Dr. Uma Borate:
Welcome to The ASCO Post Roundtable Series on Navigating the Complexities of Relapsed Refractory Acute Myeloid Leukemia: Identifying Mutations and Optimizing Targeted Therapy. I'm Dr. Uma Borate. I work in the division of hematology at Ohio State. I'm an acute leukemia physician and lead the acute leukemia section as a clinical head and the acute leukemia research program. Today with me are two of my colleagues. I'll start by introducing Dr. Naval Daver, who's a professor of medicine in the leukemia department at the one and only MD Anderson Cancer Center and leads a lot of their acute leukemia clinical investigation program. And I will also introduce Dr. Joshua Zeidner, who works at the UNC Chapel Hill Cancer Center and leads their acute leukemia clinical and research program.
So thank you everybody for being here today. We will be discussing the treatment and management of relapsed refractory AML with three patient cases. Our third and final installment will focus on the treatment of refractory AML with complex karyotype and TP53 mutation. So I'll start with Dr. Zeidner and tell you about this case.
This is MG, a 72-year-old woman with refractory AML. She was initially diagnosed with AML with 25% blasts with a complex karyotype and a TP53 mutation with a 30% variant allele frequency for this mutation. She got four cycles of decitabine and venetoclax and was unfortunately refractory at the end of these four cycles. She still maintains a good performance status, but is pancytopenic with residual AML at 8% blasts. You can still detect the complex karyotype and the TP53 mutation at a 15% variant allele frequency. She actually does have an HLA identical unrelated donor that was identified.
So given what you know about MG, what treatment options would you choose with this information after these four cycles and residual disease? Would you change to decitabine for 10 days? Would you want to do decitabine plus venetoclax for 10 days? Would you change to something like FLAG-IDA or FLAG-IDA plus venetoclax maybe, or something completely different?
Dr. Joshua Zeidner:
Yeah, well thanks for that question Dr. Borate. This is an unfortunately common area that we don't know the right answer to unfortunately. I think one of the first questions is how do we even treat MG in the frontline setting, which I think is another real unanswered question. We now know, unfortunately, that the addition of venetoclax to hypomethylating agents do not improve outcomes in TP53-mutated AML. There are higher response rates with HMA/venetoclax, azacitidine/venetoclax, compared with let's say an HMA-alone therapy, but these patients don't have any survival advantage, median survival 5 to 6 months, whether patients get azacitidine alone or azacitidine and venetoclax. So it's really challenging.
We also know that intensive chemotherapy does not lead to improved outcomes in this patient population, independent of any sort of chemotherapy regimen that can be designed. This patient is 72, so she's probably borderline candidate for intensive chemotherapy. Even if she was fit and had minimal comorbidities, intensive chemotherapy is probably not going to be my treatment of choice in the first line or second line for this patient. Even if she really is a transplant candidate, because the toxicity profile and the treatment related mortality I think are higher than the benefit of intensive chemotherapy. I'll also point out that patients who have had prior HMAs, so azacitidine or decitabine for either MDS or AML and then receive some form of intensive chemotherapy, have very poor outcomes.
So this is an unfortunate, I don't know the right answer. Drs. Borate and Daver have been very involved in an agent known as magrolimab, which is a monoclonal antibody targeting CD47 that we thought was going to be a real game changer for TP53-mutated AML in combination with azacitidine. And unfortunately this did not pan out. And there are several publications now showing that the combination of azacitidine and magrolimab does not improve outcomes compared with azacitidine and venetoclax or intensive chemotherapy. But that was the one agent that I think a lot of us held our hat on that this could be the answer for TP53-mutated AML.
Median survival across the board here is 5 to 6 months in any therapy in the frontline setting. So now in the second line setting that this patient did not respond to decitabine and venetoclax, I'm looking for a clinical trial. Any promising agent, whether or not it's targeted or specific for TP53, that's going to be my first, second or third option. If I don't have any at my institution, I'm looking across the country and asking the patient if they're willing to travel because I know that my standard therapies are inadequate here. I think outside of any of that, if there are no clinical trials, I'm talking to the patient then thinking about maybe an HMA only kind of treatment that may not lead to a response but may kind of palliate their symptoms, may lead to some sort of disease stability and minimize treatment related complications. But I unfortunately don't have the answer for this patient.
Dr. Uma Borate:
So what I'm hearing you say is some of the things that you would not do is you would not intensify therapy, right? You would not continue to add venetoclax to whatever it is you're doing because both those don't really seem to impact outcomes and obviously really looking for something novel, maybe a clinical trial wherever possible. So I'll turn it over to Dr. Daver and see if there's anything else you want to add.
Dr. Naval Daver:
Yeah, this is a very, very, very, very tough condition. Unfortunately, I would say the one group, kind of the last bastion and a ML research that we have had no progress in 25 years, right? We talked about all the nice targeted therapies. So I think anything you do here is reasonable, except I think intensifying therapy. I completely agree with Josh. I would not do intensive chemo. There's ample data now published from many, many groups, including we just published one very recently with a large cohort of 250 patients showing that intensive chemotherapy does not improve outcomes. It may give you a cosmetic higher response rate, but then you pay for that in terms of more myelosuppression, infection, complications, and in the end you still have the same transplant and survival rate.
I think for this patient now, since they have started on an azacitidine/venetoclax program and it looks like they have achieved some degree of disease control, 10%, I may just say, "Okay, I will continue with HMA." I would give less venetoclax, there's a lot of data showing that less venetoclax is equally effective and less myelosuppressive potentially. Looking forward to your study, Dr. Borate, hopefully conclusively proving that with the 14 vs 28. But I may say 7 or 10 days venetoclax here, let's see, maybe we get you into a marrow remission.
And the most important thing I think we are doing, we're trying here at MD Anderson in TP53s, working very closely with our transplanters. So we have a frontline protocol where we enroll all TP53 as soon as we know they're mutated. We have a group of transplanters working closely with us, Dr. Popat and others. And the goal is give them two to three cycles, achieve debulking marrow remission and let's go with the myeloablative if possible, for this patient, we have to see. Transplant followed by preemptive DLI or other strategies. We know this may be 20%, 25%, 30% who have some durable outcome, but hopefully it will be not zero. So that's kind of what we're doing. But yeah, in the end of the day, if I can find a trial with an NK cell, a bispecific, an engager, a MIB degrader or whatever, I think this would be what I would try in the front-line or salvage setting.
Dr. Uma Borate:
Let's say we tried one of the many options that, Dr. Daver, you just mentioned, and luckily this patient achieved what we call an MLFS, which is a morphologic leukemia-free state. Let's say she got 10 days of decitabine and got there. She still has a TP53 variant allele frequency of 10% that can be measured. What would you do next, Dr. Zeidner? And the options are, and I know this may not always be in our hands since we don't directly transplant patients, but the options are, would you wait for her counts to recover now that she does not seem to have any blasts in the marrow? Or would you ask the transplant team to take this patient to allotransplant ASAP since she does have an HLA matched unrelated donor already identified in a good performance status?
Dr. Joshua Zeidner:
Yeah, this is a really tough question and I think this is an individualized discussion with the patient and obviously with the transplant team, a patient like this hopefully would have already been evaluated by the bone marrow transplant team prior to even starting frontline therapy. Because of all the things that Dr. Daver mentioned to try to spearhead when and if you get a remission, these patients need to go to transplant ASAP for there to be any benefit. So hopefully that has already been in the works if the patient was healthy, fit and willing to pursue a transplant. I would have no problem, and in fact, I would support getting the patient to transplant ASAP if it would align with the patient's goals and the patient had a donor. And now would be the time because again, an MLFS is probably the best response we're really going to see in a patient with a TP53 mutation with any sort of therapy. So I think her chance of survival and window would be now.
I think the other question though is whether transplant is the right thing for this patient, and I think that when you look at a survival curve, there's the chance of long-term survival in this patient without a transplant is close to zero. The chance of long-term survival with the transplant may be 10, 20% depending on the scenario and the MRD and all that. So it's still quite low and the patients still have really poor outcomes. But I think there are a proportion of these patients that may have some long-term outcome with the bone marrow transplant, and that's why it's an individualized decision. I don't think it would be wrong for the patient to say, "No, I'm not going to pursue that with those statistics." But that's kind of what we're dealing with.
I think the other thing that I would want to know beyond TP53 VAF is the flow MRD and other kind of disease markers, because that is what our transplant group would use to guide whether or not the patient is high risk for relapse and so forth. I think certainly if you can clear the TP53 VAF we've seen that those patients do better, but having flow MRD negativity would also be, I think, a good sign of a deep remission here.
Dr. Uma Borate:
Dr. Daver, anything you want to add?
Dr. Naval Daver:
No, I think transplant, if the patient is willing and able and knows the risk is reasonable, if not, then you continue with the single-agent HMA, knowing this will be 6 to 8, 10 months. But decent, good quality of life in a way because it's not very toxic. So it's a tough disease, sad situation. But yeah, I think we have to keep looking at new trials here.
Dr. Uma Borate:
Okay. So with that, I will wrap up this case with some key clinical takeaways where high-risk AML not responding to HMA plus venetoclax has overall a poor prognosis with limited therapeutic options. Specifically for TP53-mutated AML, this is truly the case and everybody recognizes the challenge of these patients not responding as well to standard therapies. All of you recommended, hopefully a clinical trial available. If not, getting them to an allogeneic stem cell transplant probably offers the best chance of long-term remission and/or cure. But even with a transplant, long-term remission rates are not optimal. And I think Dr. Daver, you put it nicely. We just need to keep looking and hopefully as we continue to do trials in this setting, we'll find the right secret sauce to help these patients.
So with that, I will bring this case to an end. Please see the other segments for further discussion about the latest research in AML or visit ascopost.com. Thank you everyone, really appreciate it.
