Hagop M. Kantarjian, MD reviews the latest updates on Acute myeloid leukemia (AML) in the older population, and explains it is the most common type of acute leukemia in adults.
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It is now my pleasure to introduce Dr Hagop Contagion, who is professor and head of the leukemia division at M. D. Anderson Cancer Center. He is very well known in his field, and he is also a friend to this conference, presenting to us many years in a row on the hot topics in leukemia. Today he will be addressing acute myeloid leukemia in the older population. I really appreciate him taking the time today to give us this important lecture and please use the ask a question function in the chat box and we will address your questions afterwards during the panel discussion. Thank you, Dr Contagion. Thank you for the opportunity of the meeting and the discussion on one of the topics of leukemia, which is one of the more difficult ones today. So, as you know, most of the leukemias today have improved their outcomes significantly. If we look at chronic myeloid, leukemia is functionally and molecularly curable with the TKs chronic lymphocytic leukemia since 2000 and 15 were starting to talk about the potential tour of this incurable disease. As we make a combination of B t K inhibitors like Bruton Veneta clucks. If we move to acute lymphocytic leukemia. Since we added the antibodies to the chemotherapy, we're getting potential cure rates of 60 to 70%. And even in the younger patients with AML, with the intensive chemotherapy and targeted therapies, we're getting a potential long term survival in 60 to 70%. So we're stuck with the older patients with the M l and those unfit for intensive chemotherapy because we do not have solutions which are as good as in the other patient. Now, if you look at the European Leukemia Net or the NCC and recommendations, what they do is divide their patients into favorable, intermediate and adverse, and then you think that a minority of the patients are adverse. But the problem with those recommendations is they apply mostly to young people and people with the Novo AMs. And if you consider that the median age in the ML 68 years and if you consider that many of them have therapy related or secondary ml in fact, according to the classification, most of the patients with AML will fit into the adverse category, not by the nature of their city genetic and molecular subtypes, but by the nature that they are not the Novo young people with acute myeloid leukemia. So then we have a situation where most of the patients with AML that we see today may not benefit from the three plus seven or the variations of the intensive chemotherapy. And as of today we have nine agents which have been approved for the treatment of acute myeloid leukemia and another tense, which is oral. Decide to bean, which is approved for the treatment of MDS and CML. But that could have a potential application in acute myeloid leukemia. So now we have to flip three inhibitors middle storing and guilty written it. We have the I. D. H inhibitors in a Sydenham and I was sitting in. We have the potential of Veneto clocks, which is the most important backbone of therapy and the older unfit AML and then the two oral hyperventilating agents, which are quite different and their nature and their usages in leukemia, as I'll discuss later. So let's start first with the most curable leukemia. So if I have a patient who's older with a P l, I would still use the ultrasonic trackside here in this situation. The chemotherapy the non chemotherapy regimen is safe. As you know, in the younger patients, the curate in green is almost universal. But on the right side are older patients, and what you see is that with the ultrasonic trackside, we still can cure over 80% of the patient. Then we move to the core binding factor leukemia. So this is a conversion 16 or translocation in 21. We're using the flu that have been Arazi with my little heart. On the right side. On the left side are the younger patients, and there you can see that the potential cure rate has increased about 80%. On the right side are the older patients, so the curate is less with the intensive chemotherapy. But this is where we can continue their maintenance with hyperventilating agent like is a sighted in with Vanessa clocks, and we could consider adding the gym to zoom opt to direction. Now we come to the bulk of the patients with acute myeloid leukemia, the ones that we treat with intensive chemotherapy or what many people who are AML experts on in in the community Oncology referred to three plus seven, So this is three days of Donna Robinson or either Rubies in seven days of sight, Paraben, and then either send the patients to transplant or four courses of consolidation. So this is shown on the slide, the three plus 71 or to hide those side to Rabin and then allergenic transplantation. Otherwise you try to consolidate, and historically there has been no maintenance therapy, although now we have the availability of either is excited in Veneta clocks or the oral is excited in in this contest. Now, if you apply the three plus seven to the young fit patients they curate is still low in the range of 30 to 40%. And here we think that the new regiments with flag Ida CLIA and targeted therapies may be better. But this is not the subject of this topic. On the right side is are the older, unfit patients. So even when you give them the three plus seven, the median survival has been less than a year and the potential curate even in these highly selected patients on, uh, cooperative group protocols, the cure rate is 10% or less, so we need to do better than that. This shows the outcome at MD Anderson again to demonstrate that even in single centers, we have improved the median survival. But historically before the era of the network, like speech therapy, the potential cure rate used to be quite low less than 10%. But if you look at the patient's also historically treated with intensive chemotherapy at our institution, the curate in patients 70 and older is extremely low, and the median survival is in the range of three months. So intensive chemotherapy does not work, even in the patients who are older and quite fit. And this is the Mayo Clinic experience, which has just been reported in the American Journal of Hematology And here. The importance, um, is that in the patients who receive low intensity therapy or supportive care, they still do as badly as in patients who received the intensive chemotherapy. So we need to do better than that. Here I show the seer data again to confirm the same findings, which I showed you, and that is in patients with a PL. We can cure them at a high rate, even, um, if they are 60 or 70 and older, and the core binding factor leukemias Once they get over the age of 70 they do not do well. So this is where is a sighted in Veneto. Clocks would jump to zoo, mob would be better. And on the right side, I showed the other AML. So these are patients who are young and old, and once they are over the age of 60 the potential five year survival is less than 20% if they are 60 to 69 and it's only 4% if they are 70. And here I showed the four and eight week mortality to demonstrate that in these older patients, the four week mortality is one in four. If they are age 60 to 70 and it is, half of the patients are 70 and older, so intensive chemotherapy does not work. That's the bottom line. Intensive chemotherapy does not work, and here I show this year data again to emphasize the same situation, which is over the years, and the people 60 to 70. We improve the five year survival. It's still 20% or less because we improved on the supportive care. On the right side are people 70 and older. Most of them died during the induction. If not, there is no cure it now. Why do the older people do worse? There are patients related factors such as comorbidities bad organ functions, poor performance. But most importantly, these are patients who have adverse side to genetics. They have e m d s, that progress from AML. Uh, they have aml that progress from MDs, CML or Milo proliferated neo plasma. And they also have a lot of adverse mutations. And I detail this at the bottom. So here we need less intensive regiments and targeted approaches such as the combination of hyperventilating agents with targeted therapies, including Vonetta Clark split three inhibitors i. D. H. Inhibitors. And at the end, I will discuss the Caribbean law. Does psychotherapy in Veneto clocks, which I think is a new nice breakthrough in the management of order unfit patients with the mm. So then the question is, who is older and unfit? Do I take anybody over the age of 60 or over the age of 70? And I would say that older and unfit is any patient in whom they expected induction Mortality with intensive chemotherapy is more than 20%. The expected CR rate is less than 30%. And the median survival is short, which is less than a year. And then, if you take this definition, is that it does not apply only to patients seventh year and older, Um, and you can divide them in terms of the prognostic factors. So this is a model from our institution where we show that patients uh, 75 or older, Bad Correa type, poor performance secondary from MDS. Bad Creatinine for supportive care. These patients have hi induction mortality, which I showed in the earlier slide, but I would say that there is a bigger group of patients does not. That does not benefit from intensive chemotherapy. So these are not only the older unfit patients by virtue of poor performance comorbidities. It's also anybody who's over the age of 70. Any patient with complex carry, a type with therapy related the M L with AML progressing from MDS or my local referring to the New York Plaza and also be 53 mutated the mm so any AML where the intensive chemotherapy is associated with high mortality and the loss er a. So this constitutes actually the bulk of patients with acute myeloid leukemia if you use this definition to avoid the intensive chemotherapy and go to a low intensity based stretcher. So following this notion in 2000, we decided to shift from the intensive chemotherapy and to try the intensity therapy. So the first studies were done, uh, in England with low dosage paraben, which established them as of value. And then in 2000 and six, we started the study of this site a bean versus standard of care or low dosage Paraben, which was published in 2000 and 12. And that study showed that this site, a bean, improves the survival, but it did not show a significant survival benefits. So the median survival and keep this is, um, in mind is only eight months in this study. There was a similar study done with is a sighted in versus standard of care in Europe reported by Dr DeAndre. And then again, they showed the same findings. Here there is a sighted in medium survival of 10 months. Look at the control is slightly better than on the decide to be in trials, so 6.5 months. But still we are under a median survival of the year, so keep in mind, the median survival is about 7 to 10 months. Even with hyperventilating agent therapy. Now people wonder whether it's a sighted in or decide to bean are favored. And here I show two studies. The first one is from Korea in lower risk MDS that shows that actually decide to bean and is excited in are identical in their outcome. In fact, in the Multivariate analysis of anything this item mean is favored with the better survival. And the second study comes here from, um um, Dr Labrador and his colleagues. I think this is from Spain. They looked at about 638 patients. This is the Cosima in Spain who received either as a sighted in or this site a bean. And this was not a randomized study because most of their patients 500 received as a sighted in. But again, the report almost identical data with the median survival of 8 to 10 months. So then you can use those to interchangeably Now fast forward to the breakthrough. The breakthrough was with the addition of Veneta clocks to the site cabin is a sighted in Orlando site Caribbean and those studies showed an improvement in the survival. This led to the randomized study that we refer to as the V L. A, which are a randomized study of Is a Sighted In versus Is a cited in and Vonetta Clark. And here for the first time, we started seeing an improvement in the median survival beyond the years. So the combination of a society in Veneto clocks produced a median survival of close to 15 months versus 9.6 months, but most importantly, an estimated two year survival rate, which is close to 40%. And of course, the addition of Veneta clocks improved the response rate from 28% to 66%. So we try to improve on this, with the decider being given for 10 days with the vendetta clocks. And we reported that in fact, the decisive in 10 days Vonetta Clark has improved the marrow response rate and newly diagnosed patients up to 84%. Ah, in in secondary and therapy related um, it is less so, and then when you look at the median survival or the survival which is in white and the newly diagnosed patients, you find that the estimated median survival is now close to 18 months, with two year survival rate, which is close to 40 to 50%. So very favorable results. But still, we're not curing the majority of the patient. Now when you use the vendetta clocks, this is just to alert you that many of the patients can be on a souls. We favor pasta conoce. Also, if you use Prozac Ana Sol as your antifungal prophylaxis, then use the vendetta clocks at only 50 mg instead of 400. If you use the very Khanna's all, then use the vendetta clocks at 100 mg daily. Otherwise, you encounter excessive Milo suppression because the souls can increase the levels of the NATO clocks and the patient. So now we come to the to oral hyperventilating agents because people are starting to think well in an older patients where I want to use hyperventilating agent with genital clocks. Can I revert to a total oral therapy? So this is to alert you that the oral is excited in is approved for acute myeloid leukemia as a maintenance and the patients who are not able to complete the curative intensive chemotherapy so this would apply to the patients with uh, that we are discussing. The problem with this is oral is a sighted in is poorly absorbed in this study. It was given for 14 days, and there are no studies that have combined it yet with the Veneto clocks. So if you want to use a maintenance with Jesus cited in, it has to be. The subcutaneous is a cited in and Veneta Chloe. Now the decide to Wien is 100% absorbable because it's with the demons inhibitor. The problem is, the approval is not an acute myeloid. Leukemia is for MDs CML, where in 133 patients that were treated with oral decide to being given for five days every month. In MDs, the response rate was 60% and the median survival now has not been reached with the two year survival rate of 60%. So the Iraqi side Levin is not approved for AML. But hopefully, once we do these studies and combine it with Panetta clerks and these studies are ongoing, then once you put the patients in a complete remission, if they have a m l, then you can provide them with the total oral therapy, provided that you watch them carefully. So this is to distinguish again that this site, a bean oral and is a sighted in oral are two very different drugs. The absorption with this site, a bean is 100%. With with Jesus cited in, it's less the number of days with this item. Bean is five, and it's approved for nds CML. The number of days with the sight to be seen as a maintenance is 14, but it is approved for acute myeloid leukemia but has not yet been combined with with the Veneto clocks. So now we know that there are 53 inhibitors idea H inhibitors and vanita clocks. And then the question is, Well, if I have a patient with acute myeloid leukemia who is old or unfit, but they have an i. D. H two mutation. Do I put them on ECE cited in Veneta clocks? Or do I put them on? Is a cited in and an I. D. H inhibitor, like in a city in? So this is a subset analysis of the violated that looked at only patients where I D. H two mutated and what this study shows, is that when it clacks is in fact as powerful as the ideation inhibitors, it does increase the marrow CR eight from 11 to 80% the CR eight from 4 to 40%. But most importantly, it improves the median survival from six months to close to about two years or more. So this is to say that if you have a patient who's older, unfit, where you're giving is a cited in and they have an I. D. H mutation you can still use. There is a cited in and perhaps cycle died ehh inhibitor as a maintenance or as a temperature. Now what about if I have a patient who's older or unfair, where I want to use the ESA cited in Veneto clocks. But this patient is flipped. Three mutated. So now it's a different story because the flip three inhibitors are very powerful. So the study, the subset analysis of the villa, shows that in fact, there is a sighted in Veneta clocks improves the CR rate from 18 to 65%. Unfortunately, when you look at Figure C, which are patients with the flip three I t. D. Which are the worst. You're not improving the median survival with Vonetta Clark. Significantly, it improves from 8.5 to 11.5 months. So here I think we are better off doing is excited in with the flattery inhibitor or the triple therapy and the flattery inhibitor that I would favor would be guilty retina, because it will cover the flip three D as well as the flip three D mutation. So if you have an order unfit patients, um, with acute, my lord, leukemia has literally mutated. I would favor is a sighted in guilty written with or without the addition of the network locks. Now the third important category are patients with TP 53 mutation. So again here I show the analysis of the decide to be in 10 days with Veneta clocks because I showed you that that combination, maybe more important than decide to be in five days or is a sighted in and in our analysis in these patients, the CR rate is 54%. Still, the median survival is only about five months, so these patients are not benefiting from the addition of Veneta clocks. Now the question is, if they do not benefit from the addition of Veneto clocks. What can we offer them? So here I show the updated studies with the a p r 246 which is the P 53 modulator. The original studies looked very encouraging, but now the company, as of December 28 2020 has unveiled the results of the randomized trial of Is a cited in a PR 246 versus is a sighted in alone. And they failed to meet the primary and point where they showed that the CR rate is still only 33%. So I showed you that with the visa cited in Veneta clocks or decided being Vonetta Clark, the c r A. Was higher. Um, this is an M. D. S. But essentially for practical purposes, the current a PR 246 does not work, and we're hoping for oral a PR modulators that may be given on a daily basis and would be better. Now there's still another drug that appears to hold promise for P 53 mutated AML, and this is mongrel mob, which is C. D 7 47 antibody. So you can think of the mongrel mob the same way as the checkpoint inhibitors. But the macaroni map activates the macrophages to kill the leukemia cells. So at the last as committing, Dr Salman updated the results of the society in microglia map in MDs, where he reported very high response rate but 42% CRE and inaccurate myeloid leukemia, where the CR it is only 40% among the patients with pieces distributed a man, the response rate was high, and the median survival is the reporter to be about 12 months. So this is a drug that make survive and potentially be useful not only in p 53 mutated ML, but also in AML across the board. And the studies are ongoing now with this excited in Veneto clocks and my grow Lima. Now I want to alert you to the possibility of a new form of therapy and the mixed lineage leukemias, which, as you know, are the patients with translocation 11 Q 23 And these are patients that have done very poorly with our current standard regiments, and they usually relapse very often. Now we have what is called the minion inhibitors, and there are two of them available um One of them was updated at the a c. R. Meeting, demonstrating responses in people who have relaxed with single agent S and D x 5613 And on the right side is the update from another, um, men in inhibitor, which was at this ash meeting where they reported, uh, that four of the patients of the 80 valuable responded to the single agent drugs. So the men and inhibitors may be a potential solution for patients with 11 2 to 3 or M l acute myeloid leukemia and possibly other disorders. Now, I stated earlier that today the standard of care for older, unfit aml so patients who are older or who cannot receive the intensive chemotherapy, the current standard of care is with Jesus cited in and Vonetta Clark. What I want to show you is preliminary data from our institution, where for several years we have piloted what is called triple nucleoside therapy. So in addition to is a cited in and decide to bean, we know that low dose site Caribbean works and is safe and clad ravine, which was actually discovered. Um, at the scripts clinic also works very effectively. So before the era of the NATO clocks, we tested this triple nucleoside therapy on the right side. I showed the combination of clad ravine Arazi alternating with this site a bean where in 100 and 20 patients we had the Maroc a rate of 68% an immediate survival of 14 months, which is much better then what you get with the single agent is a sighted in or decide to be. And on this slide I showed the results of the clatter Been at a CD site, a bean so morose er 8 68% median survival close to 14 months. And I compared the results to the ISA cited in Veneta clocks. Similar Maroc are age 67% better median survivor. So what we said is, why not combine the vendetta clocks not only with the hyperventilating agent but with the triple nuclear side regiment. So this is what we've done in a pilot trial where we gave glad Rabin LoDo site Arabian Veneta clocks and alternated this with is a sighted in Veneto clocks. At this ash meeting, we reported the data in the 1st 55 patients. So what you see is they are older. The garden variety of older, unfit TML median age 68 years. The CR rate is 78%. The Moros ER rate is 93% M R D. Negativity in remission is very high, 84%. The four week mortality is 2% and for the first time we're looking at an estimated 18 months survival of 60%. Now, when you look at the right side of the slide, when the patients get better, we still refer them to transplantation. So among the 15 patients that we transplanted, only one has relapsed and died. And but among the 35 patients who were not transplanted, we're still looking not at the median survival of eight or nine months or 12 months. The 18 month survival is still close to 55% so I think that perhaps we have a low intensity, tolerable regimen that may be better than hyperventilating Agent and Veneto clocks, but we need to prove this in over 100 patients and then confirm it in a randomized study in a cooperative group trial. So this shows the updated the results, which I showed you in the previous slide Uh, and this shows on, uh, the, uh in blue the patients who do not have secondary ML. So these are patients with the Novo AML, and in these patients, they estimated 18 months. Survival is close to 70%. Thank you for your attention, and I'm happy to answer any questions.
