Yale ASH 2021 Highlights: Lymphoma

Transcript

• 00:00So the yield Cancer Center I
• 00:02wanted to welcome those attending
• 00:03as well as my participants here
• 00:05for the ash update on lymphoma.
• 00:08So my name is Scott Harrington
• 00:10lymphoma clinician as well as a
• 00:12health services researcher and
• 00:13I'm joined with Doctor Kothari.
• 00:15He'll be focusing on aggressive B
• 00:18cell malignancies and mantle cell
• 00:20lymphoma as well as doctor Taxin Sethi
• 00:22who will present some updates on
• 00:24Hodgkin lymphoma and T cell lymphomas.
• 00:27Dr Frost will be joining us
• 00:28towards the end to help lead the.
• 00:30Question and answer discussion.
• 00:36So I know many have been focused
• 00:38on COVID and would love to
• 00:40look forward into the future.
• 00:42But in terms of indolent lymphomas and CLL,
• 00:45my slides are actually mostly
• 00:47focused on on how to kind of
• 00:50navigate our patients through the
• 00:52COVID era with indolent lymphomas.
• 00:55He's in my disclosures.
• 00:59And when we think about
• 01:01approaching sealant on how,
• 01:02given the uncertainty that we are
• 01:04facing with the COVID pandemic,
• 01:05there's a few takeaways of historical
• 01:07data that really come to forefront of
• 01:10my mind when approaching a patient,
• 01:12and that's that.
• 01:13The improvement in progression free
• 01:15survival infrequently has translated
• 01:16to overall survival benefits for
• 01:18patients receiving first line treatment
• 01:20for in lymphomas very different from
• 01:22my colleagues will be talking about
• 01:24DLBCL and Ansel cell and Hodgkin,
• 01:26but in this situation where CL and lymphoma.
• 01:30This kind of association has been
• 01:33seen frequently and there were some
• 01:35updates showing out here at Ash.
• 01:37This was doctor Wack who presented
• 01:38the update on the Alliance study and
• 01:41this was a randomized randomized
• 01:43study comparing bendamustine rituximab
• 01:45to a brute model therapy or brute
• 01:49rituximab and this was an important
• 01:51study that really led to the use of
• 01:52front line of root nymph and many of
• 01:54our patients and that was based off
• 01:56of a really progression free survival
• 01:58benefit both in the model therapy.
• 02:00Farm as well as the route number toxin
• 02:02that Barm both had a hazard ratio of
• 02:051.36 in the updated median follow-up
• 02:07of 55 months that PFS benefit was
• 02:10was made to be quite impressive.
• 02:13Doctor William did a very nice job
• 02:15in terms of presenting updated PFS
• 02:18stratified by risk factors and CLL,
• 02:20but she also had this slide here,
• 02:22which was overall survival and so
• 02:23at a median follow-up of 55 months.
• 02:25Overall survival between the three
• 02:27arms was that really identical
• 02:29and it's important to note.
• 02:30Got to follow up for this analysis
• 02:33was locked at April 2020.
• 02:35Kind of right before the pandemic and
• 02:37so having both this data as well as
• 02:40the corresponding ACOG study that was
• 02:42FDR versus abroad number Tux map will be,
• 02:45I think,
• 02:45important in terms of overall survival
• 02:47and how we address our patients.
• 02:49When we think about indolent,
• 02:50non Hodgkin lymphoma is often in
• 02:53the use of maintenance is a hot
• 02:56topic and this is just a little bit
• 02:59dated data now of follicular pharma
• 03:02maintenance or following our chemo.
• 03:03This is a randomized study PRIMA study
• 03:06and this is the data at 10 years and
• 03:08what we see is that adding maintenance
• 03:10rituximab for two years certainly
• 03:12improves progression free survival type.
• 03:15The next treatment time to
• 03:17delay of cytotoxic chemotherapy.
• 03:20In pretty stark differences,
• 03:2110.5 years in median PFS compared to
• 03:254.1 for those without maintenance.
• 03:26But again,
• 03:27the overall survival in this patient
• 03:29population at 9 years was identical.
• 03:32So why do we think about that?
• 03:33As we move forward,
• 03:35is that our patients within
• 03:37lymphomas usually live for for years,
• 03:39often well over a decade,
• 03:41and if there's a new potential
• 03:43downside or new pandemic that might
• 03:46impact their long term survival,
• 03:48a focus of,
• 03:49I think of our management needs to be
• 03:51addressed in that in that situation,
• 03:53and so most of the data on concerns
• 03:56of differential impact on COVID in
• 03:58our patients has been mostly data
• 04:01from CLO. This was very nice work from the
• 04:03French innovative leukemia organization.
• 04:05From Doctor Bacchus in and what they
• 04:08looked at was just over 500 patients
• 04:11treated in 17 French groups in with
• 04:14CLL and they presented the antibody
• 04:17response to two vaccines of M RNA COVID
• 04:21vaccinations and what we see is about
• 04:2370% of patients that were treatment
• 04:26naive mounted antibody response compared
• 04:28to 60% that were treated prior but off
• 04:31therapy at the time of their vaccination.
• 04:33And that compared pretty favorable
• 04:35compared to the on treatments.
• 04:37Only 22% of patients that received
• 04:40on treatment vaccination mounted
• 04:42antibody response after two doses.
• 04:45When you look at what those therapies were,
• 04:48the vast majority of patients
• 04:50were on BTK continues BTK,
• 04:52and in those patients,
• 04:53just 22% of patients mounted antibody
• 04:55response after two vaccinations.
• 04:57If you're on Phenetics,
• 04:58monotherapy is about 50%,
• 05:00and if you run vanetta clicks along with
• 05:02either anti CD 20 or BTK inhibitor,
• 05:04there was really very minimal or
• 05:07no response in terms of human
• 05:10response to to vaccinations.
• 05:12Now you might think that we've
• 05:14moved beyond two vaccinations.
• 05:16We've done three.
• 05:16We've done 4 here in the United
• 05:18States from our patients.
• 05:19This data did look at patients that
• 05:21had no response to two vaccinations
• 05:23that then went on to get a third,
• 05:25just about 1/4 of patients will will
• 05:27respond to 1/3 dose, and again,
• 05:29most of those responses were seen
• 05:30in the treatment, naive CLL,
• 05:32or those that were off treatment.
• 05:34If you were on therapy,
• 05:36you had only about a 25% chance
• 05:38of mounting antibody response to
• 05:40three doses of vaccine.
• 05:44So that data really goes nicely with
• 05:46what's been reported at smaller
• 05:48institution studies here in United States
• 05:50have been published in the last year.
• 05:52What we really didn't have is a lot
• 05:53of data in other independent farmers,
• 05:55and so this was very nice data from Doctor
• 05:58Beaton from Australia that presented data
• 06:01looking at waldenstrom's patients as well
• 06:04as Flickr lymphoma patients in Australia.
• 06:06So smaller study only about 34 patients
• 06:10with follicular 37 with waldenstrom's about
• 06:121/3 of patients had been treatment naive.
• 06:16Many of those in follicular
• 06:18had had immunotherapy,
• 06:20including some that had just completed
• 06:22treatment a few months previously.
• 06:25BTK was quite common in the Waldenstrom's
• 06:28group and fairly representative
• 06:29population for our patients with
• 06:32follicular and waldenstrom's.
• 06:34Not only did they have antibody titers,
• 06:36but they also did some neutralization assays.
• 06:38I'm not going to present that data,
• 06:40but really there was strong correlation.
• 06:41So for antibody titers and neutralization
• 06:44correlated quite well and they also had some
• 06:47T cell acids that I'll present at the end.
• 06:50This is just the antibody titers for patients
• 06:53that had in a chemotherapy compared to
• 06:56treatment naive compared to healthy controls.
• 06:59And really the treatment naive.
• 07:00Whether you had waldenstrom's
• 07:02or for lymphoma,
• 07:03their antibody titers were very
• 07:04similar to the healthy controls.
• 07:06But if you were getting
• 07:07immunochemotherapy within six months
• 07:09of completing immunochemotherapy,
• 07:10there was really significantly reduced
• 07:12antibody titers and they had very few
• 07:14patients getting a bit of tourism.
• 07:16But it did look like that response
• 07:18or reduction in antibody titers
• 07:20persisted quite far.
• 07:21They had one patient that was 21.
• 07:23Months out from finishing up in
• 07:24a tourism map that still did not
• 07:26mountain antibody response.
• 07:29This is there kind of a snapshot
• 07:31of their functional T cell assays,
• 07:33and So what they had was
• 07:35peripheral blood mononuclear cells,
• 07:37pre vaccination and then post
• 07:39vaccination and revaccination there.
• 07:41Really there was no stimulation
• 07:43of the T cells when these T cells
• 07:46were subjugated to COVID peptides.
• 07:48But in all patients which was encouraging,
• 07:52they did see signs of activation in
• 07:54the post vaccination and so this
• 07:56data suggested that these patients
• 07:58with Wellness drums and flick.
• 08:00At least have some T cell education
• 08:02with the vaccination.
• 08:06So just to kind of summarize,
• 08:08both the the ASH presentations but
• 08:10also kind of the the growing data into
• 08:13lymphomas in CLL and COVID is that
• 08:16patients with indolent lymphomas,
• 08:18particularly CLL at baseline,
• 08:20have lower human response to COVID
• 08:22vaccinations compared to healthy controls.
• 08:24Despite I think limited and
• 08:26relatively mixed T cell data,
• 08:28there really is very little downside
• 08:29of giving our patients vaccinations,
• 08:31and so all vaccine.
• 08:32All unvaccinated patients that come
• 08:34through your office with these diseases.
• 08:36Need to be cancelled every time you
• 08:38see them to really educate them to
• 08:40try to get them vaccinated and then
• 08:42even in those that are vaccinated,
• 08:44the vaccine itself,
• 08:44I mean actually not be producing
• 08:46a huge amount of protection,
• 08:48and so I'm having discussions
• 08:50about precautions and having
• 08:52discussions about use of prophylaxis,
• 08:54including heavy shelter here at Yale.
• 08:56We have this heavy shield COVID
• 08:58prophylaxis panel order set that is
• 09:00quite helpful in will kind of walk you
• 09:02through getting every shell to our patients.
• 09:05I also think it's important
• 09:06to recognize that.
• 09:07Treatments used for our diseases.
• 09:09Skeletal infamous likely have
• 09:10differential impact on human
• 09:12response to color vaccinations.
• 09:14Not surprisingly,
• 09:15anti CD 20 can really lead to low antibody
• 09:19titers after vaccination for 6:12,
• 09:21perhaps even longer.
• 09:22It is important to to kind of think
• 09:25about and then also maybe more
• 09:27surprising was the use of BTK so
• 09:28people in Bteq seem to have lower
• 09:30responsive to go vaccinations as well,
• 09:33and so because to this all of our
• 09:35patients with CLL and lymphomas
• 09:36really need to be educated about.
• 09:38Early identification of COVID
• 09:39illness as well as perhaps using
• 09:41outpatient treatment strategies.
• 09:43Monoclonal antibodies,
• 09:44antivirals, I think,
• 09:45actually,
• 09:46that is a key take away for managing
• 09:49patients with CLL and lymphomas these days.
• 09:54So there's going to be a couple studies.
• 09:55Hopefully reading out this later
• 09:56this year that will help give us a
• 09:58little more information about our
• 09:59patients that are immunosuppressed.
• 10:01The melody study is a massive
• 10:02valuation of lateral flow immunoassays
• 10:04and detecting antibodies to SARS,
• 10:06Co V2 and this is a large
• 10:08community based study in the UK.
• 10:10So about 35,000 patients were
• 10:12enrolled and they're going to
• 10:13be looking at antibody response
• 10:15to three and four doses of M RNA
• 10:17vaccine and then really importantly,
• 10:19they're going to look at whether the
• 10:21lack of antibody response correlate's
• 10:22with the risk of COVID-19 infection.
• 10:24As well, severity of disease.
• 10:26There's also an important study
• 10:28for our patients with CLL BTK'S,
• 10:30which public Tribeca study.
• 10:31This is out of Australia,
• 10:32where they're basically going to stop
• 10:35patients on their BTK temporarily
• 10:37vaccinate them with different
• 10:38strategies in terms of holding the BTK,
• 10:41ideally to identify ways of allowing our
• 10:44BTK patients to Mona a nice antibody
• 10:47response following vaccination against Kovan.
• 10:50So, given this uncertainty,
• 10:51given the fact that our patients
• 10:53typically do very well with a
• 10:55current modern therapeutics,
• 10:57I've generally recommended fixed duration
• 10:59without maintenance for most of my patients,
• 11:01and so when we think about fixed duration,
• 11:03lack of maintenance,
• 11:04was there any studies that ash that
• 11:06might influence our therapies going
• 11:08forward and there certainly were,
• 11:10and I'll focus on those in the
• 11:12next few slides.
• 11:13So this was an important study
• 11:15presented by Doctor Eickhorst,
• 11:16which was a CLL 13 study.
• 11:19This was a large randomized European
• 11:21study where patients without deletion,
• 11:23segmenting P without TP 53
• 11:28mutations were randomized either
• 11:30to standard IMMUNOCHEMOTHERAPY FC
• 11:32RVR or Vertex magnetic locks.
• 11:35Or the triplet venetoclax
• 11:36of Britain have been,
• 11:37and I've been a choose him out.
• 11:39Standard dosing so patients
• 11:40got six months of anti CD 20s.
• 11:43They got 12 cycles of venetoclax
• 11:44and then for Brewton if if people
• 11:46were still under deposit.
• 11:47If people could get up to 36 cycles.
• 11:52So the primary outcome was a.
• 11:54It was a 2 coprimary outcomes MRD,
• 11:57undetectable rate of 15 months,
• 11:58as well as PFS. Not surprisingly,
• 12:01with this kind of early follow-up that
• 12:03PFS has interim that's assessment hasn't
• 12:04been reached and so that's still to come,
• 12:07but they didn't have the 15 month MRD
• 12:09data that they presented at Ash and what
• 12:12we see here is that the peripheral blood
• 12:15flow cytometry based undetectable Mardi
• 12:17was 86% in the jivan arm and 92.2%.
• 12:22Can be tripled arm both the
• 12:24community therapy as well as RTX.
• 12:26Magnetic locks had lower around 50%
• 12:29and overall this there was two positive
• 12:31alarms compared to the immunochemotherapy.
• 12:34Both the G Ven and Gebruik infinite clocks.
• 12:38There was a kind of companion MRD
• 12:41assessment presentation which I think
• 12:43was was was quite interesting where
• 12:45they looked at MRD by the CLL molecular
• 12:49phenotype and what we can see here is
• 12:52that the molecular subtypes of seal
• 12:54that typically do much better with a
• 12:56brute compared to immunochemotherapy
• 12:58do better on the trip with the arm.
• 13:00So patients that are 11 Q patients
• 13:02that are unmutated have at least kind
• 13:04of a 1010 absolute percent increase
• 13:07of them are deemed detectable.
• 13:09With the triplet compared to the double
• 13:11ARM patients that have the lower risk
• 13:14disease in terms of being IG HV mutated
• 13:16seem to have relatively similar energy rates.
• 13:19Whether you get the doublet or the triplet.
• 13:23This energy does come at some
• 13:25toxicity in terms of the triple
• 13:26arm compared to the double it,
• 13:27and so things like febrile neutropenic
• 13:29infections were higher in the
• 13:31triplet compared to the doublets.
• 13:32And then when you add a brute
• 13:34nib you also saw a low rate,
• 13:35although it was there at
• 13:372% in terms of eight Feb.
• 13:40So in terms of the summary, and take
• 13:42away was that in terms of MRD status,
• 13:45the advantage choosing venetoclax
• 13:48were superior to chemotherapy and
• 13:51there was two arms that met their
• 13:53Co primary endpoint Rituxan Venetic
• 13:55LEX was not superior in terms of
• 13:57MRD of detectable rate compared to
• 14:00the primary FCR chemotherapy arm.
• 14:01They were very happy to see that most
• 14:03patients tolerated treatment well.
• 14:05There was very low rates of
• 14:08discontinuation and although there was.
• 14:10Some increased,
• 14:10perhaps toxicity for the triplet in terms
• 14:13of infection in terms of pepperoncini,
• 14:15and generally people tolerate
• 14:16this this regimen as well.
• 14:20So if we think about kind of the
• 14:22majority of patients are older,
• 14:23perhaps have comedies,
• 14:25maybe the triplet is is is not
• 14:28appropriate for that patient population.
• 14:31Is there another fixed duration
• 14:32regimen that we might be able
• 14:33to use in the near future?
• 14:34And there is?
• 14:35This is the GLOBE study and this
• 14:37was a randomized trial of patients
• 14:40that were older or those that
• 14:42were younger with committees,
• 14:44about 210 patients or so were
• 14:47randomized to either have been a 2.
• 14:49I take that back.
• 14:50They are brute NIM,
• 14:51so a brute in bleeding for
• 14:53three months and then a brute
• 14:54in Veneta clicks for toy cycles
• 14:55and then everyone stopped.
• 14:57It was not MRD directed therapy
• 15:00and then the old control arm.
• 15:01Here is a bit mad with crab.
• 15:05This is the PFS data.
• 15:07This data has been presented earlier
• 15:09EHA and what the focus of this
• 15:11abstract was was really on them
• 15:13or D rates in this in this arms,
• 15:15so we can see sphere.
• 15:16Certainly clear superiority in that PFS
• 15:19benefit of the approvement phenetics
• 15:22arm compared to Carnival in two,
• 15:24with a median follow-up of of 34 months,
• 15:26although overall survival
• 15:27was actually down tickle,
• 15:29and it'll be important to see the
• 15:31long term follow up from this.
• 15:32This study as well.
• 15:35That instead of being flow,
• 15:36they used NGS a little bit more sensitive
• 15:39and a little bit more reproducible.
• 15:41And what we see here is that
• 15:43the rates of them are detectable
• 15:44with this doublet oral double.
• 15:46It was about 50% in the peripheral
• 15:49blood as well as develop Mira,
• 15:51and that was statistically significantly
• 15:53improved over claim Bissell.
• 15:55And it's also notable that the
• 15:58concordance of bone marrow to
• 16:00preferred blood MRD was much
• 16:02higher in the doublet arm compared
• 16:04to the immunochemotherapy.
• 16:06A pharmacy.
• 16:09For patients that I think are thinking
• 16:11about PFS and how long they're going to
• 16:13be in remission after stopping treatment,
• 16:15I think this was a really important
• 16:17key addition of the study,
• 16:18which was everyone stopped a therapy in at
• 16:22certainly about 30-30 months of follow up.
• 16:25Here you can see that patients that
• 16:27were still in more detectable at the
• 16:29time of stopping therapy maintained
• 16:31a response without progression,
• 16:33and so this was, I think,
• 16:34important finding moving forward.
• 16:38And together with GLOW study as well
• 16:40as other phase two studies captivate.
• 16:43For instance, it's possible that
• 16:45we'll see additional labels of doublet
• 16:47or or doublet later this year,
• 16:49and I would stay tuned to see
• 16:51whether that could be incorporated
• 16:52into standard practice.
• 16:55So when we think about flicking
• 16:56them from and fixed duration,
• 16:58we're really more thinking about the
• 17:00anti CD 20 in terms of maintenance
• 17:03Rituxan mount and this was an important
• 17:05update from Doctor Call from Washington
• 17:07St Louis of the Resort study.
• 17:09So this was a randomized study
• 17:10done here in the United States.
• 17:12Patients had low burden of silicone
• 17:14phomma they all received four
• 17:15weekly doses and Rituxan mab
• 17:17and then they were randomized.
• 17:18If patients had a stable disease or
• 17:22better in patients either got rituximab.
• 17:25Monotherapy every three months,
• 17:26indefinitely until progression or
• 17:28they were on active surveillance
• 17:30with re treatment with rituximab and
• 17:33this was a one to one randomization.
• 17:37This data was originally published in
• 17:39JCM 2014 and the conclusions are here
• 17:42where basically Rituxan every treatment
• 17:43was as effective as maintenance.
• 17:45Rituximab for treatment failure.
• 17:47However, the main instruction
• 17:49map did delay time to needing
• 17:51cytotoxic chemo and ultimately,
• 17:53as you might expect,
• 17:54there was more rituximab used in
• 17:56the maintenance compared to the
• 17:57retreatment arm a year later.
• 17:59They followed up on quality of
• 18:00life and there was really no
• 18:01difference between the maintenance,
• 18:02rituximab norm compared to the
• 18:04retreatment and based off of
• 18:06this kind of earlier follow up.
• 18:08Doctor Colin,
• 18:08his colleagues recommended that re
• 18:10treatment rather than maintenance or tuck.
• 18:12Seemab was the preferred strategy.
• 18:15So now at around 10 years of follow up,
• 18:17do we have any different signals
• 18:18here and so this was freedom from
• 18:20first sent a toxic chemo and with
• 18:22long term follow up we still see a
• 18:25separation of the curves between
• 18:26Rituxan and maintenance continuously
• 18:28compared to the RE treatment strategy.
• 18:31You also see improved duration of
• 18:33response and so 66% of patients
• 18:35treated the maintenance or tux mab
• 18:37do not have progression compared to
• 18:40just 30% of patients treated with four
• 18:42doses of Rituxan have actually so much lower.
• 18:45Obviously need of Rituxan effort in
• 18:47in in administration Rituxan effort,
• 18:49the retreatment arm.
• 18:52And then,
• 18:53importantly,
• 18:53despite improvements in and
• 18:55time to cytotoxic chemo,
• 18:57the the main kind of take
• 18:58away was that oral survival,
• 19:00transformation risk secondary malignancy
• 19:02seemed very similar between the arms.
• 19:05And so the long term follow-up conclusions
• 19:07really didn't change from doctor calls.
• 19:08Mind you know it is true that
• 19:10time to send a toxic therapy was
• 19:13improved with maintenance or toxic,
• 19:15but the glass was kind of half
• 19:17half full in the sense that 63% of
• 19:19patients treated with retreatment
• 19:21remain chemo free at seven years.
• 19:23The duration response was certainly
• 19:25better with maintenance or Tux Mab,
• 19:27but he'd argued that 30% of
• 19:28patients received just 4 doses of
• 19:30rituximab in never needed treatment.
• 19:31Again for 10 plus years.
• 19:33And because overall survival
• 19:35benefit was identical.
• 19:36The treatment the Rituxan every
• 19:38treatment strategy rather
• 19:40than maintenance remained the
• 19:41recommendation of these investigators.
• 19:45So where do we stand in the spring of 2022?
• 19:48We have wonderful therapies for
• 19:50for patients with CLL and Lynn.
• 19:53On Hodgman, Thelma and we have
• 19:55to recognize that our therapy is,
• 19:57although they're wonderful,
• 19:58are not currative.
• 19:59Patients typically derive, you know,
• 20:02decade plus long benefits.
• 20:03And historically they've been poor.
• 20:05Correlation of first on
• 20:07PFS with overall survival,
• 20:08meaning that we can we can salvage our
• 20:10patients if they relapse and because of that,
• 20:12must much of my focus has been mainly.
• 20:15Maintaining good quality of life
• 20:16and and safety in there of COVID
• 20:19and what that really means is that
• 20:21actress surveillance and remains
• 20:22the standard of care for those
• 20:24that don't have clear indications
• 20:25for lymphoma directed treatment.
• 20:27It means educating patients really ad
• 20:29nauseum about vaccinations and early
• 20:32COVID testing as well as therapeutics.
• 20:34And then it means if if we do need treatment,
• 20:36which certainly some do shifting more
• 20:38towards the fixed duration therapies.
• 20:40Ultimately, as we move forward,
• 20:42I think MRD is an important outcome.
• 20:45But I also think that things
• 20:47like I mean reconstitution,
• 20:48quality of life and non formal related
• 20:50mortality but really important key
• 20:52metrics as we look at the future
• 20:54readouts of clinical trials and
• 20:56so with that I will move over to
• 20:58Doctor Kothari who will lead us in
• 21:00our presentation of diffuse large
• 21:02B cell phone mantels on phone.
• 21:16Thank you Scott.
• 21:18So I'm going to present on.
• 21:21DLBCL and Mantle cell lymphoma.
• 21:23Ash 2021. Highlights and for DLBCL.
• 21:26I would like to focus on
• 21:29two frontline studies,
• 21:30one being a Polaris which has been
• 21:32hotly debated and discussed in various
• 21:35forums after it was presented as
• 21:37a late breaking abstract and then
• 21:39use of high dose methotrexate to
• 21:42reduce CNS relapse which was a big
• 21:47retrospective analysis that we'll
• 21:49discuss in mantle cell lymphoma.
• 21:51I'll discuss.
• 21:51From the front line, long term data on MCL.
• 21:54One younger trial,
• 21:56which is which uses hydro site urban
• 21:59containing regimens compared to R
• 22:02Chop and then in maintenance setting.
• 22:04Use of R-squared which is limited
• 22:07with rituximab versus rituximab.
• 22:08After first line in elderly patients
• 22:11and then in relapsed refractory
• 22:13setting glue which is a bite.
• 22:16Bispecific T cell engager
• 22:17after we take a I failure.
• 22:22Here are my disclosures.
• 22:25So this was probably one of the most
• 22:30exciting trials that were, you know,
• 22:33discussed and presented at ASH 2021,
• 22:35which potentially changes
• 22:37our frontline care in DLBCL.
• 22:40And hence I would like to discuss this
• 22:43so there's a bullet is alive with Odin,
• 22:45is an antibody drug conjugate which
• 22:48targets CD79-B and eventually leads to
• 22:52microtubule disruption and epic ptosis.
• 22:55And you know it was.
• 22:57It has been extensively studied and
• 23:00now approved in combination with.
• 23:02In the relapsed refractory setting.
• 23:06So the researchers here studied
• 23:10patients who were previously untreated,
• 23:12had done previously untreated
• 23:14DLBCL age 18 to 8 years.
• 23:16IPI score of two to 5 = 0 to 2.
• 23:22With stratification factors
• 23:23as mentioned here.
• 23:25Randomize one to one between
• 23:27Polar archip versus R chop.
• 23:29So when Christine was swapped
• 23:31with a political map, dowtin.
• 23:34And it's important to note that it is
• 23:36a randomized double blinded study,
• 23:37so the investigators or patients had no,
• 23:40I did not know what therapy
• 23:43they were receiving.
• 23:45And this was followed by
• 23:46two cycles of rituximab.
• 23:47This was mainly to satisfy European
• 23:51regulatory requirements as eight cycles
• 23:54of therapy is a standard in Europe.
• 23:58The primary endpoint was
• 23:59progression free survival,
• 24:00which was investigator assessed.
• 24:02Secondary endpoints are listed here.
• 24:07And these were the demographic and
• 24:09clinical characteristics at baseline,
• 24:10so you know it's very well balanced.
• 24:13The important things to note here
• 24:16are there are 10% of patients
• 24:18with early stage disease and 90%
• 24:21with stage three or four disease,
• 24:24and IPI score of two was in
• 24:28approximately 38% of patients
• 24:30versus 62% were three to five,
• 24:33and it was well balanced between ABC and.
• 24:37Subtype, interestingly,
• 24:38there were double expressor lymphomas
• 24:41quite heavily represented,
• 24:4338% versus 41%,
• 24:46and double hit lymphoma or triple in
• 24:50lymphomas were 8% and 6% respectively.
• 24:55So these are the curves,
• 24:57the number one being investigated as
• 25:00assessed progression free survival,
• 25:02which was the primary endpoint of this trial,
• 25:05and the hazard ratio was of 0.73 not
• 25:09crossing one with P value of 0.02,
• 25:12showing statistical significance of
• 25:15polar chip in comparison to our chalk.
• 25:20If you if you see here the overall
• 25:23survival then you clearly there is no
• 25:25overall survival benefit at at at the
• 25:28short term follow-up so far with a P
• 25:31value of 0.75 and hazard ratio of 0.94.
• 25:37Interestingly, this is is assessment
• 25:39of patients who received subsequent
• 25:42treatments after this frontline therapy.
• 25:44And clearly if you count
• 25:46any modality of treatment,
• 25:48then our top armed patients
• 25:50got substantially more.
• 25:5230% of patients got received.
• 25:55Subsequent treatments versus
• 25:57only 22.5% in polar artship.
• 26:02This is the subgroup analysis and I
• 26:04would like to draw your attention,
• 26:06although we would you know caution in making
• 26:09any too strong of conclusions here, but.
• 26:14Monkey disease if it was absent
• 26:16at polar Chip, showed more
• 26:18statistically significant advantage.
• 26:20ABC seller Origin, you know,
• 26:24pull our chip bit better in that
• 26:28and IPI score of three to five
• 26:31versus 2 polar chips seem to
• 26:33do better in those subgroups.
• 26:39Common adverse events.
• 26:40This is, I think, a very important slide,
• 26:42because this really tells us that the
• 26:45double blinded portion of the study
• 26:47worked well because it's identical
• 26:49between polar chip and our chop,
• 26:51including peripheral neuropathy incidents.
• 26:53There was slight higher rate of
• 26:57higher grade febrile neutropenia
• 26:58in polar archip versus R chop,
• 27:01but the rest of the side
• 27:02effects are pretty compatible.
• 27:06So the way I see this trial is
• 27:08very nicely depicted in this figure
• 27:10from a cancer cell paper published
• 27:13recently by Doctor Chu is essentially
• 27:16a patients who are at have higher
• 27:20IPI score in the current setting.
• 27:22They would get our chop and when they
• 27:23fail they would be in this pool to
• 27:25get autologous stem cell transplant
• 27:27or they would have failed and they
• 27:29would have gotten a salvage regimens.
• 27:31In the future we would re stratify
• 27:34them based on their IPI score.
• 27:36I remember that 225 was the
• 27:38inclusion criteria,
• 27:38subgroup was for the three to five,
• 27:40showing more advantage,
• 27:42but all you know the inclusion
• 27:46criteria was two to five.
• 27:48And then you would basically give
• 27:50our choppin lower IPI score.
• 27:52Patients and polar ship in the higher ones,
• 27:55and then you would have less patience.
• 27:57Who would relapse and the ones
• 27:59who would relapse.
• 28:00You have now options of autologous
• 28:02stem cell transplant if they
• 28:03have relapsed after 12 months,
• 28:05or they have achieved complete remission
• 28:08from salvage regimen or car T cell therapy,
• 28:12and if they fail then to move
• 28:13on to salvage regimen.
• 28:15So this way we hope that we
• 28:17have less patience.
• 28:18In this pool to treat.
• 28:24So my final thoughts on the politics
• 28:26trial is that PFS benefit from a well
• 28:29designed randomized control trial
• 28:31in this population is meaningful.
• 28:33Regulatory approval is pending.
• 28:36Currently, long term data will guide
• 28:38further use subgroup analysis is only
• 28:41hypothesis generating no known biological
• 28:43rationale for higher responses in ABC.
• 28:46DLBCL is known so far.
• 28:48What will be the role of polit ISM and we
• 28:50wrote in and relaxed refractory DLBCL.
• 28:52Uh, because we all use polar,
• 28:55quite commonly in relapsed
• 28:57refractory setting as salvage,
• 28:59and that is going to become a problem
• 29:02once polatuzumab wrote in moves frontline.
• 29:05The good news is that we have
• 29:07other approved therapies like Tafel
• 29:09in and Lanka struck some AB,
• 29:11so hopefully we'll have more approvals
• 29:13in the future and we can expand our
• 29:17relapsed refractory repertoire.
• 29:18While the differences are statistically
• 29:21and clinically meaningful,
• 29:22this is not a game changer.
• 29:24Other class of drugs like bites and
• 29:26car T cells should and are being
• 29:28studied in frontline,
• 29:29especially in high risk disease.
• 29:32Financial toxicity is real and
• 29:34should be discussed with patients
• 29:36on a case by case basis.
• 29:402nd is hydro methotrexate is not associated
• 29:43with reduction in CNS relapse in patients
• 29:46with aggressive B cell lymphoma and
• 29:48international retrospective study of
• 29:512300 patients presented by Doctor Lewis.
• 29:56So we know that CNS IPI score is helpful
• 29:58in knowing what kind of patients are
• 30:01going to have a CNS relapse at are
• 30:03at a higher risk of CNS relapse.
• 30:06But overall patients with those high risk
• 30:10features they fare poorly and much needs
• 30:14to be done to prevent these relapses,
• 30:18so there is no consensus on what CNS
• 30:21directed prophylactic therapy should be
• 30:24given and how it should be incorporated.
• 30:26Into the systemic therapy backbone.
• 30:30Many centers, including Yale,
• 30:32we we have used hydro methotrexate,
• 30:34which we hope mitigate CNS risk
• 30:37based on some retrospective studies.
• 30:39In the past there is no prospective
• 30:41data to guide our treatment.
• 30:43So this eligibility criteria was
• 30:45patients with CNS IP S score of
• 30:48426 high grade B cell lymphomas,
• 30:50where we automatically give
• 30:52CNS prophylaxis therapy,
• 30:54primary breast or testicular DLBCL with the
• 30:58rest of the inclusion criteria shown here.
• 31:01Including exclusion being CNS
• 31:04involvement by lymphoma at diagnosis.
• 31:092300 patients were enrolled and.
• 31:13Almost 2000 to 1800 patients did
• 31:15not get high dose methotrexate
• 31:16versus 400 patients got high dose
• 31:19methotrexate and out of those patients
• 31:21who got high dose methotrexate,
• 31:23CNS relapse was observed in
• 31:2631 patients which is 8%.
• 31:31Just to draw your attention to
• 31:34the fact that really it was,
• 31:37you know, but it percentage wise,
• 31:40well balanced study including the E,
• 31:44COG and B symptoms.
• 31:47And external sites,
• 31:48which was of course heavily heavily
• 31:51represented in high dose methotrexate group.
• 31:54Here I would like to draw your attention
• 31:56to the high risk extranodal sites.
• 31:58So clearly we have more representation
• 32:00of those patients in the high dose
• 32:03methotrexate group as we would have
• 32:06expected and in as you go higher
• 32:08up in the number of external sites
• 32:10you have high representation in
• 32:12the high dose methotrexate group
• 32:14as we would have expected.
• 32:17These these are the results,
• 32:18so in all patients,
• 32:20cumulative incidence of CNS relapse
• 32:22was not statistically significant
• 32:24between these two groups.
• 32:27It shows 9.2% in Hydros method exit
• 32:29group and eight point 1% in in patients
• 32:33who did not get high dose methotrexate.
• 32:36The similar results hold true
• 32:38for patients who achieved CR,
• 32:40so this is a subgroup analysis.
• 32:46And this is the site of CNS relapse,
• 32:48which I thought was very interesting.
• 32:50So patients who did get high dose
• 32:53methotrexate they saw less of
• 32:55parent kaimal relapse versus they
• 32:57saw higher leptomeningeal relapse.
• 32:58So that brings into question
• 33:00whether a dual strategy of high
• 33:02dose methotrexate with intrathecal
• 33:03methotrexate would be appropriate.
• 33:05Although there is no data to support that.
• 33:11And then the group describes
• 33:13multiple subgroup analysis based
• 33:15on number of external sites.
• 33:17Specific external site involvement,
• 33:19CNS IPI score and the dosage of high dose
• 33:24methotrexate and so on and so forth.
• 33:26But none of these subgroup analysis showed
• 33:28any statistical or clinically meaningful
• 33:30difference between the two groups.
• 33:39So in conclusion, in the largest
• 33:41study to date, investigating
• 33:42efficacy of high dose methotrexate.
• 33:46In reducing CNS relapse in high risk
• 33:48patients, high dose methotrexate was not
• 33:50associated with reduction in CNS relapse.
• 33:52In overall, for patients within
• 33:54CR or in any high risk subgroup.
• 34:00Up next I would like to move to
• 34:04mantle cell lymphoma and discuss
• 34:06addition of hydro site therapy into
• 34:09immunochemotherapy before autologous
• 34:10stem cell transplantation in patients
• 34:12aged 65 years or younger with MCL
• 34:15known as the MCL one younger study.
• 34:19497 patients were randomized between control,
• 34:22which is our chop and experimental group
• 34:24being our chop alternating with our dehab,
• 34:27which can contain Sitara green.
• 34:31The results in which were initially 1st
• 34:33results published in 2016 are shown here,
• 34:36which I'm going to skip over.
• 34:39The updated results from 2021 are shown here,
• 34:44so you see that there is significant
• 34:46difference between the site urban
• 34:48containing regimen versus our chop.
• 34:50With trying to treatment failure
• 34:538.4 years in our dehab arm
• 34:55versus four years in our chop.
• 34:59Similar results hold true for in PFS,
• 35:03looking at from randomization from end of
• 35:07induction and from a stem cell transplant
• 35:10and you know this is very striking.
• 35:13To note that eight years was the
• 35:16median PFS in our chat party help arm,
• 35:19which is quite significant.
• 35:24Overall survival when you look at all
• 35:27comers and intention to treat population,
• 35:30there was no statistically
• 35:32significant difference.
• 35:33But if you stratify them by nippy
• 35:35then there was statistical least
• 35:37significant difference with hazard
• 35:39ratio of .74 not crossing the midline.
• 35:45And these are the highest highest subgroup
• 35:48stratification curves for all survival.
• 35:51So here you have high
• 35:52risk in defined by high,
• 35:53intermediate or high MIDI score.
• 35:55High High P53, MHC or BLASTOID variant,
• 36:00and versus low risk where you
• 36:03have no statistically significant
• 36:05difference between the two parks.
• 36:08So conclusions are that hydro site have
• 36:10been containing induction and autologous
• 36:12stem cell transplant achieves 60%.
• 36:1660% survival at 10 years
• 36:18with acceptable toxicity.
• 36:20Benefits of hydro cytarabine in
• 36:22high and low low risk patients.
• 36:24Was observed was significantly
• 36:26improved when adjusted to 67.
• 36:29Open questions still remain.
• 36:31Salvage treatment in art shop
• 36:33patients and avoidance of TBI
• 36:36may reduce rates of secondary
• 36:38malignancies in in both arms.
• 36:44Next, I'll quickly discuss rituximab,
• 36:47a little mild maintenance,
• 36:49superior to rituximab maintenance after
• 36:51Firstline Immunochemotherapy in MCL,
• 36:54which was the R-squared,
• 36:56elderly Merle clinical trial. Uhm?
• 37:02And, uh, another abstract
• 37:04from the same trial.
• 37:07Looking at MRD and its prognostic
• 37:10value in the same trial.
• 37:12So this trial randomized 620 patients
• 37:16between control arm where 312 patients
• 37:20got our chopped versus cytarabine
• 37:22containing regimen which incorporated art
• 37:25shop alternating with hydro cytarabine.
• 37:28And then there was second randomization
• 37:31for patients who achieved a CR.
• 37:34Between R&R squared maintenance.
• 37:39So I'm not going to go over
• 37:41these patient characteristics.
• 37:42They are well balanced in both
• 37:45the arms and same thing holds true
• 37:48for the maintenance arm as well.
• 37:51These were the safety profile differences,
• 37:54quite significant blood and lymphatic
• 37:56system disorders were observed
• 37:59in R-squared versus hour and not
• 38:02unexpectedly higher grades of neutropenia,
• 38:05anemia and infections were
• 38:07observed in the R-squared arm.
• 38:10Well, these are the PFS and OS curves.
• 38:13There was no OS difference between the two.
• 38:15While there was a higher PFS
• 38:18benefit in the R-squared arm.
• 38:21What I found most interesting was the
• 38:24MRD analysis on in on this set of
• 38:28patients where we found paradoxically
• 38:30improved PFS in the R-squared arm in MRD
• 38:35negative patients versus MRD positive.
• 38:38The difference is quite striking
• 38:4161% versus 84%.
• 38:44So the conclusions are,
• 38:46I think,
• 38:48mainly that there is an MRD
• 38:50below the detection threshold of
• 38:53the currently used technique.
• 38:55Clearly,
• 38:55since there was improvement in
• 38:58the experimental arm which added
• 39:00in negative patients,
• 39:02so we have to take murded studies
• 39:05and you know analyze them carefully
• 39:09before making any big conclusions.
• 39:12Lastly,
• 39:12I would like to show a couple
• 39:14of slides on to fit the map.
• 39:15A step up dosing in relapse,
• 39:18refractory mantle cell lymphoma
• 39:20who had paid failed priority care
• 39:22therapy presented by Doctor Phillips.
• 39:25Blue Phantom AB is a 20CD3 bispecific
• 39:29antibody engager with two is
• 39:3121 configuration as shown here.
• 39:35This was done in combination
• 39:38with obinutuzumab.
• 39:39Either invest fixed dozing or step up dozing.
• 39:42What I want to draw your attention
• 39:44to is most patients.
• 39:4669% of patients had relapsed after
• 39:50therapy and many of these patients
• 39:53were refractory to prior therapy.
• 39:5690% of them including refractory
• 39:58to first line therapy.
• 40:00In half of the patients.
• 40:03Serious adverse events were
• 40:06observed in in this small study,
• 40:09including 62% of patients,
• 40:12most of them being related to Blue Fit map.
• 40:15But important to note that no
• 40:18adverse events leading to treatment
• 40:20discontinuation were reported.
• 40:22And these are the adverse events.
• 40:26Cytokine release syndrome
• 40:27being the most common one.
• 40:30This is why I thought of
• 40:32presenting this trial here.
• 40:33Very high CR rates and over our
• 40:38rates 67% in all patients and CR
• 40:42versus 81% overall response rate,
• 40:46especially in patients who
• 40:48have received prior therapy.
• 40:51So we believe that bytes bytes
• 40:55specific bispecific T cell engagers are
• 40:57going to play an important role in.
• 41:00Refractory mantle cell lymphoma
• 41:02in the future.
• 41:03Thank you and I'll pass on
• 41:05to Doctor Kirschen Sethi,
• 41:07who will present in Hodgkin
• 41:09lymphoma and diesel lymphomas.
• 41:14Hi everyone, while I'm
• 41:15trying to share my slides.
• 41:17Thank you so much for joining us.
• 41:35Alright, so I'm going to.
• 41:37I have no relevant disclosures.
• 41:38I'm going to start with Hodgkin lymphoma.
• 41:41My intention is to do a
• 41:43very broad overview of.
• 41:46Where the field is moving and
• 41:48both of these topics are.
• 41:50That is Hodgkin and T cell lymphomas.
• 41:54So first we'll start with some
• 41:56frontline trials in Hodgkin
• 41:58lymphoma and then moving on to
• 42:00some relapsed refractory trials.
• 42:02I think it's just important to note that
• 42:04all of these are basically checkpoint
• 42:06therapy based studies that I had I have.
• 42:10Included here,
• 42:11as you can see here,
• 42:14you know checkpoint in a better
• 42:16therapy is being brought into the
• 42:18frontline in Hodgkin lymphoma.
• 42:19In the in the hope of improving long
• 42:23term outcome while reducing toxicity and
• 42:26then at the same time you we also have.
• 42:30You know, relapse refractory.
• 42:33Specially the population that
• 42:35relapses post autologous stem
• 42:37cell transplant and there is a,
• 42:40uh, a need for.
• 42:42Therapy in patients who fail
• 42:44both been tax map and checkpoint
• 42:46inhibition in that line,
• 42:48and so that's where some of
• 42:49most of these studies are.
• 42:53That's the the the therapy they need
• 42:56that these studies are addressing.
• 42:58So first the frontline of the
• 43:00study that I'd like to mention
• 43:02is the by Doctor Alan at Emory,
• 43:06and this was looking at
• 43:08single agent pembrolizumab.
• 43:09I've followed by avd.
• 43:11For classical Hodgkin lymphoma,
• 43:13so this is Brett.
• 43:15This particular presentation was an
• 43:18update from a prior ASH presentation
• 43:21where they had presented the primary
• 43:24endpoint that is the complete metabolic
• 43:26response rate by pet city initially.
• 43:28So the brief background of this
• 43:30study was that as we know, 9 feet,
• 43:3424.1 amplification is common in
• 43:37patients with Hodgkin lymphoma.
• 43:39And so this study by design was.
• 43:43You had the lead in pembrolizumab
• 43:45primarily to be able to get some.
• 43:48Correlated data for febrile alone
• 43:51in these patients and to be able to.
• 43:54Again, see what is it that is
• 43:58correlating with both response
• 44:01and prognosis in these patients?
• 44:03So this particular abstract was
• 44:06presenting the secondary endpoints
• 44:08of updated PFS and overall survival
• 44:11at around the 33 month follow up,
• 44:14and then also further correlative studies.
• 44:18So this as I mentioned it was
• 44:21sequential Pembroke followed by Avd.
• 44:24The after the initial PET scan 3 cycles
• 44:28of pembrolizumab was were given and
• 44:30then the second PET scan was obtained.
• 44:33At this point of time,
• 44:35the primary endpoint of complete
• 44:36of metabolic is complete.
• 44:38Metabolic response was assessed
• 44:40and then in addition they did.
• 44:44Correlative studies that included both
• 44:47immunohistochemistry as well as fish 9.
• 44:50P, 24.1 alterations.
• 44:51Then patients went on to receive a video.
• 44:57So as you can see here, the median age.
• 45:01For this patient, cohort was 29,
• 45:04but they did include patients
• 45:06up to 77 years of age and
• 45:08about 15% for elderly patients.
• 45:12They enrolled a total of 30 patients and.
• 45:1760% were advanced stage
• 45:19Hodgkin and 40% were early.
• 45:23Unfavorable Hodgkin.
• 45:25So on the top right of the
• 45:28slide you can see that.
• 45:31The there basically assessment of
• 45:34the complete metabolic response
• 45:36after three cycles of pembrolizumab.
• 45:38They defined a parameter called near
• 45:42complete medical complete metabolic response,
• 45:44which was defined as more than 90%
• 45:47in metabolically active tumor volume,
• 45:51and they found that nearly that CR,
• 45:54along with near CR was seen in
• 45:57about 63% of patients that embryo
• 46:00alone in the frontline.
• 46:04And the remaining patients
• 46:05had a partial response.
• 46:07In addition, they also looked at.
• 46:12At this time, they reported updated
• 46:15PFS and overall survival data,
• 46:17which showed 100% progression free
• 46:20survival as well as overall survival
• 46:23at a median follow-up of 33 months.
• 46:26In addition, there.
• 46:28This study was very well designed
• 46:30in terms of Correlators after the
• 46:32lead in Pember Lizum app and they
• 46:36noted that alterations of 1924.1,
• 46:39which they defined as either die.
• 46:41So my polysemy copy number gain or
• 46:44amplification was present in one sum,
• 46:47one form or the other in all of the patients.
• 46:51It's 100% of the patients
• 46:53that they had tissue on,
• 46:55which is 28 out of the 30 patients.
• 46:57And.
• 46:59In looking at a more the
• 47:03immunohistochemistry they calculated
• 47:04and age score which was combining
• 47:07the intensity and intensity of PDL 1.
• 47:11Staining along with the percentage
• 47:13of cells that were positive.
• 47:16And they compared both of these to
• 47:20the response to response between
• 47:22responders and non responders.
• 47:24And they did not find any correlation
• 47:26between PDF and pathway markers and response.
• 47:30So in conclusion, this.
• 47:35Was a pretty well tolerated
• 47:38regiment where no additional
• 47:40signal of safety was seen and.
• 47:44Their base they looked at long term
• 47:49into 33 month overall survival at PFS,
• 47:52which was both 100%,
• 47:54so it was fairly effective regimen,
• 47:57and along with that they did not find any
• 48:01correlation between the PD one pathway
• 48:02markers and the depth of response.
• 48:04So they basically they were.
• 48:06They implied that you could see
• 48:09favorable responses and even in patients
• 48:11who had low PD L1 positive ITI.
• 48:14So this combination and are now going
• 48:17to be studied in phase three trial and
• 48:21again one of the active combinations in
• 48:26frontline using checkpoint inhibition.
• 48:28I'm only going to briefly going to go
• 48:31through the concurrent Pembroke and DVD data.
• 48:34Again.
• 48:34This was frontline here.
• 48:36There was no lead in and this
• 48:38this was basically.
• 48:40I bought the drugs were given concurrently
• 48:43and one difference between the prior
• 48:45study and this was that this was
• 48:47primarily a safety signal study that
• 48:49was the primary endpoint and then the
• 48:51secondary endpoint was the CR rate.
• 48:55So in this particular.
• 48:58Study they assess response
• 49:00after two cycles of Pembroke,
• 49:03given concurrently with Avd and
• 49:06then depending upon the stage.
• 49:09Because this study included
• 49:11patients through all stages.
• 49:14If you look at the patient characteristics,
• 49:16it included patients that were
• 49:18stay as as early as stage one
• 49:21to stage through stage four,
• 49:23so the total number of cycles
• 49:25really depend on what the stage was.
• 49:28But since their primary endpoint
• 49:30was safety after two cycles,
• 49:32they and the main secondary endpoint
• 49:35was response after two cycles that.
• 49:40So that was assessed basically regardless
• 49:41of the total number of titles.
• 49:48So since the primary endpoint was safety,
• 49:51they showed that the main.
• 49:55Non habit illogical.
• 49:57Side effects that were grade
• 50:00grade three or four they were.
• 50:03Very minimal and in terms of
• 50:05immune related side effects,
• 50:07they had grade 3-4 transmitters,
• 50:11specifically the the one patient
• 50:13with grilled 4 transmitters.
• 50:15They had a concurrent use
• 50:17of over the counter CBD oil.
• 50:19It appears like so they it was.
• 50:22They were not sure whether it
• 50:25was truly drug related versus
• 50:26related to this CBD oil use,
• 50:29but and then there were a few patients.
• 50:32Three patients with grade 3.
• 50:34Transformers and all of
• 50:36those cases were reversible,
• 50:37so overall,
• 50:38this regimen was thought to
• 50:41be well tolerated.
• 50:45In, when the two when immune
• 50:48checkpoint inhibitor and
• 50:49chemotherapy was given concurrently.
• 50:52Their pet two CR rate,
• 50:53which was the secondary endpoint,
• 50:54was 66% in all patients.
• 50:58The overall response rate was 100%.
• 51:03They reported a median follow at a
• 51:06median follow-up of 16.2 months.
• 51:08They reported a PFS in overall survival of.
• 51:14So. Basically,
• 51:17the median was not reached and.
• 51:20The one year old also I was
• 51:23100% one year, PFS was 96%.
• 51:27I think one important thing that is
• 51:29important that is keep to both of
• 51:31these studies in the frontline is that
• 51:34immune checkpoint in a better use.
• 51:37Stand result in.
• 51:39So PET scans cannot are probably
• 51:42not as it's not as straightforward.
• 51:45How do you interpret PET scans in the
• 51:49setting of immune checkpoint inhibitors?
• 51:51And so it would make sense to look
• 51:55at novel things like there is.
• 51:58There are the lyric criteria for pet
• 52:00city in patients with immune checkpoint
• 52:03in a better doctor Alan study looked at.
• 52:08The total metabolic tumor volume
• 52:10in this particular study looked
• 52:12at circulating tumor DNA and the
• 52:15reported cases where the circulating
• 52:18tumor DNA was both more sensitive
• 52:20and specific measure of residual
• 52:22disease rather than pet city.
• 52:26So. In conclusion, this was
• 52:29a safe and effective regimen,
• 52:32again given in concurrently in the frontline,
• 52:35and again one of the ways that we we see
• 52:40checkpoint inhibition being incorporated
• 52:42into the frontline and Hodgkin.
• 52:45OK, so I'm going to quickly go through
• 52:48three relapse or practice studies
• 52:50that are looking at checkpoint
• 52:52inhibition combinations in relapsed
• 52:55refractory Hodgkin lymphoma.
• 52:57The 1st of this is using drugs.
• 52:59The Jack 2 inhibitor and this is
• 53:01based on the rationale that nine
• 53:04P 24.1 amplification results in
• 53:07amplification not only of the PDL 1
• 53:11PDL 2 pathway but also of Jack 2. And.
• 53:15So that was part of the rationale,
• 53:17and so they used a combination
• 53:22of nivolumab with ruxolitinib and
• 53:25they did a 3 doors, tested 3 doors,
• 53:28levels of regulator there.
• 53:32Again, this was the patient population.
• 53:34Here was checkpoint inhibitor
• 53:36refractory so that the patient had
• 53:38already progressed on a checkpoint in
• 53:40a bit or single agent therapy before.
• 53:44So the median age of all
• 53:46patients with 38 years and.
• 53:5032% of the patients had had a prior
• 53:54autologous stem cell transplant.
• 53:58So here they saw they reported.
• 54:02Overall response rate of
• 54:0548% and the CR rate of 24%.
• 54:11The total duration of response
• 54:14you can see here that there were
• 54:17several patients that were still.
• 54:20Had continued response especially.
• 54:26So especially those who had complete
• 54:29response with this combination.
• 54:45Sorry so. As you can see here,
• 54:48the they reported the PFS and
• 54:51OS said two years it was,
• 54:53which was were 46% and 87% respectively.
• 54:57In this multiple refractory population.
• 55:03Most side effects were grade one and two,
• 55:06and primarily consisted of him,
• 55:08hematological side effects
• 55:09as well as GI side effects.
• 55:13And the immune related side
• 55:15effects that were seen were
• 55:16mostly hepatitis and pneumonitis,
• 55:18and all these were reversible.
• 55:21So in the correlative studies,
• 55:23they looked at MD after insulating them.
• 55:26And. They found that there
• 55:28was decreased expression of.
• 55:32With the use of this combination.
• 55:36So overall this was again found to be a safe.
• 55:41Combination in multiplicity refractory
• 55:44population including basically all patients
• 55:46were checkpoint in a better refractory.
• 55:49So I'm going to pause here because
• 55:51in the interest of time. And.
• 56:05Hi, we're coming up to
• 56:06the hour and I know people
• 56:08want to use their one o'clock to
• 56:09perhaps get outside and do some of
• 56:11those nice weather. So there's two.
• 56:13I think questions that I have.
• 56:16Induction appreciate the same
• 56:18one I had which was to Torshin
• 56:21in terms of frontline Hodgkin.
• 56:23You know PFS ruling overall
• 56:26survival for that.
• 56:27That one analysis out of Emory shows
• 56:30really great with Checkpoint ABA VD,
• 56:32but we also have good data on BVD.
• 56:34How do how do you think we move forward?
• 56:37Do we have a study for that?
• 56:39Where are we in terms of
• 56:40addressing that question?
• 56:42So I believe that there is a.
• 56:46There is a frontline study that is
• 56:49looking at the comparison between those
• 56:51two that can help answer that question,
• 56:53but at this point it seems like so as far
• 56:56as this particular study was concerned,
• 56:58Pembroke followed by it
• 57:00did include bulky patients.
• 57:02What they found was that most of
• 57:04the patients were bulky disease.
• 57:06After three cycles of Femoro alone they
• 57:09had a near complete metabolic response,
• 57:11not necessarily complete metabolic response.
• 57:13That was kind of one of the differentiating
• 57:16features in that particular study.
• 57:17But at the same time,
• 57:18when it comes to immunotherapy,
• 57:19it's very hard to interpret a lot
• 57:22of the patients, like for example.
• 57:24Even in the second study,
• 57:25the pet 2 positivity did not
• 57:28correlate with early relapse.
• 57:30So the it's not the same as what
• 57:32we see with non immuno therapeutic
• 57:34agents like you can sometimes
• 57:36have long term responders even if
• 57:39they have initial positivity.
• 57:41So
• 57:41and then I guess the question is
• 57:43is sequential versus concurrent.
• 57:45Do you think we need a trial randomized
• 57:47trial to really address the the
• 57:49appropriate timing of checkpoint with avd?
• 57:53In the second study,
• 57:54I think the first study was more.
• 57:56The design was more to understand.
• 57:59It was a few years it was started a
• 58:01few years ago where we didn't know a
• 58:04lot about the correlated correlations
• 58:06for this particular for Pember alone
• 58:08and the efficacy of Pembroke loan,
• 58:10and that was the reason to do the lead
• 58:12in rather than the safety measure,
• 58:14since the second study is already
• 58:16telling us that there is,
• 58:17it's safe to do the combination.
• 58:18I feel like similar to what we do with BV,
• 58:21like AVD versus BB followed by avd.
• 58:25I feel like both of those can be
• 58:28reasonable options, it seems like.
• 58:31That's helpful, thank you and
• 58:32then the one thought I had before
• 58:34we open it up to the audience.
• 58:35If there's questions, please,
• 58:37please send them in was to Doctor
• 58:39Kathari in terms of the long
• 58:41term data from Nordic and and
• 58:43the study that you presented is
• 58:44anthracycline followed by hydac.
• 58:46Do you do that or do you use
• 58:48bendamustine with your induction?
• 58:50You know how do?
• 58:51How do you put that all together?
• 58:53Yeah, so there are multiple backbones
• 58:56that that have been studied,
• 58:58but I must admit that the most studied
• 59:02regimen, and now with this data,
• 59:04especially with you know high risk
• 59:06patients having a survival benefit would
• 59:09be our chop alternating with our dehab.
• 59:11But you know there is a Nordic regimen
• 59:14where you alternate art shop with
• 59:16hydro cytarabine and then you have a
• 59:19you know sort of more of a US regimen
• 59:21of Arminda alternating with our site.
• 59:23And again, these are all high doses.
• 59:26These macaroons have been studied
• 59:30and compared with each other but
• 59:31without the site are being part.
• 59:33So, for example,
• 59:34our chop was compared with our vendor.
• 59:36So we are extrapolating that you
• 59:38know our Brenda is better than
• 59:41our top end would be better even
• 59:43when combined with a high dose.
• 59:46Of course there are some early stage,
• 59:48you know,
• 59:48small patient series of prospective
• 59:51trials of doing of using our Bender
• 59:54alternative with our high dose side.
• 59:57So what all to to answer your question,
• 60:00there are multiple possibilities
• 01:00:01in frontline mantle cell lymphoma
• 01:00:03and we really haven't established
• 01:00:051 standard of care like we have in
• 01:00:08diffuse large B cell lymphoma and
• 01:00:10that's something it remains still a bit
• 01:00:12elusive as to what will we'll all use,
• 01:00:15but you know,
• 01:00:16I think it's it's a good problem to
• 01:00:18have where you know you can really
• 01:00:20customize therapy based on the patient,
• 01:00:22comorbidities and age and stratification.
• 01:00:27Thank
• 01:00:27you why we're over the hour and I want to
• 01:00:29thank all the attendees for joining today.
• 01:00:31Feel free to email each of us if
• 01:00:33you have questions about specific
• 01:00:36presentations we you know went over
• 01:00:38today and how we interpret that
• 01:00:39and how we approach our patients.
• 01:00:41We'd be happy to to engage over that,
• 01:00:43but enjoy your Friday and thanks for joining.