up a hub and spoke type ofa transport system. The vast majority of
(14:03):
the products that we distribute are handcourier by individuals and so to be able
to make handoffs at international borders toknown individuals. To actually ensure that we
had point to point distribution and chaina custody of those products was herculean feet
at the time, but the NMDPdid amazing work during the pandemic to ensure
(14:28):
that all patients in need would receivethose products in a timely manner, and
part of that goes to the researchthat we'll be discussing today, which was
implementing a mandate to cryo preserve products, and the rationale for that being that
if we were harvesting a product froma donor, ensuring that the pain it
(14:48):
would be received at the institution wherethe patient would be receiving their transplant or
their infusion prior to initiating their condtioningtherapy. So, whether that's a reduced
intensity conditioning strategy or a mile oflate of conditioning strategy, those patients undergo
(15:09):
pretty extreme levels of chemotherapy to preparethem to receive the graph, and it
leaves them extremely neutropenic and susceptible toall sorts of opportunistic infections. The last
thing that we would want to havehappen is to not have a graph,
they're ready to infuse at that time. So cryo preservation was mandated to ensure
that those products were present prior tothe patient initiating their preparative regimen for to
(15:35):
receive their graph and that worked quitewell, but we also wanted to understand
the impacts that that may have onthe performance of those products. Hence the
research that was done in the studythat we'll be discussing today. So if
I understands correctly the moment that youhave bone marror available and there is a
patient waiting for treatment wherever that patientmay be, there is only a limited
(15:58):
time to end. The clock isseeking right? Tell me a little bit
about that. Well. In normaltimes, products are collected and infused within
about a forty eight hour window,so any disruption to that or prolonging of
that window leads to the big degradationof that stem cell product. We've published
(16:18):
some studies in the past looking atkind of shelf stability of graphs, and
once you hit about forty eight toseventy two hours, you really start to
see a degradation in the cellular compositionas well as the potency of those products.
So ensuring that a product could beharvested and processed in a way that
(16:40):
it could be preserved within that firstforty eight hours of initial collection. Then
ensures that you would have a morerobust product for infusion into the patient at
the time of need, and sowith all of the logistical issues and logistical
issues would travel. But then alsowith even donor societ the ability to infection
(17:00):
as well, which could lead todelays and harvest and being able to even
collect that product or having to shiftgears to a backup donor in the event
that a donor tested positive for COVIDnineteen during their workup process, to have
a bit of that time buffer tosupport the collection of the product, the
(17:21):
preparation of it, and ensure thatit was transported and available in a timely
manner for the patient. Now tostudy clinical impact of crier preservation of allogenetic
hemitogetic cell grafts during the onset ofthe COVID nineteen pandemic was published earlier this
year in Blood ADVENTSS, the journalof the American Society of Hematology and discusses
(17:41):
the study results, an impact ofcrier preservation and how these affected patients.
Right now, you gave us agreat introduction. But to start, what
were the major questions that you wantedto have answered by the study. I
do understand that one question you'd liketo have answered was of course about cryer
preservation and if this is an optionin the process. But were there more
(18:04):
questions? Were there other questions thatyou wanted to have answered. That's a
good place to start, because therehad been studies that have been done in
the past looking at the comparing offresh to cryopreserve products in allogenetic transplant.
There were three studies that were publishedkind of leading into the pandemic, two
(18:26):
front well, all from the CIBMTR. One that looked at the use of
cryopreserve graphs in the haploidentical setting.This is a study that was led by
Mehdi Hammadani and showed that there wasreally no impact in this haplo identical setting
using a post transplant cycloposphoma based GVHDprophylaxis strategy that didn't appear to be an
(18:48):
impact on outcomes in patients receiving eitherfresh or cryopreserve graphs. So that's one
example. Another study that was conductedlooked in severe aplastic anemia and the use
of bone marrow graphs. Now therenow was a study that was led by
doctor Mary Epan through the CIBMTR andthat showed that there was a substantial risk
(19:11):
associated with use of cryopreserved graphs inthat setting, so not recommended in the
severe plastic anemia setting. Another studythat looked at a more diverse set of
diseases and in a broader population reallywas a pre pandemic evaluation. This was
a study that was led by JackChu from the Moffitt Cancer Center down in
(19:34):
Florida and conducted through the Donor Healthand Safety Working Committee of the c IBMTR.
There it was shown that there wasan impact on overall survival considering the
use of peripheral blood stem cell graphs. There didn't appear to be a difference
with the use of bone marrow graphswhether they were fresh or cryopreserved for patients
(19:55):
receiving transplants for hematological malignancies. Indigging a bit deeper into the data,
what we didn't capture all the timewas the rationale for cryopreservation, since in
normal pre pandemic times the default wasalways to prefer fresh graphs if they could
be given and that's not just forpatient safety reasons, but also donor reasons,
(20:18):
and in the unrelated donor setting,should you be, there's always concerns
about final utilization of those products,So if they're being collected cryopreserved, they
may not be infused at the endof the day, and so just ensuring
that each project product that's collected asbeing directed to the patient that's in need.
But within that study, we didhave some data for a subset where
(20:41):
we were able to evaluate the rationalefor cryopreservation, and in over sixty percent
of those transplants, the delays andthe need for cryopreservation was mainly due to
issues associated with either disease progression,infection, or other need, other patient
(21:02):
related factors that may be associated witha more severe disease state, or other
issues that really couldn't be well welladjusted for within that analysis, and so
that was a caveat in one ofthe limitations of that study. Now moving
into the pandemic, we had aunifying rationale for the use of cryopreservation for
(21:23):
all allogenetic products and the vast majoritywere cryopreserved during that timeframe. So in
the present study, what we didwas we compared transplants that were performed in
twenty nineteen looking at AIX the firstsay six months of of twenty nineteen compared
(21:44):
to the post pandemic twenty twenty oncethe cryopreservation mandate went into effect, And
so we're able to compare transplants thatwere performed in the setting of fresh graphs
as the default and in the settingof cryopreserved graphs as the default, and
compare and contrast those results. Andso that that was one of the main
impetus for the for the present study, but then also to have that kind
(22:08):
of level playing field, so weknew that all of those products were destined
for cryod preservation. It was plannedfor at the center they were being cryo
preserved in that kind of critical windowof the vast majority being cryo preserved in
less than forty eight hours of collection, with some that maybe traveled a bit
farther, may over international borders orso being a bit more delayed in that
(22:32):
case. So there we were ableto really kind of do more of an
apples to apples comparison of a rationalefor using either a fresh or a cryopreserved
product, which was important to kindof level set the population in this case,
let's take a short break and thenwe're back with doctor Steven Spelman.
(22:57):
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(23:19):
for sarcoma. For more information onthe work of the Sarcoma Foundation of America,
go to Cure Sarcoma dot org.This is the young Gazine Brief with
Peter Hoffland and welcome back. Thisis the Youngest here in Brief. If
(23:51):
you're just joining us in today's episodeof the Youngers Seen Brief. I'm talking
with doctor Steven Spellman. I'm PeterHoffland and this is the Youngest in Brief.
Before the COVID nineteen pandemic, thestandard approach was using quote unquote fresh
bone marrow fresh crafts rather than crierpreserved. Right now, due to logistical
(24:11):
requirements, impacted by COVID and thewhole host of other reasons and circumstances.
The standard procedure needed to be changed. You successfully, and kudos to that
were able to switch the way youwere able to help patients in need.
But then the most important question iswhat impact did this have on patients?
Because what I assume is that everydoctor listening to the show wants to hear
(24:34):
this. What is the patient impact, What were the outcomes negative or positive?
And where these outcomes practice changing?What can you tell us about that?
Sure, so I can walk througha bit of the results from the
study. So what we did findin comparing fresh to crow preserved was there
was no impact on overall survival.There was also no impact on what we
(24:59):
call GVHD free relapse free survival nonrelapse mortality a q GVHD, so no
major issue with overall survival. Sothat was really encouraging. That was an
encouraging finding. However, we didsee some negative impacts, and one was
an increased risk of relapse in theuse of cryod preserved graphs as well as
(25:21):
that associating with an increase increased riskof a decreased disease free survival and all
of and that mainly due to relapserisk. We did see a slight delay
in ingraphment in using the cryopreserve graphs, but that equated to about a one
or one one to two day delayin neutrophill graphmen and a one to two
(25:45):
to day delay in platelet and graphment, which may not be clinically meaningful.
At the end of the day,we did see one positive signal which was
a little surprising to the study team, and that was a decreased risk of
on GVHD in the use of cryopreservedgraphs, where it's not really clear what
(26:07):
was driving that in the in thestudy and that is a subject of future
investigation that we will be evaluating currentlyin a Graph versus Host Disease Working Committee
study within the c I B Mt R. And that those findings were
also noted by a team at theData Farber Cancer Institute led by Kate Mauer.
Doctor Kate Maher observed that similar phenomenawhere they noted a decreased risk of
(26:33):
chronic GVHD and particularly in peripherablood stemcell graphs, which in the past have
been noted for an increased risk ofof of chronic graph versus host disease in
comparison to bone marrow graphs. Sowe do want to dig into that a
little bit more and so see whatwhat cellular factors may be manipulated by the
(26:56):
cryo preservation that maybe influencing that chronicGVHD reduction. It's good news, but
then that also in putting that allin context, though, the increased risk
of relapse and lower disease free survivalwould push us to recommend fresh products were
available. But then noting that crimepreserve products can be used when logistics do
(27:22):
not permit use of fresh products,there's the fact that this methodology, this
option is available. Does that meanthat more patients can be treated or maybe
are eligible for treatment? Well,does it expand access to patients in need
potentially by being able to adjust thetime timing of collection. So let's say
(27:42):
the only donor that's available is notable to donate on the timeline to be
able to deliver a fresh product,the clinical team could decide to harvest ahead
of time on the donor schedule tobe able to facilitate a crier preservation of
that product, and then infusion atthe time of patient needs, so that
(28:03):
can assist when there's limited donors availablefor a particular patient, so expanding access
through that mechanism, but then alsoin the event that there are logistical problems
that occur just in the moment,so a donor could be harvested in the
process of being collected, and thena patient perhaps comes down with an infection
(28:26):
that needs to be treated and they'renot ready to proceed with their transplant immediately,
those cells could be crowd preserved andused at a later date. So
there's opportunities to do that. Frankly, with centers being more familiar with the
cryo preservation process that hopefully having morestandardized procedures for that, and we're built
into their workflows to be able tofacilitate that when and if it does arise,
(28:51):
may help with a broader access totransplant as well. And it may
not necessarily happen as a pre blendedstrategy, right, but I assume that
this can be very beneficial even ina situation where, like you mentioned,
the patient is not available, maybethe patient comes down with something like the
flu or something that would require youto delay a transplant. But if that
(29:15):
happens, you still be able toharvest and get everything ready for the time
when the patient is ready. Right, yes, exactly, and the data
that we have publish does suggest thatthere is some impact on outcomes, but
they are not huge in magnitude atthe end of the day and doesn't compromise
overall survival. The disease relapse riskincrease definitely is a concern, especially in
(29:41):
malignant disease where this is intended tobe curative and eradicate the underlying disease.
However, relapse does remain one ofthe main points of treatment failure for hemanological
malignancies receiving allergenetic transplant, and sothat is an area of intense research at
this point to best understand factors thatcan help control that disease. It doesn't
(30:04):
appear that crier preservation of a productis one of those, So that's one
that we could potentially take off thetable, but then to pursue other factors
and ways that we could enrich thosefresh products to better control disease in the
future. Well, you mentioned diseaserelapse. You mentioned that these may also
happen when you use fresh graphs insteadof cryer preserved. So what is the
(30:26):
difference if you look at the numbers, if you look at the available data,
is such a disease relapse really causedby crier preservation or other underlying reasons
why this may happen. That's agood question. I mean within these multivariate
models that are used for evaluation offactor for adjustment of factors that are not
(30:48):
your primary variable of interest, therecan be limitations to those approaches. One
concern that we had at the timewas whether our populations were comparable between say,
twenty nineteen and twenty twenty, becausein the event of the pandemic,
patients that maybe had more stable diseaseand were less an urgent need for transplant
(31:15):
may have had that therapy delayed tosome degree. We tried to control for
that by selecting for the types ofdiseases that were analyzed in the population,
restricting to acute leukemias and myelodysplastic syndromeas those require more urgent treatment, as
opposed to some other diseases that maybecould may manage through additional chemotherapy or other
(31:37):
types of treatment to delay the needfor transplant. But we controlled for as
best as we could. Now stillseeing this slight increase in relapse due to
what we were attributing to the cryoprevationpreservation process remains to be explored in more
detail to better understand the underlying mechanismsthat may have influenced that, and that
(32:00):
is part of what you're trying todo in upcoming studies. How you assume,
yes, we would like to lookat that in more detail, as
well as looking at longer term outcomesas well. I mean, we were
limited to looking at one year outcomesjust due to the timeliness of the data
and wanting to get this into theliterature as quickly as we could to offer
guidance to the clinical teams that wereperforming these transplants. But then we do
(32:24):
have an intent to extend the followup so to look at longer term two
three, four year outcomes in thispopulation, as well as exploring in more
detail that chronic GVHD association and ptentand potentially that relapse risk factor. So
some of the things that we weren'table to evaluate was potentially the presence of
(32:45):
measurable residual disease in some of theacute leukemium So how deep was the remission
for these patients that were proceeding totransplant was not a valuable in this cohort,
just due to a lack of accessto samples as well as the testing
required to assess that in a uniformmanner in the population, so other things
(33:06):
that could have confounded in those results. Let's take a break. This is
the Youngest in Brief. If you'rejust joining us in today's episode of the
Youngest in Brief. I'm talking withdoctor Steven Spielman. I'm Peter Hoffland,
and this is the Youngest in Brief. My name is Jio Jean. I'm
(33:32):
the chair of a computational biology departmentat S two Children's Research Hospital. As
a data scientist that feel so excitedabout seeing the potential impact not only are
the kids treated as Saint Jude,but across the world. And I think
this is a great use of thetrust we got from our donors finding cures
(33:54):
saving children. Learn more at Stjudedot org. This is the Younger Zaine
Brief with Peter Hoffland and welcome back. In today's episode of the Youngest in
(34:22):
Brief. I'm talking with doctor StevenSpelman. Doctor Spellman is vice president and
senior Scientific director at be the Matchand the Center for International Blood and Merit
Transplant Research. I'm Peter Hoffland,and this is the youngest in brief.
So overall, if you look atwhat you've not been able to measure,
and that is probably hypothetical, howmight that change the acceptance of this approach?
(34:45):
I mean you hope, of coursethat minimal residual disease is indeed minimal.
But what might change if there aredifferent findings, different outcomes? So
what may change from use of crierpreservations standpoint if there were if there were
different findings, Well, let's justtake a hypothetical vent. So let's say
(35:06):
there was a minimal residual disease ormeasurable residual disease at an extremely low level,
and say a TP fifty three mutation, which is associated with a very
high risk of relapse post transplant.What we don't understand within our populations was
were they balanced for say TP fiftythree mutations within the twenty nineteen cohort and
(35:27):
the twenty twenty cohort, and ofthose how deep was the remission those in
those particular patients. So there mayhave been some imbalance that could be associated
with that higher risk of relapse.So if we were hypothesizing that higher risk
malignancies were those that were being transplantedduring the heart of the pandemic when it
(35:49):
was logistically difficult to perform those transplants, and there may be less tolerance for
delay in the case of those patients, that could inflows that increase risk of
relapse, but that would require moreinvestigation to better understand. But the potential
is there because the study was doneunder circumstances far from ideal, right,
(36:13):
far from ideal. In that setting, we were all learning and we were
building the plane as we were flyingin those early days of the pandemic,
and this reflects March of twenty twentythrough August of twenty twenty, so really
in that early phase when we wereall in lockdown and needing to take all
sorts of precautions, especially for immunocompromisepatients. And there has been data that's
(36:37):
come out on the risks of COVIDnineteen within transplant patients in the post transplant
period, and they are at veryhigh risk for mortality upon if they do
conduct they do contract COVID nineteen,and so good reason not to proceed with
transplant when there is a high riskof potential infection and other issues that could
(37:02):
complicate the post transplant course. So, as I've said earlier, kudos to
you and your team and your organizationand all the patients who participated in the
study because well COVID nineteen was addingrisk to medical procedures and interventions. Now,
if you look at overall outcomes crierpreservation versus fresh crafts, there is
(37:23):
a potential for practice changing strategies.Right. One thing that you can now
adjust is the way you collect andstore and make treatment available to patients overall.
How beneficial is that going to be? Just our understanding of the limited
risks associated with crier preserve versus freshgrafts. Yeah, So I think this
(37:45):
is very useful data for the fieldthat helps guide and counsel patients on the
risks that are associated with having touse either a cryo preserved or a fresh
graft and what that may mean.The risks are. I don't want to
diminish the risk. The risks arethere, but the risks of not proceeding
(38:06):
to transplant likely far outweigh the useof a cryopreserved graph versus a fresh grapt.
So in desperate times and a freshgraft is not logistically feasible that a
cryopreserve graph can be a reasonable alternativeand lead to long term emissions in these
(38:30):
patients facing these devastating humanological malignancies.So I wouldn't want to delay transplant or
withhold therapy if a fresh graph wasn'tavailable due to the monumental risks associated with
not proceeding to transplant in a timelymanner and allowing for these diseases to progress.
(38:53):
It has been shown in previous studiesgoing from say a first complete remission
and say acute leukemia and having arelapse or multiple relapses that may be controlled
with additional rounds of chemotherapy lead toa further risk associated with proceeding to transplant
(39:15):
at a later date. So transplantingan advanced disease versus in early stage diseases
can look very different, with amuch higher risk of mortality once the disease
has been been allowed to progress beyonda first or second remission. That all
things need to be taken into account. We also use this information to council
(39:36):
our donors as well, because thereis a potential risk that a product would
not be used if it is intendedfor crier preservation. Although we saw that
was relatively low. I believe itwas under three percent overall of products that
had not been infused, which isnot but still is not zero. And
(39:57):
undergoing the actual collection procedure, whetherthat be a bone marrow harvest or perifhal
blood stem cell a faresis procedure docome with risks and so we would want
to minimize that for our donors.But we've also surveyed our donors to better
understand whether they are willing to toleratethat risk that their product may not be
used in the event that it neededto be crowd preserved, and most are
(40:20):
willing, the vast majority are willingto go forward with that procedure and if
it could be beneficial to the patientat the end of the day, and
so they're willing to take on thatrisk for those patients. So overall,
with the COVID pandemic, the studyshows very positive outcomes, helping you to
improve practice and to make treatment availableto more patients in need. Now,
(40:43):
looking beyond these findings, are thereother interesting findings that may impact the future
of practice that may benefit patients.Well, I think just the understanding the
underlying risks associated with cryopreservation are important, but we still need to learn so
we need to understand the longer termimplications that may be here. So we've
(41:04):
really only looked at one year outcomesat this point, so most patients would
want to know a bit more,a bit longer term. Their hope would
be that this is curative. Sowe do want to look at say three
five years post transplant and see ifthere are potentially longer term complications that we're
not taken into account in this particularstudy. So more work to do that
on that point. But then that'sabout it. But then also this interesting
(41:29):
finding on reduce risk of chronic GVHD, which is is a it impacts a
large portion of patients receiving allogenetic transplanttoday, upwards of fifty percent, and
so anything that we can and it'svery difficult to treat, so anything that
we can do to further reduce therisk of chronic GVHD post transplant without impacting
(41:51):
the durable remission, et cetera,it would be beneficial for patients in the
long run. It'll improve quality oflife and reduce morbidity immortality post transplant so
definitely something that we want to understanda bit more, and maybe there are
opportunities for graph manipulation that could beapplied in the fresh setting that still leads
(42:14):
to that benefit in chronic GVHD reductionwithout the associated risk with crier preservation.
So more to come there and moreopportunities to further explore these data. Well.
I'm looking forward to learning more aboutthis and the results from Plenn studies
and how these outcomes may indeed benefitpatients. Dougtor Spelman, Steve, thank
(42:35):
you so much for joining me inThe Youngest in Brief Today. My pleasure.
Thanks, Peter, thank you.In this episode of The Youngest and
Brief, I spoke with doctor StevenSpielman. Dougt. Di Spelman is Vice
president and Senior Scientific Director at BThe Match and the Center for International Blood
(43:00):
and Merit Transplant Research. For moreinformation about becoming a donor, please visit
bdematch dot org Become DASH a donor. For more information about the National Merit
Donor Program, be the Match andthe Center for International Blood and Merit Transplant
Research or CIBMTR at the Medical Collegeof Wisconsin, go to CIBMTR dot org
(43:23):
and For more information about the studiespresented in this program, please go to
our online journal Ongussine at ongraisine dotcom. For us here at the Youngest
in Brief. We want to thankyou, our listeners, sponsors, and
advertisers for your ongoing support. Yoursupport makes it possible that you can hear
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(43:47):
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(44:07):
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you all, and thank you forlistening and join us again for our next
episode. I'm Peter Hoffland and thisis the Youngest in Brief. The Ongazine
(45:05):
Brief is a global medical educational servicefrom the publishers of Ongazine and adc Review,
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(45:25):
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(45:45):
about your personal health. If youhear something in this program that doesn't agree
with what your doctor has told you, ask him or her about it,
This is the Younger Zaine Brief withPeter Hoffland. In this episode of the
Younger Zam Brief, I'm talking withdoctor Steven Spellman. Doctor Spellman is vice
president and Senior Scientific director at BEthe Match and the Center for International Blood
and Merit Transplant Research. We talkabout the outcomes of a study publishing Blood
(00:36):
Advances to Journal of the American Societyof Hematology discussing the impact of choir preservation
of amopoetic cell graphs on overall survivaland other outcomes within one year after cell
transplantation. Now, at the beginningof the COVID nineteen pandemic, the National
Merit Donor Program mandated the crier preservationof amoto poetic cell graphs. Speak of
(01:00):
patients and donor safety concerns, crierpreservation was considered a method to eliminate the
risk but the use of fresh donorproducts. One of the concerns was that,
as a result of the COVID pandemic, delivery of donor products after patient
conditioning could not be guaranteed. Thiswas in part caused by logistical complexities including
(01:22):
travel bands, flight delays, flightcancelations, rewriting of couriers, and things
like closed borders. In addition,donors were at risk of being infected with
COVID, which in turn resulted inlast method cancelations of graft collection. To
address the problem, the National MerritDonor Program, together with several global donor
(01:44):
registries, required achoo preservation of mostunrelated donor products during the first six months
of the pandemic. But what wasthe impact of crier preservation on patients receiving
hemipogetic excel transplantation compared to the effectsamong patients receiving fresh donor products. Was
there a difference in overall survival indisease free survival or disease recurrence? Was
(02:07):
there a risk in graft versus hostdisease. In today's episode of the Youngest
in Brief, we talk about thisand more. I'm Peter Hoffland and this
is the Youngest in Brief. TheYoungest in Brief is developed in collaboration with
our online journal Ongoisine, where youcan find additional information and the latest news
about cancer diagnosis and treatment and cancerprevention. Support for the Youngest in Brief
(02:30):
comes from the Oncology Directory at Oncologydirectorydot com and from listeners like you.
For more information on how to supportthis program, visit our website Ongozine at
ongozine dot com. And if youare living in the United States and want
to receive our newsletter, text theword cancer to six six eight sixty six
(02:50):
and we will make sure that you'llreceive our newsletter, which includes an overview
of the latest news in oncology andhematology. This is the on Caasine Brief.
For the latest news about cancer andcancer treatment, visit our online journal
(03:12):
on Caazine at www dot oncasine dotcom. On the phone with me is
doctor Stephen Spellman. Doctor Spellman,Steve, Welcome to the Young Gazine Brief.
You're device president and senior scientific directorat bt MATCH and the Center for
International Blood and Merit Transplant Research.Right, tell me a little bit more
about yourself and about your organization youwork for and what you're trying to do
(03:38):
for patients patients that may be affectedwith cancer or hematological malignancies or other diseases.
Sure, happy to answer that,Peter, and thank you for the
invite and the opportunity to share someof our research today with the Cosine audience.
So, as you mentioned, I'mthe vice president of research in the
at the National Maridona Program or theNMDP. I'm also a senior scientific director
(04:00):
in the Center for International Blood andMero Transplant Research, which is a research
collaboration between the NMDP and the MedicalCollege of Wisconsin. So we have had
a long long standing research collaboration thatstarted in the early two thousands where we
have merged our research programs to capturedata on patients proceeding to transplant receiving either
(04:25):
atologous or self transplants allogeneics, sotransplants from donors, as well as cellular
therapies and gene therapies, and sowe have an active registry that has captured
data on over six hundred and thirtythousand patients to date. We use that
data to perform observational research studies ofwhich I'll be speaking today about that experience,
(04:46):
and use that to help guide transplantpractice. So mainly observational studies that
are coming out of the research database, but we also have an active prospective
research program facilitated through our what wecall our Clinical Research Organization Services, which
manages phase early stage, phase one, phase two trials that's based in our
Minneapolis office of the of the CIBMTRas well as participate as part of the
(05:13):
Coordinating Center for the Blood and MarrowTransplant Clinical Trials Network, which is an
NIH funded clinical trials program that supportsmainly Phase three trials in transplant and cellular
therapy. So our goal here isto utilize these data resources to provide guidance
on how transplant should be performed,cellular therapy should be performed, and offer
(05:35):
evidence based guidance for clinical practice.That's a lot. Now you've mentioned observational
studies designed to help you guide transplantpractice. To help our listeners understand the
difference between observational studies and randomized controlledclinical studies, tell me a little bit
about these differences and about these studies. What's the difference between them. Yes,
(06:00):
studies are where we are prospectively collectingobservational clinical data on patients transplanted within
the US and selective international centers thatchoose to participate in the CIBMTR. We
use standardized data collection instruments that captureinformation on donors, their patients, or
the patients, the disease, thetransplant procedure, and then outcomes post transplant,
(06:24):
capturing data at baseline one hundred dayspost transplants, so everything that occurred
from day zero to day one hundredand then at six months, one year,
and then subsequently yearly after that untileither the patients choose to not participate
in research anymore or pass away.So we do capture long term longitudinal data
(06:47):
on those patients. So where wecan use the observational data is to evaluate
things that probably isn't well suited fora randomized clinical trial, such as HLA
match for transplantation, so the ruleof thumb would be matched to the best
potential available donor. Unfortunately not everypatient has a fully matched donor available,
(07:12):
but want to be able to offerthose transplant procedures, the potentially curative therapy
to those patients, So we'll capturethat data and be able to review that
retrospectively through observational research projects to understandthe impact of various HLA mismatches and the
influence that that may have had ontransplant outcomes to better better informs a donor
(07:32):
selection going forward where that really wouldn'tbe appropriate to do, and say a
randomized trial saying assigning people to awell matched donor versus a mismatch donor in
a randomized manner. If you lookat the outcomes of observational studies, the
types of studies where researchers observe theeffect of a risk factor, diagnostic test,
treatment, or other intervention without tryingto change who is exposed to it.
(07:57):
And this is different than, forexample, a randomized UNCLE trial.
You may be able to collect morein depth and impactful data because these studies
generally run longer. Right in someways, yes, I mean you're not
controlling for an intervention as you canon a clinical trial, but so you're
better reviewing more of the overall practicethat's been seen in the community, So
(08:22):
more of a use of real worlddata or as to better understand the impacts
of trends in transplant in treatment practicesand the influence that that has had over
time. So being able to compareeras of treatments and different strategies for treatment,
and segregating even at center level tobe able to evaluate how centers are
(08:46):
actually performing. So lots of otheropportunities to continue to mine observational databases.
So this goes more towards what theUnited States Food and Drug Administration the FDA
requires for DIRUCT trials. Right nowwhat we call real world's data. Right
when you develop the observational studies,the longer time, the more in depth
(09:07):
questioning, that all may help youto get a real picture of what I
think you mentioned is what is goingon in the clinic and how you can
actually adjust studies to treatment options forpatients. Right. Potentially, yes,
it could provide some of those insightsthat maybe aren't going to be a parent
and a shorter follow up on aclinical trial. So really looking at longer
(09:28):
term outcomes, potential longer term risks, really beneficial for really benefit from the
longer term, longitudinal follow up that'sdone within observational studies. The other thing
to not with our observational database iswe do capture biological samples on a subset
of the population, and so wecan go back and review those as well
(09:50):
and explore other factors that may nothave been considered at the time of the
transplant. So in the case ofsay HLA typing, looking at extended low
side a more precise depth of matchingto see if that makes a difference in
overall outcomes where that may not havebeen feasible at the time due to technical
(10:11):
difficulties or even the limitations of theway that data was collected at the time
of those transplants, so we canadd to those databases as well, which
is really really useful for exploring newfactors. That's really interesting. It's actually
very nice to be able to enrichthat information. Let's take a break.
(10:31):
This is the Youngest in Brief.If you're just joining us in today's episode
of the Youngest in Brief. I'mtalking with doctor Steven Spielman. Doctor Spellman
is vice president and senior Scientific directorat BEA Match and the Center for International
Blood and Merit Transplant Research. I'mPeter Hoffland, and this is the Youngest
in Brief. Each day, researchersdiscoveries that bring us closer to the moment
(11:01):
when all cancer patients can become survivors. Their progress is made possible with the
health of clinical trials. Clinical trialsare the brightest torch researchers have to light
their way towards better treatments, andif you've been diagnosed with cancer, they
may be your brightest ray of hope. Speak with your doctor and visit stand
up to Cancer dot org slash clinicalTrials to learn more. Together, we
(11:24):
can stand up for all of us. This is the young Gazine Brief with
Peter Hoffland and welcome back. Thisis the Youngest in Brief. If you're
(11:50):
just joining us. In today's episodeof the Youngest in Brief, I'm talking
with doctor Steven Spellman. Now let'sswitch gears a little bit and look at
the STO you've conducted. What comesto mind is that most people around us,
and I think that involves the listenersas well, are very happy that
the COVID nineteen pandemic is to someextent over and well, COVID is expected
(12:13):
to be with us for a longtime. The actual pandemic, I hope
that's true, though, is actuallybehind us. Having said that the COVID
pandemic has had a major impact onhealthcare, how did the COVID pandemic impact
your organization? And what is moreimportant, how is pandemic impacted patients you're
(12:33):
trying to help during the pandemic.That's a great question. Well, it
was a very substantial impact on ourpatient population. So the parent organization that
I work for is the National AwareDonor Program. We facilitate unrelated donor and
related and core blood transplants, handlingall of the donor search and match,
as well as the logistics for thedistribution of those for the collection and distribution
(12:56):
of those products, unrelated donor alogenicstem cell transplant is a very international business.
About approximately half of all products crossand international border, and that's because,
well, the diaspora of the worldhas really been spread out across the
globe, and so your donor maybeanywhere in the world, and so we
(13:18):
need to be able to harvest thosecells from the donor where they happen to
reside and get them to the patientwho happens to need them. Obviously,
the travel disruptions that occurred during theCOVID nineteen pandemic necessitated a complete change to
the way that we were managing thecollection and distribution of those products due to
(13:39):
inconsistencies and travel schedules, major disruptionsand ability to travel, and even restrictions
on international border crossings during the pandemic, and so we had to work closely
with the State Department to ensure thatwe could cross international borders, also set
up a hub and spoke type ofa transport system. The vast majority of
(14:03):
the products that we distribute are handcourier by individuals and so to be able
to make handoffs at international borders toknown individuals. To actually ensure that we
had point to point distribution and chaina custody of those products was herculean feet
at the time, but the NMDPdid amazing work during the pandemic to ensure
(14:28):
that all patients in need would receivethose products in a timely manner, and
part of that goes to the researchthat we'll be discussing today, which was
implementing a mandate to cryo preserve products, and the rationale for that being that
if we were harvesting a product froma donor, ensuring that the pain it
(14:48):
would be received at the institution wherethe patient would be receiving their transplant or
their infusion prior to initiating their condtioningtherapy. So, whether that's a reduced
intensity conditioning strategy or a mile oflate of conditioning strategy, those patients undergo
(15:09):
pretty extreme levels of chemotherapy to preparethem to receive the graph, and it
leaves them extremely neutropenic and susceptible toall sorts of opportunistic infections. The last
thing that we would want to havehappen is to not have a graph,
they're ready to infuse at that time. So cryo preservation was mandated to ensure
that those products were present prior tothe patient initiating their preparative regimen for to
(15:35):
receive their graph and that worked quitewell, but we also wanted to understand
the impacts that that may have onthe performance of those products. Hence the
research that was done in the studythat we'll be discussing today. So if
I understands correctly the moment that youhave bone marror available and there is a
patient waiting for treatment wherever that patientmay be, there is only a limited
(15:58):
time to end. The clock isseeking right? Tell me a little bit
about that. Well. In normaltimes, products are collected and infused within
about a forty eight hour window,so any disruption to that or prolonging of
that window leads to the big degradationof that stem cell product. We've published
(16:18):
some studies in the past looking atkind of shelf stability of graphs, and
once you hit about forty eight toseventy two hours, you really start to
see a degradation in the cellular compositionas well as the potency of those products.
So ensuring that a product could beharvested and processed in a way that
(16:40):
it could be preserved within that firstforty eight hours of initial collection. Then
ensures that you would have a morerobust product for infusion into the patient at
the time of need, and sowith all of the logistical issues and logistical
issues would travel. But then alsowith even donor societ the ability to infection
(17:00):
as well, which could lead todelays and harvest and being able to even
collect that product or having to shiftgears to a backup donor in the event
that a donor tested positive for COVIDnineteen during their workup process, to have
a bit of that time buffer tosupport the collection of the product, the
(17:21):
preparation of it, and ensure thatit was transported and available in a timely
manner for the patient. Now tostudy clinical impact of crier preservation of allogenetic
hemitogetic cell grafts during the onset ofthe COVID nineteen pandemic was published earlier this
year in Blood ADVENTSS, the journalof the American Society of Hematology and discusses
(17:41):
the study results, an impact ofcrier preservation and how these affected patients.
Right now, you gave us agreat introduction. But to start, what
were the major questions that you wantedto have answered by the study. I
do understand that one question you'd liketo have answered was of course about cryer
preservation and if this is an optionin the process. But were there more
(18:04):
questions? Were there other questions thatyou wanted to have answered. That's a
good place to start, because therehad been studies that have been done in
the past looking at the comparing offresh to cryopreserve products in allogenetic transplant.
There were three studies that were publishedkind of leading into the pandemic, two
(18:26):
front well, all from the CIBMTR. One that looked at the use of
cryopreserve graphs in the haploidentical setting.This is a study that was led by
Mehdi Hammadani and showed that there wasreally no impact in this haplo identical setting
using a post transplant cycloposphoma based GVHDprophylaxis strategy that didn't appear to be an
(18:48):
impact on outcomes in patients receiving eitherfresh or cryopreserve graphs. So that's one
example. Another study that was conductedlooked in severe aplastic anemia and the use
of bone marrow graphs. Now therenow was a study that was led by
doctor Mary Epan through the CIBMTR andthat showed that there was a substantial risk
(19:11):
associated with use of cryopreserved graphs inthat setting, so not recommended in the
severe plastic anemia setting. Another studythat looked at a more diverse set of
diseases and in a broader population reallywas a pre pandemic evaluation. This was
a study that was led by JackChu from the Moffitt Cancer Center down in
(19:34):
Florida and conducted through the Donor Healthand Safety Working Committee of the c IBMTR.
There it was shown that there wasan impact on overall survival considering the
use of peripheral blood stem cell graphs. There didn't appear to be a difference
with the use of bone marrow graphswhether they were fresh or cryopreserved for patients
(19:55):
receiving transplants for hematological malignancies. Indigging a bit deeper into the data,
what we didn't capture all the timewas the rationale for cryopreservation, since in
normal pre pandemic times the default wasalways to prefer fresh graphs if they could
be given and that's not just forpatient safety reasons, but also donor reasons,
(20:18):
and in the unrelated donor setting,should you be, there's always concerns
about final utilization of those products,So if they're being collected cryopreserved, they
may not be infused at the endof the day, and so just ensuring
that each project product that's collected asbeing directed to the patient that's in need.
But within that study, we didhave some data for a subset where
(20:41):
we were able to evaluate the rationalefor cryopreservation, and in over sixty percent
of those transplants, the delays andthe need for cryopreservation was mainly due to
issues associated with either disease progression,infection, or other need, other patient
(21:02):
related factors that may be associated witha more severe disease state, or other
issues that really couldn't be well welladjusted for within that analysis, and so
that was a caveat in one ofthe limitations of that study. Now moving
into the pandemic, we had aunifying rationale for the use of cryopreservation for
(21:23):
all allogenetic products and the vast majoritywere cryopreserved during that timeframe. So in
the present study, what we didwas we compared transplants that were performed in
twenty nineteen looking at AIX the firstsay six months of of twenty nineteen compared
(21:44):
to the post pandemic twenty twenty oncethe cryopreservation mandate went into effect, And
so we're able to compare transplants thatwere performed in the setting of fresh graphs
as the default and in the settingof cryopreserved graphs as the default, and
compare and contrast those results. Andso that that was one of the main
impetus for the for the present study, but then also to have that kind
(22:08):
of level playing field, so weknew that all of those products were destined
for cryod preservation. It was plannedfor at the center they were being cryo
preserved in that kind of critical windowof the vast majority being cryo preserved in
less than forty eight hours of collection, with some that maybe traveled a bit
farther, may over international borders orso being a bit more delayed in that
(22:32):
case. So there we were ableto really kind of do more of an
apples to apples comparison of a rationalefor using either a fresh or a cryopreserved
product, which was important to kindof level set the population in this case,
let's take a short break and thenwe're back with doctor Steven Spelman.
(22:57):
Sarcoma. Ever heard that word before? For the forty people diagnosed with sarcoma
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(23:19):
for sarcoma. For more information onthe work of the Sarcoma Foundation of America,
go to Cure Sarcoma dot org.This is the young Gazine Brief with
Peter Hoffland and welcome back. Thisis the Youngest here in Brief. If
(23:51):
you're just joining us in today's episodeof the Youngers Seen Brief. I'm talking
with doctor Steven Spellman. I'm PeterHoffland and this is the Youngest in Brief.
Before the COVID nineteen pandemic, thestandard approach was using quote unquote fresh
bone marrow fresh crafts rather than crierpreserved. Right now, due to logistical
(24:11):
requirements, impacted by COVID and thewhole host of other reasons and circumstances.
The standard procedure needed to be changed. You successfully, and kudos to that
were able to switch the way youwere able to help patients in need.
But then the most important question iswhat impact did this have on patients?
Because what I assume is that everydoctor listening to the show wants to hear
(24:34):
this. What is the patient impact, What were the outcomes negative or positive?
And where these outcomes practice changing?What can you tell us about that?
Sure, so I can walk througha bit of the results from the
study. So what we did findin comparing fresh to crow preserved was there
was no impact on overall survival.There was also no impact on what we
(24:59):
call GVHD free relapse free survival nonrelapse mortality a q GVHD, so no
major issue with overall survival. Sothat was really encouraging. That was an
encouraging finding. However, we didsee some negative impacts, and one was
an increased risk of relapse in theuse of cryod preserved graphs as well as
(25:21):
that associating with an increase increased riskof a decreased disease free survival and all
of and that mainly due to relapserisk. We did see a slight delay
in ingraphment in using the cryopreserve graphs, but that equated to about a one
or one one to two day delayin neutrophill graphmen and a one to two
(25:45):
to day delay in platelet and graphment, which may not be clinically meaningful.
At the end of the day,we did see one positive signal which was
a little surprising to the study team, and that was a decreased risk of
on GVHD in the use of cryopreservedgraphs, where it's not really clear what
(26:07):
was driving that in the in thestudy and that is a subject of future
investigation that we will be evaluating currentlyin a Graph versus Host Disease Working Committee
study within the c I B Mt R. And that those findings were
also noted by a team at theData Farber Cancer Institute led by Kate Mauer.
Doctor Kate Maher observed that similar phenomenawhere they noted a decreased risk of
(26:33):
chronic GVHD and particularly in peripherablood stemcell graphs, which in the past have
been noted for an increased risk ofof of chronic graph versus host disease in
comparison to bone marrow graphs. Sowe do want to dig into that a
little bit more and so see whatwhat cellular factors may be manipulated by the
(26:56):
cryo preservation that maybe influencing that chronicGVHD reduction. It's good news, but
then that also in putting that allin context, though, the increased risk
of relapse and lower disease free survivalwould push us to recommend fresh products were
available. But then noting that crimepreserve products can be used when logistics do
(27:22):
not permit use of fresh products,there's the fact that this methodology, this
option is available. Does that meanthat more patients can be treated or maybe
are eligible for treatment? Well,does it expand access to patients in need
potentially by being able to adjust thetime timing of collection. So let's say
(27:42):
the only donor that's available is notable to donate on the timeline to be
able to deliver a fresh product,the clinical team could decide to harvest ahead
of time on the donor schedule tobe able to facilitate a crier preservation of
that product, and then infusion atthe time of patient needs, so that
(28:03):
can assist when there's limited donors availablefor a particular patient, so expanding access
through that mechanism, but then alsoin the event that there are logistical problems
that occur just in the moment,so a donor could be harvested in the
process of being collected, and thena patient perhaps comes down with an infection
(28:26):
that needs to be treated and they'renot ready to proceed with their transplant immediately,
those cells could be crowd preserved andused at a later date. So
there's opportunities to do that. Frankly, with centers being more familiar with the
cryo preservation process that hopefully having morestandardized procedures for that, and we're built
into their workflows to be able tofacilitate that when and if it does arise,
(28:51):
may help with a broader access totransplant as well. And it may
not necessarily happen as a pre blendedstrategy, right, but I assume that
this can be very beneficial even ina situation where, like you mentioned,
the patient is not available, maybethe patient comes down with something like the
flu or something that would require youto delay a transplant. But if that
(29:15):
happens, you still be able toharvest and get everything ready for the time
when the patient is ready. Right, yes, exactly, and the data
that we have publish does suggest thatthere is some impact on outcomes, but
they are not huge in magnitude atthe end of the day and doesn't compromise
overall survival. The disease relapse riskincrease definitely is a concern, especially in
(29:41):
malignant disease where this is intended tobe curative and eradicate the underlying disease.
However, relapse does remain one ofthe main points of treatment failure for hemanological
malignancies receiving allergenetic transplant, and sothat is an area of intense research at
this point to best understand factors thatcan help control that disease. It doesn't
(30:04):
appear that crier preservation of a productis one of those, So that's one
that we could potentially take off thetable, but then to pursue other factors
and ways that we could enrich thosefresh products to better control disease in the
future. Well, you mentioned diseaserelapse. You mentioned that these may also
happen when you use fresh graphs insteadof cryer preserved. So what is the
(30:26):
difference if you look at the numbers, if you look at the available data,
is such a disease relapse really causedby crier preservation or other underlying reasons
why this may happen. That's agood question. I mean within these multivariate
models that are used for evaluation offactor for adjustment of factors that are not
(30:48):
your primary variable of interest, therecan be limitations to those approaches. One
concern that we had at the timewas whether our populations were comparable between say,
twenty nineteen and twenty twenty, becausein the event of the pandemic,
patients that maybe had more stable diseaseand were less an urgent need for transplant
(31:15):
may have had that therapy delayed tosome degree. We tried to control for
that by selecting for the types ofdiseases that were analyzed in the population,
restricting to acute leukemias and myelodysplastic syndromeas those require more urgent treatment, as
opposed to some other diseases that maybecould may manage through additional chemotherapy or other
(31:37):
types of treatment to delay the needfor transplant. But we controlled for as
best as we could. Now stillseeing this slight increase in relapse due to
what we were attributing to the cryoprevationpreservation process remains to be explored in more
detail to better understand the underlying mechanismsthat may have influenced that, and that
(32:00):
is part of what you're trying todo in upcoming studies. How you assume,
yes, we would like to lookat that in more detail, as
well as looking at longer term outcomesas well. I mean, we were
limited to looking at one year outcomesjust due to the timeliness of the data
and wanting to get this into theliterature as quickly as we could to offer
guidance to the clinical teams that wereperforming these transplants. But then we do
(32:24):
have an intent to extend the followup so to look at longer term two
three, four year outcomes in thispopulation, as well as exploring in more
detail that chronic GVHD association and ptentand potentially that relapse risk factor. So
some of the things that we weren'table to evaluate was potentially the presence of
(32:45):
measurable residual disease in some of theacute leukemium So how deep was the remission
for these patients that were proceeding totransplant was not a valuable in this cohort,
just due to a lack of accessto samples as well as the testing
required to assess that in a uniformmanner in the population, so other things
(33:06):
that could have confounded in those results. Let's take a break. This is
the Youngest in Brief. If you'rejust joining us in today's episode of the
Youngest in Brief. I'm talking withdoctor Steven Spielman. I'm Peter Hoffland,
and this is the Youngest in Brief. My name is Jio Jean. I'm
(33:32):
the chair of a computational biology departmentat S two Children's Research Hospital. As
a data scientist that feel so excitedabout seeing the potential impact not only are
the kids treated as Saint Jude,but across the world. And I think
this is a great use of thetrust we got from our donors finding cures
(33:54):
saving children. Learn more at Stjudedot org. This is the Younger Zaine
Brief with Peter Hoffland and welcome back. In today's episode of the Youngest in
(34:22):
Brief. I'm talking with doctor StevenSpelman. Doctor Spellman is vice president and
senior Scientific director at be the Matchand the Center for International Blood and Merit
Transplant Research. I'm Peter Hoffland,and this is the youngest in brief.
So overall, if you look atwhat you've not been able to measure,
and that is probably hypothetical, howmight that change the acceptance of this approach?
(34:45):
I mean you hope, of coursethat minimal residual disease is indeed minimal.
But what might change if there aredifferent findings, different outcomes? So
what may change from use of crierpreservations standpoint if there were if there were
different findings, Well, let's justtake a hypothetical vent. So let's say
(35:06):
there was a minimal residual disease ormeasurable residual disease at an extremely low level,
and say a TP fifty three mutation, which is associated with a very
high risk of relapse post transplant.What we don't understand within our populations was
were they balanced for say TP fiftythree mutations within the twenty nineteen cohort and
(35:27):
the twenty twenty cohort, and ofthose how deep was the remission those in
those particular patients. So there mayhave been some imbalance that could be associated
with that higher risk of relapse.So if we were hypothesizing that higher risk
malignancies were those that were being transplantedduring the heart of the pandemic when it
(35:49):
was logistically difficult to perform those transplants, and there may be less tolerance for
delay in the case of those patients, that could inflows that increase risk of
relapse, but that would require moreinvestigation to better understand. But the potential
is there because the study was doneunder circumstances far from ideal, right,
(36:13):
far from ideal. In that setting, we were all learning and we were
building the plane as we were flyingin those early days of the pandemic,
and this reflects March of twenty twentythrough August of twenty twenty, so really
in that early phase when we wereall in lockdown and needing to take all
sorts of precautions, especially for immunocompromisepatients. And there has been data that's
(36:37):
come out on the risks of COVIDnineteen within transplant patients in the post transplant
period, and they are at veryhigh risk for mortality upon if they do
conduct they do contract COVID nineteen,and so good reason not to proceed with
transplant when there is a high riskof potential infection and other issues that could
(37:02):
complicate the post transplant course. So, as I've said earlier, kudos to
you and your team and your organizationand all the patients who participated in the
study because well COVID nineteen was addingrisk to medical procedures and interventions. Now,
if you look at overall outcomes crierpreservation versus fresh crafts, there is
(37:23):
a potential for practice changing strategies.Right. One thing that you can now
adjust is the way you collect andstore and make treatment available to patients overall.
How beneficial is that going to be? Just our understanding of the limited
risks associated with crier preserve versus freshgrafts. Yeah, So I think this
(37:45):
is very useful data for the fieldthat helps guide and counsel patients on the
risks that are associated with having touse either a cryo preserved or a fresh
graft and what that may mean.The risks are. I don't want to
diminish the risk. The risks arethere, but the risks of not proceeding
(38:06):
to transplant likely far outweigh the useof a cryopreserved graph versus a fresh grapt.
So in desperate times and a freshgraft is not logistically feasible that a
cryopreserve graph can be a reasonable alternativeand lead to long term emissions in these
(38:30):
patients facing these devastating humanological malignancies.So I wouldn't want to delay transplant or
withhold therapy if a fresh graph wasn'tavailable due to the monumental risks associated with
not proceeding to transplant in a timelymanner and allowing for these diseases to progress.
(38:53):
It has been shown in previous studiesgoing from say a first complete remission
and say acute leukemia and having arelapse or multiple relapses that may be controlled
with additional rounds of chemotherapy lead toa further risk associated with proceeding to transplant
(39:15):
at a later date. So transplantingan advanced disease versus in early stage diseases
can look very different, with amuch higher risk of mortality once the disease
has been been allowed to progress beyonda first or second remission. That all
things need to be taken into account. We also use this information to council
(39:36):
our donors as well, because thereis a potential risk that a product would
not be used if it is intendedfor crier preservation. Although we saw that
was relatively low. I believe itwas under three percent overall of products that
had not been infused, which isnot but still is not zero. And
(39:57):
undergoing the actual collection procedure, whetherthat be a bone marrow harvest or perifhal
blood stem cell a faresis procedure docome with risks and so we would want
to minimize that for our donors.But we've also surveyed our donors to better
understand whether they are willing to toleratethat risk that their product may not be
used in the event that it neededto be crowd preserved, and most are
(40:20):
willing, the vast majority are willingto go forward with that procedure and if
it could be beneficial to the patientat the end of the day, and
so they're willing to take on thatrisk for those patients. So overall,
with the COVID pandemic, the studyshows very positive outcomes, helping you to
improve practice and to make treatment availableto more patients in need. Now,
(40:43):
looking beyond these findings, are thereother interesting findings that may impact the future
of practice that may benefit patients.Well, I think just the understanding the
underlying risks associated with cryopreservation are important, but we still need to learn so
we need to understand the longer termimplications that may be here. So we've
(41:04):
really only looked at one year outcomesat this point, so most patients would
want to know a bit more,a bit longer term. Their hope would
be that this is curative. Sowe do want to look at say three
five years post transplant and see ifthere are potentially longer term complications that we're
not taken into account in this particularstudy. So more work to do that
on that point. But then that'sabout it. But then also this interesting
(41:29):
finding on reduce risk of chronic GVHD, which is is a it impacts a
large portion of patients receiving allogenetic transplanttoday, upwards of fifty percent, and
so anything that we can and it'svery difficult to treat, so anything that
we can do to further reduce therisk of chronic GVHD post transplant without impacting
(41:51):
the durable remission, et cetera,it would be beneficial for patients in the
long run. It'll improve quality oflife and reduce morbidity immortality post transplant so
definitely something that we want to understanda bit more, and maybe there are
opportunities for graph manipulation that could beapplied in the fresh setting that still leads
(42:14):
to that benefit in chronic GVHD reductionwithout the associated risk with crier preservation.
So more to come there and moreopportunities to further explore these data. Well.
I'm looking forward to learning more aboutthis and the results from Plenn studies
and how these outcomes may indeed benefitpatients. Dougtor Spelman, Steve, thank
(42:35):
you so much for joining me inThe Youngest in Brief Today. My pleasure.
Thanks, Peter, thank you.In this episode of The Youngest and
Brief, I spoke with doctor StevenSpielman. Dougt. Di Spelman is Vice
president and Senior Scientific Director at BThe Match and the Center for International Blood
(43:00):
and Merit Transplant Research. For moreinformation about becoming a donor, please visit
bdematch dot org Become DASH a donor. For more information about the National Merit
Donor Program, be the Match andthe Center for International Blood and Merit Transplant
Research or CIBMTR at the Medical Collegeof Wisconsin, go to CIBMTR dot org
(43:23):
and For more information about the studiespresented in this program, please go to
our online journal Ongussine at ongraisine dotcom. For us here at the Youngest
in Brief. We want to thankyou, our listeners, sponsors, and
advertisers for your ongoing support. Yoursupport makes it possible that you can hear
this program via PRX Public Radio Changeand in the United Kingdom and mainland Europe
(43:47):
via UK Health Radio, and startingthis month, the Ongest in Brief is
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(44:07):
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you all, and thank you forlistening and join us again for our next
episode. I'm Peter Hoffland and thisis the Youngest in Brief. The Ongazine
(45:05):
Brief is a global medical educational servicefrom the publishers of Ongazine and adc Review,
the Journal of Antibody Drug Conjugates.Support for the Ongazine Brief comes from
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