Yale ASH 2022 Highlights: Cellular Therapies
March 13, 2023March 10, 2023 | Hosted by Dr. Stuart Seropian
Presentation from: Dr. Iris Isufi
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- ID
- 9655
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Transcript
- 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&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&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&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&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.