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

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

October 12, 2022

Yale Cancer Center Grand Rounds | October 11, 2022

Presentation by: Dr. Hagop M. Kantarjian

ID
8159

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.