AML Current Treatment Strategies and Paradigms Ahead: Expert Discussion of Frequently Asked Questions

Key Takeaways

• Randomized data are available on the use of post-transplant FLT3 inhibitors as maintenance therapy, and data are emerging on post-transplant IDH1/2 inhibitors.
• Menin inhibitors may play a role in treatment of acute myeloid leukemia beyond patients with KMT2A rearrangements and NPM1 mutations.
• The optimal dose and schedule of venetoclax as part of the azacitidine/venetoclax backbone for triplet therapies are yet to be determined.

In this session moderated by Daniel Pollyea, MD, MS, experts Courtney DiNardo, MD, MSCE, and Eytan M. Stein, MD, answer questions regarding treatment of acute myeloid leukemia (AML) that were submitted by an audience of healthcare professionals at a live Clinical Care Options symposium during the 2022 American Society of Hematology annual meeting.

What do you recommend for a patient receiving CPX-351 who also has a FLT3 mutation? 

Eytan M. Stein, MD:
In the past, I have not felt comfortable combining CPX-351 with a FLT3 inhibitor because safety data were not available. I consider each patient individually, looking at whether they have highly proliferative disease with a rapidly rising white count or perhaps a secondary AML phenotype, with a subclonal FLT3 and other mutations that are more common in secondary AML. For patients with a FLT3 mutation, I give 7+3 plus midostaurin. For those with a phenotype that is more consistent with secondary AML, I give CPX-351.

However, there are now safety data for the combination of CPX-351 with midostaurin in a small subset of patients with FLT3-ITD and FLT3-TKD mutations from the V-FAST trial. The combination of CPX-351 and midostaurin does appear to be safe, but whether it is better than administering 7+3 with midostaurin remains an unanswered question.

Is measurable residual disease (MRD) monitoring useful for patients receiving azacitidine/venetoclax?

Courtney DiNardo, MD, MSCE: 
I monitor MRD for all patients I treat with azacitidine/venetoclax―I think it is useful information. It is nice to be able to tell your patient that they likely will do better and remain longer on this therapy. However, you also can make the argument: Are you going to make treatment changes based on MRD? If you are not, does it need to be monitored? Right now, I am not making treatment changes based on MRD results for the vast majority of my patients. If I have a patient who is persistently MRD positive, I am far less likely to want to attenuate dosing if they have various life events or if you are trying to determine if you can delay cycles. Rather, I would try to keep that patient on track to continue receiving ongoing therapy.

What are your thoughts regarding the use of IDH1/2 and FLT3 inhibitors post-transplant? 

Eytan M. Stein, MD:
This is a great question that healthcare professionals struggle with all the time. We need a randomized study in this setting to determine the right thing to do. My personal practice has been that, if a patient is MRD negative going into transplant, I do not give an IDH inhibitor posttransplant. If they are MRD positive, I would consider it. I perform very careful MRD assessments on a frequent basis. I send a digital droplet polymerase chain reaction test for the IDH mutation every 12 weeks. If there is any hint of the IDH mutation returning, I start therapy.

The other thing to consider is that these therapies are very expensive and have the potential for significant financial burden for the patient and healthcare system if they are used when they may not need to be. 

Courtney DiNardo, MD, MSCE:
There is a new publication by Fathi and colleagues that helps provide some data for the IDH inhibitors. It is a phase I trial of enasidenib post-transplant for patients with IDH2 mutations. The incidence of relapse was 16%, with 1 patient experiencing relapse while receiving maintenance enasidenib. So, there are newly published safety and efficacy data for this in a nonrandomized setting.

Eytan M. Stein, MD:
I do administer FLT3 inhibitors post-transplant; there are randomized data suggesting FLT3 inhibitors post-transplant are beneficial. There are published data of sorafenib maintenance post-transplant in patients with FLT3-ITD mutations that demonstrated a relapse-free survival benefit compared with placebo, but overall survival was not statistically significant. There also is an ongoing randomized, placebo-controlled trial that is enrolling patients post-transplant who had a FLT3-ITD mutation at diagnosis and randomizing them to receive gilteritinib vs placebo.

Courtney DiNardo, MD, MSCE:
I would encourage FLT3 inhibitor maintenance post-transplant and to start therapy early. In patients who do not have graft-vs-host disease and do have count recovery, you want to start at 30-40 days post-transplant to prevent relapse.

Do you anticipate menin inhibitors (ziftomenib, revumenib) having a role in the treatment of patients with AML that does not harbor KMT2A rearrangements or NPM1 mutations?

Eytan M. Stein, MD:
Yes, I believe it will have a role. Menin as a protein seems to be important in most leukemias that are driven by HOX gene upregulation. Most of these involve KMT2A rearrangements or NPM1 mutations, but other less common ones, such as NUP98 fusions, also exist. In the ziftomenib data from the KOMET-001 trial, there was a patient with relapsed/refractory AML with SETD2 and RUNX1 mutations who had complete remission after ziftomenib treatment. I think menin has a role beyond just NPM1 mutations and KMT2A-rearranged leukemias, and I am involved in a clinical trial that is asking this specific question (NCT05360160).

The combination of azacitidine/venetoclax has been shown to be a difficult treatment to tolerate. Should we be concerned about the possibility of such toxicity causing negative results in studies of triplet therapy with the azacitidine/venetoclax backbone?

Courtney DiNardo, MD, MSCE: 
The long-term follow-up data from VIALE-A were a bit like a glass half full and a glass half empty. The benefit of venetoclax/azacitidine is ongoing compared with azacitidine alone, but very few people who received azacitidine monotherapy are living past 1 year. I was hoping to see a nice flattening and tail to the overall survival curve at 30% to 40%, but we unfortunately did not see that.

Azacitidine/venetoclax is not a curative regimen, which is why it needs to be improved, either by sequencing or adding drugs for new triplet therapies. Unfortunately, we do not know the optimal way to give azacitidine/venetoclax because the initial trials were designed with continuous venetoclax. I am skeptical that 21-28 days of venetoclax is essential, and I suspect that far less is needed due to its synergistic nature with other drugs. I think the first week or two of venetoclax is very important. Beyond that, there are no data to say one way or the other what is most beneficial.

A retrospective analysis looking at the efficacy and toxicity of venetoclax administered on the same days as azacitidine therapy (7+7 therapy) in older, unfit patients with AML was presented at the 2022 American Society of Hematology annual meeting. Investigators reported a similar response rate to that of the recommended 28-day venetoclax administration, although significant toxicity was still noted.

The most important conclusion here is that triplet trials should not be designed with 28 continuous days of venetoclax―it is unrealistic. Ideally, I would administer 14 days of venetoclax, 7 days of azacitidine, and the third agent as appropriate. Then, if your patient is in remission, especially if MRD negative, you probably do not even need 14 days of venetoclax with subsequent cycles―perhaps only 7 or 10 days is all you would need thereafter.

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