Blanche Tullman Lectureship: Approach to Research and Therapy of ALL at MD Anderson in 2022

Transcript

• 00:00What about what come the live audience?
• 00:03And I want to welcome everybody who's joining
• 00:05us today on zoom for the Sun Special Lecture.
• 00:08So I will be introducing Dr Sears
• 00:12and today's lecture honoree.
• 00:14And and then Doctor Zaiden, who is on zoom
• 00:18will be introducing Patrick and Harden.
• 00:19So the Blanche Tom and lecture series was
• 00:22established in 2012 by Doctor Marvin Sears.
• 00:25Dr Sears was a longtime chair and founder
• 00:28of Ophthalmology and visual science at Yale.
• 00:31And the lecture was established
• 00:32in honor of his mother,
• 00:33Lange Tolman, who passed away from
• 00:36acute myelogenous leukemia.
• 00:37This was actually the first lecture
• 00:39series dedicated solely to hematologic
• 00:41malignancies at Yale and it is
• 00:43intended to bring to Yale pioneers
• 00:45that have made major contributions
• 00:47to under to our understanding of
• 00:49the current trends in hematologic
• 00:51malignancies and in particular leukemia.
• 00:53So doctors Aiden,
• 00:54I welcome you to introduce Doctor Kantarjian.
• 00:59Yeah. Thank you so much, Stephanie.
• 01:00It's really a pleasure to
• 01:03introduce Doctor Kantarjian,
• 01:04who I could not think of any,
• 01:06but anyone more suited to give
• 01:08this lecture about new developments
• 01:09on leukemia because he has been
• 01:12a major force in many of the new
• 01:14developments over the last few decades,
• 01:16really in leukemia,
• 01:18both in AML and CLL and CML as well.
• 01:22So Doctor Kantarjian is a professor and
• 01:24chair of the Department of leukemia at
• 01:26the University of Texas and the Anderson.
• 01:29Cancer Center.
• 01:29He's also the Samsung Distinguished
• 01:32Leukemia chair in cancer medicine.
• 01:34His research has focused on translation
• 01:36and clinical development therapeutics in
• 01:38leukemia over the last three decades.
• 01:41He had made significant contributions
• 01:43that improved our understanding of
• 01:46both the prognosis as well as the
• 01:49survival of patients of CMLL as
• 01:51well as discoveries of decitabine
• 01:54in myelodysplastic syndromes
• 01:55and clofarabine in the treatment
• 01:57of leukemias and many other.
• 01:59Medications.
• 01:59In fact,
• 02:00he and his group have contributed
• 02:02to more than 20 develop new drug
• 02:05developments in in this space.
• 02:07He has been an author of more than
• 02:112000 peer reviewed publications,
• 02:13and he actually has been a major
• 02:16advocate of clinical research.
• 02:17He has mentored hundreds of leukemia
• 02:20doctors and researchers all over the
• 02:22US and the world and has been a big
• 02:25advocate for introduction and use of.
• 02:28Therapy is across the world,
• 02:30especially in low resource countries.
• 02:32So it's really a pleasure to have
• 02:34doctor Kantarjian and who are very
• 02:35grateful to have you speak to us
• 02:37today about acute and plastic
• 02:38leukemia. Thank you.
• 02:40Thank you very much, Doctor Zeidan.
• 02:42It's really a great honor and a
• 02:45pleasure to give it the talk at Yale and
• 02:49particularly the special Tallman talk.
• 02:51But I'm going to do is review the
• 02:54progress and research in acute
• 02:56lymphocytic leukemia as it stands today.
• 02:58And a lot of the things I'm going
• 03:01to say may be very different from
• 03:04what you view all treatment today.
• 03:07So bear with me,
• 03:09I'll try to get you through the information.
• 03:11And perhaps convince you that the
• 03:14times are changing very quickly.
• 03:17These are my conflicts of interest.
• 03:19So this is the standard of care
• 03:22in acute lymphocytic leukemia
• 03:24as it stands today we give.
• 03:26A lot of intensive chemotherapy with
• 03:2915 chemotherapy drugs over three
• 03:31years in childhood there L on the
• 03:34left side the investigators have
• 03:36reported your rates of up to 80%.
• 03:39On the right side is the data
• 03:41and adult L MD Anderson.
• 03:43So up till 2010 we were able to
• 03:46claim A5 year survival of maybe 50%.
• 03:49This is regardless of age and
• 03:52it has improved since 2010,
• 03:54but I'm going to show you that.
• 03:56That even the red curve is outdated in 2022.
• 04:00So it's important to just keep
• 04:02an open mind about the things
• 04:05which I'm going to mention,
• 04:07because I truly believe what I will
• 04:09show will be the next standard of
• 04:12care and maybe five years from now.
• 04:15So one of the questions is why is still
• 04:19there 30% difference or 40% difference in
• 04:23the cure rate between childhood and adult L?
• 04:26With intensive chemotherapy,
• 04:28so this is because of four subsets uh which
• 04:32have different incidences and prognosis.
• 04:35So in childhood all the hyper deployed
• 04:38and ETV 6 runx 1 constitute half
• 04:41of childhood all less than 10% of
• 04:44adult all and these have a favorable
• 04:47prognosis with intensive chemotherapy
• 04:49in contrast historically Philadelphia
• 04:52positive and Philadelphia like L
• 04:55which constitute 50% of adult.
• 04:58L and the 15% of childhood L These
• 05:02have had unfavorable outcomes
• 05:04with intensive chemotherapy.
• 05:06I'm going to show you that
• 05:08this does not apply anymore,
• 05:10neither for Philadelphia positive
• 05:12nor for the Philadelphia like it.
• 05:15So if you use the intensive
• 05:17chemotherapy for three years,
• 05:19what is the cost of this
• 05:21traditional intensive chemotherapy?
• 05:23So you're using a lot of
• 05:25chemotherapy over three years.
• 05:26This could be manageable
• 05:28and the ivory towers,
• 05:30leukemia centers of excellence.
• 05:31But if you apply this to the Community
• 05:35practice and emerging nations among
• 05:38poorer and disadvantaged populations,
• 05:40there's a very high dropout
• 05:42rate due to the socioeconomic.
• 05:45Conditions as well as in the
• 05:48infrastructure and support.
• 05:49Even then the frontline therapy
• 05:51will cost half $1,000,000 in the
• 05:54United States and if the patients
• 05:56relapse that's $2,000,000.
• 05:57And moreover there are multiple long term
• 06:01complications including organ dysfunctions,
• 06:04healthcare issues,
• 06:05psychological and social issues.
• 06:07So what is the solution to this?
• 06:10So let me try to show you some
• 06:13data uh from uh other nations.
• 06:15So this is Peru and India and these are
• 06:19recent reports and what they show is
• 06:22accurate and childhood L not of 80
• 06:24or 90% but in the range of 60 to 70%
• 06:27if you go to the older patients see.
• 06:31So these are the patients
• 06:33that we treat more commonly.
• 06:34The cure rate is anywhere from 10
• 06:38to 27% and this is simply because.
• 06:41The intensive chemotherapy for three years
• 06:43is not feasible among many of the patients.
• 06:46So the solution in my view is to try
• 06:49to develop different regimens which
• 06:52incorporate the newer treatments which
• 06:54have been discovered in the last 10 years.
• 06:56So for example,
• 06:58the third generation BCR able kinase
• 07:01inhibitors like PONATINIB in Philadelphia
• 07:04positive all and also incorporating.
• 07:08New antibodies that target CD19CD20
• 07:12and CD22 and perhaps consider that
• 07:15the best role of the car T cells
• 07:18is not an active salvage disease.
• 07:20But as a consolidation in remission and
• 07:23first second transplant also we need
• 07:26to measure the disease in better ways.
• 07:28So there's a way that's called next
• 07:32generation sequencing that measures
• 07:33the immunoglobulin heavy chain of
• 07:36the particular all it can analyze
• 07:38up to 3,000,000.
• 07:40Yes.
• 07:40And this will allow us to decide on changing
• 07:43the therapy and the duration of therapy.
• 07:45So I'm going to show you at the end
• 07:48what we refer to today as the dose
• 07:51dance mini CVD in oblina regimen
• 07:53with or without the car T cells.
• 07:55This is a seven month regiment which
• 07:58I'm hoping may become some form of a
• 08:01standard of care five years from now.
• 08:04This is not fiction.
• 08:07We did these studies now and.
• 08:10ALS salvage with good results and we
• 08:12have moved it to the older patients.
• 08:14So this is something that is happening.
• 08:18So this is a regimen that
• 08:20contains blinatumomab, rituximab,
• 08:22inotuzumab,
• 08:22the three existing effective antibodies
• 08:26and we do a condensed.
• 08:29Approach with chemotherapy.
• 08:30So rather than sequencing the
• 08:33chemotherapy followed by blinatumomab,
• 08:35we are doing it as a condensed regiment.
• 08:38So this is something that can be
• 08:40still improved upon.
• 08:41I'll show you some of the results.
• 08:44So why do I believe that it is time
• 08:46to break with the 40 year old tradition?
• 08:49I I believe so because in Philadelphia
• 08:52positive L I'll show you that non
• 08:55chemotherapy regimens without the
• 08:57transplant are giving outstanding results.
• 08:59Also in the pre bhal less chemotherapy
• 09:03for shorter durations in combination
• 09:06with these antibodies are improving
• 09:09the outcome significantly.
• 09:11I'm not sure about this lol
• 09:13because we do not have.
• 09:14Antibodies,
• 09:15which are broadly available
• 09:17to treat T cell L,
• 09:19But I'll show you some of the data with
• 09:22the incorporation of venetoclax and
• 09:24asparagine is nelarabine at the end.
• 09:27Now, anytime you break with tradition.
• 09:31It it bothers some of the skeptics,
• 09:35the traditionalist.
• 09:36So I'm showing this slide just
• 09:38to show you how times change.
• 09:41So this is a slide from 1970.
• 09:43This was the time when ARC was discovered
• 09:47at three as the treatment for AML.
• 09:50And there was a debate then between
• 09:53a very eminent hematologist,
• 09:56Dr Crosby, and Doctor Friedrich.
• 09:59And the question was,
• 10:01even though we have arasse,
• 10:03should we treat or not treat
• 10:05acute myeloid leukemia?
• 10:06So the answer is obvious.
• 10:09Today we treat almost all leukemias,
• 10:12but it was not obvious 50 years ago.
• 10:14And this was 15 years after I was born.
• 10:18So what? What? What?
• 10:20Seems unusual or.
• 10:23Out of the norm can become
• 10:25very quickly standard of care,
• 10:27uh within a lifetime.
• 10:30So I think the Anderson,
• 10:31we developed the Hyper C
• 10:33Weather Regiment in 1992.
• 10:35We changed the CNS prophylaxis from
• 10:37radiation therapy to intrathecal
• 10:39that became a standard of care.
• 10:42In 2000.
• 10:42We added the rituximab
• 10:44to workout and three BL.
• 10:46This was confirmed in randomized
• 10:48trials which were published
• 10:50in 2017 and this has become a
• 10:53standard of care in Philadelphia
• 10:55positive L it was only in 2000
• 10:58that we added IMAGINATE to hyper.
• 11:01We replaced it with the Satanic
• 11:03in 2006 and with PONATINIB
• 11:05in 2010 and the Hyper Cvad.
• 11:08The satanic followed by transplant
• 11:11is what is currently the standard of
• 11:14care in the United States in 2022.
• 11:16And I'll show you that it's
• 11:19probably old fashioned,
• 11:20outdated and perhaps obsolete.
• 11:22The big breakthrough came of course
• 11:25with the discovery of the new
• 11:27antibodies that were highly effective,
• 11:29more effective.
• 11:30And intensive chemotherapy and which
• 11:33targeted 2 of the cluster designation
• 11:36so blinatumomab bispecific T cell
• 11:39engager that targets CD19 and
• 11:41you know to zoom out and antibody
• 11:44drug conjugate that targets CD 22.
• 11:47So on the left side I show the again
• 11:51the data and the younger patients.
• 11:53So this is patients up to the age of 60
• 11:56and since 2010 there is an improvement.
• 11:59So now the five year survival is over 60%.
• 12:02On the right side is the data with
• 12:05mini CD in Oblina which started
• 12:08in 2010 and this is where we had a
• 12:11big improvement in the five year
• 12:14survival from 20% to about 50%.
• 12:18So we still use the Hyper Siva
• 12:20that MD Anderson in contrast to
• 12:23many other places where pediatric
• 12:25inspired regimens are used because
• 12:27it's easier to incorporate it into
• 12:30the newer targeted therapies and
• 12:32because at our institution we found
• 12:35that Hyper Cvad which is also a
• 12:38pediatric inspired regimen performed
• 12:40as well as the asparaginase containing
• 12:42regimens during the induction.
• 12:45Now for people who use the Hyper Cvad,
• 12:47I would like to draw.
• 12:48Your attention to a review in cancer
• 12:51which gives you some vignettes
• 12:53and pearls as to how to reduce the
• 12:55myelosuppression complications.
• 12:57The key issue is in the event courses
• 13:01where reduce the methotrexate by 24 percent,
• 13:0425% and the RC from 3 to
• 13:062 grams per meter square.
• 13:09But there are other small clues to
• 13:12improve the toxicities of this regime.
• 13:15Now,
• 13:16when I'm going to show you
• 13:17the research at MD Anderson,
• 13:19you're going to be wondering
• 13:22why we're resorting to Bayesian
• 13:24designs with signal arm trials.
• 13:27And I'll try to explain my position,
• 13:29but also why is it that
• 13:31different regiments have been
• 13:33developed differently?
• 13:34And this is essentially because
• 13:36a lot of the times it is what we
• 13:40propose and the drug companies
• 13:42offer us in terms of free drugs, so.
• 13:44Uh, the the evolution of a lot of
• 13:47the Ind studies at MD Anderson
• 13:50where based on if and when the
• 13:53antibodies were available and free
• 13:56on island studies as well as on
• 13:59the maturing Bayesian based data.
• 14:02So we started with the mini CVD in 2010,
• 14:07we added the BLINATUMOMAB later
• 14:09in 2015 and the younger patients,
• 14:13the Hyper Cvad started in 2018.
• 14:16And I'll show you that.
• 14:17And I mentioned that those dense
• 14:20mini CVD started only September
• 14:232021 and we opened this study
• 14:26for the older AML year later.
• 14:29So I'm going to show you some of
• 14:32the evolution of these studies.
• 14:34So let's start with Philadelphia
• 14:36positive and then in 2000,
• 14:38this diagnosis was a death sentence unless
• 14:41the patient had an allogeneic donor.
• 14:44So if the patients did not
• 14:46have a donor even zone,
• 14:4890% of them went in a complete
• 14:51remission with intensive chemotherapy.
• 14:53They almost all relapsed and died.
• 14:55If they had the donor,
• 14:56we gave them the transplant
• 14:58and their mission and the
• 15:00cure rate was about 30 to 40%.
• 15:02At MD Anderson,
• 15:03we added the imatinib to Hyper Cvad in 2000.
• 15:07Allogeneic transplant was almost always
• 15:09done in first complete remission.
• 15:12In 2006,
• 15:12we replaced that with the SAT
• 15:15in it and we started doing the
• 15:18transplant only if the patients
• 15:20were still PCR positive in 2010,
• 15:23because 20% of the relapses
• 15:25were with the T315I clone.
• 15:28We replace the satanic with ponatinib,
• 15:30the patients who are living longer.
• 15:3210 to 15% were developing CNS
• 15:35leukemia with the 8 intraceuticals.
• 15:37So we increased this to 12 intraceuticals
• 15:40and we did the transplant less and
• 15:43only if there was no major molecular
• 15:46response in 2017 we switched.
• 15:48So this was the drastic change
• 15:51eliminating chemotherapy and
• 15:53transplant and using two targeted
• 15:56therapies for net and Lina tuna.
• 15:58So I'm going to show you the
• 16:01sequence of the studies but.
• 16:02I'd like to draw your attention that none
• 16:05of these studies were randomized trial.
• 16:07And I'm gonna come back to this
• 16:10for the sake of the younger
• 16:12students and others because they,
• 16:15we and they have been indoctrinated
• 16:17that the only way to advance
• 16:19research in medicine and in cancer
• 16:21is in through randomized trials.
• 16:24And I'm going to probably state
• 16:28that that depends on where we are.
• 16:31So this is the progress in
• 16:34Philadelphia positive L before 2000,
• 16:36the patients died since 2002,
• 16:402010 these cure rate or
• 16:43survival improved to 40%.
• 16:45Since 2010 it went to A5
• 16:48year survival of 70%.
• 16:49Now the hyper Cvad Desatino was
• 16:52taken by the SW Oncology group.
• 16:55It was tested in a single arm
• 16:57trial and they found that they
• 16:59could reproduce the data from the
• 17:02single institution CR rate of 88%
• 17:05and a three-year survival of 70%.
• 17:08And they showed at that time
• 17:11that doing allogeneic
• 17:12transplant in first remission
• 17:14improved the outcome.
• 17:15So this became and is still the
• 17:18standard of care in the United States.
• 17:20I perceive that this afternoon
• 17:23followed by allogeneic transplant
• 17:24in first complete remission.
• 17:27Now people question whether the satanic
• 17:29was superior to imatinib and they
• 17:32waited for the randomized trials.
• 17:34So this randomized trial did
• 17:36not come from the United States,
• 17:38it came actually from China where
• 17:41children with Philadelphia positive
• 17:43L were randomized to chemotherapy
• 17:45with these satanic or imatinib.
• 17:47And that study showed clearly that the
• 17:50four year survival was superior with
• 17:53desatnik 88 versus 69% but notice on either.
• 17:57From the results are better than in adult L,
• 18:00so this is a common scene.
• 18:02Children with L do better than adults with L,
• 18:05whether they receive intensive chemotherapy,
• 18:08allogeneic transplant,
• 18:09car T cells, antibodies,
• 18:12or any other modalities so far.
• 18:17Now the hyper Cvad, Ponatinib started
• 18:19in 2010 because Ponatinib was toxic.
• 18:23We reduced the dose very quickly to
• 18:2530 milligrams in CR to 15 milligrams
• 18:29in complete molecular response and
• 18:31we published the data on the 86
• 18:34patients treated with this regimen.
• 18:37CR 800%, PCR negativity 84%,
• 18:40five year survival shown on the left
• 18:44side 75% and now we have a longer follow-up,
• 18:48so we.
• 18:48This is very solid data,
• 18:50but for the first time on the right
• 18:52side of the slide we showed that
• 18:55perhaps allogeneic transplantation
• 18:56is not necessary in all patients.
• 18:59So the blue curve is actually the
• 19:01patients who did undergo transplantation
• 19:04either by physician or by patients choice.
• 19:07So this was 1/4 of the patients
• 19:10and they did worse.
• 19:13The 12 intraceuticals abrogated
• 19:15or eliminated the CNS leukemia.
• 19:18So now we're sticking with 12
• 19:21intraceuticals and this is the best
• 19:23we could do to convince people who
• 19:26wish for the randomized trials.
• 19:28We did the propensity score analysis
• 19:31that showed that ponatinib was superior
• 19:35to desatnik in our institutional studies.
• 19:38Now in the meantime,
• 19:40Lena and Inotuzumab were undergoing uh,
• 19:44the single and randomized trials.
• 19:46And the randomized trials showed
• 19:48that in the subset of patients with
• 19:51Philadelphia positive L refractory
• 19:53relapsed blinatumomab and INOTUZUMAB
• 19:56were superior to intensive chemotherapy
• 19:59in terms of improving the CRA and
• 20:02perhaps improving survival modesty.
• 20:04So because of this,
• 20:06we went to a regiment in 2017.
• 20:09That skipped the intensive chemotherapy
• 20:11and skipped the transplant.
• 20:14And we use Ponatinib and blinatumomab
• 20:17during the induction and then
• 20:19blinatumomab for five cycles.
• 20:22The Ponatinib is as of today indefinitely,
• 20:25but but based on the NGH smurd studies,
• 20:29we're thinking to follow a strategy
• 20:31similar to CML where if the patients are NGS,
• 20:35MRD negative for five years,
• 20:38maybe we'll stop the treatment,
• 20:39but we're not there yet.
• 20:41But let me show you the data which
• 20:44is going to be published in Lancet
• 20:46hematology in the next couple of months.
• 20:49So we treated 63 patients,
• 20:5243 where newly diagnosed Philadelphia
• 20:54positive L so if you look at those
• 20:5743 patients in the middle column,
• 20:59the CR rate is universal
• 21:02complete molecular response rate
• 21:04also in most of the patients and
• 21:07for the first time they estimated
• 21:082 to three years survival is 95%.
• 21:11So this is better than anything
• 21:13we've ever had and only one of the
• 21:1743 patients went to transplant.
• 21:19Now for patients with refractory
• 21:22relapsed Philadelphia positive AML
• 21:24or CML chronic phase that evolved
• 21:27into the lymphoid blastic phase,
• 21:30the outcome is still bad.
• 21:32So we still use the hyper Cvad, ponatinib,
• 21:35blinatumomab in those two subsets.
• 21:38And this is to show you how quickly
• 21:41the patients achieve PCR negativity.
• 21:43So if you treat Philadelphia positive CLL,
• 21:47you are used to the fact that the
• 21:49PCR does not become negative till
• 21:51three to six months into a remission.
• 21:54Here I show and we did this the PCR
• 21:58weekly simply to see whether we're going
• 22:01to see some major signal and we were
• 22:05surprised to notice that within the four.
• 22:09Weeks of induction therapy,
• 22:102/3 of the patients became PCR
• 22:13negative and before the next course,
• 22:163/4 of the patients had become PCR negative.
• 22:19So very quick achievement of PCR
• 22:22negativity and NGS MRD negativity.
• 22:25And now I show the survival in the
• 22:27red with the ponatinib blinatumomab
• 22:30compared to the hyper cvad ponatinib.
• 22:33So the question is will you do a
• 22:36randomized study today comparing poneto?
• 22:39Lena to map to hyper.
• 22:40See that? Um, imagine it.
• 22:44So this is an important question and
• 22:47I have to tell you that this is a
• 22:50randomized study that's ongoing in Europe.
• 22:53So you have to decide is this randomized
• 22:56trial which provides equipoise,
• 22:59which is the basis of a randomized trial,
• 23:02meaning that the investigator does not
• 23:05know whether one or the other arms
• 23:08of the randomization is superior.
• 23:11So as I mentioned,
• 23:13we still use intensive chemotherapy
• 23:15with ponatinib blinatumomab in CML
• 23:18chronic phase that evolves into
• 23:20a blastic phase and refractory
• 23:22relapsed Philadelphia positive L
• 23:24and then in two other rare subsets.
• 23:28So patients with Philadelphia
• 23:30positive L but where the fish is
• 23:33positive on the mature granular sites,
• 23:35these are patients mostly with P210,
• 23:39Philadelphia positive L and another rare.
• 23:42Upset, which we did not think existed,
• 23:45but we had now 7 cases of
• 23:48Philadelphia positive L and CRLF two.
• 23:50These do badly and they need
• 23:53the intensive chemotherapy.
• 23:55Now next I'm going to move to Philadelphia
• 23:58like so for the students and the fellows.
• 24:02Philadelphia Lucky L is an L entity
• 24:06where the cytogenetics do not show the
• 24:09translocation 922 and the molecular
• 24:11studies do not show the BCR able
• 24:14translocation molecular events,
• 24:17but they have a genomic profile
• 24:19which is identical to Philadelphia
• 24:21positive all and different from
• 24:24the other subsets of all.
• 24:26So what we've learned is Philadelphia,
• 24:28like L has a bad prognosis
• 24:31with intensive chemotherapy.
• 24:32On the left side is the data from Saint Jude,
• 24:35on the right side is the data
• 24:37from MD Anderson.
• 24:38And what you notice is historically
• 24:41with intensive chemotherapy,
• 24:42the cure rate in children was 25%.
• 24:45The cure rate and adult also was below 20%.
• 24:50We now know that this is more common
• 24:53in Hispanics because they have got
• 24:56a 3 variant that increases CRF2,
• 24:59so they have a lot of Philadelphia like.
• 25:04So Philadelphia like LL is
• 25:07divided into 2 entities.
• 25:08So this is just 1/4 of pre BL,
• 25:13but 50% of Hispanics pre B all,
• 25:17most of them 80% have CRLF two
• 25:20over expression and half of
• 25:22these have a Jack mutation.
• 25:24So if you take 100 patients with L25,
• 25:28we'll have Philadelphia like Disease,
• 25:3020 will be CRLF,
• 25:322 overexpressed and 10 of them.
• 25:35Will be Jack 2 mutated and these are bad.
• 25:38These patients may still need
• 25:41the allogeneic transplantation,
• 25:42but otherwise the other Philadelphia
• 25:44like I'll show you do well with
• 25:47the addition of the antibodies.
• 25:49Then there's an uncommon subset,
• 25:51so five of the 100 or 20% of
• 25:54the Philadelphia like that have
• 25:56able translocations.
• 25:57So this is not the BCR able,
• 26:00but they are able translocations
• 26:02to other genes and these patients.
• 26:05Respond to BCR able kinase inhibitors.
• 26:08So here I show it more schematically.
• 26:11In blue are the translocations of able one.
• 26:17To other genes that produce enable
• 26:21translocation that responds to the BCR
• 26:24able kinase inhibitors also the same
• 26:28applies to PDGFR beta translocations.
• 26:31So these patients with Abel
• 26:34or PD GFR fusions,
• 26:36we treat them on the
• 26:38Philadelphia positive protocols.
• 26:40There is another subset with not
• 26:42Jack 2 mutations but with Jack to
• 26:45translocations and it is possible.
• 26:47That these may respond to resolution
• 26:49and we do not know and they are rare,
• 26:51so we haven't been able to
• 26:54treat them on our studies.
• 26:57This is a study from France where
• 27:0124 patients with essentially
• 27:03able translocations were treated
• 27:05with BCR able kinase inhibitors
• 27:08and intensive chemotherapy.
• 27:10And they showed in this study that
• 27:13like Philadelphia positive all these
• 27:15patients who receive chemotherapy
• 27:17and BCR ABL kinase inhibitor have
• 27:20a high response rate close to 90%
• 27:23and the four year survival of 60%.
• 27:26So these able.
• 27:27Mislocated lol.
• 27:28We treat the same way as Philadelphia
• 27:31positive L.
• 27:32So to summarize,
• 27:33Philadelphia like L has the same genomic
• 27:36profile as Philadelphia positive L,
• 27:38but not the 922 translocation and
• 27:42not the BCR able molecular events.
• 27:45It constitutes 25% of the adults.
• 27:48Historically it has a poor prognosis,
• 27:50but not anymore.
• 27:52It is more common among Hispanics
• 27:55and it is 2 distinct entities.
• 27:58The CRF2 overexpressed and
• 28:00they're able translocated.
• 28:02Which we treat like Philadelphia positively.
• 28:04And so the newer approaches are
• 28:07actually improving the outcome
• 28:09in both of these entities.
• 28:11And I'll show you that for the
• 28:14particular subset of CRF2 overexpression.
• 28:18Next I'm going to talk about the
• 28:20therapeutic revolution in the
• 28:22L and I show it on the slide.
• 28:23It comes from 2 subsets.
• 28:25The first one are the newer
• 28:29antibodies including antibody
• 28:31drug conjugates and by specific T
• 28:34cell engagers that are targeting
• 28:37CD19CD20 and CD2CD22 and CD20.
• 28:41So you may be aware of the CD 20 bytes
• 28:44which have shown very high efficacy in
• 28:47lymphoma. So we'd like to use
• 28:50them to replace rituximab.
• 28:51And that way we have 3 antibodies
• 28:53which are highly effective.
• 28:55On the right side are the cartel cells,
• 28:57which are a revolution in
• 28:59both lymphoma and myeloma.
• 29:01But I think for them to
• 29:03be important in the L,
• 29:05they have to be used in the setting
• 29:08of minimal residual disease.
• 29:10So in 2009 at MD Anderson,
• 29:14we were aware of the INOTUZUMAB
• 29:18studies and lymphoma.
• 29:19And so we convinced the company to
• 29:22give us an investigator in this study,
• 29:25which we did initially with
• 29:28single dose per course and then in
• 29:31fractionated doses and that study
• 29:34matured into 90 patients that showed
• 29:37that a single antibody produced.
• 29:40Mario CR rate of 58%.
• 29:42In the meantime,
• 29:43the randomized trials and
• 29:45lymphoma with INOTUZUMAB failed.
• 29:47So the company went ahead with the
• 29:50randomized trial and I show here the
• 29:53the data in the randomized trial.
• 29:55So there were two studies.
• 29:58Two parallel trials with Blinatumomab
• 30:02and these were both randomized
• 30:05trials that compared the antibodies
• 30:07to intensive chemotherapy and both
• 30:10trials showed that blinatumomab and
• 30:13inotuzumab were superior to intensive
• 30:16chemotherapy in refractory relaxed.
• 30:19I want you all to also notice
• 30:21that even though we reported
• 30:23Amaro CR rate in the MD Anderson
• 30:26studies of 59% because of the.
• 30:28Better selection in the randomized trials.
• 30:30Actually the randomized trial showed higher
• 30:33mercy RA than our institutional study.
• 30:37So both these agents became FDA approved
• 30:42in 2014 and in 2017 as single agents for
• 30:46the treatment of refractory relapse AML.
• 30:50But what you see is the
• 30:52benefit is very modest.
• 30:54So very quickly we decided this is
• 30:56not how we are going to use them
• 31:00and we incorporated them rapidly
• 31:02into the standard chemotherapy.
• 31:05So I'm going to show you next the data
• 31:08with Hyper Cvad blinatumomab in pre Bal.
• 31:11So the design of the original
• 31:14study was four cycles of intensive
• 31:16chemotherapy and because the prevailing
• 31:19notion was you cannot dose dense.
• 31:21With the chemotherapy,
• 31:23because the chemotherapy kills
• 31:24the these T cells,
• 31:26so theoretically blinatumomab
• 31:28would be less effective.
• 31:31The company allowed us only to use
• 31:33it in sequence and then we shorten
• 31:36the duration of the maintenance
• 31:38from two years to one year.
• 31:40And later on the other company uh
• 31:42allowed us to add inotuzumab um.
• 31:45So we had two of the antibodies as
• 31:48three drugs that we incorporated into
• 31:51the high perceived blinatumomab inotuzumab.
• 31:54So we are going to publish the
• 31:57data in the 1st 63% again unless it
• 32:00hematology in the next couple of months.
• 32:02The CR8 was 100%,
• 32:05MRD negativity 95% and for the
• 32:08first time in pre BLA in adult pre
• 32:12BL the three-year survival was 85%.
• 32:15On the right side I showed the the
• 32:19data since we added the inotuzumab,
• 32:22so by adding inotuzumab.
• 32:24To the high perceived blinatumomab
• 32:27we improved the outcome,
• 32:29perhaps because we so far have
• 32:32not seen any relapses.
• 32:33So that's why I think that this
• 32:36is perhaps a potential standard
• 32:38of care in the future.
• 32:40Now let's look at the data compared to the
• 32:43previous high perceived ofatumumab, a 20%
• 32:46difference in the survival at three years.
• 32:49And this shows the subset in blue of patients
• 32:53with Philadelphia like disease where the
• 32:57survival is not anymore 20% as I showed you,
• 33:00but it has gone up to 70% and this shows the.
• 33:04Survival with or without the transplant,
• 33:07again suggesting that the role of
• 33:10transplant is not that important
• 33:12and not for all patients with ALS.
• 33:15So I showed you the top two slides,
• 33:18the top two studies from MD Anderson and
• 33:21what you see is this is a common trend now.
• 33:25So even though randomized trials has been or
• 33:28is the standard of care in Cancer Research,
• 33:32what you see is many of
• 33:34the studies from Germany,
• 33:35France and other places,
• 33:37they are using single arm trials in
• 33:40order to optimize the regimens before
• 33:43taking them to a final randomized.
• 33:46One and they are showing similar data with
• 33:49high CR rates and high survival rates.
• 33:52Now, I mentioned randomized trial and
• 33:55Bayesian designs for several times
• 33:58and I want to explain myself perhaps
• 34:01not to the senior physicians who.
• 34:07May be skeptical about this,
• 34:09but perhaps for the fellows and students
• 34:12who have been educated to appreciate
• 34:15randomized trials as the only way to
• 34:19advance research in medicine and in cancer.
• 34:22So we started the studies with INOTUZUMAB
• 34:26in 2010, with BLINATUMOMAB in 2012.
• 34:29These drugs were FDA approved in
• 34:322014 and 17 in 2022 a decade later.
• 34:37We still use Blinatumomab and inotuzumab
• 34:41as single agents in ASL solvers.
• 34:44We have not yet established the
• 34:47combinations as a standard of care.
• 34:49Now what?
• 34:50Let's go back to the history
• 34:52of randomized trials.
• 34:54What people may not know is the
• 34:58randomized trial started only in 1955.
• 35:00The first randomized trial in
• 35:02cancer was done by Doctor Friedrich.
• 35:05This was a time when he was at the
• 35:08NIH and he showed a correlation
• 35:11between low platelets and bleeding.
• 35:14So people ask him to do a randomized
• 35:17trial where he and he gave fresh blood
• 35:19and he showed that the bleeding decreased.
• 35:22In those days,
• 35:23we did not have to resist machines,
• 35:26so he was asked to do a randomized trial
• 35:29of fresh blood versus stored blood.
• 35:32To show that fresh blood would
• 35:34reduce the bleeding in children
• 35:36with a L and he showed that and when
• 35:39the trial turned to be positive,
• 35:41they accused him of falsifying the data.
• 35:44So this shows you a trend that perhaps a
• 35:48randomized trials are established today,
• 35:51but maybe we can question them.
• 35:53So let me tell you why we should
• 35:56question them.
• 35:56So today in Europe there is
• 35:59a phase three study of 1.
• 36:02Versus intensive chemotherapy, imagine.
• 36:04I do not believe there is real equipoise,
• 36:08so the basis of all randomized trials.
• 36:11Is that they assume there's
• 36:13the knowledge equipoise.
• 36:15So you're sitting in the room
• 36:16with the patient and you say,
• 36:18I'm going to randomize you to this
• 36:21protocol and I truly and honestly do
• 36:24not believe that the new treatment
• 36:26is better than the old one.
• 36:28Now randomized trials are OK if
• 36:30you are in a research desert.
• 36:33So if you were in 1965 or 1970 or
• 36:371980 where there was very little
• 36:39to offer to the patients,
• 36:42you could do a randomized trial with
• 36:44the new drug X or if you have a highly
• 36:47curable disease like ALS today,
• 36:49we are in the land of research plenty.
• 36:51There are multiple targeted therapies
• 36:54in ASL and if you do a randomized
• 36:58trial that randomizes.
• 36:59The patients to the standard of
• 37:02care versus standard of care versus
• 37:04drug X that the results of that
• 37:07randomized trial will be outdated
• 37:09by the time the data matures.
• 37:11And if you think about it,
• 37:12our whole life experience is actually
• 37:15not randomized. It's Bayesian.
• 37:17The way we raise our children,
• 37:19the the schools we choose for them,
• 37:22the restaurants we choose,
• 37:23the careers, the partners.
• 37:24You do not go out 50 times with
• 37:28a new person and 50 times with
• 37:30another new person and then look
• 37:33at your experience and decide which
• 37:35one you're going to marry.
• 37:37You actually switch from person A to B&C.
• 37:41Very quickly and gain a cumulative experience
• 37:45that allows you to decide on what to do.
• 37:49Now in in the editorials you you
• 37:54may have read those two examples,
• 37:57which are obvious examples.
• 37:58So parachutes were not
• 38:00based on randomized trials.
• 38:02We did not throw 50 people without
• 38:05a parachute and 50 people with
• 38:08a parachute from airplanes to
• 38:10decide that parachutes save lives.
• 38:12And the same applied to seatbelts and so on.
• 38:15Now for the young people,
• 38:18they search Google all the time
• 38:20for the truth.
• 38:21So there are Google algorithm that we
• 38:24use in our daily practice to decide
• 38:27what's good and what's not good.
• 38:30So I'm going to propose that perhaps
• 38:32what we have to do in Cancer Research
• 38:36and in medical research is develop
• 38:38apps that incorporate the research.
• 38:41In cancer for example and then we
• 38:44ask the app based on the preclinical
• 38:47data and the clinical trials so far,
• 38:49what would be the best design
• 38:52to investigate a new drug in in
• 38:55the Cancer Research.
• 38:56So think about it and see if if if it's
• 39:00something that could that could maybe
• 39:03challenge the concept of randomized
• 39:06trials and this is not new knowledge.
• 39:08So what you notice is that
• 39:10the A today is approving.
• 39:12Several drugs not based on randomized trials,
• 39:15but based on the results of even
• 39:18phase one studies and we were
• 39:21told historically that phase one
• 39:23studies are purely to identify
• 39:26toxicities and the phase two dose.
• 39:29Now we know that there are several
• 39:32drugs like crizotinib and non small
• 39:35cell lung cancer and then roughly
• 39:37in Melanoma that were approved based
• 39:40on the results of Phase 1/2 trials.
• 39:44So I'm going to propose at least for
• 39:46a L which is a land of the resource
• 39:49plenty that we hold the randomized
• 39:51styles because they will slow the
• 39:54progress and the discoveries and
• 39:56replace them with Bayesian trials.
• 39:59Actually randomized trials which are
• 40:01poorly designed can give you false leads.
• 40:03So there was in fact an all study
• 40:06using a pediatric inspired regimen.
• 40:09It was a cooperative trial in
• 40:12the United States that had.
• 40:14Randomized patients to using a
• 40:17regimen with ASPARAGINASE and
• 40:19randomization to inotuzumab.
• 40:21I objected vehemently to that study
• 40:24because I said that Asparaginase
• 40:26and Inotuzumab will cause vino
• 40:28occlusive disease and mortality.
• 40:31This was not believed and the study
• 40:33was stopped two months ago after 400
• 40:36patients were entered because as expected,
• 40:39there was a higher mortality in
• 40:41the investigational arm because
• 40:43of the anticipated.
• 40:45A synergistic toxicity of
• 40:47asparaginase and inotuzumab.
• 40:48So I think at least in ASL we have
• 40:51to revert to single arm trials until
• 40:53we optimize the regimen that could
• 40:56be compared to the standard of care.
• 40:58Now next I'm going to discuss
• 41:01minimal residual disease.
• 41:02I'm going to draw your attention
• 41:04to figure the this is,
• 41:07this is patients with adult AL who are
• 41:10in remission and who are MRD positive.
• 41:13So what you see is their cure rate is at
• 41:16best 10% compared to over 50%
• 41:19for the patients who become MRD
• 41:22negative by any methodology.
• 41:24But this was mostly by flow cytometry.
• 41:28So this is. Where we started using
• 41:31BLINATUMOMAB for five courses in the
• 41:34setting of MRD positive L in first or
• 41:37second remission we observed that 80%
• 41:40of the patients became MRD negative
• 41:43and the four year survival was not 10%,
• 41:47it went up to 60%.
• 41:49And on the right side I showed that
• 41:52the effect of transplant was minimal.
• 41:55So perhaps this is where we can
• 41:57do the cartel cells.
• 41:58Instead of transplant,
• 42:00because if you avoid the
• 42:02transplant related mortality,
• 42:03maybe the cure rate will be even higher.
• 42:06So This is why it's important
• 42:09to Measure Mart not by flow
• 42:11cytometry looking at 10,000 cells,
• 42:14but by the next generation sequencing
• 42:17for the immunoglobulin heavy chain that
• 42:20looks at the million to three million cells.
• 42:23So this is a study in the older AL,
• 42:26so I'm going to show you an update
• 42:28for just for information purposes.
• 42:30So this is the study that we did and
• 42:34we took from the L salvage where we did
• 42:37minimal chemotherapy with inotuzumab
• 42:39and added the BLINATUMOMAB later on.
• 42:42And we showed that by matched analysis
• 42:45that the new study was superior
• 42:49to the old study of Hyper Siva.
• 42:52The question?
• 42:53Is can we do a randomized trial and what
• 42:56it would be the control arm now that
• 42:59there's a significant difference in
• 43:01the outcome compared to historical data?
• 43:04And this is the same happening elsewhere.
• 43:07So in the United States there was a
• 43:10single arm swork trial of chemotherapy
• 43:12with blinatumomab and similar studies
• 43:15were conducted again in Germany and
• 43:17Australia and by the French group.
• 43:20All of them are single arm trials
• 43:23combining chemotherapy with one of
• 43:26the two antibodies producing high
• 43:28CR rates and good early outcomes.
• 43:31Now in this LL, as I mentioned,
• 43:34we do not have an antibody.
• 43:36But what we have is something
• 43:38that might work,
• 43:40so intensive chemotherapy with a lot
• 43:42of methotrexate and asparaginase and
• 43:45recently we have seen that nelarabine
• 43:48works there and venetoclax might work.
• 43:52So we have started combining these
• 43:55drugs in a trial and error formulation.
• 43:59And the other thing that is
• 44:02important is the fact that T cell L,
• 44:06there's a subset of T cell AL shown here
• 44:10that has a genomic profile more like AML.
• 44:14I think this is the precursor T cell
• 44:17all where we need to start considering
• 44:21treatments that incorporate AML therapies.
• 44:23So this is the subset of the
• 44:26cell L with methylation profile.
• 44:30Identical to acute myeloid leukemia
• 44:32and perhaps these are the patients
• 44:34that should be treated like M so
• 44:37this is the multiple reiterations
• 44:40of the hyper cvad asparaginase,
• 44:43nelarabine regimen and not yet
• 44:46ready for prime time,
• 44:48but in the past two studies where we added
• 44:52venetoclax and nelarabine asparaginase,
• 44:55we're getting survivals not of 60%,
• 44:58but over 70%.
• 44:59And we are,
• 45:01we hope that this will continue
• 45:03with the updates.
• 45:05Now one of the questions is then when do we
• 45:08use allogeneic transplantation in remission.
• 45:11So we still use it in the patients with
• 45:15translocation 11Q23IN precursor TLL
• 45:17and patients with complex karyotypes,
• 45:20so abnormalities more than five and
• 45:23in the Philadelphia like L with CRLF
• 45:27two with Jack 2 mutations otherwise.
• 45:30So this constitutes.
• 45:31About maybe 15 to 20% of adult
• 45:35AML where we still use allogeneic
• 45:38transplant today and where we may
• 45:41use car T cells in the future.
• 45:43So this is an update in the AL solver.
• 45:46So this is where it all started.
• 45:48So even though I'm showing it at
• 45:50the end because it's L salvage,
• 45:52this is where all the research
• 45:54started with the MACD,
• 45:56you know to Zuma blinatumomab and
• 45:59I showed the update in the 112
• 46:01patients treated so far,
• 46:03marrow CR 883%,
• 46:05MRD negativity,
• 46:0783% define occlusive disease after
• 46:10we fractionated the inotuzumab.
• 46:13And kept the doors has gone from 9% to 1%.
• 46:18AML relapse used to be again death
• 46:21sentence and the overall 112 patients.
• 46:25The five year survival is 30%.
• 46:27Since we added the blinatumomab
• 46:29we have shown like in the younger
• 46:32patients when we added in auto blina
• 46:35we showed an improvement in the
• 46:37survival and the salvage when we added
• 46:40BLINATUMOMAB to the mini CD you know.
• 46:43We have shown an improvement in
• 46:46the three-year survival to 50%.
• 46:48In salvage one,
• 46:50the potential five year survival is now
• 46:5340% and we do not see a difference with
• 46:55or without alot transplant because I
• 46:58think we're losing a lot of patience
• 47:00to the transplant complications.
• 47:03So if we do the car T cells maybe we'll
• 47:06improve the survival further than 40%.
• 47:10Now people may say, well,
• 47:11we have the cartee cells,
• 47:12why have you ignored them?
• 47:14So on the left side,
• 47:16I showed you data with inotuzumab.
• 47:18We're not curing too many patients,
• 47:20maybe 20%.
• 47:21And we need the transplant here in
• 47:24the middle or the newer car T cells,
• 47:27the approved car T cells for the
• 47:30older patients and what you see is the
• 47:33two year survival is probably 20%.
• 47:36And now I show you the the UM in blue,
• 47:40the post amendment where the
• 47:42three-year survival is 50%.
• 47:44So I think in L salvage if I
• 47:47have a patient who has relapsed,
• 47:50I would use the mini CVD in oblina
• 47:52and then I would do the Carticel to
• 47:55improve the potential cure rate.
• 47:56Now why have I insisted several
• 47:59times on the CART sales to be
• 48:02tested in minimal residual disease?
• 48:05I think the car T cells today
• 48:06are being used the same way.
• 48:08We use allogeneic transplant
• 48:09in the 1970s in active disease
• 48:12and we're curing 20 to 30%.
• 48:15If we start using the car T cells and
• 48:17minimal residual disease the same way
• 48:20as allogeneic transplant is used today,
• 48:22then perhaps we we will cure
• 48:24many more of them.
• 48:26Now people will object to this saying,
• 48:28well no,
• 48:29you need active disease to
• 48:32to expand the car T cells.
• 48:35But the real world data shows
• 48:37that in fact when you do the car T
• 48:39cells in minimal residual disease,
• 48:41which are the red and the blue curve,
• 48:43you potentially cure more patients
• 48:45than if you do it in the setting
• 48:49of minimal residual disease.
• 48:51So in summary,
• 48:53I think in Philadelphia positive
• 48:55L Ponatinib BLINATUMOMAB will be
• 48:57the future form of therapy and I
• 49:00think the future of pre BL will
• 49:02be with much less chemotherapy
• 49:04for shorter duration combined with
• 49:07the antibodies using the car T
• 49:10cells in the setting of minimal
• 49:13residual disease and monitoring
• 49:15patients by next generation MRD.
• 49:18Now can we do better than this?
• 49:20So this is what I showed you with
• 49:23what I call the break or the dose
• 49:26dense mini CBD regimen and this is
• 49:28what we are testing today in older
• 49:31all and we may move it to younger all.
• 49:34So this is very similar to what
• 49:36you do in lymphoma,
• 49:37just six courses of therapy and perhaps
• 49:40the need of car T cell consolidation,
• 49:44but can we do better than this.
• 49:45So you may be aware that.
• 49:48There are T cell engagers which
• 49:52target more than CD19 or CD20.
• 49:55This is what we call the Tetra
• 49:58specific T cell engagers.
• 50:00This is not science fiction.
• 50:02These will be developed and there
• 50:04are also cartee cells which target
• 50:07more than one target,
• 50:08so dulci 19 and 20 cart set.
• 50:11So it is possible that in the future
• 50:14we will use very little chemotherapy
• 50:16to induce the patients in remission.
• 50:19Consolidate them with the Tetra
• 50:21specific T cell engagers and then
• 50:24we'll further consolidate them
• 50:26with Karti cells.
• 50:27So in total duration of therapy
• 50:29of three to four months,
• 50:31which will not be toxic and which
• 50:33will be highly effective and
• 50:36potentially highly curable.
• 50:38Thank you for your attention and
• 50:40I'm happy to answer any questions.
• 50:52Did I thank you for this absolutely fantastic
• 50:56lecture? And we actually have hematology
• 50:59faculty and trainees in the room.
• 51:01So I encourage everybody to
• 51:03ask questions in person.
• 51:04You're welcome to come up to the
• 51:07podium or I'm happy to repeat
• 51:09your questions from the audience.
• 51:11And then are you seeing
• 51:13questions from in soon?
• 51:21So I don't see questions
• 51:22in either that. Question.
• 51:27OK. Thank you for that
• 51:30excellent presentation.
• 51:31I think the pH positive word is largely
• 51:33driven by what happens at MD Anderson.
• 51:36And it's interesting to see
• 51:38it's negative disease and ALS is
• 51:39going that direction as well.
• 51:41Thank you for those excellent slides.
• 51:44You show a couple of interesting but
• 51:47equally provocative slides, right?
• 51:50Innovate and leaner trials,
• 51:51when published historically
• 51:52compared them against standard of
• 51:54chemo while the Cartesian trials.
• 51:57At INA and Lena failure in my mind,
• 52:00those were probably more refractory diseases.
• 52:03Based on the CR and the MRD rate
• 52:05that are reported across Kartes as
• 52:07is approved with the FDA agents.
• 52:10What's the hesitation of you
• 52:12trying them first?
• 52:13And why are we still pursuing with Inar
• 52:15Deena approaches with chemotherapy?
• 52:17I think the answer to that
• 52:18will lead to my next question.
• 52:20So that's a very important question.
• 52:22And the answer to this is I do
• 52:24not compare the single agent
• 52:26antibodies to the cartica results,
• 52:29but you have to do is compare the hyper
• 52:32cvad in oblina and salvage to the Carticel.
• 52:35So with the cart cells,
• 52:36if you take 100 patients,
• 52:38you're infusing probably only 2/3 of them
• 52:41because you lose some of the patients.
• 52:43In the process with the mini CD and
• 52:46Oblina you are treating 100% of
• 52:49the patients and you're getting a
• 52:51mirror CR rate of 85% and that does
• 52:54not negate the need and potential
• 52:56use of either allogeneic transplant
• 52:59or Cathy cell as a consolidation.
• 53:02So I do not see the antibodies and Carty
• 53:05cells as either or or competitive modalities,
• 53:09I see them as in fact
• 53:12synergistic modalities that.
• 53:14Have to be used in the proper sequence.
• 53:16I think that begs the question,
• 53:18since we're competing for the
• 53:20CD19 targets with Lena and Carti,
• 53:23why not just stick to your mini
• 53:25hyper Cvad prasina to Zoom app and
• 53:27then a different target, right?
• 53:28Because it's 19 or 22 expressions.
• 53:31Because the bigger question
• 53:32of how to sequence this,
• 53:34should blina be avoided,
• 53:37especially in car?
• 53:39Likely coordinating patients
• 53:40or however you design it,
• 53:42because there are some issues of
• 53:43competing for the same antigenic targets.
• 53:46So that's an important question
• 53:47and the Carticel experts have
• 53:49always brought the issue.
• 53:50If you treat the patients with blinatumomab,
• 53:53you may lose the target.
• 53:55And there were data that showed
• 53:57that the outcome may be worse.
• 53:58But there is this real world data
• 54:01which I've shown you have updated the
• 54:04results and they've shown that the
• 54:06results were worse with blinatumomab
• 54:08only in the patients who failed
• 54:11blinatumomab and the patients who respond
• 54:13to blinatumomab when they relapse.
• 54:15And they get the car T cells,
• 54:17the results are still as good.
• 54:19So it was a selection of the patients
• 54:23who are refractory to blinatumomab who
• 54:25were also refractory to the cartesius.
• 54:28So I have no hesitation and no issues with
• 54:32using blinatumomab before the car T cells,
• 54:35because loss of the target is minimal,
• 54:39if at all,
• 54:41and also because the updated data.
• 54:46Does not show that exposure to blinatumomab
• 54:48worsens the outcome of the car T cells.
• 54:50It was an epiphenomenon of the
• 54:53patients who are refractory,
• 54:55truly refractory to blina that also
• 54:57are refractory to the cortices.
• 55:01OK. Thank you. And last comment was
• 55:02going to make was now I'll let others
• 55:04take the question because a couple of my
• 55:06other colleagues have to go for Nicola.
• 55:10It's a nickel.
• 55:11I guess you have just one question.
• 55:12Have you noticed that you know
• 55:14by maybe not running phase
• 55:16three trial randomized trials,
• 55:18but these early phase trials that you
• 55:20have better inclusion of you know,
• 55:22people who may be more
• 55:24hesitant to enroll in trials,
• 55:25so underrepresented population.
• 55:29Well that's one issue because
• 55:30as I mentioned today with all
• 55:33the targeted therapies with the
• 55:35multitudes of targeted therapies,
• 55:37it's very difficult for an investigator.
• 55:39We truly and transparently
• 55:42states a situation of equipoise,
• 55:45meaning that you tell the patient,
• 55:47look, I have hyper cvad. Um.
• 55:55Imagine versus ponatinib, blinatumomab
• 55:58and I truly believe that I do not know
• 56:02the answer to to that, to that strategy.
• 56:05So I think if you tell the patient,
• 56:09look, we have gathered all our knowledge
• 56:11and to the best of my knowledge
• 56:14this is a trial that will help you.
• 56:16First, it would reduce the restrictive
• 56:21eligibility criteria, which was.
• 56:24You can. You can negotiate better within
• 56:27your own Ind studies and in single
• 56:30ARM trials to reduce the obstacles.
• 56:33And second, you probably can
• 56:35convince the patients better that
• 56:37what you're offering them is truly
• 56:39what you believe is best for them.
• 56:42Thank you so much Doctor Baldev,
• 56:43come on to the podium.
• 56:48Doctor Contagion, thank you very
• 56:49much for excellent presentation.
• 56:50My question is about use of Ponatinib
• 56:53and BLINATUMOMAB and pH positive
• 56:55L so you know this is applicable
• 56:57to younger and older patients and
• 56:59obviously there is a lot of concern
• 57:01about the natib related toxicity.
• 57:03Would you see any contraindications
• 57:04and what do you think about long
• 57:06term use of management after
• 57:08you finished initial treatment,
• 57:09how long should we continue?
• 57:11So you're absolutely correct that
• 57:14Ponatinib has significant toxicities.
• 57:16That's why we reduce it from 45.
• 57:19Actually in the ponatinib Lina,
• 57:21we start with 30 milligrams and we
• 57:23reduce it to 15 milligrams usually
• 57:26within a month as I showed you.
• 57:28But your question is very legitimate.
• 57:31What do we do with all the patients who
• 57:33have already existing arterial occlusive
• 57:36events or cardiovascular events.
• 57:39So in those situations there's.
• 57:41One could design a trial
• 57:45with Bosutinib Blinatumomab.
• 57:47Or with the satanic Blinatumomab,
• 57:51but you're going to encounter
• 57:53perhaps relapse rate of maybe
• 57:5610 to 20% with 315I clones.
• 57:59You hope that the Blinatumomab
• 58:02will suppress these clones,
• 58:03and if you try to design A regimen like this,
• 58:06I would encourage to use the blinatumomab
• 58:09starting day one with the induction
• 58:11rather than as the Italians did where
• 58:14they used it three months into a remission.
• 58:17So today if I have a patient with
• 58:21cardiovascular contraindications,
• 58:22arterial occlusive events.
• 58:24Then by all means I I could start
• 58:29them with with desatino blinatumomab,
• 58:32but then you have to somehow carve
• 58:36out a time space where you give
• 58:39them ponatinib to try to eliminate
• 58:42those perhaps 10% of the patients
• 58:44who can relapse with the T315 icron.
• 58:47Alternatively you can see what
• 58:49the residual disease is left with
• 58:52next generation sequencing and if
• 58:54you see it there then you can.
• 58:56Change 2.18.
• 58:58So following with Jim, next Gen
• 59:00sequencing rather than with PCR is
• 59:02what you suggest because you know
• 59:03PCR is reasonably sensitive as well.
• 59:06So the PCR detects 100,000 cells.
• 59:09The NGS when successful can
• 59:12measure 3,000,000 cents.
• 59:14We're doing both of them.
• 59:16Another interesting finding which
• 59:18I didn't mention is we have
• 59:20patients who are NCGS negative
• 59:23and PCR positive at low levels.
• 59:25So you could say, well is this a fluke,
• 59:27how can that be?
• 59:28And we think that the eggs,
• 59:31because it measures the immunoglobulin heavy
• 59:33chain is looking only at the lymphoblast.
• 59:36But there could be some BCR able
• 59:41signals in the myeloid cells which
• 59:44will not cause an ACL relapse.
• 59:47And in fact this is what we are noticing.
• 59:50There's a subset of patients
• 59:52who are NGS MRD negative,
• 59:54PCR positive at low level 0.01 or 0.1%.
• 59:58And these patients are not relapsing,
• 01:00:01so we're not sending them to transplant
• 01:00:03if they are NGS MRD negative.
• 01:00:06But we haven't published on this.
• 01:00:08It's A twist.
• 01:00:11To some patients so more specialized
• 01:00:14than what? What one needs to know.
• 01:00:18And duration of Inactive and
• 01:00:19younger patients receive treatment
• 01:00:21with minor ponatinib combination.
• 01:00:23So we do not know,
• 01:00:24but here's what we're going to do.
• 01:00:26We're going to adopt strategy similar to CML.
• 01:00:29We're going to say if the
• 01:00:31patient is NCGS negative,
• 01:00:33MRD negative for five years,
• 01:00:35we are going to either stop the
• 01:00:37treatment for toxicities or accidentally
• 01:00:39if the patient doesn't want it or
• 01:00:42perhaps in the future on purpose,
• 01:00:44we're going to tell them you have been NGS,
• 01:00:46MRD negative for five years.
• 01:00:48They think the disease is not going to
• 01:00:51relapse and perhaps ponatinib will will
• 01:00:54buy you more problems than benefits.
• 01:00:56So we're going to stop and see what
• 01:00:59happens the same way as we do in
• 01:01:01chronic myeloid leukemia with the
• 01:01:03concept of treatment free remission.
• 01:01:04But we're not there yet.
• 01:01:06We need to get to a population of
• 01:01:08patients who are NGS MRD negative
• 01:01:10for five years or at least three
• 01:01:12years to offer them that kind
• 01:01:14of a treatment option if they
• 01:01:16have toxicities or side effects.
• 01:01:19Thank you.
• 01:01:21Right. I think we're at the top
• 01:01:22of the hour at Doctor Kantarjian.
• 01:01:23Thank you so much for this
• 01:01:25absolutely spectacular lecture.
• 01:01:26And Dr Sears, thank you for
• 01:01:29bringing these amazing advances
• 01:01:31to our lecture hall today.
• 01:01:33So thank you so much and thank you,
• 01:01:34Amar, for the wonderful introduction.
• 01:01:36Thank you very much for the honor of
• 01:01:38inviting me to this special lecture.