Many patients with acute myeloid leukemia (AML) receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) following intensive chemotherapy to reduce their risk of relapse. However, clinicians must carefully select patients for allo-HSCT and must be prepared for the possibility of relapse following transplant.

When working to optimize decisions regarding allo-HSCT, there are a number of clinical factors to take into account. The first are the patients themselves. The ideal patient for an allo-HSCT has a good performance status and does not have significant underlying comorbidities, complications, or uncontrolled infections.

Another important consideration before a patient with AML transitions to transplant is disease control. The better we can do in terms of decreasing the disease burden prior to transplant, the better the patient’s outcome will be. That reinforces the need for better therapies, both in terms of more effective treatments leading to deeper remissions and better-tolerated therapies, which are currently in development. In older and borderline-fit patients, when the goal is allo-HSCT, many providers increasingly opt for venetoclax combinations. This is because, even if these individuals are potentially fit for intensive chemotherapy, especially if they have adverse risk criteria, they are potentially as likely to respond to azacitidine plus venetoclax as an intensive approach, with less toxicity, which allows for an increased opportunity to successfully transition to curative transplant. The choice of conditioning regimen and graft-versus-host disease prophylaxis, which are topics that are outside the scope of this brief review, are also important clinical considerations in optimizing allo-HSCT.

The choice between a reduced-intensity or a fully ablative transplant is another key decision that is generally dictated by the patient’s age and performance status but also links back to the point of disease burden. With a reduced-intensity transplant, you really do not want that patient to go into transplant with measurable residual disease (MRD) because there is a greater possibility of relapse post transplant in such cases. For patients going into transplant with MRD that cannot be eradicated, the early initiation of maintenance therapy post allo-HSCT is an important consideration. This was highlighted by recent data from the MORPHO trial, in which an FLT3 inhibitor post transplant benefited patients with AML who had FLT3 MRD in the peri-transplant setting. Individuals with FLT3 mutations and persistent/MRD-positive disease have a higher chance of relapsing post transplant, and the early initiation of an FLT3 inhibitor in post-transplant maintenance can absolutely help improve outcomes.

Timelines are important to consider. If a patient is destined to relapse post transplant, it typically happens within the first 2 years, and actually often within the first 6 months. After that, the new immune system/graft has typically taken over, and we can consider them, hopefully, cured. That is reassuring to a lot of patients. When a patient does relapse, there can be many different types of relapse. Some patients with relapsed disease can be salvaged with effective therapy and can potentially go to a second transplant. For instance, I have a patient with FLT3-mutated disease that relapsed quickly after their first transplant. It is now 6 months after the patient’s second transplant, and they are doing great. Importantly, they went into their second transplant in a deeper, MRD-negative remission after effective combination targeted therapy, and this is likely why they are doing better with their second transplant, which is a bit counterintuitive otherwise.

Any time we treat a patient with a leukemia, the underlying genomics of their disease can change based on the treatment they received. This type of clonal evolution can definitely occur post transplant, with the genomic fingerprint differing from what it was at diagnosis. So, it is important to recheck for an FLT3 mutation, IDH1/2 mutations, KMT2A rearrangements, and NPM1 mutation status, for instance. These targeted therapies are as effective as intensive treatment options in the relapse setting, if not more so; thus, inhibitors of FLT3, IDH1, and IDH2 are all possibilities to consider for patients with AML who relapse after allo-HSCT.