Yale ASH 2022 Highlights: Cellular Therapies

March 13, 2023

Information

March 10, 2023 | Hosted by Dr. Stuart Seropian

Presentation from: Dr. Iris Isufi

ID9655

To CiteDCA Citation Guide

00:00OK. Good afternoon, everybody.
00:04Welcome to our. Next, ash review.
00:08This is a review on cellular therapies,
00:12and we have, I think,
00:142 exciting presentations
00:16for you this afternoon.
00:18The first is going to be with
00:20Doctor Iris Isufi. Dr.
00:21Isufi is associate professor in the
00:24Department of Medicine and Hematology
00:27in the Yale Cancer Center and the
00:30director of our Cell Therapy research
00:33team and our Clinical Care T.
00:37Program and she's gonna talk to
00:39you about some advances in cell
00:42therapy at the latest ash meeting.
00:44So, Doctor Suffi, take it away.
00:49Thank you Stuart. I'm gonna share my screen.
01:00Before you start, can I just
01:02remind everybody if you'd like
01:04to submit questions, there will
01:06be a question and answer period.
01:09Possibly between the
01:10presentations and at the end,
01:12but you can submit questions
01:15through the chat or Q&amp;A during the
01:19talk and we'll possibly answer
01:22them during or during during the
01:25talks or at the end. OK.
01:30Thanks. So I'll take welcome everyone.
01:32I'll take the first half of the session
01:35just to present some of the ash data
01:39on cell therapies and I know this
01:43was talked about that the myeloma.
01:46View as well, but today I'll focus
01:49particularly on non Hodgkin lymphomas
01:52and some also exciting data on AL.
01:59These are my disclosures. So the 1st.
02:08Presentation, the first abstract
02:10that I wanted to present is abstract
02:13655 that's looking at Lysol cell,
02:16Lysol catagen, mariluz cell and this
02:21is a cellular therapy product that is
02:26different from the prior ones on the
02:29market because it has a defined CD4
02:32to CD8 ratio and this has already been
02:35approved in the third line setting.
02:38And more recently also in the second
02:40line setting for diffuse large
02:42B cell lymphoma, so.
02:45Here they presented their primary
02:47analysis of the randomized phase
02:50three transform study where lyso
02:53cell was compared to standard of care
02:57with salvage chemotherapy alone,
02:59so patients had a good performance status.
03:02The ones that were randomized to the
03:07standard of care arm who had relapsed.
03:11Um were randomized to receive 3
03:14cycles of chemo immunotherapy.
03:16These were high risk patients.
03:17They were patients who were either
03:20primary refractory to their first line
03:22or patients who had relapsed within
03:2412 months of their initial therapy.
03:26So they took this highest risk group
03:28to compare it to stem cell transplant.
03:30And so the patients who received
03:33salvage chemotherapy and achieved
03:35either a complete or a good partial
03:37response proceeded to high dose
03:40chemotherapy and autologous.
03:41Them self rescue a typically with
03:44a beam regimen and then.
03:47The other arm was randomized to receive
03:50lysis cell and so they underwent
03:52lymphodepletion with fludarabine
03:54and cyclophosphamide and they were
03:57allowed to get some bridging if their
03:59disease was rapidly progressing.
04:01Importantly,
04:02in this trial,
04:04crossover was allowed for patients
04:07who received standard of care and
04:10were not deemed to be good candidates
04:13for autologous stem cell transplant.
04:16For multiple reasons.
04:17So they crossed over and the primary
04:20endpoint was event free survival and
04:22then they looked at complete response rates,
04:25progression free and overall survival.
04:28They do have now a 17.5 month follow up.
04:31And you know that's important because
04:34we know that the majority of these
04:36patients with primary refractory or
04:39early relapse disease will again
04:41relapse within typically within
04:43the first year of of salvage.
04:46So, uh,
04:46with that median follow-up you can see here,
04:50there was a significant improvement
04:52in the event free survival where
04:54the median event free survival was
04:56actually not reached compared to
04:58a median event free survival of
05:01only 2.4 months in.
05:02The standard of care arm with
05:05stem cell transplant with a with
05:08a hazard ratio of 0.35.
05:13And this was.
05:16For a self therapy trial,
05:17relatively large trial
05:20with about 184 patients,
05:2292 on each arm.
05:24So you can see here that for their
05:28secondary endpoints there is also
05:31statistically significant complete
05:33response rate of 68% compared to
05:3640% in the standard of care arm and
05:39an improvement in progression free
05:42survival that was not reached for the cell.
05:46Therapy group versus only 6.2 months in
05:48the standard of care arm for patients
05:51who received chemotherapy and transplant.
05:53And importantly,
05:55despite 67% of patients at crossing
05:58over from the transplant arm,
06:02the chemotherapy arm to receive Lisa cell,
06:05there was,
06:06you know,
06:06there still seem to be a
06:08trend favoring overall survival in patients
06:11who received licea cell where overall
06:14survival was not reached versus about
06:1730 months in the standard of care arm.
06:20So this primary analysis with almost
06:24two year of follow-up confirmed
06:27the significant clinical benefit
06:28of Lisa cell over the standard of
06:31care and given these very meaningful
06:33improvements in complete response rates,
06:36event free and progression free survival this
06:39and and a trend towards overall survival.
06:42This has now been approved and is
06:45considered the standard of care in the
06:48second line for patients with primary.
06:50Refractory or early relapsed lymphoma
06:53and there is another product on
06:57the market but this was the one
07:00that had the the updated at ASH.
07:03At the next one that I was also interested
07:07in is abstract 154 where they looked
07:10at really aggressive lymphomas that
07:13are high grade with Mick and BCL 2
07:16plus or minus BCL 6 rearrangements.
07:18So the so-called double or triple hit
07:21lymphomas and also double expressor
07:23lymphomas with dual overexpression
07:24of MYC and BCL two.
07:26And we know that those are very
07:29inferior responses to frontline
07:31and later lines of chemotherapy.
07:34They have very poor outcomes
07:36with stem cell transplantation.
07:38There have already been some
07:41presentations in terms of the role of
07:43cartee for this patient population,
07:46which has led to similar overall
07:49response rates.
07:50However,
07:50until this abstract,
07:52there had not been any data or
07:55update on the duration of response
07:57for these high risk groups and so
08:00this multicenter retrospective
08:02analysis evaluated survival.
08:04Outcomes with Carti and also what
08:06happened to patients who produced
08:09double hit lymphoma or dual overexpress
08:12or who progressed after court.
08:14And there was a large group of patients,
08:17they looked at 408,
08:19eighty of which had double hit
08:22and 328 non double hit.
08:24Some of them received access cells,
08:27some Tessa cell and a minority
08:29received licea cell and the clinical
08:32characteristics were similar between the
08:35double hit and the non double hit group.
08:38So the median follow-up was also
08:40about 18 months for from Carty
08:43for surviving patients.
08:44So relatively long follow up.
08:47And what?
08:49What they saw actually was that sorry
08:55was that patients did very well or
08:58whether they had double hits or dual
09:01overexpress or lymphoma compared
09:03to other subtypes of lymphoma.
09:06In terms of their progression free survival,
09:09overall response rates were no different,
09:12no statistically significant in
09:14the order of 65 to 70% complete
09:18response rates also.
09:20About 50%,
09:21which is what we expect with the
09:25run-of-the-mill diffuse large
09:26B cell lymphoma and.
09:29The median all overall survival was
09:31not reached actually for the double
09:33hit group versus 21 months in the non
09:36double hit and not statistically significant.
09:40However,
09:41importantly,
09:42patients with double hit lymphoma
09:45who progressed after court had
09:48a very poor outcome with overall
09:52survival that was very short only
09:55in the order of 2.7 months.
09:57So this is a group of patients.
10:00That you know,
10:01if they progress after Carti,
10:02where they do need better salvage
10:06strategies for.
10:07So this was the largest analysis basically
10:10that provided some update as to what
10:14happens with these patients with double
10:16hit or dual overexpress or lymphomas.
10:19So those patients should be encouraged
10:22to participate in car T trials and and
10:25should be considered to receive it as
10:28as part of standard of care without
10:30fear that they're not going to respond
10:33as well as the as the regular DLBCL.
10:36So umm, what about patients who progress
10:40after CD19 directed cortisol therapy?
10:42This is a very challenging group of patients.
10:45As you know they die within typically
10:47die within three months of progressing
10:50after cartee.
10:51And so this was a study from Stanford
10:54that looked at City 22 directed car T.
10:57In patients who had previously received
10:59CD 19 directed car T cell therapy,
11:01this was initially published in
11:03Blood where they treated five.
11:05They treated three patients who
11:07had had all high risk features with
11:10five prior lines of therapy.
11:12Including Carte,
11:13in fact one of the patients had had
11:16commercial parties and targeting City
11:1819 and then also a by specific City
11:2119 and City 20 core T and had relapsed
11:24and all of those patients achieved a
11:27complete remission with the city 22
11:30targeted car T so that led to this.
11:35Moving forward to a larger study with
11:3938 participants rate up to 84 years
11:43old with a good performance status.
11:46They were heavily pretreated
11:47with three to 8 lines of therapy.
11:50The median was four.
11:52In fact, about 33rd of patients did not
11:56have remission to any prior line of therapy.
12:00About 20% had had a transplant
12:02and they had all had.
12:05Prior City 19 core T cell therapy.
12:08And umm.
12:09The median time from Luca Fresas to
12:12the Court 22 infusion was 18 days,
12:16so a bit shorter than what we would typically
12:20expect with the commercial products.
12:23And some patients did receive bridging.
12:26So the median follow-up has
12:28not reached the the two year
12:31mark for some of the cohorts.
12:34But very importantly the overall
12:37response rate and complete
12:39response rates were very high,
12:41higher than predicted 72% and CR of
12:4653% which is similar to what we see
12:48with first line card T and all of the
12:51complete responses have actually.
12:53Been very,
12:54very durable with only one patient
12:57who achieved the CR having relapsed.
13:00And and you can see there the
13:02progression free survival and
13:03overall survival curves on the left
13:05look look actually very good for a
13:08second line cartee and and compare
13:10very favourably to first line chart.
13:13And as you can see the majority of
13:17the patients experienced grade one
13:20or two cytokine release syndrome and.
13:25Neurologic toxicity associated
13:27with immune effector cell therapy
13:30or or eye canyons. And um.
13:35Interestingly,
13:35what they saw in the higher dose level,
13:38which was dose level 2 is that
13:41there was a significant number of
13:44patients that experienced what is
13:48a syndrome that's very much like.
13:52Of falsity claim for histiocytosis
13:55and it's it's.
13:56Got a name of its own of carnage LH
13:59where it's a syndrome of five ferritin,
14:01cytopenia square apathy and liver
14:03abnormalities and there was just in
14:06general more toxicity in those level 2.
14:09So dose level one had very was the one
14:13that had the results I showed you.
14:14So that's the dose that they're
14:17moving forward with.
14:19And then one patient developed
14:21treatment related MSDS and AML without
14:24evidence of lymphoma relapse which again.
14:27Underscores the importance of us
14:29following this patients long term.
14:34Um, so another study of interest is actually?
14:41Engineered allogeneic core T cell therapy,
14:45all the commercial products are
14:47autologous products and also the
14:50the one that I just presented the
14:52city 22 was an autologous product.
14:54This is a an aloe gamma delta cortisol
14:58therapy and actually it's a first in
15:01class it instead of targeting C19 like
15:04the commercial products it targets
15:07CD 20 and it has both adaptive and
15:10innate cytotoxic effector function.
15:11Which complement card targeting
15:14potentially enhancing is is
15:16efficacy and reducing antigen loss.
15:19It expresses MHC independent
15:21gamma delta T cell receptor.
15:24So the risk of GVHD is low without
15:26the need for gene editing which
15:29is more complex and takes longer.
15:31So this is the industry's most advanced
15:33core asset using Gamma Delta and they
15:36presented the multicenter phase one trial
15:39for relapsed refractory B cell lymphoma.
15:41Patients had to have CD20
15:43expression on their tumor cells.
15:45They had to have received at least two
15:48prior lines of therapy and at ash they
15:51presented the data for their first
15:54dose cohorts in a three by three dose
15:57escalation scheme and in dose Level 3.
15:59They did allow patients to be reduced
16:02a week later without any lymphodema,
16:04additional lymphodepletion chemotherapy.
16:08So the median number of therapies
16:10was four range two to five,
16:13they were heavily pretreated.
16:15And four of the nine patients who
16:20were evaluable had received prior
16:23anti CD19 car T cell therapy.
16:26It was very well tolerated.
16:28There was no reported graph versus
16:30host disease and there were no
16:33Grade 3 cytokine release syndrome
16:35or neurologic toxicity.
16:37And this is their preliminary efficacy data.
16:40So as you can see there's six months
16:44complete response rate was in the order
16:46of 67% and for patients in those Level 3,
16:51actually a small number of three patients,
16:53they had a complete response rate of 100%.
16:56So this compares very favorably to
16:59autologous products and the advantage
17:01being that it's an off the shelf product,
17:05so the turnaround time.
17:08It's extremely short.
17:09The cells perhaps are fitter than those
17:15obtained from a heavily pretreated patient,
17:18without much in the way of toxicity.
17:22And then more recently,
17:24the company opened a dose level 4 cohort,
17:28so now they have a larger number of patients.
17:34However,
17:36they do not have particularly the higher
17:39dose levels of three and four do not
17:42have have very short follow-up and the
17:45patients who have been treated so far,
17:47a good number of them if you see
17:50her in red have actually relapsed
17:52and so the durability of responses
17:57is still questionable and.
18:00You know,
18:01it has investors pretty much really worried.
18:05You know about how this product
18:07is going to do in the long run.
18:10But again we just need to to
18:12see what's gonna happen to these
18:14patients who are getting the higher
18:17doses with longer follow up.
18:19And you can see that the patients here
18:22highlighted in yellow are patients
18:24who all had prior cortisol therapy,
18:27anti CD19 cortisol therapy
18:30and they all have achieved
18:33complete remission and.
18:35Some of them are still.
18:39Responding to treatment.
18:42So I'm not going to spend a lot of time here,
18:45but just to shift gears to bring
18:48your attention that car T cell
18:51therapy is also approved for
18:53patients with follicular lymphoma.
18:55In the third line setting and
18:58this is based on two trials,
19:01Zuma five with the access cell and
19:04Elara with the TISAGENLECLEUCEL.
19:07So this was the Zuma 5 update
19:09with a 3 year survival.
19:11You can see here that the
19:14overall response rates and the
19:16complete response rates with.
19:18Car T cell therapy are very high
19:21in the third line setting in both
19:24patients with follicular lymphoma and
19:26also in patients with marginal zone
19:29lymphoma and progression free survival
19:32is very good and overall survival
19:35is very good for these patients.
19:38With relatively long term follow-up,
19:41because in the third line setting,
19:44typically what we would expect
19:46from a third line therapy is a
19:49shorter duration of response that
19:51is typically less than two years
19:53and sometimes less than one year
19:55depending on the product used.
19:57But here you can see that the median
19:59PFS for follicular lymphoma was
20:01fourteen months and was not reached
20:04for a marginal zone lymphoma.
20:08Umm. And then uh, similar data from the
20:13Elara study looking at Tisagenlecleucel,
20:17so also targeting CD19, but if with a
20:20different Co stimulatory molecule that
20:23is 41B with over two years of follow-up,
20:29patients who achieved complete response
20:31represented here in the top curve have
20:35not reached their median progression
20:37free survival and the anticipated.
20:40For all two year progression
20:42free survival is about 60%.
20:44Umm. So umm.
20:45There was also this additional
20:48presentation that compared access
20:50cell to other third line standard of
20:54care therapies for relapse refractory
20:57follicular lymphoma and this was
21:00retrospective in nature but compared
21:05to scholar five study that does
21:08show a substantial improvement with
21:11axicom tagen with with the cellular
21:15therapy compared to other third line.
21:18Therapies.
21:20But again,
21:21it's not a randomized study and
21:25it's different to.
21:26There may be differences in
21:28baseline characteristics that do
21:30restrict cross study comparisons,
21:32but this is what the progression
21:35free overall survival and time to
21:37next treatment look like in blue for
21:40patients who had cortisol therapy
21:42versus at the bottom in red for
21:45patients who have who would have had
21:48other third line standard of care therapies.
21:52And this was published recently in in blood.
21:55And then I I want to also bring
21:58attention to the study published
22:01by by our very own group led by
22:03Kunal under the mentorship of
22:06Scott Huntington where the cost
22:09effectiveness of car T cell therapy
22:11was compared in adults with relapsed
22:15refractory follicular lymphoma and.
22:19The cost of core T cell therapy
22:22is about $730,000 as opposed to
22:26$450,000 for the standard of care
22:29with an eyesore of about 80,000
22:32for quality adjusted life years.
22:34But I think considering the.
22:39Risks associated with car T cell
22:41therapy in terms of cytokine release
22:44syndrome and neurologic toxicity.
22:49We need to do a better job and have
22:53a longer follow-up and and randomized
22:55comparisons to other lines of therapy.
22:58So that we subject these patients
23:01to who have the majority of them
23:04have long progression free survival
23:06so that we subject them to minimal
23:09as as minimal toxicity as we can.
23:12And particularly now we have a new
23:15bispecific antibody approved for
23:17follicular lymphoma which is not.
23:19A part of these?
23:22Cost effectiveness comparison here,
23:25but I think that's also going to play
23:28a role and we need to see how in the
23:31long run we're going to best sequence
23:34these these therapies based on.
23:38The the way of administration
23:40you know multiple times versus
23:42one time patient preference,
23:44toxicities and cost effectiveness.
23:47So um. I'm going to switch gears
23:50now to mantle cell lymphoma.
23:52This is abstract 623 which is phase
23:55one to two two study of a tandem
23:59by specific anti CD20, anti CD 19.
24:02We do have a product that's
24:04Brexit prapta gene that's already
24:07approved but it is very toxic and.
24:13There are. There's the hypothesis
24:17of this study was that if we use a
24:20bispecific tandem targeting product
24:22targeting both City 20 and city 19 with.
24:27Expansion with the I7 and I-15
24:29that we might get less exhausted
24:31car products with more durable,
24:34even more durable clinical activity.
24:37And this product actually is manufactured
24:43using climax prodigy device.
24:45It's a fresh infusion and the
24:47manufacturing time is quite short,
24:49is somewhere between 8:00 and 12 days.
24:52So for patients with rapidly
24:55progressive mantle cell lymphoma.
24:57It's a great product to have that we
25:00can infuse rapidly and you can see here
25:03that the manufacturing rate was very high,
25:06100% with its closed system.
25:09There were no Grade 3 cytokine release
25:12syndrome cases and there was only one
25:15patient with grade three eye cans.
25:17They were patients that had
25:19at least 4 lines of therapy.
25:21They were all exposed to BTK
25:23inhibitors and you can look at a
25:25long term progression free survival.
25:27Looks excellent and and the we already
25:29have the diffuse large B cell lymphoma
25:32study but we're gonna go ahead and open
25:35this for mantle cell lymphoma at Yale.
25:37And then finally,
25:38I'm going to switch gears to talk a little
25:42bit about T cell and B cell leukemia.
25:44So this was published in blood this year.
25:49As we know,
25:51finding a target for T cell lymphomas
25:55and leukemias has been challenging.
25:58City 7 is a very commonly expressed antigen,
26:01but it is expressed in the T cells and
26:05there is concern that there's going to be.
26:08Fratricide the way this is a Chinese
26:11group that they actually developed
26:13a novel methyl method of CD7 antigen
26:17masking that makes the cells fratricide
26:20resistant and this was their initial
26:24study was published earlier of these
26:28naturally selected core T cells without
26:31genetic modification and then abstract
26:34980 looked at 53 patients that had.
26:37Relapse refractory T cell all or T cell
26:41lymphoblastic lymphoma treated with
26:43this therapy you can see they were very
26:47heavily pretreated group of patients
26:49about half of them had more than 5%
26:53and blast and their mayoral some of
26:57them had extramedullary disease even and.
27:02They had.
27:04Very decent overall end event free survival
27:07in this relapse refractory setting.
27:10So the median follow-up is pretty long,
27:13206 days.
27:14Some of the data is here.
27:17I'm not going to go into it in detail,
27:20but suffice it to say that the
27:2518 month overall survival 75% and
27:29event free survival of 53% and.
27:32Some patients were bridged to an
27:36allogeneic stem cell transplant,
27:38but many patients were not and
27:42and the ones that achieved CR were
27:45able to maintain the CR.
27:48So umm, this was highly effective.
27:52They including in patients with
27:55extramedullary involvement or patients
27:57with have prior cart and they did
28:00identify a patients with the SIL
28:04tile one having a Porter response
28:08and early relapses and when relapses
28:11occur occurred they did see loss
28:14of city 7 expression.
28:17Now the Stephan Grupp group at
28:20Penn presented this abstract
28:22of City 22 targeted cartes in children
28:26and young adults after having relapsed
28:29post city 19 car T cell therapy for ALS
28:35and they enrolled 19 patients that had
28:39a product successfully manufactured.
28:4117 patients were infused.
28:43All of them had sitting negative
28:45disease that had relapsed.
28:47Postcard T and some of them had received
28:51blinatumomab and inotuzumab and nine
28:53had had a prior transplant including
28:56three with multiple prior transplants.
28:59They the bone marrow blasts pre infusion
29:02were high and you can see here that the
29:06probability of survival for this group
29:08of patients getting city 22 therapy.
29:12Is is pretty good the 18 month?
29:18Uh, overall survival,
29:21actually they have been even longer
29:24follow-up for this study, but.
29:28You can see here that the
29:31probability of survival.
29:33At 18 month at 18 month Mark is still
29:39relatively decent for patients who
29:42otherwise most of them as you all
29:45know would have very poor outcomes
29:47and would succumb to their disease.
29:50So now they have almost 30 months of
29:55follow-up and the median relapse free
29:58survival is about five months and
30:01overall survival is about 16 months.
30:04So there were two patients that also
30:08worried treated with this for city 22
30:11relapse disease after initial infusion
30:13and one of them went into remission again.
30:17So there is a possibility of of retreating
30:20these patients and all of that data is here.
30:24But I just want to emphasize that we can
30:28salvage a portion of patients who fail CD 19.
30:31You can see here 77% achieva.
30:34CR and including undetectable MRD by flow.
30:39Um.
30:41So you know,
30:43they do develop toxicity and particularly.
30:47The risk of infections in is extremely
30:50high and cytopenias after back-to-back
30:52Carter cell therapies like this.
30:54So they had successful manufacturing
30:58again with an autologous product and
31:02there were high initial response rates
31:05but there are later recurrences and
31:08I think what was being looked at now
31:12is how to combine City 19 and City 22
31:15to to decrease the risk of relapse.
31:17I'm not gonna.
31:18I know we're running out of time,
31:20so I'm not going to spend too
31:22much time on on this abstract,
31:26but it did compare.
31:28Car T cell therapy in both patients
31:31who had received a blinatumomab and
31:33inotuzumab and patients who had not
31:36received blina or inotuzumab and this is
31:39in the adult population where they did
31:42this propensity score matching analysis.
31:44And what they actually find found
31:47is that the group that received car
31:50T cell therapy with access cell had
31:53much higher complete response rates
31:55of 85% versus patients who had.
31:59Other standard of care approaches also
32:02predominantly chemotherapy of 35% with
32:05a median overall survival that was
32:07higher at 16 months versus about five months.
32:11And this was true in both patients who
32:14were treated with blue 99-O2 zimat before,
32:17but also patients who were treatment
32:19naive that they both of those groups.
32:22For both of those groups we should consider
32:25car T because patients do respond.
32:28And and may have improved outcomes compared
32:31to other standard of care approaches.
32:34The the relapse phenotype is very important
32:37and it informs our therapeutic decisions.
32:40So about 22% of patients will relapse
32:43with City 19 positive disease,
32:46about 15% with city 19 negative AL
32:50and about 3% have lineage switched.
32:52And the group that has lineage switch
32:54actually is the group that has the poorest
32:57outcomes and they have quite poor.
32:58Outcomes, even with cartee cell therapy.
33:02And then post Cartee there is even more
33:06increasing complexity of the relapse
33:08immunophenotype and the most difficult of
33:10all group to to deal with is the group
33:14that postcard team now have both city
33:1719 and CD20 negative AL and again the
33:20patients with this lineage switch, So what?
33:25This is uh the the the group from the
33:29NCI new Rally that published recently
33:33and also presented at ASH that patients
33:36who get blinatumomab prior to car
33:38T cell therapy and do not achieve a
33:42complete response to blinatumomab have
33:45the have very poor outcomes postcard
33:48T and and that again having city 19
33:52damn disease pre Carty will influence.
33:55The postcard T cell relapse phenotype
33:58that a lot of those patients will
34:01have city 19 negative disease at,
34:04at the time of relapse and they
34:06will also have very poor outcomes.
34:08So it's very important in a L for us
34:10now to really break down the groups
34:13and follow these patients not just
34:16with B cell aplasia but actually
34:18follow them even more closely with
34:22MRD by NGS techniques because.
34:26Some patients.
34:29May still have some persistent B cells there,
34:31but still relapse early and we really
34:33need to move those patients toward
34:35clinical trials or or doing an urgent
34:38allogeneic stem cell transplant.
34:40So I think that perhaps we'll leave
34:42questions at the end to allow
34:44also doctor Gowda to present.
34:46So I'm going to stop sharing.
34:51All right. That was an awful
34:55lot of exciting information.
34:57There is one question
34:59in the Q&amp;A doctor Soufi,
35:00maybe you can take a look while
35:03Doctor Gowda is presenting.
35:05So next is Doctor Lohith Gowda.
35:08He's assistant professor
35:10in the transplant room.
35:11Cell therapy program here at Yale,
35:13and he's going to go over some
35:15new and exciting transplant
35:17results from the ASH meeting.
35:20Hello everyone and and
35:21it's a Friday afternoon.
35:23I promise I'll get you
35:24guys out for lunch in time.
35:27No conflicts of interest.
35:28Here are my thoughts comments for
35:31from the study investigators,
35:32the study groups, and different
35:35individuals who shared their slides.
35:37The main objective of today's talk is
35:40largely club under three main headings.
35:42Yeah, as we all know,
35:43allergenic transplantation as
35:44a 70 year track record of cure,
35:47but relapses do happen.
35:48So I'm I'm going to present you some
35:51data about the role of preemptive
35:53maintenance post transplant.
35:54One of the Achilles heel of
35:56alleged extract point has been
35:57graph to source disease normally
35:58would present under 2 headings,
36:00acute and chronic graft resource disease.
36:03Based on the most recent data
36:03that I'm going to present,
36:04looks like you might have one drug
36:06which is taking care of both of that.
36:07So that's the phase three study
36:09that I'm going to be talking about.
36:11And finally,
36:11I know it's the last talk of our CME series,
36:14but throughout my life group discussion,
36:17we've learned that, you know,
36:18there are many novel,
36:19exciting advances that drugs
36:20are coming through.
36:21But I'm here to convince you guys
36:23that despite those drug advances,
36:25allergenic stem cell transplant
36:27is actually is at the forefront
36:28and we anticipate a high number of
36:30patients going forward to receive
36:32other transplant because outcomes
36:33have gotten significantly better.
36:35And I'll bring about some data to
36:38support that statement. Alright.
36:40And the first study that I'm going
36:42to be talking to you is,
36:43is a study that was done across
36:46from CFO which was using ID,
36:48its two mutation sub group which
36:51happens in about 20% of the cases,
36:5320% of patients.
36:54We all know that Doug Anderson
36:56name is approved in mutant ideas
36:59plus two types index subgroup.
37:02Those with the last refractory AML
37:04D or R is about 40% but there are
37:07responses do not last long with the
37:08median duration of response about 5.8 months.
37:11So the group here actually tried
37:12to do a maintenance concept post
37:15transplant wherein they introduced
37:16the drug post transplant from days 50
37:19to 18120 at about 100 milligrams per day.
37:21The plan was to give for about
37:23two years and each cycle would
37:24last for about 20-8 days.
37:26It's a small group study.
37:27The total was 15.
37:28They included patients and had
37:30a transparent CR1CR2 onward MRD
37:32positive cases post alert CT as well.
37:35In this study,
37:35the median time to start the drug was
37:37105 days. Download various craft.
37:40Various GVHD and various
37:42transparent relative conditionings.
37:43The median age is population
37:45with about 58 years and all great
37:48adverse events during the study was
37:50reported for the first two cycles,
37:51whereas for grade 3 or higher for
37:55subsequent cycles were reported.
37:57In the first two cycles,
37:58it's usually all of them was included.
38:00The methodology used to monitor
38:02for DS2 was a digital doctor PCR.
38:05And as has been shown here,
38:07if you focus on the right and
38:08one of the
38:09commonest concern that we have of
38:11using these drugs is cytopenias.
38:13The risks of cytopenias, lymphopenia,
38:14anemia and neutropenia is was pretty
38:16modest and and it's it's not really
38:18significant for those of you use the
38:20drug in the pre transplant context that's
38:22that's a major issue but those are
38:24usually the people that have an abnormal
38:26marrow and the disease in association.
38:28So I was surprised to see the
38:29side opinions although existing
38:31wasn't significantly high and GI
38:33side effect was rather common side
38:35effect interestingly at least as was
38:37presented with the median follow-up
38:39of 17 months the one and two are
38:41progression free survival was about 100%.
38:43Common when we talk about maintenance,
38:45we talk about flip 3 limited studies.
38:47We're waiting on the full data of the BMT
38:50CTN three that used the three Nevada.
38:52But I think outside of that idea as
38:53to where we have targeted agents is
38:55an important subgroup and I thought
38:57this would be of meaningful practical
38:58use as we treat our patients.
39:02The other maintenance stadium going
39:04to talk about is a phase one study.
39:06Some of you might be aware that when
39:08the clients has also been integrated
39:11in the transplant preparative regimens.
39:12The study was published by Garcia
39:15and colleagues from Boston.
39:16What they're now presenting is
39:18when you integrate whether class to
39:20flow data and cell phone which is
39:22appropriate regiment that's commonly
39:23used in the transplantation context.
39:25There are trying to add the HMM and when
39:28it reflects as a maintenance post transplant.
39:32The last ticket put on really is
39:34focused on using is a Satanism
39:35maintenance and there are many many
39:37interesting reports in that regard.
39:39But the combination as you realize
39:41the doublets and triplets are making
39:43forays in the non transparent context.
39:44And I also see this now coming
39:46in the post transplant context.
39:48And this is one of those phase
39:50one study to identify the doses.
39:51So they started out with 400
39:53milligrams from Day 1 to 14 is the
39:55cycling was used at 36 milligrams
39:57per meter square on days one to five.
39:59A lot of user trials in the
40:01past have tried different.
40:02This is different days and and I think
40:03at least in this study they kind of
40:05narrowed it down to a slightly lower
40:07dose which with the hope that perhaps
40:09the combination is well tolerated.
40:12As was expected.
40:13You know, cytopenias worst thing.
40:16Neutropenia was 95%,
40:17thrombocytopenia was 91%.
40:18So cleverly the DLT definition
40:20that study was grateful.
40:22Looping or thrombocytopenia greater
40:24than two weeks with a median follow-up
40:26of 12 months follow-up regardless
40:27of the patient got maintenance.
40:29The one year progression free
40:31survival was in relapse report here.
40:33The OS was 70%, PFS was 57%.
40:36There was no non relapse mortality
40:38suggesting it's it's a safer combination
40:39to push you in the post transplant context.
40:42But relapse was still of concern
40:44despite using a doublet.
40:46Nomination in the post transplant context.
40:51Now let's switch gears and talk about GVHD.
40:54Now many of you know that calcination
40:57based combination tachyons for
40:59methotrexate has been a standard of care
41:01for sorry for the last four decades.
41:04So in order to explore more on how
41:06we can optimize and identify the best
41:09combination BMT CTN 1203 study ran A3
41:11ARM study where in the the check to
41:14conventional arm track methotrexate
41:15with Bortezomib tack methotrexate
41:17with the chemokine inhibitor.
41:19Versus a full side arm,
41:21the phase two study and the winner
41:24of that study was the post I am
41:26which we call the PCI.
41:28This was then taken to a phase three study
41:30where PCI tackled Amos and microphone.
41:32It was compared against the historical
41:34control which is stacked and methotrexate.
41:37The study allowed reduced intensity
41:39conditioning for individuals 18
41:41years or older that have controlled
41:43disease and and and peripheral
41:45blood stem cell grafts were chosen.
41:47Donors could be 6 out of 6L
41:50matched or 7 to 8 or 8 sorry,
41:52six out of 6 actually matched
41:55donors or 11 antigen mismatched.
41:57Unrelated donors were also aligned.
41:59The primary endpoint of the study was
42:01one year GRFS has been defined here,
42:03even being defined as grade three
42:05to four Q GVHD, chronic GVHD.
42:07Requiring systemic must suppression,
42:09relapse, progression, adapt,
42:10and there were a few traditional
42:12standard transplant,
42:13Putin and secondary endpoints chosen.
42:15Here's just a summary of what happened.
42:20There was slightly more men.
42:21The median Asia was about 66%.
42:24Almost half of the people had kind
42:26of performance score less than 90.
42:29It had a wide range of hematologic
42:31malignancies.
42:32And and here's the percentage
42:34of related unrelated,
42:35unrelated donors with unrelated
42:37donor being the Communist platform.
42:39They did allow different regiments
42:41to be chosen.
42:42That is blue flu,
42:44flu, mail.
42:44To go with which perhaps in modern day
42:47or some of the commonest options used.
42:50Planned post transplant maintenance
42:52therapies was used in about approximately
42:5425% of the people in the post I am orsus,
42:5622% in the non Siam.
42:59The study did meet the primary endpoint,
43:02the one year graft also source
43:04disease relapse with survival was
43:05superior with the post transplant
43:07cyclophosphamide as has been shown
43:09here with that has a ratio of 0.64.
43:12The rates of great three to four Q GVHD
43:16was 6.3% versus 14.7% suggesting post
43:18size able to decrease graph resource
43:21disease and same with chronic graft
43:25associated requiring suppression.
43:26The Posi arm had about 12.5%
43:29methotrexate armor 25% basically
43:31halfing the risk of chronic GVHD
43:34requiring suppression and importantly
43:36GVHD prelapsarian survival was
43:39almost 62% compared to 45% off.
43:42Is concerned that when using your
43:44depleting agents there's the GL impact.
43:46Gmail is impacted as is shown here.
43:48It seems to be disentangled and
43:50relapse and progression was not a
43:52concern with the application of
43:54post transplant cyclophosphamide
43:55compared to tack methotrexate.
43:57Treatment related mortality,
43:59it's 12% if, if,
44:00if,
44:00if you all read our books back
44:02about 10-15 years or treatment
44:04later mortality transplant used to
44:06be about 2530%. Now that number has
44:08come down significantly and the
44:10overall survival in this arm was
44:13about 77% of interest to note here
44:16is that overall survival at this
44:18time point actually didn't change,
44:19it was 77%, also 72%.
44:22But remember the study endpoint was GRFS.
44:25So then people tend to ask what
44:27what about the secondary outcomes
44:28in highlighted in purple are the
44:29ones that were not significant
44:30and in the dark bright yellow is
44:32the ones that are significant.
44:34When your survival didn't change,
44:36when your disease with survival
44:37didn't changed, TRM did not change.
44:40Statistically,
44:40cumulative incidence or Q GVHD
44:42grades two to four did not change.
44:44But what did change though is
44:46cumulative incidence of acute GBS
44:48day 100 grades three to four.
44:50You know if you have grade one and
44:52two GSD most times it's not of a
44:54significant concern, the higher grade.
44:55It's the other one we are
44:57concerned about with the post.
44:58I was 6.3% compared to about 14.7%.
45:02Similarly chronic GVHD at 12
45:04months was 21% compared to 35%.
45:07The salary carrier was slightly slower
45:10both for neutrophils and platelets and
45:13as is commonly expected and and the
45:16risk of breakthrough infections will
45:18not not significantly higher at 12
45:20months now is the risk of CMV reactivation,
45:23importantly immunosuppression
45:24free survival at one.
45:26Yeah,
45:26was was better off as has been shown here.
45:31The other other question
45:32people ask is about, you know,
45:34what's the risk of graft failure or
45:36how does the chimerism play out?
45:38As shown here, they have definitions
45:39for what's the full chimerism?
45:40Mixed graph projections.
45:41There's really no significant
45:43differences based on that
45:44between the two treatment arms.
45:49Specifically people ask that, you know,
45:51this is making significant progress in
45:53the field of acute and chronic GVHD.
45:55Does it have any other side effects?
45:57Well, you know the risk of acute or
45:59chronic GVHD was significantly lower,
46:01but they did come up a concern about
46:03some organ failure and we're looking
46:04for the full manuscript to see which
46:06particular organs were affected as
46:08it was slightly higher in the post
46:10transplant cyclophosphamide arm
46:11compared to the conventional care.
46:16In summary, you know the superior GRS
46:18went to the reduced even and Q GVHD led
46:20to the post I am winning in this truck.
46:23There was no increase in
46:25relapse slash progressive,
46:26which is critical importance to our people.
46:28There was slightly delayed
46:30hematopoietic recovery.
46:30There was more grade 2 GI
46:32events in the infection forms,
46:34but they're mostly in the first month.
46:36Based on the findings,
46:38the field is slowly moving towards
46:40the option of using postai as a
46:42reduced intensity conditioning GVS 3
46:45prophylactic options going forwards
46:47in patients who are well matched.
46:50There there are ongoing studies
46:51to look and look for suitable
46:52biomarkers and those will be coming
46:54out over the next few months.
46:59In that is available,
47:00who's one of our leaders in the
47:02leukemia program asked me to condense
47:03some of the TCP slides with the ash.
47:06Hematology slides because those are
47:08are really practice changing here.
47:10I'm presenting a study that's called
47:11the CRF study that's Seropian was the
47:14principal investigator on site for this.
47:16This was a multicenter pivotal
47:17phase three study of ISOMAP which is
47:19going to talk to you about prior to
47:20allogeneic stem cell transplant versus
47:22conventional care in older patients
47:24with acute relapse refractory leukemia.
47:26Remember the majority of the patients
47:28actually don't get to transplant.
47:30Look at the median age for these
47:32patients that developed leukemia is
47:33somewhere around late 60s, early 70s.
47:35And they're transplant ineligible.
47:37So in that patient population
47:39while we were at multiple new drug
47:42developments transplanted historically
47:43considered not suitable.
47:45So into that domain,
47:46this trial is trying to now make
47:48headways with some interesting results
47:50as I'm going to show to you all here.
47:56As I was mentioning last, in fact,
47:58Emilyn generally has got poor prognosis.
48:00On top of that,
48:01if you add old rays it makes it complicated.
48:05There are several reasons for that.
48:06Historically always believed intensive
48:07induction and accessory to keep
48:09permission going for long term.
48:10But most of these patients are not able
48:12to tolerate it and even if they tolerate it,
48:14the toxicities are higher if you
48:16continue to long terms and that leads
48:18to substantial treatment related mortality.
48:20Now since transplant is a higher
48:22intensity of treatment compared
48:23to the non transparent option,
48:24the term tends to go up in the population.
48:27However we are able to get some of those.
48:31Patients who have relapsed or practicing
48:34at back into remission and one of the.
48:37Conventions that we tend to fall in
48:39relapse refractory AML is we we tend
48:41not to transplant those patients in
48:43active disease because you know back
48:45maybe prior to 2000 when we used to
48:47do labs attracts AML who had active
48:49disease when the data is normal drugs
48:51though you know risk of relapse was
48:52pretty high in the Tiana was high.
48:54So based on that there are multiple
48:56novel drug development strategies
48:57that have come on.
48:59But what I have is not trying to do
49:00is trying to address the question
49:02slightly differently.
49:03So first of all, what is our map?
49:05Ahmad is basically a combination of things.
49:08They have a CD45 antibody that's
49:10conjugated to radioactive iodine and
49:12it is designed to deliver targeted
49:15myeloablative radiation dose to the
49:17hematopoietic cells and immune cells
49:19and then supplemented with reduced
49:21intensity conditioning priority
49:22analogy and stem cell transplant.
49:23Remember good old days when we
49:25used to do transplant,
49:26we used to use radiation based regimens,
49:28TBI kind of.
49:29While it's useful to suppress your immune
49:31system and radical Kenya and the narrow,
49:34it can cause significant argument toxicity
49:36because it's a total body radiation.
49:38Here they're trying to develop
49:40targeted radiation to leukemia cells,
49:41bone marrow stem cells,
49:43to address the primary problem
49:44of cute myeloid leukemia.
49:46With induction and conditioning,
49:48the hope here is that usage of this
49:51drug would allow rapid access to bone
49:52marrow transplant for multiple patients
49:54who relapsed refractory phenotype.
49:56So this was a prospective randomized
49:57strain study which is a phase three
49:59study exclusively for patient
50:01populations greater than 55 to compare
50:03rates of durable complete remissions
50:04that would last greater than 180
50:06days following initial complete
50:07remission between the two arms.
50:09So the study was randomized for
50:10IMAP followed by transplant versus
50:12physicians choice of conventional
50:14care for transplant and physicians.
50:16The Commission came included more
50:18than 20 different drugs that reflect
50:20on contemporary practice,
50:21including the BCL 2 inhibitor,
50:23split three inhibitors, etc.
50:26Ohh here's how the study design goes.
50:29People have relapsed practice
50:30phenotype greater than 55,
50:32randomized 1 to one.
50:33I am mapped to conventional care.
50:35Well then look for whether they're
50:36here or not and if it's a CR,
50:38what's the duration of CR
50:39whether the last six months
50:40or not. And that's the pre specified primary
50:43endpoint lasting greater than 180 days.
50:45Whereas with the conventional care arm
50:47depends whether they get into CR no CR.
50:49If they're the CR then they could go
50:51to the standard of care transplant.
50:53Our standard of care physicians choice.
50:57This, this concept of drug delivery
51:01needs hospitalization slightly earlier
51:02than what we would normally do in the
51:05context of a bone marrow transplant.
51:06So those patients were admitted
51:08around day 19 to get a test dose.
51:11After radioactive iodine and then
51:13they have to be kept in the hospital
51:16for a few days until the body
51:19eliminates all the radioactive doses.
51:21The then the data is then sent across to
51:24develop a therapeutic dose of the ILAB
51:26which is then given around day minus 12.
51:28You wait for about 8 days
51:31for that to take effect.
51:32Remember these are people who have
51:34active glass and activities coming
51:36into this this drug would you know
51:38Oblate most of those patients and
51:39then you go and use the principles of.
51:41Transplant just to use low dose of
51:43immuno ablation with fludarabine and
51:45TBI which lymphodepletion and also
51:47eradicate some of the disease followed
51:49by hematopoietic stem cell rescue and
51:51the option of GST prophylaxis is tactile
51:54limus cyclist form with microphone.
51:58Here's the concept now.
51:59Equal number of patients randomized.
52:01I'm unconventional.
52:03Case 767766 patients received
52:05therapeutic dose.
52:0666 were able to get a transplant.
52:08Per protocol analysis,
52:0959 were eligible.
52:10In contrast,
52:11a number of people in the conventional
52:14care that were able to get to CR was 14.
52:17Not able to get to CR was 62.
52:19For those who got to CR and were
52:21fourteen of them were all fourteen
52:22were able to go to transplant those
52:24who did not get to CR of 6218.
52:26Did not receive any further care.
52:28Likely went on to receive what
52:30you call palliative care options
52:31or no further treatment.
52:33Crossed over to IMAP.
52:34The costs over was allowed for people
52:36who did not reach CR after having
52:38been in the conventional care arm,
52:40but 44 crossed over to MMA.
52:42Of those,
52:434440 did get to allergenic
52:44stem cell transplant,
52:46and 38 were protocol and were
52:48eligible for protocol analysis.
52:50I'm interested,
52:51I'm trying to run through this past.
52:53The median age is about in the mid 60s.
52:56We had favorable intermediate
52:57and adverse risk.
52:58It included primary induction
53:00failure earlier relapse,
53:02relapse,
53:02refractory second plus relapse
53:03and I mentioned that with an
53:05emphasis because those of you
53:07are familiar with asset trial did
53:08not include later relapses and
53:10only with their earlier relapses,
53:11all of them at about 3 lines
53:14of medium therapies,
53:16people had already exhausted
53:18targeted therapies.
53:19About 60% of the patient actually
53:21had a KPS score performance score
53:23less than 90% and the matter
53:25presented and the matter of last
53:27percentage was around 30% and 28%
53:29which is significantly high truly
53:31reflecting active disease population.
53:34And I'm here are the doses that
53:36are being presented,
53:36whether you got amab or crossover
53:39doses of the matter was about
53:421616 Gray here where the divided
53:44the crossover time to UTC from
53:47the randomization was 29 days.
53:48With the standard of care on
53:50the median time was 66 days.
53:52In the crossover arm the median
53:54days was 61 days.
53:55Engraftment was very good.
53:56The median time was 14 days
53:58which is what we normally see
54:00with our standard transplant.
54:01Somewhere around there for platelet
54:03was about 19 days and the standard
54:06HCT the kind of matching up nicely
54:08and the comorbidity index as I was
54:11showing here approximately 5050.
54:13When when you look at durable yards.
54:17Here's the number.
54:18About 22% of the patients that I
54:20had durable CR on the study endpoint
54:22versus none in the conventional
54:24curriculum in the crossover arm,
54:2691% received transplant with
54:2852% of those receiving CR CR.
54:31Posted city maintenance with the TK,
54:34I was only allowed for a more
54:36patient with three mutations,
54:37those toward BCR able
54:39TRANSLOCATIONS that screening.
54:42And these are the the survival cost.
54:46The oral survival was doubled with Irma Bomb.
54:48It was 6.4 months compared to 3.2 months.
54:50One year survival was almost doubled,
54:5326 months was 13 months.
54:56In the crossover covert showing,
54:58the blue line was about 7.1 month and
55:01the survival there was about 3535.8%.
55:05First, sorry.
55:08Forest plots essentially showing
55:10hazard ratios was applicable across
55:12most group except the KPS of 9200.
55:16I relapsed. Refractory now those are
55:19the ones where they crossed the line.
55:22And and when you look at evently
55:24survival and intent to trade group,
55:26I'm at a better rate of 28% of 0.2%.
55:30Specifically, when you follow these
55:32patients for long term survival,
55:34six months survival is 100%,
55:35twelve months, 92 percent,
55:3718 months 71% are two years.
55:39Almost 60% of the patients that had
55:42remission were alive and ongoing.
55:44Here are some of the adverse events.
55:46As you can see here,
55:47we were anticipating a high dose of
55:49chemotherapy might cause problems and
55:51neutropenia was on similar rates both sides.
55:53The mucositis was almost
55:54similar on both sides.
55:56The rates of GVHD was not really different,
55:59but sepsis was lower in the conventional
56:02compared to conventional now.
56:05So in summary,
56:06in patients greater than 55
56:08years with active disease,
56:09I'm not followed immediately by reduced
56:12intensity transplant in his population
56:14that's typically not transplant eligible
56:16is now made feasible and possible.
56:19As a result of the study I am having
56:21general was well tolerated and resulted
56:22in engraftment in all those patients
56:24and had a high rate of durable CR
56:26lasting greater than six months.
56:28And for those who have CR lasting
56:29more than six months about 60% of
56:31our life on the long run the rates
56:33of serious adverse events were small.
56:36I am at office of very normal solution
56:38to increase access to transplant
56:39and improve outcomes in patients
56:41that are relapsed and refractory.
56:43You know,
56:43I have two more slides and I'm going to,
56:46I'm going to wind up with that.
56:48Some of you who were at Ash probably
56:50heard of this trial ASAP trial,
56:53which is kind of trying to gain access
56:55for alternate transplant for those
56:57who have primary induction failure,
56:59trying to make a case saying that,
57:01you know the need for further
57:03intensification chemotherapy to
57:05achieve CR is perhaps not needed as
57:07long as you can sequentially give
57:08chemotherapy and take them to transplant
57:11if you have a donor available.
57:13Thereby the kind of trying to show that
57:15you probably don't need to achieve
57:17CR if you have a donor availability.
57:19But some of the practices in that study
57:21might not be applicable in the United States.
57:23But for the purposes of discussion
57:24I've left it here.
57:25But I would end my talk by summarizing
57:27this for those of you who are interested.
57:29Since ARMA but ASAP are now trying
57:32to advance transplant in the context
57:34of relapse refractory study,
57:36let's let's see what they both talked about.
57:38ASAP Trap was predominantly looking
57:40into fit early relapsed patients
57:42that was primary induction.
57:43They're faster laps.
57:45It uses intensive sequential conditioning.
57:48Our chemotherapy rather followed by
57:49transplant preparation regimen which
57:51is bluemel TB in an eighth grade.
57:52The flip side to that is one of the
57:54novel therapies that we used to treat
57:56relapsed refractory leukemia was allowed.
57:58So you can argue maybe that's not suitable
58:00for practicing in the United States.
58:01And even then if you know when we've
58:04known in the past that we use repeated
58:06chemotherapy for labs refractory
58:07disease to make them get into see how
58:09to get the transparent perhaps that's
58:11only about 15 to 20% of the patients.
58:12We think that might impact even
58:14if you are if you decide to give a
58:17sequential therapy maybe about 700
58:19to 1000 patients as you're Gerald
58:21summarized it beautifully and may
58:23be eligible to become transparent
58:25using that intensive chemo approach.
58:27In contrast,
58:27Sierra included fit or unfit patients
58:30both with primary induction failure or
58:32first relapse who have traditionally
58:34been considered transplant ineligible.
58:36And also included second of later.
58:40Encompassing a extensively relapse
58:42cases including those who are
58:44relapsed with contemporary available
58:46medications but most people might
58:48have gone into palliative care are
58:50now getting eligible to consider
58:52as an extension of transplant.
58:54And I think as as Doctor Gerard mentioned
58:56he thinks with this concept approximately
58:588000 patients who were historically
59:00considered not transparent eligible
59:01may be eligible for other transplant
59:03if you have a donor ready and be available.
59:06And I posted this drug being explored for
59:08different donors conditioning regimen.
59:10Both in a hematologic,
59:12both neoplastic and non
59:14neoplastic conditions.
59:15Going forwards with that I'm going to
59:16invest and thank you all for your attention.
59:18I'll open up the platform provider questions.
59:20Thank you so much.
59:30You muted Stewart. Sorry.
59:32Thanks. Thanks, Louis.
59:35So we have just a few minutes to field
59:37some questions if people want to submit.
59:40I'll just start with a quick one that
59:42came through the chat that we couldn't
59:44respond to and this is for Doctor Sophie,
59:46can you just comment on the use of
59:49corticosteroids and card T patients?
59:51Are these allowed?
59:52Do they impact therapy?
59:53On paraphrasing the question,
59:56but the question was really
59:58what is the impact of using
01:00:00steroids in these patients?
01:00:03Yeah. So we generally try to limit the
01:00:05use of steroids before cartee collection.
01:00:09It's it's critical that they have at least.
01:00:13One week window before Cartee.
01:00:16We do know that steroids are very lympho
01:00:19depleting and the early postpartum
01:00:21period when they developed toxicity.
01:00:23Though it has been shown that giving
01:00:26a short course of either steroids or
01:00:29other antibodies like tocilizumab to
01:00:31treat cytokine release syndrome or
01:00:34neurologic toxicities does not impact
01:00:36the long term outcome of these patients.
01:00:39But again the steroid tapers are.
01:00:43Rather quick, typically less than a week.
01:00:49OK, thanks. And I see one other one
01:00:52other question in the chat from
01:00:55Doctor Zeiden and that's regards.
01:00:57The whole issue of remission status
01:01:01prior to transplant and asking if in
01:01:04the ISOMAP study was there a need to
01:01:08document CR before the transplant.
01:01:10So is the short answer is no.
01:01:11iMac was part of the transplant conditioning.
01:01:15So these are people who relapse,
01:01:17refractory disease had bone marrows
01:01:19with an average of 30% blasts who
01:01:22instead of our paradigm of going to
01:01:25salvage therapy and requiring remission
01:01:28that was the that was the control arm.
01:01:31They just went right to the transplant.
01:01:33So they got the therapeutic dose
01:01:35and the the 12 days before the
01:01:38transplant and that's ablative.
01:01:40So there's no doing a bone marrow to look.
01:01:42You saw the average delivery of
01:01:45radiation there was 16 Gray,
01:01:47that's about 3 to 4 Gray higher
01:01:49total body radiation dose that
01:01:51we can safely give any patient.
01:01:53So this is a very ablative
01:01:56dose of radiotherapy.
01:01:59And and then marrows are not done
01:02:02prior to delivering the transplant you
01:02:04have to rescue the patient with the
01:02:07graft and the high CR rate confirms
01:02:09the efficacy of of that agent.
01:02:15I think how much? How much?
01:02:18So in Americas asking about acquiring
01:02:21CR in one arm and not the other,
01:02:23so the other arm was to choose
01:02:27conventional treatment, you're right.
01:02:29And then those patients
01:02:30don't go to transplant.
01:02:31Remember this is a a group restricted age 55.
01:02:36And we don't have,
01:02:40if you're referring to the ASAP study,
01:02:42we don't have flame PSA regimen,
01:02:44which is the popular German regimen.
01:02:47And if one looks over 40 years of
01:02:51evaluations of outcome for allograft
01:02:54being the single most predictive.
01:02:58Variable for treatment
01:03:00failure is disease status.
01:03:02It's an increase in blasts in
01:03:04the marrow pre transplant.
01:03:06So remember these these
01:03:07were people with actively.
01:03:08These weren't people with just
01:03:106% blasts in their marrow.
01:03:13So they, they,
01:03:14they were allowed to to crossover,
01:03:17but these are people who are
01:03:19conventionally don't go to transplant
01:03:21around around the world really,
01:03:23unless they're on a clinical
01:03:25trial like that German study.
01:03:28There's actually an excellent review,
01:03:29but Zeidan armor and Dan Polia
01:03:31Dan Polio about even the need
01:03:33for CR after induction therapy.
01:03:35I'm sure Rama can extrapolate
01:03:37that into labs refractory setting.
01:03:38How CR one came into the foreplay,
01:03:40whether it's of essence.
01:03:41I'll refer him back to his own
01:03:43publication with that which tells you
01:03:45the real utility of CR in modern times.
01:03:49Yeah, what's probably a good subject for
01:03:53further discussion in our transplant
01:03:57leukemia meetings. I I slept see
01:04:00guard also just wanted to say that
01:04:02this type of therapy is also very
01:04:04exciting for other forms of adoptive
01:04:06cell therapy because I know that they
01:04:08are looking at giving non myeloablative
01:04:11doses of this type of radioimmunotherapy
01:04:14actually at lower doses rather than
01:04:17ablative for patients pre adoptive
01:04:19cell therapy and we already have
01:04:21data on how radiation might actually.
01:04:26Decreased T Reg populations for example,
01:04:31and that may be actually important
01:04:33in the postcard T setting as well.
01:04:37One last question for Doctor Isufi in
01:04:39the Q&amp;A, how to choose between car T
01:04:43cell therapy or immunotherapy, very,
01:04:46very appropriate question not just for
01:04:48lymphoma, but iris what do you think?
01:04:50Yeah, so I mean I think that's
01:04:52a that's a very valid question.
01:04:54Unfortunately you know immunotherapy
01:04:56in terms of PD1 PDL one access has
01:05:01not had very good outcomes in the
01:05:04setting of non Hodgkin lymphoma.
01:05:07Particularly aggressive lymphoma and so.
01:05:12And you know that those particular
01:05:14drugs are not are not have very low
01:05:17CR rates as single single agents and
01:05:19they do not add much to combination.
01:05:22So I think a court would be preferred
01:05:25in terms of antibody drug conjugates.
01:05:29I mean I think that's that's a whole
01:05:31other class of drugs that is competing
01:05:33with car T cell therapy in all fronts
01:05:36including non Hodgkin lymphoma,
01:05:38AML and multiple myeloma and I think
01:05:41we have to look at the targets.
01:05:44To make sure that when we give these
01:05:47therapies the patients retain the
01:05:49target and and how to sequence them
01:05:52is actually a matter of very hot
01:05:54debate and ongoing trials right now,
01:05:56what the best approach might be
01:06:00with these by specifics I know.
01:06:03There was another question in the in the Q&amp;A,
01:06:06for example for, for.
01:06:11For leukemia in patients who for
01:06:15example receive blinatumomab precarity
01:06:18you know how do those patients fare
01:06:20and that because both of those are
01:06:23city 19 targeting therapies and so
01:06:26sequencing is very important there.
01:06:28And the interpretation of of the
01:06:30data so far is that if they have a
01:06:34good response to blinatumomab and
01:06:36they maintain their CD 19 status
01:06:38pre cartes that they do well.
01:06:40However,
01:06:40if they do not have a good
01:06:42response to blinatumomab,
01:06:44they will also respond poorly to
01:06:47car T unfortunately that's a high
01:06:50risk group and if they lose City
01:06:5319 after blina then they actually
01:06:55have very poor responses to court.
01:06:58So we have to be careful about
01:07:01how we we sequence these therapies
01:07:04and we have to really monitor.
01:07:07I mean I know many academic centers
01:07:09now when they look at city.
01:07:1119 and C22,
01:07:12they do not just report for
01:07:15example whether it's dim positive,
01:07:18you know,
01:07:19or they will actually report a
01:07:20number for the level of expression.
01:07:22And that becomes very important in
01:07:24terms of I know that's what the NCI
01:07:27does and that becomes very important
01:07:29in terms of what the next therapy
01:07:31that they use is going to be.
01:07:34You know if if I can add to that
01:07:37comment that you know the nature of
01:07:39drug development was such that we had
01:07:41to go with enabling and then Karti,
01:07:43Karti despite having heavily
01:07:45treated population had highest
01:07:47CR and MRD negative data rates.
01:07:49So that kind of tells you that it's a
01:07:51potential drug just that we may not be
01:07:53able to get it in time whereas other
01:07:55drugs may be dispensing it off the shelf.
01:07:57In terms of the potential,
01:07:58it's clearly there despite a
01:08:00heavily treated population the
01:08:02rates of CR compared to Unism.
01:08:05Under Marty negatively,
01:08:05there is something that we need to look
01:08:07into it if we're looking into that.
01:08:12OK. I think we're out of time.
01:08:15Thanks, Doctor Sophie and Doctor Garin,
01:08:17thanks for all the good questions.
01:08:20I hope everybody has a good weekend.
01:08:24Thank you.