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

October 12, 2022

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Yale Cancer Center Grand Rounds | October 11, 2022

Presentation by: Dr. Hagop M. Kantarjian

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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&amp;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.