"Transformation and Quality: Building a Cancer Network" and "Post Transplant Lymphoproliferative Disorders"

February 03, 2021

Information

Yale Cancer Center Grand Rounds | February 2, 2021

Anne Chiang, MD, PhD, and Francesca Montanari, MD

ID6157

To CiteDCA Citation Guide

00:00Substituting today very happy to be here.
00:03So we have two talks today and I think
00:06it should be a very interesting hour.
00:10Our first talk will be by Anne Chang and
00:13actually ends very much in the news today.
00:16Congratulations.
00:17And so an is associate Professor of Medicine,
00:20medical oncology and Deputy Chief medical
00:22Officer and Chief Integration Officer
00:24Officer for Smile Cancer hospital.
00:26As of about 3 hours ago.
00:29She specializes in thoracic
00:31oncology with a background in
00:32translational research and metastases,
00:34and a clinical focus has been built
00:36has been to build an amazing small
00:38cell lung cancer program here with a
00:41comprehensive portfolio of clinical
00:42trials testing novel therapeutics.
00:44Her research interests focus on focus
00:46and development of clinical trials and
00:49translational studies to test novel
00:51agents and combinations with immune
00:53checkpoint inhibitors for both small
00:54cell and non small cell lung tumors.
00:58Over now nine years an she's helped
01:00to build our smiling network,
01:02which I think will hear about today
01:05and overseas operations quality
01:06efforts in clinical research,
01:08adult care centers.
01:09She's a particular focus in quality
01:11measurement and improvement and
01:12his work to achieve ASCO copy
01:15certification for the entire smell.
01:16Academic clinical practice
01:17of actually received.
01:18Actually, the Joe Simone Award,
01:20just recently in Q just passed away
01:23last week, but a big honor for Masco,
01:26so an it's a pleasure to have
01:28you here for our first talk.
01:30Transformation in quality building
01:32a cancer network,
01:34and.
01:35Thanks Roy, it's really a pleasure
01:37to be able to talk to you today
01:41and thanks for the invitation.
01:43I was trying to decide between
01:45lung cancer and the network,
01:47but because of the timing of the
01:50announcement this morning and I
01:52thought that it would be nice to
01:54highlight the work that has gone
01:57into building a cancer network.
01:59So that's what I'm focusing,
02:01but I did put in a couple
02:03of slides with my trials so.
02:06I suck that in.
02:08OK, so I'm sharing my screen my disclosures.
02:14And this is for four.
02:16If you recognize it,
02:17it's South Ferry terminal farmers
02:19market in San Francisco and it's amazing
02:21place because the quality of the food
02:23and the shops are really outstanding.
02:26I had the best Peach I've
02:28ever had in my life.
02:29The atmosphere is buzzing in
02:31the shops are full of colorful,
02:33beautiful produce as far as you
02:35can see and when I was here which
02:38was pre covid the last time it
02:41seemed to me that this was more
02:43than a farmers market where.
02:45Each farmer sets up their shop
02:48individually next to each other,
02:49but somehow there was a transformation
02:52of the individual stands into
02:54a different collective entity,
02:56real community,
02:56and so in the same way that in
03:00the same way I want to talk about
03:03cancer or cancer network today,
03:05there really has been a trend
03:07over the past 10 years of academic
03:10institutions or other entities buying
03:13up practices or putting up their names on.
03:16Affiliated practices,
03:17but what I wanted to focus on is
03:20how to how I think we've built
03:23a real transformative network,
03:24a community that is better than
03:27the individual units where cancer
03:29delivery is really somehow transformed.
03:32And so you know, this is,
03:34let's go to transformation theory too
03:37as a guiding principle for this work.
03:39As it is,
03:41Carter said transformation is a process,
03:43not an event.
03:44And you start with a sense of
03:47urgency form a coalition and you
03:49create and share that vision.
03:51You empower others to act on that vision.
03:55You plan, create short term wins,
03:57consolidate those advances,
03:58and hardwire new systems.
04:00And I think the bottom line.
04:02Here is that quality improvement
04:05methodology is really been the basis
04:08of my job in the network and formed
04:10the foundation of building our vision
04:13over the past almost 10 years.
04:15So the objectives for today's talk
04:18really are two number one provider,
04:21network development, overview,
04:22describe quality concepts and
04:24metrics and network development
04:26to discuss ways to further the
04:28research mission in the network.
04:30And then finally recognize the
04:32benefits of expanded community.
04:34So this is how it all began.
04:38We we when I started my job this was in 2011.
04:43There was no network.
04:44We had hired anybody but we did have
04:47Yale Smilow state of the art disease based,
04:51patient centered clinical operation.
04:52We had outstanding faculty,
04:54staff,
04:54trainees,
04:55cutting edge clinical research
04:57resources and across organizational
04:59commitment for expansion and really
05:00a powerful coalition of folks
05:02to carry out that vision,
05:04which was really to provide
05:06comprehensive care to all patients.
05:08Close to home in Connecticut and to
05:11provide a platform for Yale Clinical
05:13Research and expand access to trials.
05:16So this is really the result.
05:199 1/2 years later the this.
05:21This is our clinical footprint in
05:24Connecticut and in Rhode Island.
05:26This stars are where our our care centers
05:29are and we do provide care to patients
05:33within 30 minutes of where they live.
05:36In Connecticut.
05:37We provide care to about 45% of
05:40newly diagnosed cancer patients in
05:43Connecticut and we also provide about or.
05:46We accrue about 25% of of therapeutic
05:49clinical trial enrollments as,
05:51as Roy mentioned,
05:53we have achieved ASCO quality
05:55oncology certification throughout our
05:57entire network in the main campus.
05:59This is away.
06:01This is actually the only way to
06:03certify ambulatory practices.
06:06Many of you are familiar with the AC OS,
06:10which certifies cancer programs.
06:13In all of the physicians are what YM?
06:18With the exception of Hartford,
06:21where the physicians are still
06:23Saint Francis employed,
06:24but do have a faculty appointments and
06:27are a stipend from from Yale and all
06:31of the staff are smilow employed or least,
06:35and we do have cross system policies
06:38and procedures and quality initiatives.
06:42This is a timeline where I started
06:44here in in in 2011 and and we did
06:47not have a network and then over
06:50the course of the next 9 1/2 years.
06:53We we brought in a practices and
06:56in in the in the.
06:59In doing so really had the opportunity to.
07:04Have multiple PDF a cycles in
07:06terms of improving our process and
07:09improving our in perfecting our
07:12onboarding process and now as I said
07:15we have 15 locations in two states.
07:17We have all we have almost 50 MD's,
07:2116 aips and over 400 staff we see
07:24over 9000 new patients 100 and
07:2625,000 treatment visits yearly and
07:29the contribution margin on an annual
07:32basis is greater than 110,000,000.
07:35So I think that this is really been
07:38successful and I'm going to talk a
07:41little bit about the onboarding practice
07:43the onboarding process first, so.
07:47This is where we really utilized
07:49integration and transformative change
07:51strategies to engage the stakeholders.
07:54The physicians that the staff
07:56in the practice, and we.
07:58There's at the bottom line is that
08:02there's really no shortcut here.
08:04It really is hard work having
08:07regular meetings on transition
08:09issues such as epic pharmacy,
08:11workflow changes,
08:12and those transitioned into practice
08:15meetings which were very useful.
08:18On an ongoing are useful on an ongoing basis.
08:22We developed a formal onboarding curriculum,
08:25and this utilized leaders and peers
08:27is faculty and it really included
08:30the Smilow vision and structure.
08:32Faculty roles and expectations.
08:34What does it mean now to be part of
08:38Yale and Smilow? How does quality work?
08:41How does the research apparatus work?
08:44Who are the dart leaders?
08:46What is that mean?
08:48What is what are academic mentors and and?
08:53So going through that that curriculum
08:56also involving team building
08:58and leadership training and
09:00including our multidisciplinary
09:01members not only met Aachen Heme,
09:04but our surgical colleagues are rat out
09:08colleagues pain and palliative care so.
09:12Um? Be the next.
09:16Either or the next part of quality
09:19improvement is really measurement,
09:21and this is a graphic of the really PDS.
09:24A cycle you have multiple.
09:28You know, iterations of
09:30how do you improve care,
09:32but measurement is really important,
09:34and so we started measuring at baseline
09:37because we wanted to make sure that we
09:40could measure progress and not just,
09:42you know, stick a sign on the door.
09:46That said, Yale Smilow and this paper
09:48published in 2018 really showed
09:50improvements in multiple domains of quality,
09:53including volume, clinical integration,
09:54quality metrics, and patient satisfaction.
09:57I'm going to show you. Few of those.
10:00At some of that data now.
10:03So in annual visits for chemo
10:05this you can see the main campus
10:08in blue over the years and then.
10:11When the Kirsten's Care Center
10:13started in in 2012,
10:15you could see the growth has really
10:17been significant and we do give
10:20now more chemo in our care centers
10:22closer to home for our patients
10:24than we do in the main campus.
10:28In terms of standardization,
10:30we utilized coping.
10:32Measurement Copy is a program through
10:35ASCO called quality Oncology Practice
10:39Initiative and it consists of.
10:41Go up to 90 metrics of of oncology
10:45of ambulatory oncology,
10:47quality that have been developed
10:49national iyanar consensus based
10:51and evidence based when available,
10:54so we had a measurement at baseline.
10:59Representing the practices before they
11:01joined and then this is four years
11:04later we looked at the significant
11:06differences and saw that really the
11:08only changes were in the positive.
11:10These are actually shown here and and
11:13so this was really important to me
11:16because I wanted to make sure again
11:18it wasn't just putting in a sign on the door,
11:22but that we were actually using.
11:26National consensus based metrics
11:28to show that we were improving
11:32quality for our patients.
11:34We also,
11:35as Roy mentioned at the beginning,
11:37did copy certification across our
11:39network and the academic campus.
11:41This is similar to the ACOs
11:44certification there.
11:4526 standards and you really have to
11:48show in document that the process
11:51from soup to nuts of chemotherapy
11:54administration and policies and
11:56procedures are in place that show us.
11:59That are up to snuff for ASCO
12:01certification and we re certified in 2019.
12:07Um, regarding clinical integration.
12:09I'll just show you the.
12:12And this represents cases
12:14President care Center cases
12:16presented at smilow tumor boards.
12:18We have 13 disease specific multi
12:20D tumor boards and we've asked all
12:23of our physicians to present one
12:26to two cases a month understanding
12:29that we can't present all of them.
12:32But really, those complex cases that
12:35need that multi D discussion needs to be
12:38presented and so you can see in 2013.
12:42This was difficult because the
12:44logistics around dialing in,
12:46which is so easy now by assume it.
12:50But at that time was very difficult.
12:52Getting the path reviewed, getting the.
12:56Radiology diagnostic imaging to be
12:58available that was really hard at the
13:02time and now I think we've received
13:04we've we've sort of the steady state,
13:07is right around 500.
13:09That's the case also.
13:10Sorry, this is 2018-2019, 2020,
13:12right around the 500 mark,
13:14which I think represents sort
13:18of the steady state.
13:20Um, with respect to customer service.
13:23Those of you who have.
13:26You know,
13:27pay attention to press ganey know that
13:30we always cluster in this 90s area.
13:33It's very difficult to make any changes here,
13:36but if you look at again baseline
13:38press ganey scores for practices that
13:41we acquired and six years later,
13:43you can see that in all of the
13:46cases we actually stayed the same.
13:48We're actually improved with one
13:50exception here is is this the site,
13:53but in some cases really significantly
13:55improved patient satisfaction.
13:59Um? This highlights some of
14:02the innovative projects that
14:04we've taken on in the network.
14:07This was a pilot with Asko Asko
14:09has a quality training program that
14:12is 6 months and has three didactic
14:15sessions and and a very aggressive
14:18curriculum every two weeks around
14:20process mapping and barrier analysis
14:22and and ultimately multiple PDS a cycles.
14:25In this case, we had a team from
14:29every care center at the time in 2000.
14:3217 and we did it again,
14:352018 which were interdisciplinary team.
14:38So we had doctors partnering
14:41with nurses or nutrition,
14:43or and in one case in MA Pharmacy
14:46to conduct quality improvement
14:48projects and all of those groups were
14:53able to complete at least one PDS,
14:56a cycle over two years or each year,
15:01each year getting through.
15:03Ipedia say cycle and this work
15:06ultimately resulted in nine story
15:09in five national presentations,
15:11and one of those projects that
15:15Jane Kanowitz lead in water Ferd
15:19in in 2018 is actually the care
15:23center quality goal for 2021.
15:27Um?
15:29I think many of the participants in
15:32these projects were really energized
15:34by the teams and the and what they
15:38learned around quality improvement.
15:40And one question was how
15:43do we sustain that gain?
15:45You know, I think that it's it's
15:48those it's important to be able to
15:51use those tools in Q I2 to better
15:54care and recognize opportunities to
15:57reuse them to face challenges and.
16:00And this is actually what we're
16:03doing now in the ambulatory
16:06transformation Work group we have.
16:08A number of groups that are
16:11really using the same Qi tools
16:13and change tools in lockstep.
16:15Action across multiple teams to
16:17respond to the pandemic and work
16:20towards transformation of care,
16:22whether it's relocation of sites
16:24or rapid uptake of Tele health.
16:27Or you know,
16:28developing and disseminating best practices.
16:30I think that this this this is the
16:34same process as the ASCO Smiler
16:36pilot but now applied to the.
16:39Immediate.
16:43Covid pandemic.
16:46Now that we're in, so you,
16:49I think you'll hear more about these.
16:52The work these groups are
16:54doing over the coming months,
16:57and I think it's been really exciting.
17:01So now I'm going to turn to clinical
17:04research, and as I mentioned before,
17:07we have about 25% of our YCC therapeutic
17:10enrollments from the care centers.
17:12This is also a process that
17:14needed to be built and hardwired.
17:17This is back in 2012.
17:19We had three cooperative group trials open
17:22and we had to figure out how to do ESO.
17:26Peas, around drug shipment and lab
17:28processing and training the staff and the.
17:31The docs to do trials where they
17:34hadn't done that before and as
17:36well as the Pisa trials to make
17:39sure that they were comfortable
17:41and had oversight of the process.
17:44Overtime we developed a monthly clinical
17:46research working group that has research
17:49champions from each site that meet
17:51monthly and vote on their portfolio.
17:53The disease team leaders come
17:55to those meetings and present
17:57their portfolio and new trials,
17:59and I think that this process is really.
18:03Grown obviously here in the next slide you
18:07can see that the accrual per the yearly
18:11accrual by sight and the highest sites.
18:14Saint Francis Northaven Trumbull,
18:16Fairfield.
18:17I think one of the things we've learned
18:21is that they need to have or they have
18:25a ACRSL lab which allows all protocols.
18:30No, let's which.
18:31Means that there's no limit on protocols that
18:36they can open due to lab processing times.
18:40Certainly the 2020 accrual
18:41was affected by Covid Inc.
18:44In our in 2018 we had 224 this year.
18:48If you take out the months that
18:50we had covid and we had very good
18:54accrual prior and and have really
18:57picked up now we would have certainly
19:00hit 200 between 200 and 220.
19:04If not for the for covid,
19:07so we activated a new site
19:09this year in Westerly.
19:11They are now treating some of the patients
19:15who were started in Waterford and.
19:19Now,
19:19in Rhode Island and you can
19:21see it actually in Waterford,
19:23which opened three years ago.
19:25There's been really great
19:27accrual growth there as well,
19:28so I think that there's really
19:31a lot of potential here if the
19:33next slide shows you the the
19:36yearly accrual by the DART.
19:37So which kinds of trials are are
19:40having the best accrual breast in
19:42GI have are certainly at the top.
19:47The long and heme are not far behind as
19:50well as T rad ngu that are increasing,
19:53so I think again, there's a tremendous
19:56potential here in the care centers,
19:58and as we have all.
20:00Our docs aligning with disease teams.
20:02I think this will just increase
20:06in the future. Um, this is the.
20:10I will quote Kurt Sabbath,
20:12who is one of our care center docs who
20:15helped to lead research initially.
20:18Now now hand it over to Neil Fishback.
20:22Kurt always said that he felt that clinical
20:24research is synonymous with quality,
20:27quality care because there's
20:28so many eyes on the patient.
20:30There's so much emphasis
20:32on important communication,
20:33shared decision making,
20:34and that really epitomizes quality.
20:36In our case,
20:37the vision had always been to
20:39to provide research as access
20:41to our patients close at home,
20:43and I think that even more
20:46than the numbers per site,
20:48this is what really strikes me.
20:50Every year we have somewhere around.
20:5285 to 87% of our physicians who put
20:55at least one patient onto trial.
20:58So I think we really changed that culture.
21:01We've had a research summit every year,
21:04usually around 80 people.
21:06That includes our care center docs or DART
21:09team members or CTO staff get prizes.
21:12We have about 13 care center
21:14physicians who served as PII on
21:17trials and right now we have 83
21:20trials open in nine disease types.
21:22About 50% cooperative group 43%
21:26industry sponsored in 10% IIT's.
21:31Here you see that our care
21:34center accruals form about 60%
21:36of our cooperative group trials,
21:38so that's really important.
21:42This is one of my trials.
21:44This is a national trial that we
21:47have opened in about guess 900
21:49sites across the US in Canada,
21:52but in our care centers as well.
21:54I'm National Co chair with has
21:57poor guy and it's a first line PDL
22:00positive trial for non squamous non
22:03small cell and I think that this is
22:06an important trial because it either
22:08randomizes you 2 two arms which
22:10start with immunotherapy and then
22:13if you progress you going to chemo.
22:15Or you add chemo to the pen
22:18bro Appan progression.
22:19That's an important question.
22:21This is the the chemo IO control arm and
22:25and this this trial I think will tell us.
22:28Very important.
22:31Give us information on sequencing of chemo.
22:34If you can spare it upfront.
22:36If you add it to the
22:38immunotherapy if that will help.
22:40And ultimately because we are
22:42collecting tissue from this trial,
22:44we're going to be looking for
22:46prognostic signatures for Pember Lizum
22:49app and predictive signatures for
22:51addition of chemo to immunotherapy.
22:53This is also an IIT of mine in small
22:57cell which with the biopsy upfront
22:59and then on treatment at week four
23:03after after treatment with EPI,
23:05Nevo and this trial has 17 patients
23:08who started on it with 10 paired pre
23:12and on treatment biopsies and this
23:15trial is open in our network and we've
23:18had 11 accruals from our network and
23:21I think that's important because.
23:24Talking to colleagues of bars
23:26across the country who have networks
23:29and who are trying to do.
23:32Clinical trials they've really relied
23:34on industry sponsored the cooperative,
23:36and very few actually have have
23:39diploid Iits in in the network.
23:42So this this just shows you a number
23:45of the items that we have and you can
23:49see that here's 12 accruals or 30% of
23:53Doctor Lacey's modified folfirinox,
23:55and in this case Doctor Kim Johans.
23:58That's 88% of her seven out of eight
24:02accruals for her and you know,
24:04for Doctor Nipper,
24:06it's a 4040% of her her accruals
24:09for her IIT as well so.
24:12I think this is really important research
24:16and support of our investigators at Yale.
24:21So what is the future hold?
24:23Among other things,
24:24I think there are certainly opportunities
24:27for building multidisciplinary care
24:29to enhance our Smiler signature of
24:32care in the network and to build
24:34on our current Med.
24:35Onken Hemang Craddock networks to
24:37support and our surgical oncology
24:39representation.
24:40We are developing formalized multi
24:42D clinics and that some of the work
24:45that I'm going to carry on in my
24:47integration role and strengthen
24:49our alignment with disease teams.
24:52And certainly our disease centers
24:54to provide service excellence
24:56and positive patient outcomes.
24:58This is my favorite slide.
25:00This is what I think is the most
25:03exciting piece of all of this
25:05is not not numbers of patients,
25:08but really I think the faculty that have
25:11joined his care center is one of them.
25:14Francesca is going to give a
25:16grand rounds right after me.
25:18They all master clinicians.
25:20They have devoted their really the
25:23clinical arm of a female cancer and
25:26smilow cancer hospital within the
25:28within the community and all have
25:31joined with the disease teams to
25:33do you know any number of really
25:37exciting things.
25:38BPI on trials do collaborative
25:40research projects, develop Qi projects,
25:42help teaching our house staff and
25:45anymore so it has really been my
25:48honor to represent these folks and
25:50to work with them. And I I can't.
25:55I can't emphasize enough that it's
25:58really been a work collaborative
26:00work of many, many,
26:02many hands to to build the network,
26:05including Charlie and Lori.
26:07Kevin Billingsley,
26:08Kim's lesser art flim, Aleesa Chomsky,
26:11Monica Fradkin, Connie Engelking,
26:12Roy Herbst,
26:13Stephanie Pauline, have invested so forth.
26:16Jeremy Court Manske will take over as the
26:20Chief Network Officer for Medical Services
26:23and head up the medication he Monk.
26:26And I will be focused on really developing
26:29the service lines and integration
26:31with our delivery care networks.
26:33So thank you for the time and.
26:37Think I. I'm done so I'd love to
26:40answer any questions if if there
26:42were any. Thanks and that was wonderful.
26:44And congratulations on a very well
26:46deserved promotion and we see why.
26:48So we have a few questions.
26:50Please put them in the chat.
26:52Melinda Erling comments were lucky to have
26:54this infrastructure with the care centers.
26:56I know a lot of non therapeutic
26:58interventional research being done in the
27:00care centers related to tobacco control,
27:01nutrition, exercise and obesity,
27:03so I will just follow up and say no.
27:07Make it secure.
27:08Diverse state as you go up
27:09and down the 95 corridor.
27:11How are we trying to help increase the
27:13diversity of our patient population at
27:14our care centers to get more patients
27:16from diverse backgrounds on trials?
27:18That's certainly something that
27:19we can now do that we have so
27:21much integration within the state.
27:25Great great great question.
27:26I'm just going to go back and share
27:29my screen again so you can see
27:31who's doing a lot of this work.
27:33You know, Melinda, that's a that's a
27:36planted question because we just put
27:39together a narrow one to study the
27:41lean interventions in the care centers,
27:44and I think that's going to be really
27:48exciting groups if you look here.
27:51This is Andrea Silver and she's
27:53done a lot of work actually devoted,
27:56you know, one of her passions is
27:59in in increasing under increasing
28:02representation of of of.
28:04In clinical trials and and
28:06addressing disparities of care,
28:08and she's done a number of things,
28:11including that grant the
28:13initial grant called own it,
28:15which was oncology works
28:17with New Haven getting.
28:20Community representatives to
28:21weigh in on what kind of research
28:24is done in the in at smilow and
28:27building those relationships.
28:28I think that you know our our latest
28:31cancer Grant has been incredibly.
28:35You know there's been a big focus on
28:38trying to increase representation of of
28:39of of folks in our in our clinical trials,
28:43and that certainly is a focus for us.
28:47Right, that's that wonderful one.
28:48More question.
28:49And then we'll move on.
28:50Someone comments. It's amazing
28:51how you built these tumor boards,
28:53even before anyone knew what zoom was.
28:55So now that we have zoom in,
28:58everyone can zoom from their
28:59phone from their walk.
29:00Can we use this technology to
29:02further integrate?
29:03You know multi modality,
29:04care subspecialty care with you
29:06showed us 55 or so doctors around the state.
29:08Are we using these tools of
29:10Tele Health to do even better
29:12now to integrate our care?
29:15Yeah, I mean, I think that with
29:18covid we've really we toggled up
29:20to over 50% of usage and adoption
29:23of telehealth during last spring.
29:25And and I think that we have.
29:28You know initiatives on next day
29:30access and improving access that
29:32we can utilize Tele health for,
29:35and certainly within our multi D clinics
29:37were thinking about doing that as well.
29:40I think there's a lot of innovation and
29:43you know I'll I'll mention you know again,
29:46Melinda's talked.
29:47I didn't talk about the non therapeutics,
29:50but we certainly have used the care
29:52centers as places to participate
29:54with the smoking cessation.
29:56Joe Biden Moon shot initiative.
29:58As well as.
30:00You know collect samples for Stephanie,
30:02Aliens, NDS,
30:03registry and and and and you know attempts
30:06to understand the science behind that.
30:08So I think there's just you know no
30:11end to what you can do with with the
30:14resources and the team that we have.
30:17Great well thanks Anne.
30:19Wonderful talking again,
30:20congratulations.
30:20So we have a second speaker,
30:23it's Doctor Francisca Montinari,
30:25Doctor Martner.
30:26Doctor Martin Ari is an assistant
30:28professor of clinical medicine in the
30:30hematology section and cares for patients
30:32with hematologic malignancies at our
30:34southernmost care center in Greenwich.
30:36Documentary recently joined Yell from
30:38the New York Presbyterian Hospital,
30:40Columbia University Medical Center,
30:42College of Physicians and Surgeons,
30:43which she was assistant Professor
30:45of medicine and Experimental
30:47Therapies Therapeutics in the
30:49Center for Lymphoid Malignancies.
30:51Doctor Montanari received her medical degree
30:53from the University of Pavia in Italy,
30:55which she graduated Magna ***
30:56laude and completed both residency
30:58and Fellowship and New York
30:59University School of Medicine,
31:00but she was awarded the Fellow
31:02of the Year Teaching Award.
31:04She served on the Institutional Review
31:06Board Committee and as director of
31:07the Institutional Lymphoma Tumor
31:09Board at Columbia University,
31:10and he is part of the steering committee
31:12of the Lymphoma Research Foundation,
31:14New York.
31:15Lymphoma rounds were so lucky to have
31:16been able to recruit Francisca recently,
31:19and she's going to talk to us now.
31:21About post transplant
31:23lymphoproliferative disorders franceska.
31:28Thank you for the introduction,
31:30so I'll share my screen.
31:38OK, so good afternoon everybody.
31:41I will review today was transparently
31:44proliferative disorders.
31:46So here's my disclosures. So we are.
31:50We will review together and how PLD
31:53are classified according to the
31:56most recent WHL classification,
31:59the Epidemiology, the risk factors
32:01at timing of onset prognosis,
32:04and therapeutic options including
32:06a current treatment paradigms,
32:08ongoing clinical trials and
32:11future directions.
32:13So let's start with the classification under
32:17the revised 2016 W 2 classification post.
32:21Transplant lymphoproliferative disorder
32:22are classified under the immune deficiency.
32:26Associated lymphoproliferative disorders,
32:28along with lymphoproliferative diseases
32:30associated with primary immune disorder,
32:33HIV infection and other
32:36iatrogenic immunodeficiency.
32:37Um, by definition they are any lymphoid
32:40or plasmacytic proliferation that develop
32:43as a consequence of immuno suppression.
32:45In order sequence of a solid
32:48organ or stem cell allograft,
32:50it is considered officiality.
32:52And based on the new classification,
32:55the device classification detailed
32:57include nondestructive PTL.
32:59These further subclassified
33:00into plasmacytic hyperplasia.
33:02Infectious modern closes like and
33:04Florida follicular pleasure which is
33:07a new entity under the new revision,
33:10polymorphic deity monomorphic TLD
33:12that comes into the B cell neoplasm
33:15and T cell nail Plaza and the
33:18classical Hodgkin lymphoma.
33:20So purely nondestructive,
33:22these diseases are classified based
33:24on the is the is the pathology major
33:28findings and undersell prevalence.
33:29There is usually preservation
33:31of the architecture,
33:33and these are polyclonal B cell
33:35proliferation by immunophenotyping
33:37genetic studies.
33:38There typically be positive the
33:40responsive to MENA suppression
33:43reduction in most of the cases and
33:45they are usually seen in kids.
33:48So in the pediatric population.
33:50So we do see on the bottom an example
33:53of plasmacytic hyperplasia with the
33:56preservation of the architecture
33:58of the lymph node and infiltrates
34:01of abundant plasma cells. Peter D.
34:04Polymorphic this is an entity that
34:07is characterized by either a genius
34:10mix of immunoblastic plasma cell
34:12and different size. The lymphocytes.
34:14The architectural is the architecture
34:17is usually faced.
34:18These are mostly polyclonal but
34:20presence of monoclonal B cell have
34:23been described and detected by
34:25immuno phenotype and genetic tool.
34:28There mostly EBV positive and
34:30some of them have been sealed.
34:33Six somatic hypermutation.
34:34So here's an example of
34:37architectural effacement on the left,
34:39with the associated to a large area
34:41of necrosis and on the right variable
34:44size and shape lymphoid infiltrate.
34:49Monomorphic PTSD, those are the one
34:51that do fulfill the criteria for non
34:54Hodgkin lymphoma or plasma cell neoplasm,
34:56small B cell lymphoma are not considered
34:59at not the designated as PTLT,
35:02with the exception of the beaded positive
35:05extranodal marginal zone lymphoma that
35:07usually arise in the cutaneous or
35:09subcutaneous tissue and this is because
35:12their standardized incidence ratio
35:13is not different than in the regular
35:16population and they're not started to happen.
35:19As a consequence of the immune suppression,
35:22besides those any other kind of non Hodgkin
35:25lymphoma is considered uppity ality.
35:27So the architecture defacement
35:29is usually present.
35:30Immuno, phenotypic and genetic features
35:32are typically recapitulating what we do
35:34see individual competent counterpart.
35:36And here I included an example
35:39on the left of.
35:42You should be selling for infiltrating.
35:45Lymph node and underwrite dereza.
35:47An example.
35:48This is a renal allograft biopsy with the
35:52showing about this planning T cell gamma,
35:56Delta,
35:56T cell lymphoma with the characteristic
36:00infiltration of the small blood vessels.
36:03Finally,
36:04classical Hodgkin lymphoma has
36:06also been associated and described
36:09in the setting of post transplant
36:11and is considered to be APTLD.
36:13It fulfills the criteria for the
36:15high school informing that we do
36:18see and immunocompetent population,
36:20but is typically mixed cellularity.
36:22It's always EBV positive and we
36:24do see that predominantly in the
36:27renal transplant recipients.
36:29Therapies treated like the Hodgkin
36:31lymphoma and immuno competent counterpart
36:34and here an example of a release time.
36:37Excel on the bottom surrounded
36:39by an inflammatory background of
36:41lymphocytes and using a fields.
36:44And this is our typical greatest number
36:47Excel with the city 20 CD 30 positive ITI.
36:50So very very Inter genius group of diseases.
36:53And so how?
36:55How frequently are our diesel informers?
36:58So we do about 40,000 transplant
37:00every year in the United States and
37:03period is the second most common
37:05malignancy in this patient population
37:08behind non Melanoma skin cancer.
37:10So it accounts for 21% of all the
37:13cancers in recipients of solid organ
37:16transplant as compared to only four
37:18to 5% of the cancers and immuno
37:21competent population.
37:22The incidence has increased over
37:24the past two decades and this is
37:27for a variety of reasons.
37:29The increased age at the older age
37:31of the Gilded Age of and owner and
37:35recipients new immunosuppressive treatment.
37:38The introduction of the haploidentical stem
37:41cell transplant and improved awareness
37:43of the disease and diagnostic schools.
37:46So after a solid organ transplant,
37:49the risk of developing a PLD
37:52varies for over 20% two point,
37:558% depending on the organ transplanted
37:57multi visceral intestinal being associated
38:00with a higher risk followed by lung,
38:03heart,
38:04liver,
38:04pancreas and with kidney being
38:06the carrying the lower risk for
38:09multiple attic stem cell transplant.
38:12The risks varies based on the
38:14HLA degree of the HLA matching.
38:17And the and the need for T cell depletion.
38:21So it is a highest for upload denticle
38:25without this addition 20% and it goes
38:28down to 3% in recipients of matched
38:31related dollar hematopoetic stem
38:32cell transplant. So what do we know
38:36in terms of risk factors besides
38:38the type of the transplant of the
38:41transplanted organ or the type of
38:44allogeneic stem cell transplant?
38:46For recipients of solid organ transplant,
38:48it is an established risk factor.
38:51The degree of Mr.
38:52EBV mismatch at the time of transplantation
38:54with the recipients being a big
38:57negative and the donor EBV positive.
39:00Also, the intensity of the induction,
39:03immunosuppression,
39:03treatment and duration of
39:05maintenance therapy,
39:05including increased the need of
39:07treatment due to graft rejection episodes.
39:10There is a strong evidence
39:12associated with the use of
39:13certain immunosuppressive drug.
39:18And in contact with others that
39:21are less associated and weak,
39:23evidence of risk is associated
39:26with infectious diseases and
39:28non EBV infection for instance,
39:31and other characteristics,
39:32genetic characteristics or
39:34underlying comorbidities of the host.
39:37For hematopoietic stem
39:38cell transplant recipient,
39:40age seems to be the biggest risk
39:43factor for development of these
39:46diseases and the conditioning.
39:48Regiment. Um also, um.
39:54So in terms of timing,
39:56typically PTSD arrives early in
39:58the setting of hematopoetic stem.
40:00The transplant and leader in the
40:03setting of a solid organ transplant,
40:06but it's not really that predictable.
40:08We considered an early onset if the
40:11PTSD arise in the first year after
40:14the transplant and the late onset,
40:17if it arises a year later.
40:19Starting one year after the transplant and.
40:24And the reason the battle,
40:26the pathogenesis is associated in the
40:29early onset to an acute EBV infection
40:32or a reactivation of the virus in
40:35the setting of a reduction of the
40:38MTV cytotoxic T cell lymphocytes,
40:40usually early PTLDREB positive,
40:41and frequently there is the
40:44allograft is involved.
40:45In the late onset there have been
40:49many hypothesis so hidden around
40:51the infection with the baby,
40:54then resolved and lymphoma keeps
40:57developing other viruses besides
40:59BV has been hypothesized as
41:01playing a role such as CMV,
41:04a persistent antigenic stimulation
41:06done by the allograft and lymphocyte
41:09deregulation in the setting of a
41:12chronic immuno suppressed state.
41:14These are usually.
41:16More likely,
41:17extra node with Extranodal involvement,
41:19not necessarily involving
41:21the graft and the monomorphic
41:24subtype is the most common.
41:27So what do we know about the prognosis
41:29of this disease that are regarding
41:32prognosis are mostly from single
41:34institution retrospective analysis and
41:36during my time at Columbia University
41:38I work on setting up a tumor bank
41:41for this disease with pathological
41:43specimen link to clinical information,
41:45and this is what we have learned
41:48from the analysis of 120 patients.
41:50This is the largest series published
41:52so far on this specific disease.
41:55Interestingly,
41:55most of the clinical.
41:57Features that we think might
41:59predict an outcome might have an
42:02impact on the overall survival.
42:04Did not correlate with overall
42:06survival in our patient population,
42:08including the subtype of the PTSD,
42:11the decade of diagnosis prior or after
42:14the introduction of their attack.
42:16Some organ do kind of organ transplanted
42:19DV status, graft involvement,
42:20and extranodal involvement
42:22or stage of diagnosis.
42:23So using a recursive partitioning model,
42:26we separated patient.
42:28Recursively,
42:29at each step into two distinct
42:31groups based on the variables that
42:33provided the maximal separation based
42:35on survival and using this model,
42:37we were able to identify based on
42:39age CD 20 expression and equal status
42:42for groups that were well separated
42:45in terms of roll survival and with
42:47an even number of patient and in the
42:50lowest group we can see that the
42:53medium overall survival was not reached.
42:55Those were essentially mostly pediatric
42:57patients with a good performance status.
42:59What is in the very high risk group
43:02elderly with a foot Burma status and
43:04essentially all patients with the
43:06CD? Twenty negative disease,
43:07the median overall survival was
43:09as short as one point 3 months.
43:11So what else we have learned,
43:14we know very well that T cell lymphoma
43:17have a much worse prognosis than Bissell
43:20informal immunocompetent population.
43:22But what are?
43:25What is the behavior of this LPT?
43:27LD is not well, no,
43:29not due to the rarity of these diseases.
43:32So we did analyze in our series of
43:34pulling over monomorphic PTSD and the
43:37differences between B cells and T cell TLD.
43:40And we do see that they sort of
43:42recapitulate what we do see and
43:44immuno competent counterpart in
43:46terms of prognosis with the median
43:48overall survival being very low
43:50for the T cell and compared to
43:53the diesel in monomorphic PLD.
43:55Also, we did observe that the time
43:57of the median time to answer it was
44:00much longer for T cell nine years
44:02compared to three years for the B
44:05cell type and all T cell period in
44:08our series were leaving negative.
44:11Another thing that that we we have
44:14also learned is that importance of more
44:17marrow of staging and the incidents
44:20of more involvement in the in PLD.
44:23It is very common in our series of
44:26patients at 23% of monomorphic PLD
44:29had bone marrow involvement compared
44:32in the in the T cell subtypes 50%.
44:35Also,
44:36polymorphic exhibited our very
44:37high bone marrow involvement.
44:3915.7 All the cases of polymorphic with
44:42where bone marrow involvement was detected.
44:46This resulted in up stage of the disease.
44:51And ever involvement was
44:52associated with poorer outcome.
44:54So we did compare the incidence of
44:57the involvement of Lombardy Boomer
44:59involvement in monomorphic PTSD compared
45:01to the normal diffuse large B cell
45:04lymphoma and HIV diffuse large B cell
45:06lymphoma patients diagnosed during
45:08the same time frame at our institution
45:11and we do see here that monomorphic,
45:14detailed involvement compared to
45:15the HIV positive diffuse large B
45:18cell involvement and this is suggest
45:20that that immuno compromised.
45:22State regardless of videology
45:24vial associated or higher trajanic
45:27maybe is a major risk factor for
45:31dissemination to the marrow.
45:32Finally,
45:33this is a loser.
45:36Analyze last year actually two years ago
45:38and this was presented at ASH in 2019.
45:40We did analyze the data regarding
45:42the cell of origin and the impact
45:45of treatment on the outcome of
45:47diffuse large B cell lymphoma.
45:49So these type and in our series
45:51non germinal center was more
45:53common than germinal center.
45:55I just want to highlight here that as
45:58previously reported and non germinal
46:00center PTSD is usually be positive
46:02versus germinal center is usually it will
46:05be negative clinical characteristic,
46:07organ transplant,
46:08immunosuppressive,
46:08treatment time of onset was not different
46:12in these two subtypes and there is a
46:14trend suggesting a better outcome,
46:16a better PFS and OS in patients with.
46:19Germinal standard compared to non
46:21germinal center mirroring the outcome
46:23in Indiana competent population
46:25and RE broker did not improve
46:27overall survival or progression.
46:28Free survival were compared
46:30to R chop but in not
46:32resulted also either in an increase
46:35toxicity in our series was
46:37extremely low and only one patient
46:39died in each treatment group.
46:43So the current challenges for PT LDR
46:45that this is an uncommon disease,
46:47as we saw there is a bigot originality
46:50in in the type of PTSD that is it
46:53originality in the patient population,
46:56in the allograft or multiply
46:58attic stem cell transplant,
46:59and immunosuppressive treatment they
47:01receive that is a high mortality rate
47:04that is associated with the chemotherapy
47:06and this is usually in length to
47:08the increased risk of infection
47:10that we do see in these patients.
47:13Population and unique to this patient
47:15population is the risk of graft failure.
47:18So currently general principle of treatment
47:23include immunosuppression reduction.
47:26I just want to mention that the
47:29only perspective trial that utilize
47:31immuno suppression reduction as part
47:33of a sequential treatment for this
47:36disease on a very large sample of
47:39you know on a very large number of
47:42patients 160 patient showed a 40%
47:45incidence of acute graft reaction.
47:47So typical in the adult population
47:50immunosuppression reduction
47:51is utilized at the same time.
47:53Other interventions such as
47:55rituximab are or combination.
47:56Chemotherapy surgery, radiation therapy.
47:58Unlikely.
47:59What we do see in Hodgkin and an
48:02article in former is a well established
48:06the treatment for stage one disease,
48:09PTSD and in the relapsed and
48:12refractory setting.
48:13There are adoptive immunotherapy
48:16utilizing EBV specific cytotoxic
48:18T cells and high dose chemotherapy
48:22with a toddler stem cell transplant
48:25or both being explored.
48:27So there are only few prospective trials,
48:31primarily on polymorphic and
48:33monomorphic beissel. PTSD and hold the.
48:37Stop for trials here.
48:39Um,
48:39use their attack some as a single
48:42agent with a very high with a good
48:45overall response rate under an CR rate,
48:48but not exciting overall survival
48:49due to early relapse is the best
48:52results that have been achieved
48:54that utilizing either a sequential
48:56treatment or a risk stratifies
48:58sequential treatment and this is the
49:00PTL D1 trials that is the largest
49:02phase two trial ever conducted
49:04in this patient population and
49:07reported by the German.
49:08Study group so will review
49:11the results of the PD L D1.
49:14The risk stratified sequential treatment.
49:17This was published in JCO in 2017.
49:21Patients were with that newly diagnosis
49:24of PTSD received an induction treatment
49:26with rituximab and then based on
49:28their response they received the
49:30consolidation with rituximab alone
49:32or they were escalated to our CHOP
49:35and 152 patients were enrolled again.
49:37This is the largest study in this
49:39disease that has ever been conducted
49:42and we do still at 1/4 of them
49:45after the initial induction with
49:47maximum achieved a CR and these were
49:50the patient that did not receive.
49:52Um,
49:53instead of toxic treatment,
49:55the overall response rate was a
49:58dieta CR rate 70%.
50:00Army generation of response was
50:02not reached and let me down.
50:04Overall survival was 6.6 years
50:06treatment related mortality in this
50:08study was 8% which is the lowest
50:11reported in this patient population and
50:13this is a attribute.
50:14This has been attributed to the
50:16fact that a quarter of the patients
50:19were spared cytotoxic chemotherapy.
50:21So. What's new in PID.
50:24Recently over the past five
50:26years it has been more and more
50:29recognized than PTSD tend to be.
50:32CD 30 positive So this is a study by vision.
50:36Others that showed that out of
50:38108 patients with PTSD diagnosed
50:40between 1994 and 2011, it was 85%.
50:43Of this patient expresses CD 30 including
50:4681% of the diffuse large B cell lymphoma.
50:50This is very particular to
50:52the query after the PTLD.
50:54Because in the immunocompetent,
50:56if you started selling for my
50:58usually city third expression is
51:00probably less than 20% and not only
51:03demonstrated a high CD 30 expression.
51:05They also demonstrated that it was
51:08associated with a better outcome. So.
51:11Twice this interesting or important,
51:14we now have a drug that targets
51:17specifically city 30 brentuximab windowed
51:19and is an antibody drug conjugate
51:22that binds to the city 30 and one.
51:26Since the internalised release,
51:27monumental restarting E which is
51:30microtubule disrupting agent which
51:32end up like causing apoptosis.
51:34As we all know,
51:35grant access method Odin is now
51:37approved with various indication in
51:40Hodgkin lymphoma anaplastic large.
51:42Calling from.
51:45So in 2019,
51:46at the ASH meeting,
51:48the results of these Phase 1 two
51:51trial of Brentuximab in Jordan plus
51:53rituximab as frontline treatment for
51:56patients with immuno suppression
51:58associated lymphoma were presented and
52:00in the this was a very small study.
52:0422 patients with previously untreated
52:07immunosuppression associated.
52:09Little pretty effective disorder,
52:10including 1516 patients were PTSD
52:12post transplant clipart affective
52:13disorder patients who receive
52:15an induction were attacks.
52:17In other words,
52:18given in combination with Brent
52:19accidents and Odin and patient worry
52:22stage and according to their response,
52:24they either received more out
52:26attacks immigrant tax map in loading
52:28as consolidation and maintenance,
52:29or if they had progression of
52:32disease were removed from the study.
52:35Again, small study,
52:36very short follow-up about
52:38encouraging result with a very
52:40high overall response rate,
52:41and see a rate of 60% so.
52:45I'm I'm very excited to announce
52:47that I that we're about to open a
52:50phase two trial for this patient
52:53population here in the Yale network,
52:55and this is going to be a trial
52:58in collaboration with them.
53:00Are you clinic and with UVI so is
53:021/2 is just trial where patients with
53:05post transplant lymphoproliferative
53:07disorder CD 20 and CD 30 positive
53:10which essentially is the vast
53:12majority of PTSD will receive
53:14an induction treatment with.
53:15Maximum burn toxin overload and
53:17and then based on the response
53:20at a pet city after induction,
53:22they will receive more of the same
53:24treatment so and there will be spared
53:27of cytotoxic treatment or will be
53:29escalated to rituximab, Pentax,
53:31Melvin Gordon, and Bendamustine,
53:33for a total of 6 cycles.
53:35Primary objective of the study.
53:37Our overall response rate complete
53:39and partial at the end of the
53:42treatment and PFS secondary objective.
53:44Intend to explore.
53:45Additional responsibilities at
53:47the end of the
53:48induction phase,
53:50which include the grant axiom of
53:52windowed in on top of rituximab,
53:55duration of response and overall survival,
53:57and we're planning to also deep dive
54:00into the frequency of infection.
54:02Peripheral sensory neuropathy,
54:04then rate doesn't craft of interaction
54:06and treatment related mortality.
54:08Exploratory studies.
54:10Are at the end to identify new biological
54:13and genetic markers that might be
54:15productive to response resistance
54:17to this therapeutic combination.
54:19So. Um?
54:23I'm going to leave you with this last slide,
54:26future strategies and these are.
54:28This is a list of the clinical trials
54:30that are currently about to recruit
54:32or recruiting for this for post
54:35transplant lymphoproliferative disorder.
54:37This top line is the study is our
54:40study that I just mentioned and
54:42we're about to open here at Yale
54:45and then the reason I just want to
54:48highlight the days a second study is.
54:53Study that follows up the PLD
54:56one trial from the German group,
54:58whether increasing where they're
55:00integrating the IPI score and the organ
55:03transplanted to further risk stratify
55:06patients after induction with rituximab
55:08and I have substituted rituximab
55:10subcu to the regular attacks enough
55:13that they used in the PTL D1 trial.
55:17Another trial that I would keep an
55:19eye on is there tax amount plus
55:22a club routine atrial that is not
55:24yet recruiting and is going to be
55:27done in Cleveland and besides this
55:29retrial which address the untreated
55:31population in the refractory setting,
55:32there are a lot of trials with
55:34the adoptive T cell treatment.
55:38And with this and this,
55:40is it? So thank you for your attention.
55:46Thank you, that was a wonderful
55:49talk and it's great to see that
55:51you have a trial and I guess
55:53it's opening Greninger will be.
55:55So very very well linked to the
55:57first talk we heard from Ann.
55:58Do you have any questions or comments
56:00where we're just about a time,
56:02but we might have time for one or two?
56:04If there are any.
56:09Are you seeing a lot of this
56:11in your practice right now?
56:13Princeska in Greenwich?
56:15Currently have one patient which is,
56:17which is a lot considering that
56:19I've just started two months ago.
56:21So we have we typically used to have.
56:25Colombia is a big transplant
56:27center and we we tend to.
56:29We were we were seeing a lot of
56:32these patients, but to say a lot
56:36was about 20-30 cases per year.
56:38Just to put this in context, so this is
56:41a rare disease weapon.
56:43As we grow Greenwich as a expert site,
56:45you know for these types of
56:47diseases you'll get you'll draw
56:49more and more from Manhattan,
56:50and where I'm sure there are
56:52many post transplant patients,
56:53Francine Flash has a question.
56:55She asks any role for checkpoint
56:57inhibitors in these EBV driven tumors.
57:00This is a very good good question and
57:03I think that due to the peculiarity
57:06of these patients population,
57:08which are recipients of hematopoietic
57:09stem cell transplant or solid organ
57:12transplant, there is a lot of.
57:16We're very worried about causing
57:18it'd have to be action or graft
57:21versus host disease, and so I don't.
57:24I'm not aware of any study
57:26utilizing checkpoint inhibitors in
57:29this specific patient population.
57:33OK, maybe I see a study in the making,
57:35maybe an investigator initiated trial.
57:38Well, our Francisco that was great.
57:40Thank you so much.
57:41Welcome to the group you've.
57:42It's great to have you and this
57:44will end grand rounds for today.
57:46I want to thank Renee and her team
57:48for helping get this set up and I hope
57:50everyone has a good rest of the day.
57:53Will see you see you soon.
57:56Thank you, thanks everyone.