Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 19
Patient selection for maintenance therapy post-allogeneic transplant in myeloid malignancies and thoughts on treatment of FLT3-mutated disease post-transplant with agents such as midostaurin.
Harry P. Erba, MD, PhD: Before I finish this section, I want to come back to Corey. I am going to give you a wide-open topic. We talked about the first and only FDA-approved continued therapy for AML [acute myeloid leukemia] as oral azacitidine being just recently approved. How about after an allogeneic transplant? How do you think about which patients should receive a maintenance therapy there? I am going to have Sasha talk about FLT3 mutations in a second, but why don’t you talk about anything other than FLT3? What are you doing for those patients?
Corey S. Cutler, MD, MPH, FRCPC: It is critical that we do something in the post-transplant setting because relapse remains the main cause of failure for patients with myeloid malignancies. It is far more important than graft-vs-host disease or infection these days. As you develop these novel, genomically inspired therapies to get people into remission, we are actively examining ways to use them in the post-transplant setting to minimize relapse. We are actively testing venetoclax in the post-transplant setting, and we are actively testing the APR-246 compound in the post-transplant setting for patients who are coming in with known TP53 mutations.
Not to speak about FLT3, but certainly based on the SORMAIN trial data, most of us use some form of FLT3 inhibition in the post-transplant setting, and the BMT CTN [Blood and Marrow Transplant Clinical Trials Network] is formally testing it in a randomized phase 3 trial looking at gilteritinib. All these targeted agents are fair game in the post-transplant setting. We need to learn how to use them properly in the sense of understanding drug-drug interactions and tolerability on a fresh marrow, so all that needs to be learned. Clearly, as you all develop novel agents to get people into remission, we are going to learn how to use these compounds in the post-transplant setting with a goal of maintaining remission.
Harry P. Erba, MD, PhD: Your points are well taken. The risk of relapse remains high, especially in some patients who go into transplant with MRD [minimal residual disease] or certain biological subsets of patients. It is not the end of the road; it should be seen as a therapy that we may be able to improve upon, as you mentioned.
Sasha, let me come back to you. Nowadays, we are treating patients who are ultimately going to be fit for a transplant. Most of them will have received intensive chemotherapy with midostaurin. In the near future, there may be a second-generation drug, but right now it is the first-generation type 1 inhibitor midostaurin. What do you recommend for patients with FLT3-mutated disease who have undergone allotransplant? As Corey mentioned, there are the SORMAIN trial data with sorafenib. There was also a smaller trial in the United States of midostaurin. I think it’s the RADIUS trial if I remember correctly. Do you try to get a second-generation drug like gilteritinib off-label for these patients because we do not know the BMT CTN study results? What do you do?
Alexander E. Perl, MD, MS: We do not have those data. To put everything out there in terms of what we know and expand on what Corey said, there are not 1 but 2 randomized studies that show either a disease-free survival or an overall survival benefit adding sorafenib post-transplant to patients who got an allogeneic transplant primarily in first remission, although the SORMAIN study included patients transplanted out of remission or in second remission.
One question from that study and from the Chinese study that followed it as well is this: In patients who primarily did not get frontline FLT3 inhibitor like midostaurin added to their induction chemotherapy, is the benefit still maintained there? The simple answer is that we do not know. One important takeaway from this is a) it is feasible, b) it looks like it works, and c) you would have to be nuts not to add it unless you thought there was going to be toxicity that you could not keep up with. Outside of a trial, I have been adding sorafenib for years when it was available and since then gilteritinib, but I did so without knowing whether it was better.
What we have learned in the intervening time is that there are real benefits to this approach, but we do not know that those benefits extend to everybody. Now that we are using a frontline FLT3 inhibitor, we do not know just how big that benefit is and if it is counterbalanced with toxicity issues that do not show up until years later. We are curing more and more patients who have FLT3 ITD mutation with transplant, so late effects are going to be important. That is not to say that these drugs do not have toxicities. They do, and we will see them borne out over years of exposure that we would never see in the relapsed/refractory setting treating patients with gilteritinib who would not necessarily go on to a transplant.
In patients who I treat with gilteritinib, who then go on to transplant, I give those patients maintenance as well. These long-term follow-up studies are going to be important, and 1 advantage of the BMT CTN trial is that it has a long follow-up. It is 2 years of therapy and then some to see the readout, plus it will get MRD data measured prior to transplant, and it enrolls a lot of patients from the United States, where the approval of midostaurin led to a large number of patients having received frontline TKI [tyrosine kinase inhibitor].
We will learn everything we need to know to see who benefits and if is this across the board, if it is for MRD-positive cases, if it is for people who did not have a prior TKI, etc. If there are these differences, then let’s tease them out and give this most rationally. If there are no differences, but there is a benefit to the TKI, then give it. If I am surprised, and there is no benefit, then I guess there is no benefit. We are going to learn all that from the study.
Transcript Edited for Clarity