Skip to Main Content

Yale ASH 2022 Highlights: Cellular Therapies

March 13, 2023

March 10, 2023 | Hosted by Dr. Stuart Seropian

Presentation from: Dr. Iris Isufi

ID
9655

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.