Maintenance Therapy after Transplant: Acute Myeloid Leukemia (AML)

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Maintenance Therapy after Transplant: Acute Myeloid Leukemia (AML)

Thursday, May 4, 2023

Presenter: Eytan Stein MD, Memorial Sloan Kettering Cancer Center

Presentation is 15 minutes long with 22 minutes of Q & A

Summary: Treatment for many cancers now involves maintenance therapy after a remission is achieved. This presentation examines whether maintenance therapy is appropriate for various sub-types of AML after transplant and after some non-transplant therapies.

Highlights:

• The data on maintenance therapy for AML is mixed and inconclusive. This underscores the need for more clinical trials to clarify the conditions under which maintenance therapy would be beneficial to maintain remission in AML patients.
• Azacitidine is an oral medication that has been approved for AML patients who do not receive a transplant. It has become the standard of care for these AML patients.
• Giving maintenance therapy to all AML patients after transplant, without evidence of which patients would actually benefit, could result in overtreatment of some patients and an unnecessary increase in side effects and financial toxicity.

Key Points:

(01:24): Treatment for acute myeloid leukemia (AML) typically involves an induction phase and a consolidation phase.

(03:03): Maintenance therapy to maintain remission is an emerging third stage of AML treatment.

(03:32): Maintenance therapy may be an option whether patients have a stem cell transplant or not.

(04:44): Consolidation therapy for AML can take one of three forms.

(05:09): Maintenance therapy is low-intensity treatment to prevent a relapse after consolidation is complete, but it may not be necessary for all AML patients.

(09:28): For patients who receive a stem cell transplant for AML, azacytidine as maintenance therapy does not appear to produce additional benefits.

(10:49): For a subset of AML patients with the FLT3 mutation, maintenance therapy may have benefits.

(11:27): Several FLT3 inhibitors improve survival for AML patients if administered during induction and consolidation.

(12:45): The data on using FLT3 inhibitors after stem cell transplant for AML is mixed.

(14:12): While maintenance therapy for AML has a future, the exact drugs to fill that role remain unclear. The best candidates may be patients with an elevated risk of relapse.

Transcript of Presentation:

(00:01): [Lynne Spina]:  Introduction. Hello. Welcome to the workshop, Maintenance Therapy After Transplant: Acute Myeloid Leukemia. My name is Lynne Spina, and I will be your moderator for this workshop.

(00:14):  It is my pleasure to introduce today's speaker, Dr. Eytan Stein. Dr. Stein is the Chief of the Leukemia Service and Director of the Program for Drug Development in Leukemia at Memorial Sloan Kettering Cancer Center. He conducts novel Phase I clinical trials of compounds that target myeloid malignancies such as acute myeloid leukemia, also referred to as AML. Dr. Stein serves as the Lead Investigator at Memorial Sloan Kettering for the Beat AML Master Clinical Trial. Please join me in welcoming Dr. Stein.

(00:59): [Dr. Eytan Stein]:  Overview of Talk. Hi there. My name is Eytan Stein, and I'm the Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center and the Director of the Program for Drug Development in Leukemia. I'm really, excited to be here to talk to you about maintenance therapy after allogeneic stem cell transplantation, specifically when it comes for acute myeloid leukemia.

(01:24): Treatment for acute myeloid leukemia (AML) typically involves an induction phase and a consolidation phase. One of the things to remember when you think about the treatment of acute myeloid leukemia is that for younger patients with AML, we split up the timeframe of the treatment into really three different categories. The first category, as you see on the far left-hand side, is induction chemotherapy. The goal of induction chemotherapy, which is typically done with high-dose chemotherapeutic agents such as daunorubicin and cytarabine, is to get the disease into complete remission. A complete remission is defined as the absence of leukemia cells in the bone marrow and recovery of the blood counts to their normal range. That is, you must get rid of the leukemia, and then your bone marrow has to prove to you and to the doctors that it can produce healthy normal cells again.

(02:23): When that happens, we move on to what's called consolidation treatment. Consolidation treatment can take several forms. One form of consolidation treatment is to give repeated rounds of additional chemotherapy. The other form of consolidation treatment is to have an allogeneic stem cell transplant, so a stem cell transplantation from a donor where the goal of the therapy is to get those donor cells into the bone marrow to produce a new immune system and blood system for the patient so that they no longer have any issues with acute myeloid leukemia.

(03:03): Maintenance therapy to maintain remission is an emerging third stage in AML treatment. A question that always comes up is, is there something that can be done after consolidation treatment? There are other diseases that are cancers of the blood system where we do use what's called maintenance therapy, so that's therapy after consolidation therapy. That maintenance therapy is meant to maintain the remission, maintain the disease being completely gone from the bone marrow.

(03:32): Maintenance therapy may be an option whether patients have a stem cell transplant or not. I think some fundamental questions that we have to talk about are what do we mean when we talk about maintenance therapy, and how does this differ from consolidation? We talked about this a couple of seconds ago. What are some maintenance therapies that have been used to treat patients with AML who don't have a transplant? There are patients with acute myeloid leukemia who don't need an allogeneic stem cell transplant, or we don't think it's in their best interest. Are there maintenance therapies that can be used in that situation? Is there data to support the benefit of maintenance therapy for those patients who do have an allogeneic stem cell transplant? Finally, what is the future of maintenance therapy after a transplant for patients with acute myeloid leukemia?

(04:18): As we talked about on the first slide, there are a number of phases to AML treatment. The treatment of AML is generally divided into two phases. Induction, where chemotherapy is given to obtain a complete remission and consolidation, where additional therapy is given to eliminate residual leukemia cells that may not be identified on a bone marrow biopsy.

(04:44): Consolidation therapy for AML can take one of three forms. You can give repeated rounds of additional chemotherapy without doing an allogeneic stem cell transplant. You can do an autologous stem cell transplant, although this is not typically done in the United States. An Autologous transplant use stem cells from the patient's own body. An allogeneic stem cell transplant uses donor cells that come from another individual.

(05:09): Maintenance therapy is low-intensity treatment to prevent a relapse after consolidation is complete, but it may not be necessary for all AML patients. What is maintenance therapy then? Maintenance therapy is low-intensity treatment that is easy to take and has few side effects. It aims to keep a lid on any leukemia cells that might want to come back and cause a relapse of leukemia. Maintenance therapy has proven effective in patients with other kinds of hematologic malignancies, such as acute lymphoblastic leukemia and multiple myeloma.

(05:38): If maintenance therapy were given to everyone, there  would be cases of unnecessary over-treatment with its own drawbacks. Now why don't we just give maintenance therapy to everyone? Maybe a doctor could come up with a chemotherapy that they think will potentially help that patient down the road. There are a variety of issues with just giving maintenance therapy to everyone. I think one big issue is overt-reatment. It is possible that many patients are already cured after a transplant and don't need maintenance therapy to prevent a relapse. So, if you end up treating patients who wouldn't have actually needed treatment, you can get side effects from the maintenance treatment with long periods of therapy. You're committing patients to indefinite treatment without an endpoint, and there's financial toxicity, right? I mean, these medications that we use for any cancer treatment tend to be quite expensive. If the treatment is expensive, you're potentially asking a patient to spend a lot of money out-of-pocket for unclear benefit.

(06:37): Okay, so what is the role of maintenance therapy for patients who don't have an allogeneic stem cell transplant? Again, these are patients who received induction and consolidation chemotherapy, and their doctor feels like they can be cured without a stem cell transplant. Is there a role for maintenance therapy in that setting?

(06:57): Azacitidine is an oral medication that has been approved for AML patients who do not receive a transplant. Well, there is a medication called azacitidine, and there is an oral formulation of azacitidine that has recently been approved as maintenance therapy for AML patients who do not have a stem cell transplant. This approval was based on the following clinical trial. It was an international multicenter placebo-controlled double-blind, which means that no one knew what they were getting. it was a randomized phase III study that enrolled patients from 148 sites in 23 countries. The enrolled patients were older than 55, and they had intermediate or unfavorable risk acute myeloid leukemia. These patients did not have an allogeneic stem cell transplant, and they were randomized to receive oral azacitidine or a matched placebo as maintenance. Those who received the oral azacitidine had an increased median overall survival of 9.9 months longer than those who received placebo.

(07:59):  Azacitidine has become the standard of care for AML patients who do not receive a transplant. Just to highlight that, the patients who received the oral maintenance therapy had a median overall survival of about 10 months longer than those patients who received placebo. For those patients with intermediate or unfavorable risk AML who don't go on to receive a stem cell transplant, oral azacitidine has really become the standard of care for those patients. Now, the thing I think that is a little unusual is that in 2023, almost all patients with intermediate or unfavorable risk AML actually do have a stem cell transplant, so the number of patients for whom we give oral azacitidine as maintenance therapy who fit into the parameters of the clinical trial is actually very, very low.

(08:45): These survival curves on this slide show you the survival of the patients who received oral azacitidine in blue and then the survival of the patients who didn't receive oral azacitidine and who received placebo in gray. You can see the median overall survival of the group of patients in blue is 24.7 months, while the median overall survival of the patients who received placebo in gray is 14.8 months.

(09:12): Now, what we're really talking about today is giving maintenance therapy after an allogeneic stem cell transplant. So what about in that situation? What is the benefit or is there a benefit to giving maintenance therapy after an allogeneic stem cell transplant?

(09:28): For patients who receive a stem cell transplant for AML, azacytidine as maintenance therapy does not appear to produce additional benefits. There actually was a randomized trial to give intravenous azacitidine to patients with AML after they received an allogeneic stem cell transplant. 50% of patients were allocated to receive the intravenous formulation of azacitidine and 50% were randomized to receive placebo alone, or not get the active treatment. What you can see in these survival curves ... It doesn't take a doctor or a scientist to understand this ... is that the red line, which is the patients who received observation and the blue line in the survival curve of the patients who received 5-azacitidine are overlapping. That means that there was no benefit in this clinical trial to give intravenous azacitidine as maintenance after an allogeneic stem cell transplant.

(10:19): So, it begs the question, what are we doing with maintenance when it comes to patients who've had an allogeneic stem cell transplant? In addition, not only is there no survival benefit, but there's the same relapse rate between the patients who got IV azacitidine and the patients who got observation, in red and blue respectively. There's the same incidence of transplant-related mortality, on the right-hand side, between the two groups.

(10:49): For a subset of AML patients with the FLT3 mutation, maintenance therapy may have benefits. One place where there may be a benefit to giving maintenance therapy after a transplant are in those patients who have a specific mutation as part of their acute myeloid leukemia called a FLT3 mutation. So what is FLT3? FLT3 is a gene that is mutated in approximately 30% of patients with AML. In the past, the presence of a FLT3 mutation was considered a negative prognostic factor, and the use of FLT3 inhibitors with chemotherapy has really improved the outcome of patients with FLT3 mutant AML.

(11:27): Several FLT3 inhibitors improve survival for AML patients if administered during induction and consolidation. We know that for patients who are newly diagnosed with FLT3 mutant AML, there is a FLT3 inhibitor called midostaurin. The drug midostaurin, when given in combination with induction and consolidation chemotherapy, leads to an improvement in overall survival. This is depicted in the survival curves on the lower left-hand side where you can see the group of patients who received the midostaurin in blue had an overall survival that was about 7% better than the group of patients who received placebo in red at five years.

(12:01): There's a new FLT3 inhibitor that is being given in combination with induction chemotherapy, as part of a clinical trial that may get approved by the FDA, called quizartinib. Quizartinib is also for newly diagnosed AML patients of any age. There was a randomized trial of chemotherapy with quizartinib versus chemotherapy with placebo, and the primary outcome of this trial was overall survival.

(12:24): You can see the median overall survival of the patients who received quizartinib in blue is 31.9 months, while it is only 15.1 months in the group of patients who received placebo in green. We don't know whether quizartinib or midostaurin is better than one another because these have never been compared head-to-head.

(12:45): The data on using FLT3 inhibitors after stem cell transplant for AML is mixed. Now what about giving a FLT3 inhibitor after an allogeneic stem cell transplant? So, what I just showed you was data on giving a FLT3 inhibitor before an allogeneic stem cell transplant. What about giving a FLT3 inhibitor after an allogeneic stem cell transplant? There was a randomized clinical trial giving a drug called sorafenib, which is another FLT3 inhibitor, after an allogeneic stem cell transplant for patients with a FLT3 mutation. You can see on the left-hand side, the relapse-free survival, and on the right-hand side the overall survival. The group of patients who got sorafenib in blue had a better survival rate than the group of patients who got placebo in red.

(13:26): I think we all assume that patients who get maintenance therapy after a transplant with a FLT3 inhibitor will do quite well, but in fact, a recent clinical trial was just released where patients were randomized to receive yet another FLT3 inhibitor after a transplant called gilteritinib (Xospata®). Again, this was a randomized placebo-controlled trial where patients received either gilteritinib or placebo. In this press release from the BMT CTN, what you can see is that the patients who received the FLT3 inhibitor as maintenance therapy did not have benefit compared to the patients who received placebo as maintenance therapy. So really, where does that leave us?

(14:12): While maintenance therapy for AML has a future, the exact drugs to fill that role remain unclear. The best candidates may be patients with an elevated risk of relapse. I think where that leaves us is that after an allogeneic stem cell transplant, there is no high-quality data, except for maybe the sorafenib data in FLT3 mutant AML, that maintenance therapy actually helps anybody. While there is a future to maintenance therapy, I think what drugs we're going to use for maintenance are a little bit unclear. The future is that the benefit of maintenance after a transplant is unclear, based on randomized data both in genetically defined and more general subsets of patients with AML. It may be that the best candidates for maintenance therapy are those patients who have an elevated risk of relapse because they have measurable residual disease at the time of their transplant. For now, the best strategy is frequent monitoring for disease recurrence by sensitive molecular methods and early intervention for disease eradication. Finally, multiple trials are aiming to use newer agents as maintenance therapy, but the results are unknown so far.

(15:09): With that, I thank you very, very much for your time, and I look forward to ongoing discussion and answering your questions.

Question and Answer Session

(15:20): [Lynne Spina]:  Thank you, Dr. Stein, for your excellent presentation. We will now begin the Q&A session. The first question is, do outcomes differ between patients who are young adults versus those who are older at the time of transplant for AML?

(15:54): [Dr. Eytan Stein]:  Thanks for that question. It's a really good one. I think the outcomes for patients with acute myeloid leukemia after a transplant are not directly related to the age, in and of itself, but it's related to things that go along with being older or being younger. What I mean by that is that older people, not always, but they tend to have genetic abnormalities that have a higher risk of relapse after a transplant. Also, their bodies aren't as young as a younger person, so a 75-year-old will have a 75-year-old heart and a 25-year-old will have a 25-year-old heart. The 25-year-old heart, in almost all cases, is going to work better than the 75-year-old heart. The answer is that the outcomes can be different, but it's not different by age, in and of itself. It tends to be different based on the genetics of the disease in older people and the comorbidities that the patients have.

(17:12): [Lynne Spina]:  Thank you. You mentioned younger, and this person is asking actually, "What is considered a younger patient?" We talk about younger and young adults and older. In a medical standpoint, how would you answer that?

(17:29): [Dr. Eytan Stein]:  Well, as I get older, everyone's getting younger, so I think that's how I answer the question. It's a tough question. I think we typically think of younger people as people under the age of 50 or so, but that is a completely arbitrary line that's drawn. To be honest, older and older people are healthier and healthier. In my practice, it's interesting. 10 years ago or 13 years ago when I started this, when people came into my practice at the age of 70 or 72, they seemed old to me, but now people don't really seem old until they're 80 or 82. Now again, that might be just because I'm 10 years older than I was before, but I do think that in general we think of 60, 65 as that cut off point between old and young.

(18:28): [Lynne Spina]:  Thank you. The next one does have to do with genetics. "I was transplanted for AML. There is a history of leukemia and lymphoma in my family, father, and uncle. Is there some test my children should take to see if they are predisposed to getting leukemia?"

(18:50): [Dr. Eytan Stein]:  Yeah, so our current feeling is that in patients with a family history, certainly in first-degree relatives with leukemia, especially if it's the same kind of leukemia, with acute myeloid leukemia, then genetic testing is warranted. I mean, I don't know the specifics of your situation, but usually what we do is that when we have a patient who has a family history that is concerning, we send the patient themselves for genetic testing. If the genetic testing identifies in the patient a gene that is associated with inheriting a propensity to develop leukemia, that's when you call in the family members and the children to get them tested. I would say that for someone like you, usually the testing is done in the patient themselves, but if that's not possible for some reason, then it would be reasonable for the kids to go see a genetic counselor.

(20:02): [Lynne Spina]:  "You mentioned ongoing monitoring by sensitive molecular methods beyond standard post-transplant labs. Should we be asking our transplant doctors about other tests?"

(20:17): [Dr. Eytan Stein]:  Yeah, so it's a really good question. Usually post-transplant, they're doing bone marrow biopsies every so often to monitor for relapse, and those bone marrow biopsies typically include the sensitive molecular test that I'm talking about and the sensitive testing that I'm talking about. I presume that's being done as a matter of course in someone who's had a bone marrow transplant. There are certain people who've had a bone marrow transplant who have specific genetic abnormalities that can be followed slightly differently, so yes. If the answer is yes, I would ask your doctor to be sure that they're using sensitive genetic and flow cytometric methods to monitor for relapse.

(21:11): [Lynne Spina]: This person asks, "Is there data available on frequency of relapse of AML after a successful allogeneic transplant?"

(21:22): [Dr. Eytan Stein]:  Yes, so there is data available, but the data is all over the place because it depends on many, many different things, so it's hard to give you an answer of what the relapse rate is after an allogeneic stem cell transplant for AML. It depends on the risk group the patient was in when they were first diagnosed with acute myeloid leukemia. That is, were they in a favorable risk group, an intermediate risk group or an unfavorable risk group? Patients in an unfavorable risk group have a higher chance of relapse than patients in a favorable risk group after a transplant, so that's number one.

(22:00): Then the other thing that's becoming increasingly important is whether the patient has minimal residual disease or any evidence of genetic abnormalities that can lead to leukemia before the transplant. Some of you may know that it used to be that anyone with leukemia that had gone away, we called that complete remission. But it's become clear that for some people who are in complete remission, you can still find some leukemia cells floating around with highly sensitive methods.

(22:35): What that's called is MRD-positive complete remission, MRD standing for measurable residual disease. So, in patients who have an MRD-negative complete remission that is a complete remission without measurable residual disease, then the chances of relapse after a transplant are lower than those patients who have an MRD-positive complete remission, which means that there is some evidence of leukemia cells floating around before they have a transplant. So those are the different factors that go into what the relapse rate might be. What I would do if you had a question about that is to ask your doctor, "In me particularly, given the genetic findings in my disease and whether I was MRD-positive or MRD-negative before I had a transplant, what are my rates of relapse?"

(23:34): "I have been on IDHIFA before and after stem cell transplant due to an AML mutation. How long after transplant do you recommend I take it?" For the benefit of all listening, Doctor, would you explain that treatment?

(23:54): [Dr. Eytan Stein]: Okay, so everyone knows that when you're diagnosed with acute myeloid leukemia, there are a variety of mutations that can pop up and be the things that actually are causing the leukemia. One of those mutations is a mutation in a gene called IDH2, and there is a targeted treatment against IDH2, against that genetic mutation called enasidenib or the trade name is IDHIFA®. It sounds like this person had been on IDHIFA® before a transplant, presumably got into remission, and then after the transplant went back on IDHIFA® to help prevent a relapse.

(24:33): There are a couple things that are important to note. So one is that there's actually no data that being on IDHIFA ®after a transplant helps or doesn't help prevent a relapse. That doesn't mean you shouldn't do it, and it doesn't mean that a lot of doctors don't prescribe it. I mean, I prescribe it in certain cases, but just from being a real purist, we don't have data that after a transplant giving an IDH2 inhibitor like IDHIFA® prevents people from relapsing. So because of that, it's very, very hard to say how long someone should be on it because we don't even know if it's doing anything at all.

(25:18): What I've recommended to my patients is that while you're on it post-transplant, if you are doing bone marrow biopsies, and there's absolutely no evidence of that IDH2 mutation anymore, or of leukemia anywhere anymore, and it's been a couple of years, then I have a discussion with patients about whether they want to stop. But it's a very, very hard decision to make because we just don't have data to guide us.

(25:53): [Lynne Spina]:  Thank you. "I had a six-month maintenance course of decitabine and Neupogen based on a trial conducted in China. Are you familiar with this, and can you comment? I was post-BMT intermediate risk."

(26:12): [Dr. Eytan Stein]:   Yeah, I am familiar with that trial. It's interesting that you were placed on this. Just to get everyone on the same page, there was a randomized trial in China, a Phase II randomized trial, which I did not discuss in my presentation, where patients were randomized after a transplant to receive either very low dose decitabine with Neupogen. I'm not sure if it was placebo or they just knew they weren't receiving anything. That trial actually showed some benefit to getting this very low dose of decitabine with Neupogen.

(26:54): The truth is, I have never seen anyone in the United States adopt that until three days ago. Maybe your doctor is Dr. James Foran in Jacksonville because he is the person who at this meeting spoke up and told me that he had adopted this practice. I'm not aware of it being widely adopted in the United States. I don't think it's wrong to do. There's definitely a randomized study, but for whatever reason it has not been widely adopted in the United States yet.

(27:30): [Lynne Spina]:  Thank you. That leads to a question about clinical trials. In general, how does the subject of clinical trials fit into what we're talking about today, maintenance therapy? We did have a question about why is it so difficult to learn the outcome of clinical trials? Could you comment about clinical trials relating to AML maintenance therapy and options?

(28:00): [Dr. Eytan Stein]:  Yeah, so I think one of the things that obviously bothers everyone, doctors and patients, is that a patient goes through the treatment for their leukemia, which is not easy, and then they go through an allogeneic stem cell transplant, which is not easy. Then there's still a chance, a small chance, but a chance that the patients can relapse. All of us, patients and their doctors, want to keep that from happening. The risk, as I said in the talk, is that if you just put everyone on maintenance therapy, you're overtreating people who are probably cured already, and theoretically you could cause harm for those patients that don't need maintenance therapy. You're also potentially costing people a huge amount of money for something that's not going to benefit them.

(28:55): The importance of clinical trials, when it comes to maintenance therapy, is that the only way we're going to make progress is if we can do clinical trials where we can investigate whether various maintenance therapies are beneficial to patients or not. I'll give you an example or the example I talked about in the presentation. Everyone thought that patients with a FLT3 mutation after a stem cell transplant should go on gilteritinib as a FTL3 inhibitor. I mean, that was a universally acknowledged idea, in the absence of randomized clinical data, to the point that people felt that maybe this randomized clinical trial that I talked about in the presentation of the FLT3 inhibitor gilteritinib versus placebo was unethical. How can you randomize a person to placebo when you, in your mind, think you know that gilteritinib is going to work?

(30:03): Of course, as has happened in many trials over the years, this isn't something that is new or novel, but as has happened in many trials over the years, everyone was wrong. Everyone was wrong in the sense that, at least for the large population, for the entire group of patients, gilteritinib was no better than getting placebo. That's an important thing to know because what would've happened without that trial is that everyone in the world with a FLT3 mutation would've gotten gilteritinib, where it seems to be that not everyone in the world should be getting gilteritinib.

(30:35): It's a long way of saying that the only way we make progress in this field is when people participate in clinical trials. When people don't participate in clinical trials, or we don't do clinical trials for whatever reason, people follow what they think the right thing to do is. They'll yell and scream that they know what the right thing to do is, but as you get taught in medical school, 50% of the stuff that you think is right ends up being wrong when they actually do a clinical trial, so that is one of the reasons that clinical trials are so important.

(31:07): [Lynne Spina]:  Thank you. The next question is, "Are there CAR T-cell therapies available in your specialty to treat patients or is it only stem cell transplants available?"

(31:24): [Dr. Eytan Stein]:  So the answer in acute myeloid leukemia is that, right now, there are no approved CAR T-cell therapies for acute myeloid leukemia. There are efforts being made to develop CAR T-cell therapies for acute myeloid leukemia, but so far, they have not been successful. I think that at this point, we're not in a place where CAR T-cell therapy would replace a stem cell transplant. I think the hope is, with AML, that if we can find the right CAR T-cell therapy, what it would do is it would put a patient into remission. Maybe a patient that wasn't able to get into remission any other way, it would put a patient into remission. Then after that remission, you would do a stem cell transplant to keep them in remission and cure them.

(32:14): [Lynne Spina]:  Thank you. "I am the person who commented on the Neupogen® trial. I also wanted to let you know that I am female, 71-, and two-years post-transplant." She thanks you for your response. Just with this new information, would that change your answer or add to your answer?

(32:43): [Dr. Eytan Stein]:  I have nothing else to say for that question.

(32:47): [Lynne Spina]:  Sure. No problem. "I had a transplant for AML in 2006. Is there anything I can do to improve toxicity of the cerebellum?"

(33:04): [Dr. Eytan Stein]:  That's an interesting question. I don't see a lot of cerebellar toxicity. I have not seen a lot of cerebellar toxicity in patients post-transplant, and I don't have a great answer of how to improve that, unfortunately.

(33:26): [Lynne Spina]:  This person was a patient with ALL PH+ and received a bone marrow transplant four months ago, happens to be a former patient of yours. "I have been prescribed ponatinib for preventative relapse. How does the medication prevent relapse and how effective is it?"

(33:55): [Dr. Eytan Stein]:  First of all, I want to thank you for asking that question. I know exactly who you are. I don't have former patients. Everyone's always my patient, even if you're not seeing me with the same regularity that you saw me before. You're always welcome to come back, stop by the 14th floor of the Koch building. Ponatinib, so we're not talking about AML now, just for the general group. We're talking about acute lymphoblastic leukemia, which is another acute leukemia.

(34:25): Ponatinib is a small molecule inhibitor of the abnormality which is this p190 abnormality. I believe that fundamentally it's the thing that probably led to the development originally of the acute lymphoblastic leukemia. Because ponatinib is generally very well-tolerated, generally speaking, and because there's always a concern that maybe there could be a leukemia cell floating around that wasn't eradicated by the stem cell transplant, your transplant doctor put you on ponatinib to try to suppress that particular genetic abnormality. Even though we can't find it, it's just a concern that maybe it could be there. I think that's why the transplant doctor put you on it, and I think that that is the right thing to do. You're welcome to call me or come back for another appointment if you want to talk in more in detail about it.

(35:48): [Lynne Spina]:  Now this last question, we have a little bit of time so I'll read it, even though it is relating to chronic myeloid leukemia, but out there, there is quite a lot of interest in CAR T-cell therapy. The question is, "CAR-T therapy, is it available for CML?"

(36:07): [Dr. Eytan Stein]:  CAR T-cell therapy is not available for CML, and the reason is because CML is essentially curable. I mean, it is curable with just small molecule inhibitors like Gleevec® or imatinib and dasatinib and all the other small molecule tyrosine kinase inhibitors, so there's really no need for CAR T-cell therapy for chronic myeloid leukemia. CAR T-cell therapy, again, is a very effective therapy, but it comes with a lot of side effects. If you can prescribe a pill that generally doesn't have significant or severe side effects, that seems to be the right thing to do rather than developing CAR-T cells for patients with CML.

(36:51): [Lynne Spina]:  Closing. All right. Thank you. Well, this concludes our session. I'd like to thank you for your excellent presentation, doctor, and also would like to thank the audience for their great questions. Please contact BMT InfoNet if we can be of any help to you.