Dr. Daver: My name is Naval Daver. I am an associate professor in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas. My primary focus is developing clinical trials in patients with acute myeloid leukemia and myelodysplastic syndrome, especially immunotherapies and targeted therapies and novel combinations.
Will New Treatments and Personalized Medicine Improve Outcomes for AML Patients?
At this time, we have a number of new therapeutic options available for acute myeloid leukemia. This is very exciting, and there have been nine new FDA drug approvals in the United States in the last three-and-a-half years for AML. And this includes targeted therapies, such as FLT3 inhibitors, IDH inhibitors, as well as novel immune drugs, antibody-drug conjugates like gemtuzumab (Mylotarg) that work in specific chromosome subsets and new chemotherapy formulations like CPX-351 or Vyxeos (daunorubicin and cytarabine). And then probably the one drug that has made the most important shift is a Bcl-2 inhibitor, venetoclax (Venclexta) that has been especially active in older AML patients when combined with azacitidine (Vidaza).
So, the point here is that with all these new drugs now available, it really is important to select the most appropriate drug for the appropriate molecular or chromosome changes in a given patient. We know this could have a major impact, not only on the initial response and remission but also on long-term survival. And so, the key recommendation that we have been giving our colleagues and fellows and community oncologists is to check a molecular panel and chromosomes, whether it's by routine chromosome analysis or by what we call FISH probes, before deciding and starting therapy. So, for example, if you have a young patient, a 50 or a 55-year-old AML patient, one would want to know certain features. Do they have a FLT3 or FLT3 mutation? If they do, then using FLT3 inhibitors in addition to the standard induction chemo could dramatically improve response and survival.
Do they have what we call core-binding factor leukemia? There's a group of cytogenetic changes that can be easily picked up with a chromosome analysis or a FISH chromosome probe. And if they do, then adding an immune drug gemtuzumab to the standard therapy, again, significantly improves the outcomes. The third is looking for a type of leukemia called acute promyelocytic leukemia, again, can be picked up by rapid cytogenetics within 24 to 48 hours, if that is ordered appropriately, and for this there's actually chemotherapy-free treatment with two agents, ATRA (all-trans retinoic acid) and arsenic (ATO), with 95% long-term cure remission rates.
And then for others, we're also looking for now what we call MDS-related changes, MDS-related cytogenetics therapy-related AML and for these patients, there's a new drug called a CPX-351 or Vyxeos that actually is much better than the standard induction 3+7. So, the point is that knowing this chromosome and molecular information can really change treatment or lead the treating physician to add important additional targeted drugs that could improve the remission and survival and really should be done.
And not only in the new diagnosis, but we actually see that there are some patients who may not have these mutations like FLT3 or TP53 or IDH or NPM1 at baseline but may sometimes have these detectable at relapse. And that's important as well, because if we don't check it at relapse, we may be missing what we call a newly emergent FLT3 mutation or IDH mutation, an NPM1, that could then be targeted with potential targeted therapy. This is actually well known with FLT3. Doesn't occur as much with IDH, TP53 and others, but it does rarely. So my recommendation is to check all targetable mutations, FLT3, IDH1, IDH2, TP53, NPM1 and MLL rearrangement at the time of relapse, as these may give us therapeutic options with targeted therapies, either in standard practice or on clinical trials which actually are showing very, very, very high efficacy.
Dr. Subklewe: My name is Marion Subklewe, I'm an attending in hematology-oncology with a focus on cellular immunotherapy at the LMU University of Munich and my particular specialty is AML.
What Is the Status of Current AML Immunotherapy Research?
So, you might be wondering what's happening in the field of immunotherapy for AML, as there are lots of developments in the immunotherapy area happening. So, for AML, two important novel treatment immunotherapy options are evolving. These are the T-cell bispecifics and the CAR T-cells. I'd like to explain both platforms and where we stand in the field of AML. So first, the T-cell bispecifics are antibody constructs that have two arms that bind to the T-cells.
These are specific immune cells in your body, and with the other arm bind to leukemic cells, bring these two together, which lead to killing of the leukemic cells. And proof of concept that T-cell bispecifics work in acute leukemia has been shown in acute lymphoblastic leukemia, where one of these antibody constructs, blinatumomab (Blincyto), is already approved. And currently, multiple clinical trials are running using the same concept of these bispecific antibody constructs in the setting of AML. As always, the first step is to check for toxicity, and these are used in very advanced AML patients.
Once we see that the toxicity, that the drug is safe, phase two clinical trials will start to look for efficacy. So, we have to be patient and see how the data is evolving. And the big challenge in this setting is finding a suitable target antigen as the AML cell looks very similar to a healthy hematopoietic cell. The second platform, again, relies on T-cells. These are the chimeric antigen receptor T-cells. So, in this case, you take the T-cells, so these immune cells, out of the body of the patient, you change the T-cells, you put a receptor into the T-cells, you activate the T-cells, and then do a one-time transfusion again to the patients. You get your own T-cells back, slightly modified. And again, these T-cells now have a receptor on their surface to target the leukemic cells.
And again, very similar to the T-cell bispecifics, proof of concept that this is working has already been shown in the setting of acute lymphoblastic leukemia where we already have approval of certain CD19 CAR T-cells in pediatrics and young adults and there are clinical trials running also in older patients. And also, here, we have clinical early trials running in the AML setting. There are lots of clinical trials currently running, again, assessing toxicity and then we'll go on and check efficacy. This is again, really promising and very effective.
However, again, we have the challenge of identifying suitable target antigens, and a lot of these treatment and clinical trials are currently running in conjunction with an allogeneic stem cell transplantation. But there are also clinical trials running which try to utilize CAR T-cells without an allogeneic stem cell transplantation. So, I think now two very promising treatment options evolving. Currently, they're still in early phase one, beginning phase two trials and we have to be patient and see how this is evolving. But I think in the next two to four years, there's going to be a lot of data and hopefully promising data so that we can utilize these platforms also in the AML setting.
What Is on the Horizon for AML Patients?
Dr. Daver: I think the progress in AML is very rapid-dramatic. Absolutely, I do feel that this is the best time in AML research, but I actually think it will actually be better even in five years from today, just because that is the nature of research. Progress usually does not happen at a continuous base, it's usually logarithmic. So, I think the future is going to be much better. Already today, we have nine drugs approved in the last three years, which is fantastic. And I think we will have many, many more and new combinations coming out.
I again think the key for AML patients and research is to, and now more than ever, focus on clinical trials because we really now have effective drugs and the trials that are ongoing now, the combinations of these drugs, the different sequences targeting low volume diseases are going to be very beneficial to the patients who get those new combinations beyond standard of care and for the field, to push the research and establish the best combination. So I think, good to be hopeful, definitely look out for trials. There's many, many, many trials that will be open even close to your center. If not, then considering going to the very large academic centers like Sloan, MD Anderson, Dana-Farber and others. But I think we are going to make a lot of progress and improve the cure rates in the next five to 10 years across all types of AML.
